MXPA06001508A - Geometrically restricted 3-cyclopentylidene-1,3-dihydroindol-2-ones as potent protein kinase inhibitors - Google Patents

Abstract

The present invention relates to certain sulfonamido-substituted geometrically restricted indolinones of the formula (I):wherein R1 - R12 and X are variables defined herein. The sulfonamido-substituted geometrically restricted indolinones of the preferred embodiments of the present invention modulate the activity of protein kinases ("PKs"). The compounds of this invention are therefore useful in treating disorders related to abnormal PK activity. Pharmaceutical compositions comprising these compounds, methods of treating diseases utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.

Description

3-CICLOPENTIL1DEN-1.3-DIHIDROINDOL-2-ONAS GEOMETRICALLY RESTRICAS POWERFUL PROTEIN INHIBITORS KINASE FIELD OF THE INVENTION The present invention relates to certain sulfonamido-substitugeometrically restricindolinones that modulate the activity of protein kinases ("PKs"). The compounds of this invention are, therefore, useful for treating disorders relato abnormal PK activity. Also described are pharmaceutical compositions comprising these compounds, methods of treating diseases using the pharmaceutical compositions comprising these compounds and methods for preparing them.

BACKGROUND OF THE INVENTION The following is offered only as background information and is not admitto be prior art to the present invention. Protein kinases ("PKs") are enzymes that catalyze the phosphorylation of hydroxy groups on protein tyrosine, serine and threonine residues. The consequences of this seemingly simple activity are staggering; cell growth, differentiation and proliferation, that is, virtually all aspects of cell life in one form or another depends on PK activity. In addition, abnormal PK activity has been linked to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer). PKs can be conveniently broken down into two classes, protein tyrosine kinases (PTKs) and serine-threonine kinases (STKs). One of the main aspects of PTK activity is its involvement with growth factor receptors. The growth factor receptors are cell surface proteins. When they bind to a growth factor ligand, the growth factor receptors become an active form that interacts with proteins on the inner surface of a cell membrane. This leads to phosphorylation on receptor tyrosine residues and other proteins and to the formation within the cell of complexes with a variety of signaling cytoplasmic molecules that, in turn, effect numerous cellular responses such as cell division (proliferation), cell differentiation, cell growth, expression of metabolic effects to the extracellular microenfome, etc. For a more complete discussion, see Schlessinger and Ullrich, Neuron 9: 303-391 (1992), which is incorporaby reference, including any drawings, as if fully set forth herein. Growth factor receptors with PTK activity are known as receptor tyrosine kinases ("RTKs"). They comprise a large family of transmembrane receptors with diverse biological activity. Currently, at least nineteen (19) distinct subfamilies of RTKs have been identified. An example of these is the subfamily called the "HER" RTKs, which includes EGFR (epithelial growth factor receptor), HER2, HER3 and HER. These RTKs consist of an extracellular ligand binding glycosyladomain, a transmembrane domain and a catalytic intracellular cytoplasmic domain that can phosphorylate tyrosine residues on proteins. Another subfamily of RTK consists of the insulin receptor (IR), insulin-like growth factor I receptor (IGF-1R) and insulin receptor-relareceptor (IRR). IR and IGF-1R interact with insulin, IGF-I and IGF-II to form a heterotetramer of two fully extracellular glycosylasubunits and two β subunits that cross the cell membrane and that contain the tyrosine kinase domain. Another subfamily of RTK is referred to as the platelet-derived growth factor receptor ("PDGFR") group, which includes PDGFRα, PDGFRβ, CSFIR, c-kit and flt-3. These receptors consist of glycosylaextracellular domains composed of 5 loops similar to immunoglobulin and an intracellular domain in which the tyrosine kinase domain is interrupby an inert kinase domain. Another group that, due to its similarity to the PDGFR subfamily, sometimes included in the latter group is the subfamily of the fetal liver kinase receptor ("flk"). This group, which contains extracellular immunoglobulin loops composed of receptor with insert domain kinase-1 kinase of fetal liver (KDR / FLK-1), and tyrosine kinase 1 of fms type (flt-1 and flt-4). An additional member of the tyrosine kinase growth factor receptor family is the subgroup of fibroblast growth factor ("FGF"). This group consists of four receptors, FGFR1-4, and many ligands. Although there is considerable alternative splicing, the receptors generally consist of a glycosylated exfracellular domain containing 3 loops of the immunoglobulin type and an intracellular domain in which the tyrosine kinase sequence is interrupted by regions of an insert-kinase domain. Yet another member of the tyrosine kinase growth factor receptor family is MET, often referred to as c-Met also known as human hepatocyte growth factor receptor tyrosine kinase (hHGFR). It is thought that c-Met plays a role in primary tumor growth and metastasis. A more complete listing of the known RTK subfamilies is described in Plowman ef al., DN &; P, 7 (6): 334-339 (1994), which is incorporated as a reference, including any drawing, as if it were fully presented in the previous report. In addition to the RTKs, there is also a family of completely intracellular PTKs called "non-receptor tyrosine kinases" or "cytoplasmic tyrosine kinases". In the present report, this last designation will be used, abbreviated "CTK". The CTKs do not contain extracellular and transmembrane domains. Currently, more than 24 CTKs have been identified in 11 subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes, Fak, Jak, LIMK and Ack). So far the Src subfamily seems to be the largest group of CTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk. For a more detailed discussion of CTKs, see Bolen, Oncogene, 8: 2025-2031 (1993), which is incorporated by reference, including any drawings, as if fully set forth herein. Serine / threonine kinases, STKs, like CTKs, are predominantly intracellular although there are a few receptor kinases of the STK type. STKs are the most common of cytosolic kinases; that is, kinases that carry out their function in that part of the cytoplasm other than the cytoplasmic organelles and the cytoskeleium. The cytosol is the denium region of the cell in which much of the biosynthetic and metabolic intermediary activity of the cell occurs; for example, it is in the cytosol that proteins are synthesized on ribosomes. STKs include CDk2, Raf, the ZC family of kinases, the NEK family of kinases and BUB1. All RTKs, CTKs and STKs have been implicated in a host of pathogenic diseases that include, significantly, cancer. You will hear pathogenic diseases that have been associated with PTKs include, without limitation, psoriasis, liver cirrhosis, diabetes, angiogenesis, fibrosis, restenosis, eye diseases, rheumatoid arthritis and other inflammatory disorders, immune disorders such as autoimmune disease, cardiovascular disease such as atherosclerosis and a variety of kidney disorders. With respect to cancer, two of the main advanced hypotheses to explain the excessive cell proliferation that leads to tumor development are related to functions that are known to be regulated by PK. That is, it has been suggested that malignant cell growth results from a failure in the mechanisms that control cell division and / or differentiation. It has been shown that the protein products of several proto-oncogenes are involved in the signal transduction pathways that regulate cell growth and differentiation. These proto-oncogene protein products include the extracellular growth factors, the transmembrane PTK receptors of the growth factor (RTKs), the cytoplasmic PTKs (CTKs) and the cilosolic STKs, discussed above. In view of the apparent link between cellular activities related to PK and the wide variety of human disorders, it is no surprise that a great deal of effort is being spent in an attempt to identify ways to modulate PK activity. Some of these have involved biomimetic approaches using large molecules modeled on those involved in actual cellular processes (eg, mutant ligands (U.S. Patent Application Serial No. 4,966,849); soluble receptors and antibodies ( International Patent No. WO 94/10202, Kendall and Tomas, Proc.Nat'l Acad. Sci., 90: 10705-10709 (1994), Kim, et al., Nature, 362: 841-844 (1993)); RNA ligands (Jelinek, et al., Biochemistry, 33: 10450-56); Takano, et al., Mol. Bio. Cell, 4: 358A (1993); Kinsella, et al., Exp. Cell Res., 199: 56-62 (1992), Wright, et al., J. Cellular Fis., 152: 448-57) and tyrosine kinase inhibitors (WO 94/03427; WO 92/21660; WO 91/15495; 94/14808; U.S. Patent No. 5,330,992; Mariani, et al., Proc. Am. Assoc. Cancer Res., 35: 2268 (1994)). In addition to the aforementioned, attempts have been made to identify small molecules that act as PK inhibitors. For example, bis-monocyclic, bicyclic and heterocyclic aryl compounds have been described (PCT WO 92/20642), vinylene-azaindole derivatives (PCT WO 94/14808) and 1-cyclopropyl-4-pyridylquinolones (US Pat. USA No. 5,330,992) as tyrosine kinase inhibitors. Styryl compounds have been described (U.S. Patent No. 5,217,999), styryl-substituted pyridyl compounds (U.S. Patent No. 5,302,606), quinazoline derivatives (EP Patent Application No. 0 566 266 A1), selenoindoles and selenides (PCT WO 94/03427), tricyclic polyhydroxy compounds (PCT WO 92/21660) and benzylphosphonic acid compounds (PCT WO 91/15495) as PTK inhibitors useful in the treatment of cancer. However, more effective PTK inhibitors are needed.

COMPENDIUM OF THE INVENTION In one aspect, the invention relates to a compound of Formula wherein A, B, D and E are each independently selected from the group consisting of carbon and nitrogen such that when A is nitrogen, B and E are carbon and when E is nitrogen and A is carbon, then B is carbon or nitrogen; wherein when A, B, D, or E is nitrogen, R2, R3, R4 or R5 do not exist respectively; provided that the ring containing A, B, D and E contains no more than two nitrogens; Ri and R6 are each H; R2, R3, R4, R5, R7 and Rs are each independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, trihaloalkyl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio , -SOR-? 3, -SO2R13, -SO2NR13R14, R? 4SO2N (R13) -, N-trihalomethanesulfonamido, -C (O) R? 5, -C (O) OR-? 5, R? 5C (O) O-, cyano, nitro, halo, cyanate, isocyanate, isocyanate, isocyanate, isothiocyanate, -OC (O) NR13R14, R14OC (O) NR? s-, -OC (S) NR 3R? 4, R14OC (S) NR? 3-, -C (O) NR13Ri4, RC ( O) NRi3- and -NR13R14; R2 and R3 or R3 and R4 or R4 and R5 or R and R8 together with the atoms to which they are attached may be associated to form a methylenedioxy group, a ylenedioxy group, an alicyclic ring or a heteroalicyclic ring; R13 and R14 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, heteroalicyclic, -C (O) R5, acetyl, -SO2Ri5 and - (CH2) nNRi3Ri4; or R13 and R14 together with the atoms to which they are attached can form a five or six membered heteroalicyclic ring; R15 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, and heteroalicyclic; R9, R10, R11 and R12 are each independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, haloalkyl, halo, cyano, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, -SO2R15, -S (O) Ri5, - (CH2) nC (O) ORi5, cyanate, isocyanate, fiocyanate, isothiocyanate, -C (O) NR13R, Ri4C (O) NR? 3- and -NR13R? 4; n is an integer from 0 to 20; X is selected from the group consisting of nitrogen, oxygen, and sulfur; and in which when X is oxygen or sulfur, then Re does not exist; or a prodrug or pharmaceutically acceptable salt thereof.

In preferred embodiments, the invention relates to compounds of Formula I, wherein A, B, D and E are carbon. In other preferred embodiments, the invention relates to compounds of Formula I, wherein A, B, D and E are carbon and X is nitrogen. In still other preferred embodiments, the invention relates to compounds of Formula I, wherein R2, R3, R4, R5, R7 and Rs are each independently selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, -SOR- | 3, -SO2R13, -SO2NR13R-i4, -C (O) OR? 5, halo and -C (O) NR? 3R14. In other preferred embodiments, the invention relates to a compound of Formula I, wherein R2, R3, R4, R5, R7 and Rs are each independently selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, - SOR? 3, -SO2R13, -SO2NRI3RH, -C (O) OR? 5, halo and -C (O) NR? 3R? 4 and A, B, D and E are carbon. In still other preferred embodiments, the invention relates to a compound of Formula I, wherein R, R3, R4, R5, R7 and Rs are each independently selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy , -SOR13, -SO2R13, -SO2NR? 3R? 4, -C (O) OR? 5, halo and -C (O) NR-i3R?; A, B, D and E are carbon; and X is nitrogen. In still other preferred embodiments, the invention relates to a compound of Formula I which is: 2-methyl-6- [2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -1 ethyl ester 4,5,6-tetrahydro-cyclopenta [b] pyrrole-3-carboxylic acid; Ethyl 6- [5- (2,6-dichloro-phenylmethanesulfonyl) -2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -2-methyl-1,4,5,6- ethyl ester tetrahydro-cyclopenta [b] pyrrole-3-carboxylic acid; 2-meyyl-6- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indol- (3Z) -iIiden] -1, 4,5,6-teirahydro-cyclopentephic acid ester [b] pyrrole-3-carboxylic; 3- [2-methyl] -4,5-dihydro-1 H-cyclopenia [b] pyrroI (6Z) -ylidene] -2-oxo-2,3-dihydro-1H-indol-5-sulphonic acid amide; 2-methyl-6- [5-methylsulfamoyl] -2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -1,4,5,6-tetrahydro-cyclopenta [b] pyrrolidone -3-carboxylic acid; ethyl ester of 6- [5-methanesulfonyl-2-oxo-1,2-dihydro-indoI- (3Z) -ylidene] -2-methylene-1,4,5,6-tetrahydro-cyl ester clopenta [b] pyrrole-3-carboxylic acid; 6- [5-dimethylsulphamoyl-2-oxo-1,2-dihydro-indole (3Z) -ylidene] -2-methyl-1, 4,5,6-tetrahydro-cyclopenta [b] pyrrole-3-cyclic acid ethyl ester -carboxylic; ethyl ester of 6- [5-isopropylsulphamoyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -2-meityl-1,4,6,6-tetrahydro-cyclopenia [b] pyrrol- 3-carboxylic acid; 6- [5-ethanesulfonyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -2-methyl-1, 4,5,6-tetrahydro-cyclopenta [b] pyrrol- 3-carboxylic; 2- (2-meyyl-6- [5-meylsuifloxy-2-oxo-1,2-dihydro-indole- (3Z) 2-hydroxy-3-pyrrolidin-1-yl-propyl) -amide -ylidene] -1,4,5,6-и tetrahydro-cyclopenia [b] pyrrole-3-carboxylic acid; 2-Methylo-6- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indol- (3Z) -iIiden] -1,5,5-cyclopropylamino-2-hydroxy-propyl) -amide. 6-α-tetrahydro-cyclopen-a [b] pyrrole-3-carboxylic acid; 2-Methyl-6- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -1,4,5,6-tetrahydroxy-2-dimethylamino-ethyl) -amide. -cyclopenta [b] pyrrole-3-carboxylic acid; 3- (2-Mephyl-3 - ((R) -2-pyrrolidin-1-methylmethyl-pyrrolidin-1-carbonyl) -4,5-d-hydroxyl-1H-cyclopenta methyl amide b] pyrrol- (6Z) -ylden] -2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid; ethyl ester of 2-methyl-6- [2-oxo-5-sulfamoyl] -1,2-dihydro-indoI- (3Z) -ylidene] -1,4,5,6-teirahydro-cyclopenta [b] pyrrole-3-carboxylic acid; 3- [3-methanesulfonyl-2-methyl-4,5-dihydro-1 H -cyclopenta [b] pyrrol- (6Z) -ylidene] -2-oxo-2,3-dihydro-1H- methyl-amide indole-5-sulphonic; acid { 6-methoxy-3- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -indan-1-yl} -acéíico; 5-fluoro-3- [2-meyyl-3 - ((S) -2-pyrrolidin-1-ylmeiyl-1-pyrrolidin-1-carbonyl) -4,5-dihydro-1H-cyclopenia [b] pyrrole - (6Z) -ylidene] -1,3-dihydro-indol-2-one; 6-mephoxy-3- [2-mefl-3 - ((S) -2-pyrrolidin-1-ylmeryl-pyrrolidine-1-carbonyl) -4,5-dihydro-1 H-cyclopenpha [b] pyrrole- (6Z) -iIiden] -1,3-dihydro-indol-2-one; 4-methoxy-3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1 -carbonyl) -4,5-dihydro-1 H -cyclopenta [b] pyrrol- (6Z) -iIiden] -1,3-dihydro-indol-2-one; 7-Chloro-3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-carbonyl) -4,5-dihydro-1H-cyclopenia [b] p R- (6Z) -ylidene] -1,3-dihydro-indoI-2-one; 3- [2-methyI-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-carbonyl) -4,5-dihydro-1H-cyclopenta [b] pyrrole- ( 6Z) -ylidene] -1,3-dihydro-pyrrolo [2,3-b] pyridin-2-one; and 6- (4-methoxy-phenyl) -3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-carbonyl) -4,5-dihydro- 1H-cyclopenia [b] pyrrol- (6Z) -ylden] -1,3-dihydro-indol-2-one; or a prodrug or pharmaceutically acceptable salt thereof. In another aspect, the invention relates to a compound of Formula II: R2, R3, R4, R5, R7 and Rs are each independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, trihaloalkyl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio , -SOR13, -SO2R13, -SO2NR? 3Rw, R14SO2N (R13) -, N-trihalomethanesulfonamido, -C (O) R15, -C (O) OR15, R? 5C (O) O-, cyano, nitro, halo , cyanate, isocyanate, isocyanate, thiocyanate, isocyanate, -OC (O) NR13Ri4, R OC (O) NR13-, -OC (S) NR13R? , R14OC (S) NR13-, -C (O) NR13R? 4 > R? C (O) NR13- and -NRi3R? 4; R2 and R3 or R3 and R4 or R4 and R5 or R and R8 together with the atoms to which they are attached may be associated to form a methylenedioxy group, an ethylendioxy group, an alicyclic ring or a heteroalicyclic ring; R13 and R are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, heteroalicyclic, -C (O) Rs, acetyl, -SO2R15 and - (CH2) nNR-i3R ?4; or R13 and R together with the atoms to which they are attached can form a five or six membered heteroalicyclic ring; wherein R15 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl and heteroalicyclic; Rg, R10, R11 and R12 are each independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, trihaloalkyl, halo, cyano, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, - SO2R15, -S (O) R-i5, - (CH2) nC (O) ORi5, cyanate, socianafo, isocyanate, isothiocyanate, -C (O) NR13Ru, RHC (O) NR13- and -NR? 3R? 4; and n is an integer from 0 to 20; or a prodrug or pharmaceutically acceptable salt thereof. In a preferred embodiment, the invention relates to compounds of Formula II, wherein R 2, R 3, R 4, R 5, R 7 and R 8 are each independently selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, - SOR13, -SO2R13, -SO2NR? 3R14, -C (O) OR? 5, halo and -C (O) NR13R14. In another preferred embodiment, the compound of Formula II is: 2-methyl-6- [2-oxo-1,2-dihydro-indole- (3Z) -ylidene] -1,4,5,6- eyl ester εtrahydro-cyclopenta [b] pyrrole-3-carboxylic acid; Ethyl esters of 6- [5- (2,6-dichloro-phenylmefanosulfonyl) -2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -2-methyl-1, 4,5,6- tetrahydro-cyclopenia [b] pyrrole-3-carboxylic acid; ethyl ester of 2-methyl-6- [5-methylsulfamoyl-2-oxo-1,2-dydrohydro- (3Z) -iIden] -1, 4,5,6-tetrahydro -cyclopenta [b] pyrrole-3-carboxylic acid; 3- [2-methyl-4,5-dihydro-1H-cycloopen-ta [b] pyrrole (6Z) -ylidene] -2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide; 2-methyl-6- [5-methyl-sulfamoyl-2-oxo-1,2-dihydro-indoI- (3Z) -Iiden] -1, 4,5,6-tetrahydro-cyclopenta [b] pyrrole- 3-carboxylic; 6- [5-methanesulfonyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -2-methyl-1,4,5,6-tetrahydro-cyclopenta [b] pyrrole- 3-carboxylic; 6- [5-dimethylsulphamoyl-2-oxo-1,2-dihydro-indole (3Z) -ylidene] -2-methyl-1, 4,5,6-tetrahydro-cyclopenta [b] pyrrole-3-ethyl ester -carboxylic; ethyl ester of 6- [5-isopropylsulphamoyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -2-methyl-1, 4,5,6-tetrahydro-cyclopenta [b] pyrrol- 3-carboxylic; Ethyl 6- [5-ene-sulfonyl-2-oxo-1,2-dihydro-indol- (3Z) -iIden] -2-methyl-1,4,5,6-tetrahydro-cyclopenta b) pyrrole-3-carboxylic acid; (2-Methyl-6- [5-methylsu-fluoyl-2-oxo-1,2-dihydro-indoI- (3Z) -ylidene) 2-hydroxy-3-pyrrolidin-1-yl-propyl) -amide] -1,4,5,6-tetrahydro-cyclopenta [b] pyrrole-3-carboxylic acid; 2-MethyI-6- [5-methylisoamino-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -3-cyclopropylamino-2-hydroxy-propyl) -amide; 4,5,6-tetrahydro-cyclopen-ta [b] pyrrole-3-carboxylic acid; 2-Methyl-6- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indol- (3Z) -iIiden] -1, 4,5,6-telrahydro acid (2-dimethylamino-ethyl) -amide - Cyclopenia [b] pyrrole-3-carboxylic acid; 3- [2-Methyl-3 - ((R) -2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl) -4,5-dihydro-1H-cyclopenta [b] pyrrole- (6Z) - methylamide - ilidene] -2-oxo-2,3- dihydro-1 H-indol-5-sulphonic; ethyl ester of 2-methyl-6- [2-oxo-5-sulfamoyl-1,2-dihydro-indole- (3Z) -ylidene] -1, 4,5,6-feirahydro-cyclopenia [b] pyrrol- 3-carboxylic; 3- [3-methanesulfonyl-2-methyl-4,5-dihydro-1H-cyclopenta [b] pyrrol- (6Z) -ylidene] -2-oxo-2,3-dihydro-1H-indole acid methylamide -5-sulfon; acid { 6-methoxy-3- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -indan-1 -iI} -acetic; 5-fluoro-3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl) -4,5-dihydro-1H-cyclopenta [b] pyrrole- (6Z) -ylidene] -1,3-dihydro-indoI-2-one; 6-meioxy-3- [2-meityl-3 - ((S) -2-? -rolidolidin-1-ylmeryl-pyrrolidin-1 -carbonyl) -4,5-dihydro-1H-cyclopenpha [b] pyrrol- (6Z) ) -liden] -1,3-dihydro-indol-2-one; 4-methoxy-3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmeryl-pyrrolidin-1-carbonyl) -4,5-dihydro-1H-cyclopenia [b ] pyrrole- (6Z) -ylden] -1,3-dihydro-indol-2-one; 7-Chloro-3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrroline-1-carbonyl) -4,5-dihydro-1 H -cyclopenta [b] pyrrol- (6Z) -ylidene] -1, 3-dihydro-indoI-2-one; 3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrroIdin-1-carbonyl) -4,5-dihydro-1 H -cylopenia [b] pyrrole- (6Z) ) -ylidene] -1,3-dihydro-pyrrolo [2,3-b] pyridin-2-one; and 6- (4-meioxy-phenol) -3- [2-methy1- 3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1 -carbonyl) -4.5- dihydro-1 H-cyclopenia [b] pyrrol- (6Z) -ylidene] -1,3-dihydro-indol-2-one; or a prodrug or pharmaceutically acceptable salt thereof. In another aspect, the invention relates to a pharmaceutical composition comprising a compound of Formula I or II, or a prodrug or a pharmaceutically acceptable salt of a compound of Formula I or II and a pharmaceutically acceptable carrier or excipient. In yet another aspect, the invention relates to a method for modulating the catalytic activity of a protein kinase comprising contacting said protein kinase with a compound of Formula I or II or a prodrug or pharmaceutically acceptable salt of a compound of Formula I or II. In a preferred embodiment, the protein kinase is selected from the group consisting of a tyrosine kinase receptor, a non-receptor tyrosine kinase and a serine-ireine kinase. In yet another aspect, the invention relates to a method for treating or preventing a disorder related to protein kinases in an organism comprising administering to the organism a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I or II or a prodrug. or a pharmaceutically acceptable salt of a compound of Formula I or II and a pharmaceutically acceptable carrier or excipient. In a preferred embodiment, the proinein kinase related disorder is selected from the group consisting of a tyrosine kinase receptor related disorder, a disorder related to non-receptor tyrosine kinases and a disorder related to serine-freonine kinases. In another preferred embodiment, the protein kinase related disorder is selected from the group consisting of a PDGFR-related disorder and a flk-related disorder. In a preferred embodiment, the protein kinase related disorder is a cancer selected from the group consisting of squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer , prostate cancer, breast cancer, small cell lung cancer, glioma, colorectal cancer, genitourinary cancer and gas-intestinal cancer. In another preferred embodiment, the protein kinase related disorder is selected from the group consisting of diabetes, an autoimmune disorder, a hyperproliferation disorder, restenosis, fibrosis, psoriasis, von Heppel-Lindau disease, osteoarthritis, rheumatoid arthritis, angiogenesis, an inflammatory disorder, an immune disorder and a cardiovascular disorder. In a preferred embodiment, the organism is a human being.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS A family of new geometrically restricted indolones substituted with sulfonamide has been discovered which manifest PK modulatory capacity and have an effect of improvement against disorders related to abnormal PK activity. The compounds presented herein are only examples and should not be construed as limiting the scope of this invention in any way. In another aspect, the invention is directed to a pharmaceutical composition comprising one or more compounds of the Formula (I), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. It is also an aspect of this invention that a compound described in the present specification, or its salt, can be combined with other chemotherapeutic agents for the treatment of the diseases and disorders discussed above. For example, a compound or salt of this invention could be combined with alkylating agents such as fluorouracil (5-FU) alone or in additional combination with leucovorin; or other alkylating agents such as, without limitation, other pyrimidine analogs such as UFT, capecitabine, gemcyanabine and cytarabine, alkyl sulfonates, for example, busulfan (used in the treatment of chronic granulocytic leukemia), improsulfane, and piposulfane; aziridines, for example, benzodepa, carbocuone, meiuredepa and uredepa; efilenimines and methylmelamines, for example, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; and nitrogenous mustards, for example, chlorambucil (used in the treatment of chronic lymphocytic leukemia, primary macroglobulinemia and non-Hodgkin's lymphoma), cyclophosphamide (used in the treatment of Hodgkin's disease, multiple myeloma, neuroblastoma, breast cancer, cancer ovarian cancer, lung cancer, Wilm's tumor and rhabdomyosarcoma), estramusin, ifosfamide, novembricin, predimusin and uracil mustard (used in the primary thrombocytosis, non-Hodgkin's lymphoma, Hodgkin's disease and ovarian cancer); and Iriazines, for example, dacarbazine (used in the soft tissue sarcoma). It can also be expected that a compound or salt of this invention has a beneficial effect in combination with other chemoatheremic antimetabolite agents such as, without limitation, folic acid analogues, for example meiorexate (used in the treatment of acute lymphocytic leukemia, choriocarcinoma, breast cancer mycosis fungiodes, cancer of the head and neck and osteogenic sarcoma) and pferopferin; and purine analogues such as mercaptopurine and thioguanine which would find use in the treatment of acute granulocytic, acute lymphocytic and chronic granulocytic leukemias. A compound or salt of this invention can also be expected to be effective in combination with chemotherapeutic agents based on natural products such as, without limitation, vinca alkaloids, for example, vinblaslin (used in the treatment of breast and testicular cancer). ), vincristine and vindesine; epipodophyloxysines, for example, etoposide and teniposide, which are useful in the treatment of testicular cancer and Kaposi's sarcoma; Antibiotic chemotherapeutic agents, for example, daunorubicin, doxorubicin, epirubicin, mitomycin (used to treat cancer of the stomach, cervix, colon, breast, bladder, and pancreas), dactinomycin, temozolomide, plicamycin, bleomycin (used in the treatment of skin cancer) , esophagus and genitourinary nerve); and enzymatic chemoathereal agents such as L-asparaginase.

In addition to the aforementioned above, it can be expected that a compound or salt of this invention has a beneficial effect in combination with platinum coordination complexes (cisplatin, etc.), susíifuidas ureas such as hydroxyurea; methylhydrazine derivatives, for example, procarbazine; adrenocortical suppressors, for example, mitotane, aminoglutethimide; and hormones and hormone antagonists such as adrenocorticosteroids (e.g. prednisone), progestogens (e.g. hydroxyprogesterone caproaio); esírógenos (for example dieilelstilbesterol); antiestrogens such as tamoxifen; androgens, for example tesfoserone propionate; and aromatase inhibitors (such as anastrozole). Finally, the combination of a compound of this invention can be expected to be particularly effective in combination with mitoxanihrone or pacliaxel for the blunting of solid tumor cancers or leukemias such as, without limitation, acute myelogenous (non-lymphocytic) leukemia. The aforementioned method can be carried out in combination with a chemotherapeutic agent selected from the group consisting of mitogenic inhibitors, alkylating agents, lipid metabolites, cell cycle inhibitors, enzymes, inhibitors of iopoisomerase, biological response modifiers, antihormones, ani-angiogenic agents such as the inhibitors of MMP-2, MMP-9 and COX-2, and antiandrogens.

Examples of useful COX-II inhibitors include Vioxx®, CELEBREX® (alecoxib), valdecoxib, paracoxib, rofecoxib and Cox 189. Examples of matrix metallopropyrenase inhibitors are described in WO 96/33172 (published on 24 October 1996), WO 96/27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed October 29, 1999), WO 98/07697 (published February 26, 1999). 1998), WO 98/03516 (published January 29, 1998), WO 98/34918 (published August 13, 1998), WO 98/34915 (published August 13, 1998), WO 98/33768 ( published August 6, 1998), WO 98/30566 (published July 16, 1998), European Patent Publication 606,046 (published July 13, 1994), European Patent Publication 931,788 (published July 28). 1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published October 21, 1999), WO 99/52889 (published on October 21, 1999), WO 99/29667 (published June 17, 1999), PCT International Application No. PCT / IB98 / 01113 (filed July 21, 1998), European Patent Application No. 99302232.1 ( filed on March 25, 1999), the Great Brefa patent application number 9912961.1 (filed on June 3, 1999), the US Provisional Application. No. 60 / 148,464 (filed August 12, 1999), U.S. Pat. No. 5,863,949 (made public on January 26, 1999), US Pat. No. 5,861,510 (made public on January 19, 1999), and European Patent Publication 780,386 (published June 25, 1997), all of which are incorporated herein by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred are those that selectively inhibit MMP-2 and / or MMP-9 relative to the other matrix meialoproteinases (ie MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7). , MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13). Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, RS 13-0830, and the compounds listed in the following list: 3 - [[4- (4-fluoro-phenoxy)] -benzenesulfonyl] - (1-hydroxycarbamoyl-cyclopenyl) -amino] -propionic; 3-Exo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] ocfan-3-carboxylic acid hydroxyamide; (2R, 3R) 1- [4- (2-Cyoro-4-fluoro-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-p-peridin-2-carboxylic acid hydroxyamide; 4- [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyrran-4-carboxylic acid hydroxyamide; 3 - [[4- (4-fioro-phenoxy) -benzenesulfonyl] - (1-hydroxycarbamoyl-cyclo-butyl) -amino] -proponic acid; 4- [4- (4-Cyoro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic acid hydroxyamide; (R) 3- [4- (4-Chloro-phenoxy) -benzenesulfonylamino] -phehydro-pyran-3-carboxylic acid hydroxyamide; hydroxyamide of (2R, 3R) 1- [4- (4-fluoro-2-methyl-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidine-2-carboxylic acid; 3 - [[(4- (4-Fluoro-phenoxy) -benzenesulfonyl] - (1-hydroxycarbamoyl-1-methyl-ethyl) -amino] -propionic acid 3 - [[4- (4- fluoro-phenoxy) -benzenesulfonyl] - (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -aminoj-propionic acid hydroxyamide 3-exo-3- [4- (4-chloro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid, 3-endo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamine] -8-oxa-bicyclohydroxyamide [3.2.1] octane-3-carboxylic acid and (R) 3- [4- (4-fluoro-phenoxy) -benzenesulfonic acid] -tearyhydro-furan-3-carboxylic acid hydroxyamide and pharmaceutically acceptable salts and solvates of said Other anti-angiogenesis agents, including other COX-II inhibitors and other MMP inhibitors, may also be used in the present invention The compounds of Formula (I) may also be used with signal transduction inhibitors, such as agents that can inhibit the EGFR (growth factor receptor phermic), such as EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; inhibitors of VEGF (vascular endo-vascular growth factor); and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, e.g., HERCPTIN® (Genentech, Inc. of San Francisco South, Calif., USA), EGFR inhibitors are described, for example, in WO 95/19970 (published July 27, 1995), WO 98/14451 (published April 9, 1998), WO 98/02434 (published January 22, 1998), and US Patent No. 5,747,498 (made public on May 5, 1998), and those claims can be used in the present invention as described herein. EGFR inhibiting agents include, but are not limited to, C225 and anti-EGFR 22Mab monoclonal antibodies (ImClone Systems Incorporated of New York, NY, USA), compounds ZD-1839 (AsfraZeneca), BIBX- 1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc. of Annandale, NJ, USA), and OLX-103 (Merck &Co. of Whiiehouse Station, NJ, USA), VRCTC-310 ( Ventech Research) and the EGF fusion toxin (Seragen Inc. of Hopkinton, Mass.). These and other EGFR inhibiting agents can be used in the present invention. VEGF inhibitors, for example SU-5416, SU11248, SU-6668 (Sugen Inc. of San Francisco South, Calif., USA), may also be combined with a compound of Formula (I). VEGF inhibitors are described, for example, in WO 99/24440 (published May 20, 1999), PCT International Application PCT / IB99 / 00797 (filed May 3, 1999), in WO 95/21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999), U.S. Pat. No. 5,834,504 (issued November 10, 1998), WO 01/60814, WO 98/50356 (published November 12, 1998), US Pat. No. 5,883,113 (issued March 16, 1999), U.S. Pat. No. 5,886,020 (made public on March 23, 1999), US Patent. No. 5,792,783 (made public on August 11, 1998), WO 99/10349 (published March 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published on June 26, 1997), WO 98/54093 (published December 3, 1998), WO 98/02438 (published January 22, 1998), WO 99/16755 (published April 8, 1999), and WO 98/02437 (published January 22, 1998), which are incorporated herein by reference in their entirety. Other examples of some specific VEGF inhibitors useful in the present invention are IM862 (Cytran Inc. of Kirkiand, Wash., USA); anti-VEGF monoclonal antibody from Genentech, Inc. of San Francisco Sur, Calif .; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Coló.) and Chiron (Emeryville, Calif.). These and other VEGF inhibitors can be used in the present invention as described herein. Inhibitors of the erbB2 receptor, such as GW-282974 (Glaxo Welcome foot), and the AR-209 monoclonal antibodies (Aronex Pharmaceuticals Inc. of The Woodlands, Tex., USA) and 2B-1 (Chiron), can also be combined with a compound of the Formula (I). ) for example those indicated in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO 98/02437 (published January 22, 1998), WO 97/13760 (published April 17, 1997), WO 95/19970 (published July 27, 1995), U.S. Pat. No. 5,587,458 (issued December 24, 1996), and US Pat. No. 5,877,305 (published on March 2, 1999), which are herein incorporated by reference in their entirety. ErbB2 receptor inhibitors useful in the present invention are also described in the US Provisional Application. No. 60 / 117,341, filed on January 27, 1999, and in the US Provisional Application. No. 60 / 117,346, filed on January 27, 1999, which are incorporated herein by reference. The erbB2 receptor inhibitor substances and compounds described in the aforementioned PCT applications, US patents, and US provisional applications, as well as other compounds and substances that inhibit the erbB2 receptor, can be used with the compounds of Formula (I), in accordance with the present invention. The compounds of Formula (I) may also be used with other agents useful for bringing cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 antibodies (cytotoxic lymphocyte antigen 4). , and other agents capable of blocking CTLA4; and anti-proliferative agents such as other famesyl proieinus transferase inhibitors, for example the famesyl protein transferase inhibitors described in the references given in the "Background" section of US Pat. No. 6,258,824 B1. Specific CTLA4 antibodies that can be used in the present invention include those described in the U.S. Provisional Application. 60 / 113,647 (filed December 23, 1998) which is incorporated by reference in its entirety, however other CTLA4 antibodies can be used in the present invention. The aforementioned method can also be carried out in combination with radiotherapy, in which the amount of a compound of the formula (I) in combination with radiotherapy is effective for treating the aforementioned diseases. The level of radiotherapy administered can be reduced to a sub-effective dose when administered in combination with the compounds of the preferred embodiments of the present invention. Techniques for administering radiotherapy are known in the art, and these techniques can be used in the joint treatment described herein. The administration of the compound of the invention in this joint preparation can be determined as described herein. Another aspect of the invention is directed to the use of compounds of Formula I or II in the preparation of a medicament, which is useful for the treatment of a disease mediated by abnormal protein kinase activity. In one aspect, a preferred embodiment of the present invention relates to the use of compounds of Formula I or II in the preparation of a medicament, which is useful for the treatment of a disease as measured by abnormal protein kinase activity. "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to salts that retain the properties and biological efficacy of free bases and that are obtained by reaction with organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, acid hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, acetic acid, benzenesulfonic acid (besylate), benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, acid pamoic acid, pantothenic acid, succinic acid, tartarite acid, and the like. A "pharmaceutical composition" refers to a mixture of one or more of the compounds described in the present invention, or of physiologically acceptable salts thereof, with other chemical components, such as vehicles and physiologically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism. As used herein, a "physiologically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not negate the properties and biological activity of the compound administered. An "excipient" refers to an inert suspension added to a pharmaceutical composition to further facilitate the administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders , disintegrating agents, and the like. "Alkyl" refers to a saturated aliphatic hydrocarbon that includes straight chain, branched chain or cyclic groups.

Preferably, the alkyl group has 1 to 20 carbon atoms (whenever a numerical range is indicated herein, for example "1-20", it means that the group, in this case the alkyl group, may contain 1 carbon atom. carbon, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). More preferably, it is an alkyl of average size having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted. When substituted, each substituent group is preferably one or more individually selected from halogen, -hydroxy, -COR ", -COOR ', OCOR', CONRR ', -RNCOR', -NRR? -CN, -NO2, -CZ3, -SR ', -SOR', -SO2R ', -SO2OR', -SO2NRR ', thiocarbonyl, -RNSO2R ", perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-Iiocarbamyl, silyl, ammonium, lower alkyl , lower alkynyl, lower alkynyl, cycloalkyl, heteroaryl, heteroaryl, and aryl R and R 'are independently H, alkyl, or aryl, in which the alkyl or aryl may be further substituted with halogen, (CH2) nN (R " ) 2, (CH2) nCO2R, (CH2) nOR ", (CH2) nOC (O) R", alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, a heiEROalicyclic ring, aryl, alkoxy, -OCZ3, aryloxy, C (O) NH2, or heeroaryl. R "is H, alkyl or aryl, N is 0-3." Alkenyl "refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, which includes straight chain, branched chain or cyclic groups that are Preferably, the alkenyl group has 2 to 20 carbon atoms (whenever a numerical inervant is indicated herein, for example "2-20", it means that the group, in this the alkenyl group may contain 2 carbon atoms, 3 carbon atoms, etc., and including 20 carbon atoms.) Most preferably, it is a medium-sized alkenyl having 2 to 10 carbon atoms. is a lower alkenyl having 2 to 6 carbon atoms The alkenyl group can be substituted or unsubstituted When sub stituted, each substituent group is preferably one or more individually selected from halogen, -hydroxy, -COR ', -COOR " , OCOR ', CONR R ', -RNCOR', -NRR ', -CN, -NO2, -CZ3, -SR', -SOR ', -SO2R', -SO2OR ', -SO2NRR-thiocarbonyl, -RNSO2R', perfluoroalkyl, O-carbamyl , N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium, lower alkyl, lower alkynyl, lower alkynyl, cycloalkyl, heteroalicyclo, heteroaryl, and aryl. In which R and R 'are defined herein. "Alkynyl" refers to an aliphatic hydrocarbon that has at least one carbon-to-carbon bond, which includes straight chain, branched chain or cyclic groups having at least one carbon-carbon multiple bond. Preferably, the alkynyl group has 2 to 20 carbon atoms (whenever a numerical range is indicated herein, for example "2-20", it means that the group, in this case the alkynyl group, may contain 2 carbon atoms. carbon, 3 carbon atoms, etc. up to and including 20 carbon atoms). More preferably, it is an alkynyl of average size having 2 to 10 carbon atoms. Most preferably, it is a lower alkynyl having 2 to 6 carbon atoms. The alkynyl group can be substituted or unsubstituted. When it is substituted, each susíiuyenyenie group is preferably one or more individually selected from halogen, -hydroxy, -COR ', -COOR', OCOR ', CONRR', -RNCOR ', -NRR \ -CN, -NO2, -CZ3, -SR ", -SOR", -SO2R \ -SO2OR ', -SO2NRR', liocarbonyl, -RNSO2R ', perfluoroalkyl, O-carbamyl, N-carbamyl, O-Iocarbamyl, N-Iiocarbamyl, silyl, ammonium, lower alkyl, lower alkynyl, lower alkynyl, cycloalkyl, heteroalicyclo, heteroaryl, and aryl Wherein R and R 'are defined herein A "cycloalkyl" or an "alicyclic" group refers to a monocyclic group or fused ring (s) say, rings that share an adjacent pair of carbon atoms) with all carbon atoms in which one or more of the rings do not have a completely conjugated pi ring system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane and cycloheptairiene. A cycloalkyl group may be substituted or unsubstituted. When substituted, each substituent group is preferably one or more individually selected from halogen, -hydroxy, -COR ', -COOR', OCOR ', CONRR', -RNCOR *, -NRR ', -CN, -NO2, -CZ3 , -SR \ -SOR ', -SO2R', -SO2OR ', -SO2NRR', thiocarbonyl, -RNSO2R ', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium, lower alkyl , lower alkynyl, lower alkynyl, cycloalkyl, heteroalicyclo, heteroaryl, and aryl. In which R and R 'are defined herein. An "aryl" group refers to a monocyclic or polycyclic fused ring group (ie, rings that share an adjacent pair of carbon atoms) with all carbon atoms that have a fully conjugated pi electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anryrazinyl. The aryl group can be suspended or unsubstituted. When substituted, each susíiuyenyenie group is preferably one or more selected from halogen, -hydroxy, alkoxy, aryloxy, -COR ', -COOR', OCOR ', CONRR', -RNCOR ', -NRR ", -CN, -NO2 , -CZ3, -SR \ -SOR ', -SO2R', -SO2OR ', -SO2NRR \ thiocarbonyl, -RNSO2R', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium, lower alkyl, lower alkynyl, lower alkynyl, cycloalkyl, heteroalicyclo, heteroaryl, and aryl Wherein R and R 'are defined herein As used herein, a "heteroaryl" group refers to a group monocyclic or fused ring (that is, rings that share an adjacent pair of atoms) that have in the ring (s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur and, in addition, that have an electron system Completely conjugated examples, examples, without limitation, of heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole , pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine and carbazole. The heteroaryl group can be substituted or unsubstituted. When substituted, each substituent group is preferably one or more selected from halogen, -hydroxy, -COR ', -COOR', OCOR ', CONRR', -RNCOR ', -NRR', -CN, -NO2, -CZ3, -SR ', -SOR', -SO2R ', -SO2OR', -SO2NRRthiocarbonyl, -RNSO2R ', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N -iocarbamyl, silyl, ammonium, lower alkyl, lower alkynyl, lower alkynyl, cycloalkyl, heteroalicyclo, heteroaryl, and aryl, wherein Z is halogen. In which R and R 'are defined herein. A "heteroalicyclic ring" or "heteroalicyclic group" refers to a monocyclic group or fused ring having in the ring (s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, the rings can not have a pi system completely conjugated. The heteroalicyclic ring can be suspended or unsubstituted. The heteroalicyclic ring may contain one or more oxo groups. When substituted, the substituting group (s) is preferably one or more selected from halogen, -hydroxy, -COR ', -COOR', OCOR ', CONRR', -RNCOR ', -NRR', -CN, -NO2, -CZ3, -SR ', -SOR', -SO2R ', -SO2OR', -SO2NRR ', thiocarbonyl, -RNSO2R', perfluoroalkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, ammonium , lower alkyl, lower alkynyl, lower alkynyl, cycloalkyl, heteroalicyclo, heeroaryl, and aryl. In which R and R 'are defined in the present memory. Z refers to a halogen group selected from the group consisting of fluorine, chlorine, bromine and iodine. A "hydroxy" group refers to an -OH group. An "alkoxy" group refers to both an -O-alkyl group and an -O-cidoalkyl group, as defined herein. An "alkoxycarbonyl" refers to a -C (O) -O. An "aminocarbonyl" refers to a -C (O) -NRR '. An "aryloxycarbonyl" refers to -C (O) -Oaryl. An "aryloxy" group refers to both an -O-aryl group and an -O-heteroaryl group, as defined herein. An "arylalkyl" group refers to -alkyl-aryl, wherein alkyl and aryl are defined herein. An "alkylaryl" group refers to -aryl-alkyl, wherein alkyl and aryl are defined herein. An "arylsulfonyl" group refers to an -SO2-aryl. An "alkylsulfonyl" group refers to an -SO 2 -alkyl. A "heteroaryloxy" group refers to a heteroaryl-O- group with heteroaryl as defined herein. A "heyeroalicycloxy" group refers to a heteroalicyclic-O- group with the heteroalicyclic group as defined herein. A "carbonyl" group refers to a -C (= O) -R. An "aldehyde" group refers to a carbonyl group in which R is hydrogen. A "thiocarbonyl" group refers to a group -C (= S) -R. A "trihalomelancarbonyl" group refers to a group Z3C-C (0 >; A "C-carboxyl" group refers to a -C (O) O-R group.

An "O-carboxyl" group refers to a group R-C (O) O-. A "carboxylic acid" group refers to a C-carboxyl group in which R is hydrogen. A "halo" or "halogen" group refers to fluorine, chlorine, bromine or iodine. A "trihalomethyl group" refers to a -CZ3 group. An "urohalomethanesulfonyl" group refers to a group Z3CS (O) 2 A "trihalomethanesulfonamido" group refers to a group Z3CS (O) 2NR-. A "sulfinyl" group refers to a -S (O) -R group. A "sulfonyl" group refers to a -S (O) 2R group. An "S-sulfonamido" group refers to a group -S (O) NRR '. An "N-sulfonamido" group refers to a group -NR-S (O) 2R. An "O-carbamyl" group refers to a group -OC (O) NRR '. A "N-carbamyl" group refers to an ROC (O) NR- group. An "O-thiocarbamyl" group refers to a group -OC (S) NRR '. A group "N-iocarbamyl" refers to a group ROC (S) NR'-. An "amino" group refers to a group -NHS or a group -NRR. A "C-amido" group refers to a group -C (O) NRR '. An "N-amido" group refers to a group R'C (O) NR-. A "child" group refers to a group -NO2. A "cyano" group refers to a -CN group.

A "silyl" group refers to a -Si (R) 3 group. A "phosphonyl" group refers to a group -P (= O) (O) 2. An "aminoalkyl" group refers to an -alkylNRR'-group. An "alkylaminoalkyl" group refers to an -alkyl-NR-alkyl group. A "dialkylaminoalkyl" group refers to an -alkyl-N- (alkyl) group. A "perfluoroalkyl" group refers to an alkyl group in which all hydrogen atoms have been replaced with fluorine atoms. The definitions of Ri-R 12, X, R, R 'and R "are defined herein.Compounds that have the same molecular formula but differ in the nature or sequence of the bonding of their atoms or the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers" and those that are non-superimposable mirror images. they are called "enantiomers." When a compound has an asymmetric center, for example, it is attached to four different groups, a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the rules of sequence R- and S- of Cahn and Prelog, or by the way in which the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (that is, as somers (+) or (-) respectively). A chiral compound can exist either as a single enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture." The compounds of this invention may have one or more asymmetric centers; such compounds can therefore be prepared as individual stereoisomers (R) - or (S) - or as their mixtures. Unless otherwise indicated, the description and naming of a particular compound in the specification and claims has the purpose of including both the individual enantiomers and their mixtures, racemic or otherwise. Methods for the determination of stereochemistry and separation of stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 1992) . The compounds of Formula I or II can exhibit the phenomena of tautomerism and structural isomerism. For example, the compounds described herein can adopt an E or Z configuration around any double bond in the molecule. This invention encompasses any tautomeric or isomeric form and mixtures thereof that have the ability to modulate the activity of RTK, CTK and / or STK and is not limited to any iaulomeric or isomeric structural form. A "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, with other chemical components, fales as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism. The compound of Formula I or II can also act as a prodrug. A "prodrug" refers to an agent that becomes the precursor drug jn vivo. Often the prodrugs are useful because, in some situations, they may be easier to administer than the precursor drug. For example, they may be bioavailable by oral administration while the precursor drug is not. The prodrug may also have better solubility in pharmaceutical compositions than the precursor drug. An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug") to facilitate transport across a cell membrane in which aqueous solubility is detrimental to mobility but then metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where the aqueous solubility is beneficial. A further example of a prodrug may be a short polypeptide, for example, without limitation, a polypeptide of 2-10 amino acids, linked by a terminal amino group to a carboxy group of a compound of this invention in which the polypeptide is hydrolyzed or metabolizes jn alive to release the active molecule. Prodrugs of a compound of Formula I or II are within the scope of this invention. Additionally, it is contemplated that a compound of Formula I or II would be metabolized by enzymes in the body of the organism such as a human being to generate a metabolism that can modulate the activity of the proinin kinases. Such metabolisms are denien of the scope of the present invention. As used in the present invention, a "physiologically / pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not negate the properties and biological activity of the compound administered. A "pharmaceutically acceptable excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. As used herein, the term "pharmaceutically acceptable salt" refers to salts that retain the efficacy and biological properties of the precursor compound. Such salts include: (1) acid addition salt which is obtained by reaction of the free base of the precursor compound. with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid , mephanosulfonic acid, ethanesulfonic acid, p -oluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like, preferably hydrochloric acid or (L) -malic; or (2) salts formed when an acidic proton is present in the precursor compound or is replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or is coordinated with an organic base such as ethanolamine, diethylamine, urea-amino-amine, amylamine, N-methyl-glucamine, and the like. "PK" refers to receptor protein tyrosine kinase (RTKs), non-receptor tyrosine kinase or cellular tyrosine kinase (CTKs) and serine-ireine kinases (STKs). "Meiodum" refers to ways, means, techniques, and procedures for carrying out a given area that includes, but is not limited to, the manners, means, techniques, and procedures known to, or readily developed from, ways, means, techniques and procedures by, chemistry, pharmacy, biochemistry and medicine professionals. "Modulation" or "modular" refers to the alteration of the catalytic activity of the RTKs, CTKs and STKs. In particular, "modular" refers to the activation of the catalytic activity of the RTKs, CTKs and STKs, preferably the activation or inhibition of the catalytic activity of the RTKs, CTKs and STKs, depending on the concentration of the compound or salt to which it is added. exposes the RTK, CTK or STK or, more preferably, the inhibition of the catalytic activity of the RTKs, CTKs and STKs. "Caíalitic activity" refers to the rate of tyrosine phosphorylation under the direct or indirect influence of RTKs and / or CTKs or the phosphorylation of serine and threonine under the direct or indirect influence of STKs. "Bridging" refers to putting together a compound of this invention and an objective PK such that the compound can affect the catalytic activity of the PK, or directly, ie, by interaction with the kinase alone, or indirectly, that is, by interaction with another molecule that is dependent on the kallial activity of the kinase. Such "contacting" can be carried out "in vitro", that is, in a test tube, a peiri plate or the like. In a test tube, contacting may involve only one compound and one PK of interest or may involve whole cells. The cells can also be maintained or cultured in cell culture plates and contacted with a compound in this environment. In this context, the ability of a particular compound to affect a PK-related disorder, ie, the IC50 of the compound, defined below, can be determined even if the use of the compounds is attempted in vivo with more complex living organisms. For cells outside the organism, there are multiple methods, and are well known to those skilled in the art, for contacting PKs with compounds including, but not limited to, direct cell microinjection and numerous transmembrane transport techniques. "w" refers to the procedures carried out in an artificial environment such as, for example, without limitation, in a test tube or culture medium. '77 Vo "refers to the procedures carried out within a living organism such as, without limitation, a mouse, raía or rabbit. "Transorhine related to PK", "PK-induced diaspore", and "abnormal PK activity" refer to a disease characterized by inadequate, that is, sub- or, more commonly, over-, PKalytic activity of PK, in the that the particular PK may be an RTK, a CTK or an STK. Inadequate caylalitic activity may arise as a result of: (1) PK expression in cells that do not normally express PKs, (2) increased PK expression leading to unwanted cell proliferation, differentiation and / or growth, or, (3) decreased expression of PK leading to undesired reductions in cell proliferation, differentiation and / or growth. The over-activity of a PK refers to the amplification of the gene encoding a particular PK or to the production of a level of PK activity that can be correlated with an irasorution of cell proliferation, differentiation and / or growth (i.e., when the PK level increases, the severity of one or more symptoms of cellular transient increase). The sub-activity is, of course, the inverse, in which the severity of one or more symptoms of a cellular transient increases when the level of PK activity decreases. "Treat", "bringing" and "treatment" refer to a method of alleviating or abrogating a PK-mediated cell disorder and / or its corresponding symptoms. With respect particularly to cancer, these terms simply mean that the life expectancy of an individual affected with a cancer will increase or that one or more of the symptoms of the disease will be reduced. "Organism" refers to any living entity formed by at least one cell. A living organism can be as simple as, say, a single eukaryotic cell or complex fan like a mammal, which includes a human being. "Therapeutically effective amount" refers to that amount of the compound that is administered, which relieves to some extent one or more of the symptoms of the disorder that was brought. In reference to the duration of cancer, a therapeutically effective amount refers to that amount which has the effect of: (1) reducing the size of the tumor; (2) inhibiting (ie, relieving to some extent, preferably stopping) tumor metastasis; (3) inhibit to some extent (i.e. refract to some extent, preferably stop) the tumor growth, and / or (4) alleviate to some extent (or, preferably, eliminate) one or more symptoms associated with cancer. "Supervising" means observing or detecting the effect of contacting a compound with a cell expressing a particular PK. The observed or detected effect may be a change in the cellular phenotype, in the catalytic activity of a PK or a change in the interaction of a PK with a naive bond partner. Techniques for observing or detecting such effects are well known in the art. The effects referenced above are selected from a change or an absence of change in a cellular phenotype, a change or absence of change in the caffeine activity of a protein kinase or a change or absence of change in the interaction of the protein kinase with a partner of naive union in a final aspect of this invention. "Cell phenotype" refers to the external appearance of a cell or tissue or to the biological function of the cell or tissue. Examples, without limitation, of a cellular phenotype are cell size, cell growth, cell proliferation, cell differentiation, cell survival, apoptosis, and absorption and use of nutrients. Such phenotypic characteristics are measurable by techniques well known in the art. "Natural binding partner" refers to a polypeptide that binds to a particular PK in a cell. Natural binding partners can play a role in propagating a signal in a PK-mediated signal transduction process. A change in the interaction of the napural binding partner with the PK may manifest itself as an increase or decrease in the concentration of the PK / copartite complex of natural binding and, as a result, in an observable change in the capacity of the PK to mediate signal transduction.

Indications The PKs whose caylalitic activity is modulated by the compounds of this invention include protein tyrosine kinases of which there are two types, tyrosine kinase receptors (RTKs) and cell tyrosine kinases (CTKs), and serine-threonine kinases (STKs). RTK-mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of the intrinsic activity of protein tyrosine kinase and phosphorylation. Thus, binding sites for infracellular molecules of signal transduction are created and the formation of complexes is carried out with a cytoplasmic signaling signal spectrum that facilitates the appropriate cellular response (for example, cell division, metabolic effects on the extracellular microenvironment, etc.). .). See, Schlessinger and Ullrich, 1992, Neuron 9: 303-391. It has been shown that the tyrosine phosphorylation sites in the growth factor receptors function as high affinity binding sites for the SH2 domains (src homology) of signaling molecules. Fantl et al., 1992, Cell 69: 413-423, Songyang et al., 1994, Mol. Cell. Biol. 14: 2777-2785, Songyang et al., 1993, CeJl 72: 767-778, and Koch et al., 1991, Science 252: 668-678. Several intracellular substrate proteins have been identified that are associated with RTKs. They can be divided into two main groups: (1) substrates that have a catalytic domain, and (2) substrates that lack such a domain but that serve as adapters and are associated with molecules caíalíticamenfe acíivas. Songyang et al., 1993, Cell 72: 767-778. The specificity of the interactions between receptors and SH2 domains of their substrates is determined by the amino acid residues immediately around the phosphorylated tyrosine residue. The differences in the binding affinities between the SH2 domains and the amino acid sequences around the phosphotyrosine residues in particular receptors are consistent with the differences observed in their substrate phosphorylation profiles. Songyang et al., 1993, Cell 72: 767-778. These observations suggest that the function of each RTK is determined not only by its expression pattern and binding capacity but also by the series of downstream signal transduction pathways that are activated by a particular receptor. Thus, phosphorylation provides an important regulatory step that determines the selectivity of the signaling pathways acquired by specific receptors of the growth factor, as well as receptors of the differentiation factor. STKs, which are mainly cytosolic, affect the internal biochemistry of the cell, often as an automatic response to a PTK event. STKs have been implicated in the signaling process that initiates DNA synthesis and the subsequent miyosis that leads to cell proliferation. Thus, PK signal transduction results, among other responses, in cell proliferation, differentiation, growth and metabolism. Abnormal cell proliferation can result in a wide range of frasures and diseases, including the development of renal neoplasia such as carcinoma, sarcoma, glioblasíoma and hemangioma, disorders such as leukemia, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy and other disorders related to uncontrolled angiogenesis and / or vasculogenesis. A precise understanding of the mechanism by which the compounds of this invention inhibit PKs to put the present invention into practice is not required. However, while not being hereby bound to any particular mechanism or theory, it is believed that the compounds interact with the amino acids in the caylalific region of the PKs. The compounds described herein can thus be useful as in vitro assays for PKs as well as show therapeutic effects in vivo by interaction with PKs. Additionally, the compounds of the present invention provide a therapeutic approach to the breakdown of many kinds of solid lumens, including but not limited to carcinomas, sarcomas including Kaposi's sarcoma, erilroblasima, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma. The treatment or prevention of non-solid tumor cancers such as leukemia is also contemplated. The indications may include, but are not limited to, brain cancers, blood cancers, lung cancers and bone cancers. Additional examples, without limitation, of the types of disorders related to inappropriate PK activity that the compounds described herein may be useful for preventing, treating and studying, are cell proliferative disorders, fibrotic disorders and mephabolic isophornes. The cellular proliferative phenomena, which can be prevented, brought or additionally studied by the present invention, include cancer, proliferative and blood vessel vectors. proliferative disorders of mesangial cells. Blood vessel proliferative disorders refer to disorders related to abnormal vasculogenesis (blood vessel formation) and abnormal angiogenesis (blood vessel extension). Although vasculogenesis and angiogenesis play an important role in a variety of normal physiological processes such as embryonic development, corpus luteum formation, wound healing and organ regeneration, they also play a critical role in the development of cancer in which they result the formation of new capillaries needed to keep a tumor alive. Other examples of disorders of blood vessel proliferation include arthritis, in which new capillary blood vessels invade the joint and destroy cartilage, and eye diseases, such as diabetic retinopathy, in which new capillaries in the retina invade the vitreous, bleed and cause blindness. Two structurally related RTKs that bind to VEGF with high affinity have been identified: receptor 1 tyrosine of the fms type (flt-l) (Shibuya et al., 1990, Oncoqene 5: 519-524; De Vries et al., 1992, Science. 255: 989-991) and the KDR / FLK-1 receptor, also known as VEGF-R2. Vascular endothelial growth factor (VEGF) has been reported to be a specific myelogen of endothelial cells with endoyelial cell growth promoting activity. Ferrara and Henzel, 1989, Biochein. Biophvs. Res. Comm. 161: 851-858; Vaisman et al., 1990, J. Biol. Chem. 265: 19461-19566. The information expounded in the US Requests. Nos. 08 / 193,829, 08 / 038,596 and 07 / 975,750, strongly suggest that VEGF is not only responsible for endothelial cell proliferation, but is also the main regulator of normal and pathological angiogenesis. See generally, Klagsburn and Soker, 1993, Current Biology. 3 (10) 699-702; Houck, et al., 1992, J. Biol. Chem., 267: 26031-26037. Normal vasculogenesis and angiogenesis play important roles in a variety of physiological processes such as embryonic development, wound healing, organ regeneration and female reproductive processes such as the development of the follicle in the corpus luteum during ovulation and the growth of the placenta after of pregnancy. Folkman and Shing, 1992, J. Bioloaical Chem .. 267 (16): 10931-34. The vasculogenesis and / or angiogenesis inconíroladas have been associated with diseases such as diabetes as well as malignant solid tumors that depend on the vascularization to grow. Klagsburn and Soker, 1993, Curreni Bioloav. 3 (10): 699-702; Folkham, 1991, J. Naíl. Cancer Inst. 82: 4-6; Weidner, et al., 1991. New Enal. J. Med .. 324: 1- 5. The supposed role of VEGF in the proliferation and migration of endothelial cells during angiogenesis and vasculogenesis indicates an important role of the KDR / FLK-1 receptor in these processes. Diseases such as diabetes meliitus (Folkman, 198, in Xlth Congress of Thrombosis and Haemosiasis (Versilia, et al., Eds.), Pp. 583-596, Leuven Universiíy Press, Leuven) and arthritis, as well as growth of malignant tumors can result from uncontrolled angiogenesis. See, for example, Folkman, 1971, N. Engl. J. Med .. 285: 1182-1186. The receptors to which VEGF binds specifically are an important and powerful therapeutic target for the regulation and modulation of vasculogenesis and / or angiogenesis and a variety of serious diseases that involve abnormal cell growth caused by such processes. Plowman, et al., 1994, DN & P. 7 (6): 334-339. More particularly, the highly specific role of the KDR / FLK-1 receptor in neovascularization makes it a target of choice for therapeutic approaches to the treatment of cancer and other diseases that involve the uncontrolled formation of blood vessels. Thus, the present invention provides compounds that regulate, modulate and / or inhibit vasculogenesis and / or angiogenesis by affecting the enzymatic activity of the KDR / FLK-1 receptor and interfering with the signal transduced by KDR / FLK-1. Thus the present invention provides a therapeutic approach to the treatment of many kinds of solid tumors including, but not limited to, glioblastoma, melanoma and Kaposi's sarcoma, and carcinoma of the ovary, lung, breast, prostate, pancreas, colon and epidermoid. In addition, the data suggest that the administration of compounds that inhibit the signal transduction pathway mediated by KDR / FIk-1 can also be used in the treatment of hemangioma, restenosis and diabetic retinopayia. In addition, this invention relates to the inhibition of vasculogenesis and angiogenesis by other receptor-mediated pathways, including the pathway comprising the flk-1 receptor. Tyrosine kinase receptor-mediated signal transduction is initiated by ex-cellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transient stimulation of the intrinsic activity of protein tyrosine kinase and phosphorylation. Thus, binding sites are created for iniral molecules of signal transduction that lead to the formation of complexes with a specimen of cytoplasmic signaling molecules that facilitate the appropriate cellular response, for example, cell division, mechabolic effects in the extracellular mitochondrion. See, Schlessinger and Ullrich, 1992, Neuron 9: 1-20. The close homology of the intracellular regions of the KDR / FLK-1 with that of the PDGF-β receptor (50.3% homology) and / or the related flt-1 receptor indicates the induction of superimposed signal transduction pathways. For example, it has been shown that for the PDGF-β receptor, the members of the src family (Twamley et al., 1993, Proc.Nat.Accid.Sci.USA.90: 7696-7700), phosphatidy [inositol-3] '- kinase (Hu et al., 1992, Mol. Cell. Biol., 12: 981-990), phospholipase c? (Kashishian and Cooper, 1993, Mol.Cell. Biol .. 4: 49-51), ras-GTPase activation protein (Kashishian et al., 1992, EMBO J .. 11: 1373-1382), PTP-ID / syp (Kazlauskas et al., 1993. Proc. Nati.

Acad. Sci. USA. 10 90: 6939-6943), Grb2 (Arvidsson et al., 1994, Mol Cell. Biol., 14: 6715-6726), and adapter molecules Shc and Nck (Nishimura et al., 1993, Mol. Cell. Biol., 13: 6889-6896), bind regions that involve different sites of autophosphorylation. See generally, Claesson-Welsh, 1994, Prog. Growth Factor Res., 5: 37-54. Thus, it is likely that the signal transduction pathways activated by KDR / FLK-1 include the ras path (Rozakis et al., 1992, Nature. 360: 689-692), the PI-3'-kinase path, the pathways mediated by src and the roads mediated by plc ?. Each of these pathways can play a critical role in the angiogenic and / or vasculogenic effect of KDR / FLK-1 on endothelial cells. Accordingly, a still further aspect of this invention relates to the use of the organic compounds described herein to modulate angiogenesis and vasculogenesis which, as such, are controlled by these pathways. Conversely, disorders related to retraction, contraction or closing of blood vessels, such as restenosis, are also involved and can be trampled or prevented by the methods of this invention. Fibrotic disorders refer to the abnormal formation of extracellular matrices. Examples of fibrotic disorders include liver cirrhosis, mesangial cell proliferative disorders and pulmonary fibrosis. Liver cirrhosis is characterized by an increase in extracellular matrix constituents that results in the formation of a hepatic scar. An increase in the extracellular matrix that results in a liver scarring can also be caused by a viral infection such as hepatitis. Lipocytes seem to play a very important role in liver cirrhosis. Other fibrotic disorders involved include atherosclerosis. Pulmonary fibrosis can result from radiation treatment or irradiation with chemotherapeutic drugs. Mesangial cell proliferative disorders refer to disorders caused by the abnormal proliferation of mesangial cells. Mesangial proliferative disorders include various human renal diseases such as glomerulonephritis, diabetic nephropathy and malignant nephrosclerosis as well as disorders such as thrombotic microangiopathy syndromes, transplant rejection, and glomerulopaphias. RTK PDGFR has been implicated in the maintenance of mesangial cell proliferation. Floege et al., 1993, Kidnev International 43: 47S-54S. Many cancers are cell proliferative disorders and, as previously noted, PKs have been associated with cell proliferative disorders. Thus, it is not surprising that natural PKs, such as members of the RTK family, have been associated with the development of cancer. Some of these receptors, such as EGFR (Tuzi et al., 1991, Br. J. Cancer 63: 227-233, Torp ef al., 1992, APMIS 100: 713-719), HER2 / neu (Slamon et al., 1989, Science 244: 707-712) and PDGR-R (Kumabe et al., 1992, Oncogene 7: 627-633) are overexpressed in many tumors and / or are persistently activated by autocrine loops. In fact, receptor over-expressions have been demonstrated (Akbasak and Suner-Akbasak et al., 1992, J. Neurol, Sci .. 111: 119-133, Dickson et al., 1992. Cancer Treatment Res. 61: 249-273, Korc et al., 1992, J. Clin. Invest. 90: 1352-1360) and autocrine loops (Lee and Donoghue, 1992, J. Cell. Biol. 118: 1057-1070, Korc et al., Supra. Akbasak and Suner-Akbasak et al., Supra) in the most common and serious cancers. For example, EGFR has been associated with squamous cell carcinoma, astrocytoma, glioblasíoma, head and neck cancer, lung cancer and bladder cancer. It has been associated with HER2 with breast, ovarian, gastric, lung, pancreatic and bladder cancers. It has been associated with PDGFR with glioblastoma and melanoma as well as with lung, ovarian and prostate cancer. RTK c-met has been associated with the formation of malignant tumors. For example, c-met has been associated with, among other cancers, colorectal, thyroid, pancreatic, gastric and hepatocellular carcinomas and lymphomas. In addition, c-mei has been linked to leukemia. The over-expression of the c-met gene has also been detected in patients with Hodgkin's disease Burkift's disease. IGF-IR, in addition to being involved in nutritional support and type II diabetes, has also been associated with several types of cancers. For example, IGF-1 has been implicated as an autocrine growth stimulator for several types of tumors, for example human breast cancer carcinoma cells (Arteaga et al., 1989, J. Clin. Inves., 84: 1418- 1423) and small lung tumor cells (Macauley et al., 1990, Cancer Res., 50: 2511-2517). In addition, IGF-I, although fully involved in the normal growth and differentiation of the nervous system, also appears to be an autocrine stimulator of human gliomas. Sandberg-Nordqvisf et al., 1993, Cancer Res. 53: 2475-2478. The importance of IGF-IR and its ligands in cell proliferation is further supported by the fact that many cell types in cultures (fibroblasts, epithelial cells, smooth muscle cells, T lymphocytes, myeloid cells, chondrocytes and osteoblasts (cells mother of bone marrow)) are stimulated to grow by IGF-I. Goldring and Goldring, 1991, Eukaryotic Gene Expression. 1: 301-326. Baserga and Coppola suggest that IGF-IR plays a central role in the transformation mechanism and, as such, may be a preferred target for therapeutic interventions for a broad spectrum of human cancers. Baserga, 1995, Cancer Res .. 55: 249-252, Baserga, 1994, CeN 79: 927-930, Coppola et al., 1994, Mol. Cell. Biol .. 14: 4588-4595. STKs have been implicated in many types of cancer including, in particular, breast cancer (Canee, et al., Int. J. Cancer, 54: 71-77 (1993)). The association between abnormal PK activity and disease was not limited to cancer. For example, RTKs have been associated with diseases such as psoriasis, diabetes mellitus, endometriosis, angiogenesis, atheromatous plaque development, Alzheimer's disease, restenosis, von Hippel-Lindau disease, epidermal hyperproliferation, neurodegenerative diseases, macular degeneration related to age and hemangiomas. For example, EGFR has been indicated in the cicatrization of corneal and dermal wounds. Defects have been reported in the insulin receptor (Insulin-R) and IGF-R in type II diabetes mellifus. A more complete correlation between the specific RTKs and their therapeutic indications is set forth in Plowman et al., 1994, DN & P 7: 334-339. As previously indicated, not only the RTKs but also the CTKs that include, but were not limited to, src, abl, fps, yes, fyn, lyn, Ick, blk, hck, fgr and yrk (reviewed by Bolen et al., 1992, FASEB J .. 6: 3403-3409 ) are involved in the pathway of proliferation of proliferative and mephabolic signal and thus it could be expected, and has been demonstrated, that they are involved in many disorders mediated by PTK to which the present invention is directed. For example, it has been shown that the mutated src (v-src) is an oncoprotein (pp60v "src) in chicken, and its cellular counterpart, the pr60-oncogene pp60c" src, transmits oncogenic signals from many receptors. The overexpression of EGFR or HER2 / neu in tumors leads to the consti-ufic activation of pp60c "src, which is charac- teristic of malignant cells but absent in normal cells.For part, mice deficient in the expression of c-src exhibit an osteopetrophic phenotype, which indicates a key participation of c-src in the function of osfeociaslo and a possible implication in related disorders, and Zap70 has been implicated in the T cell signaling that can be related to autoimmune disorders. They have been associated with inflammation, autoimmune disease, immune responses, and hyperinsulinemia such as restenosis, fibrosis, psoriasis, osteoarthritis, and rheumatoid arthritis.KPs have also been implicated in embryo implantation. effective method of preventing such embryonic implantation and therefore be useful as agents of birth control Additional disorders that may be delayed or prevented using the compounds of this invention are immune transforms such as autoimmune disease, AIDS and cardiovascular disorders such as atherosclerosis. Finally, it is currently suspected that both RTKs and CTKs are implicated in hyperimmune disorders. The comps and data presented should not be construed as limiting the scope of this invention in any way whatsoever.

Pharmaceutical Compositions and their Use A compound of the present invention or a physiologically acceptable salt thereof, can be administered as such to a human patient or can be administered in pharmaceutical compositions in which the above products are mixed with vehicles or excipient (s) adequate. Techniques for formulating and administering drugs can be found in the latest edition of "Remington's Pharmacological Sciences," Mack Publishing Co., Easton, PA.

Administration Routes Suitable routes of administration may include, without limitation, oral, intraoral, rectal, transmucosal or intestinal administration or intramuscular, epicutaneous, parenteral, subcutaneous, transdermal, intramedullary, intrathecal, direct intraventricular, intravenous, intravitreal, intramuscular injections, initial, iníranasal, iníramuscular, iniradural, inirorespiratory, nasal or infraocular inhalation. The preferred administration routes are oral and parenteral. Alternatively, the compound can be administered in a local rather than aseptic manner, for example, via injection of the compound directly into a solid tumor, often in a depot or sustained release formulation. In addition, the drug can be administered in a targeted drug delivery system, for example, in a liposome coated with tumor-specific antibody. The liposomes will be targeted to and selectively absorbed by the lumor.

Composition / Formulation The pharmaceutical compositions of the present invention can be manufactured by methods well known in the art, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, immobilizing, lyophilizing or spray drying.

The pharmaceutical compositions for use in the methods of the present invention can be prepared by any of the pharmacy methods, but all methods include the step of bringing into association the active ingredient with the vehicle constituting one or more ingredients. necessary. In particular, pharmaceutical compositions for use in accordance with the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and excipients that facilitate the processing of the active compounds in the preparations that can be used. pharmaceutically The appropriate formulation depends on the chosen administration rufa. Pharmaceutical forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, syrups, elixirs, gels, powders, magmas, pills, ointments, creams, pastes, plasters, lotions, discs, suppositories, nasal or nasal sprays, aerosols and similar. For injection, the compounds of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such buffers with or without a low concentration of surfactant or cosolvent, or physiological saline buffer. For transmucosal administration, penetrating substances appropriate for the barrier to be permeated are used in the formulation. Such penetrating substances are generally known in the art.

For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such vehicles allow the compounds of the invention to be formulated as tablets, pills, pills, dragees, capsules, liquids, gels, syrups, suspensions and the like, for oral ingestion by the patient. Pharmaceutical preparations for oral use can be made using a solid excipient, optionally by grinding the resulting mixture, and processing the granule mixture, after adding other auxiliary substances if desired, to obtain tablets or dragee cores. Useful excipients are, in particular, fillers such as sugars, including lactose, sucrose, manifold, or sorbium, cellulose preparations such as, for example, corn starch, starch, rice starch, and starch. pataia and other natural materials such as gelatin, gum arabic, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as enriched polyvinyl pyrrolidone., agar, or alginic acid. A salt such as sodium alginate can also be used. Dragee cores are supplied with the appropriate coatings. For this purpose, concentrated sugar solutions may be used which optionally may contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. Pharmaceutical compositions that can be used orally include pressure-closure capsules made of gelatin, as well as sealed soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Pressurized capsules may contain the active ingredients in admixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, liquid polyethylene glycols, cremophor, capmul, medium or long chain mono- or di-glycerides. Stabilizers can also be added in these formulations. For administration by inhalation, the compounds for use according to the present invention are conveniently administered in the form of an aerosol spray using a pressurized pack or a nebulizer and a suitable propellant, for example, without limitation, dichlorodifluoromethane, rubofluoromethane, dichloroethylfluoroethane or sodium dioxide. carbon. In the case of a pressurized aerosol, the dosage unit can be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin can be formulated for use in an inhaler or insufflator containing a powder mixture of the compound and a suitable powder base such as lactose or starch. The compounds can also be formulated for parenteral administration, for example, by single bolus injection or by continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulation materials such as suspending, destabilizing and / or dispersing agents. Pharmaceutical compositions for parenteral administration include aqueous solutions of a water-soluble form, such as, without limitation, a salt, of the active compound. Additionally, suspensions of the acidic compounds can be prepared in a lipophilic vehicle. Suitable lipophilic vehicles include fatty oils such as sesame oil, syngeneic esters of fatty acids such as ethyl oleate and triglycerides, or materials such as liposomes. Aqueous suspensions for injection may contain substances which increase the viscosity of the suspension, such as carboxymethyl cellulose sodium, sorbitol, or dextran. Optionally, the suspension may also contain stabilizers and / or agents that increase the solubility of the compounds to allow the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for preparation with a suitable vehicle, eg, sterile, pyrogen-free water, before use. The compounds can also be formulated in rectal compositions such as suppositories or retention enemas, using, for example, conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations previously described, the compounds can also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. A compound of this invention can be formulated for this administration route with suitable polymeric or hydrobophilic materials (for example, in an emulsion with a pharmacologically acceptable oil), with ion exchange resins, or as a moderately soluble derivative such as, without limitation, a moderately soluble salt. A non-limiting example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a non-polar surfactant, an organic polymer miscible with water and an aqueous phase such as the co-solvent system VPD. VPD is a solution of 3% w / v of benzyl alcohol, 8% w / v of the non-polar surfactant Polysorbate 80, and 65% w / v of polyethylene glycol 300, prepared by volume in absolute ethanol. The VPD co-solvent system (VPD: D5W) consists of VPD diluted 1: 1 with 5% dextrose solution in water. This co-solvent system dissolves hydrophobic compounds well, and by itself produces low toxicity after systemic administration. Naturally, the proportions of such a co-solvent system can be varied considerably without disclosing their solubility and toxicity characteristics. In addition, the identity of the components of the co-solvent can be varied: for example, other non-polar low-toxicity surfactants can be used instead of Polysorbate 80, the size of the polyethylene glycol fraction can be varied, other biocompatible polymers can replace polyethylene glycol, for example polyvinyl pyrrolidone, and other sugars or polysaccharides can substitute for dextrose. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of vehicles and administration carriers for hydrophobic drugs. In addition, certain organic solvents such as dimethyl sulfoxide can also be used, although often at the cost of greater toxicity. Additionally, the compounds can be administered using a sustained release system, such as the semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained release materials have been established and are well known to those skilled in the art. Sustained-release capsules can, depending on their chemical nature, release the compounds for a few weeks to more than 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for the stabilization of the proiein can be used. The pharmaceutical compositions herein may also comprise suitable solid phase or gel carriers or excipients. Examples of the carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Many of the PK modulator compounds of the invention can be provided as physiologically acceptable salts in which the claimed compound can form the negatively charged or the positively charged species. Examples of salts in which the compound forms the positively charged moiety include, without limitation, quaternary ammonium salts (defined elsewhere herein), such as hydrochloride, sulfate, carbonate, lactate, tartrate, maleate, succinate. , malate, acetate and methylsulfonate (CH3SO3), in which the nitrogen atom of the quaternary ammonium group is a nitrogen of the selected compound of this invention which has reacted with the appropriate acid. Salts in which a compound of this invention forms the negatively charged species include, without limitation, the sodium, potassium, calcium and magnesium salts formed by the reaction of a carboxylic acid group in the compound with an appropriate base (e.g. hydroxide) sodium (NaOH), potassium hydroxide (KOH), calcium hydroxide (Ca (OH) 2), etc.). Dosage Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount sufficient to achieve the intended purpose, ie, the modulation of PK activity or the eradication or prevention of a related disorder. with PK. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate the symptoms of disease or prolong the survival of the subject to be harnessed. The determination of a therapeutically effective amount is in accordance with the ability of those skilled in the art, especially in light of the detailed description provided herein. For any compound used in the methods of the invention, the therapeutically effective amount or dose can be estimated initially from cell culture assays. The dosage can then be formulated for use in animal models to achieve a concentration range in circulation that includes IC5o as determined in the cell culture (i.e., the concentration of the test compound that reaches a half-maximal inhibition). of the c-Met activity). Then such information can be used to more accurately determine the useful doses in humans. The toxicity and therapeutic efficacy of the compounds disclosed herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the IC5o and the LD50 (which are discussed elsewhere herein). ) for a subject compound. The data obtained from these cell culture assays and studies with animals can be used to formulate a dosage range for use in humans. The dosage may vary depending on the pharmaceutical form used and the route of administration used. The exact formulation of my administration and dosage can be chosen by the individual doctor in view of the patient's condition. (See for example, Fingí, ef al., 1975, in "The Pharmacological Basis of Therapeutics," Chapter 1, p.1). The amount and range of dosage can be adjusted individually to provide plasma levels of the active species that are sufficient to maintain the kinase modulating effects. These plasma levels are called minimum effective concentrations (MECs). The MEC will vary for each compound but can be estimated from the in vitro data, for example, the concentration necessary to achieve 50-90% inhibition of a kinase can be ascertained using the assays described herein. The dosages necessary to achieve the MEC will depend on the individual characteristics and the route of administration. HPLC analysis and bioanalysis can be used to determine plasma concentrations. Dosing intervals can also be determined using the MEC value. The compounds should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and more preferably between 50-90%. Currently, the therapeutically effective amounts of the compounds of Formula (I) can range from about 10 mg / m2 to 1000 mg / m2 per day. Even more preferably 25 mg / m2 to 500 mg / m2. In cases of local administration or selective absorption, the local concentration of the drug may not be related to plasma concentration and other methods known in the art may be employed to determine the correct amount and range of dosage. The amount of a composition administered will, of course, be dependent on the subject to be treated, the severity of the condition, the manner of administration, the judgment of the prescribing physician, etc. Packaging The compositions may be presented, if desired, in a container or dispensing device, such as an FDA approved kit, which may contain one or more pharmaceutical forms containing the active ingredient. The package can for example comprise a sheet of mefal or plastic, such as a blister. The package or dispensing device may be accompanied by instructions for administration. The container or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a government agency that regulates the manufacture, use or sale of pharmaceutical substances, notice that is reflective of the agency's approval of the form of compositions or human or veterinary administration. Such notice, for example, can be found in the draft approved by the Food and Drug Administration of the United States. for the prescription of drugs or in an approved product leaflet. Compositions comprising a product of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for the treatment of an indicated disease. Suitable diseases indicated on the label may include the treatment of a tumor, inhibition of angiogenesis, fibrosis, diabetes, and the like. The following examples are given to illustrate the present invention. It should be understood, however, that the invention should not be limited to the specific conditions or specific features described in these examples. Through memory, any and all references to publicly available documents are specifically incorporated into this patent application as a reference.

EXAMPLES General Synthetic Scheme General Scheme Intermediates Example A 2-meyyl-6-oxo-1, 4,5,6-tetrahydro-cyclopenta [b] pyrrol-3-carboxylic acid eyl ester Method 1 Polyphosphoric acid (20 g) and P2O5 (1.0 g) were mixed together and heated at 70 ° C for 20 min. To the mixture was added 3- (4-ethoxycarbonyl-5-meityl-3-pyrrolyl) propionic acid (1.0 g, 4.44 mmol) and heating continued for 20 hours. The reaction was poured into ice-water, extracted with EOAc. The organic layer was washed with brine and sat. NaHCO3, and dried (MgSO). After removing the solvent, the crude product was recrystallized from CH 2 Cl 2 -hexane to give (0.78 g, 85%) of the 2-metii-6-oxo-1, 4,5,6-tetrahydro-cyclopenia-2-methylester. [b] pyrrole-3-carboxylic acid as a white solid. Method 2 A mixture of methanesulfonic acid (170.0 g) and P2O5 (17.0 g) was stirred at room temperature at 100 ° C for 1 hour until it was converted to an ransparent solution. The solution was cooled to 30 ° C and then 3- (4-ethoxycarbonyl-5-methyl-3-pyrroyl) propionic acid (10.0 g, 44.4 mmol) was added in portions with stirring. The mixture was stirred at 30-40 ° C for 4 hours and then allowed to stand at room temperature overnight. The reaction was poured slowly into ice-NaHCO3 (60.0 g). The precipitate was collected by filtration, washed with water, sat. NaHCO3. and water in shifts to give 8.59 g (97%) of the title compound as a gray white solid. 1HNMR (400 MHz, CDCl 3) d 10.8 (broad s, 1H, NH), 4.29 (c, J = 7 Hz, 2H), 3.03 (m, 2H), 2.88 (m, 2H ), 2.68 (s, 3H, CH3), 1.36 (t, J = 7 Hz, 3H). MS m / z 206 [M-1]. Example B 2-Methyl-6-oxo-1,4,5,6-fetrahydro-cyclopen-fa [b] pyrrole-3-carboxylic acid A suspension of the ethyl ester of 2-methyl-6-oxo-1, 4,5,6-teirahydro-cyclopenpha [b] pyrrole-3-carboxylic acid (Example A, 8.28 g, 40 mmol) in aqueous LiOH 1 N (150 mL) was stirred at 50-60 ° C for 48 hours. A clear yellowish solution was obtained. The reaction was cooled, poured onto ice and acidified with 6 N HCl to pH 3.0. The solid was collected by filtration, washed with water and dried to give 6.55 g (91%) of the title compound as a white solid. 1HNMR (400 MHz, DMSO-d6) d 12.12 (broad s, 1H, NH), 12.0 (broad s, 1H, COOH), 2.83 (m, 2H), 2.66 (m, 2H ), 2.44 (s, 3H, CH3). MS m / z 178 [M-1]. Example C 2-methyl-6-oxo-1, 4,5,6-tetrahydro-cyclopenia [b] pyrrole-3-carboxylic acid benzylamide A mixture of 2-methyl-6-oxo-1,4,5,6-fetrahydro-cyclopenta [b] pyrrole-3-carboxylic acid (Example B. 268.5 mg, 1.5 mmol), HOBt (202, 5 mg, 1.5 mmol) and EDC (573.5 mg, 3 mmol) in dry DMF (5 mL) was stirred at room temperature for 20 min. Then aniline (3.0 mmol) was added to the mixture and stirring was continued for 24 hours. The reaction was diluted with Na2CO3 sai. and water, the solid was collected by vacuum filtration, washed with sat Na2CO3. and water in shifts, and dried to give 315 mg of the title compound as a white solid. 1HNMR (400 MHz, DMSO-d6) d 11, 96 (s, 1H, NH), 7.63 (t, 1 H), 7.27-7.33 (m, 4H), 7.18-7.23 (m, 1H), 4.4 (d, J = 6 Hz, 2H, NCH3), 2.96 (m, 2H) , 2.69 (m, 2H), 2.43 (s, 3H, CH3). MS m / z 267 [M-1]. Example D 4-Chloro-benzyl amide of 2-meityl-6-oxo-1, 4,5,6-teirahydro-cyclopenta [b] pyrrole-3-carboxylic acid Procedure as that of Example C, but 4-chloroaniline was used to give 403 mg of the title compound as a white solid. 1HNMR (400 MHz, DMSO-d6) d 11.98 (s, 1 H, NH), 7.65 (t, 1 H), 7.29-7.37 (m, 4H), 4.38 (d , J = 6 Hz, 2H, NCH2), 2.96 (m, 2H), 2.69 (m, 2H), 2.42 (s, 3H, CH3). MS miz 301 [M-1]. Example E 2,6-Difluoro-benzyl amide of 2-methyl-6-oxo-1, 4,5,6-tetrahydro-cyclopenta [b] pyrrole-3-carboxylic acid Procedure as that of Example C, but 2,6-difluoroaniline was used to give 401 mg of the title compound as a white solid. 1HNMR (400 MHz, DMSO-d6) d 11, 93 (s, 1 H, NH), 7.52 (t, 1 H), 7.37 (m, 1H), 7.05 (m, 2H), 4.45 (d, J = 6 Hz, 2H, NCH2), 2.87 (m, 2H), 2.66 (m, 2H), 2.38 (s, 3H, CH3). MS miz 303 [M-1]. Example F 2-Methyl-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1 -carbonyl) -4,5-dihydro-1 H -cyclopenta [b] pyrrol-6-one A mixture of 2-methyl-6-oxo-1,4,5,6-tetrahydro-cyclopenta [b] pyrrole-3-carboxylic acid (Example B, 3.58 g, 20 mmol), HOBt (2.7 g , 20 mmol) and EDC (5.74 g, 30 mmol) in dry DMF (50 mL) was stirred at 0 ° C at room temperature for 20 min. Then (S) - (+) - 1- (2-pyrroidinylmethyl) pyrrolidine (24 mmol) was added and stirring was continued for 48 hours.

The solvent was removed under reduced pressure and the residue was dissolved in EtOAc, washed with sat Na2CO3, dried, concentrated and purified on a column of silica gel to give 5.1 g (81%) of the title like a yellowish foam. 1HNMR (400 MHz, DMSO-d6) d 11, 85 (s, 1 H, NH), 4.2 (broad m, 1H), 3.38 (m, 2H), 2.75 (m, 1H), 2.66 (m, 2H), 2.65 (m, 1 H), 2.4 (m, 6H), 2 , 24 (s, 3H, CH3), 1.96 (m, 1 H), 1.81 (m, 3H), 1.6 (m, 4H). MS / 77 / z 314 [M-1]. EXAMPLE 1 2-Methyl-6- [2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -1,6,5,6-tetrahydro-cyclopenta [2-methyl] ethyl ester ] pyrro -3-carboxylic acid A mixture of oxindole (44 mg, 0.33 mmol) and 2-methyl-6-oxo-1, 4,5,6-tetrahydro-cyclopenta [b] pyrrol-3-carboxylic acid ethyl ester co (Example A, 62 mg, 0.3 mmol) in DMF (5 mL) -piperidine (0.5 mL) was heated at 110 ° C with stirring for 72 hours. The majority of the solvent was removed under reduced pressure and the residue was diluted with ethanol. The resulting precipitate was collected by filtration, washed with ethanol and dried to give 56 mg (58%) of the title compound as a yellow solid. 1HNMR (400MHz, CDCl 3) d 11, 61 (broad s, 1 H, NH), 7.6 (s, 1 H, NH), 7.44 (d, 1 H), 7.15 (t, 1 H ), 7.07 (i, 1H), 6.91 (d, 1H), 4.3 (c, J = 7 Hz, 2H), 3.57 (m, 2H), 3.17 (m, 2H) ), 2.66 (s, 3H, CH3), 1.37 (t, J = 7 Hz, 3H). MS miz 321 [M-1]. Example 2 6 - [5- (2,6-Dichloro-phenylmethanesulfonyl) -2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -2-methyl-1, 4,5-eic acid ester 6-Hydro-cyclopentel [b] pyrrole-3-carboxylic acid Procedure similar to that of Example 1 to give 48% of the title compound as a yellow solid. 1HNMR (400 MHz, DMSO-d6) d 11.67 (s, 1H, NH), 1.14 (s, 1H, NH), 7.49 (m, 4H), 7.39 (dd, 1 H) , 7.03 (d, 1H), 4.85 (s, 2H), 4.2 (c, J = 7 Hz, 2H), 3.34 (m, 2H), 3.04 (m, 2H) , 2.63 (s, 3H, CH3), 1.28 (t, J = 7 Hz, 3H). MS m / z 543 [M-1]. Example 3 2-Methyl-6- [5-methyl-sulphamoyl-2-oxo-1,2-dihydro-indole- (3Z) -ylidene] -1,4,5,6-hydroacetic acid cyclopenta [2-methyl-6- [5-methylsulfamoyl]] b] pyrrole-3-carboxylic acid Procedure similar to that of Example 1 to give 63% of the title compound as a yellow solid. 1HNMR (400 MHz, DMSO-d6) d 11.69 (s, 1H, NH), 11.01 (s, 1H, NH), 7.75 (d, 1H), 7.53 (dd, J = 2 and 8 Hz, 1H), 7.3 (c, 1H, NH), 7.0 (d, J = 8 Hz, 1H), 4.18 (c, J = 7 Hz, 2H), 3.56 ( m, 2H), 3.07 (m, 2H), 2.61 (s, 3H, CH3), 2.37 (d, J = 5 Hz, 3H, NCH3), 1.27 (t, J = 7 Hz, 3H). MS / 77 / z 414 [M-1]. EXAMPLE 4 3- [2-Methyl-4,5-dihydro-1H-cycloopenia [b] pyrrol- (6Z) -liden] -2-oxo-2,3-dihydro-1H-indoI- acid methylamide 5-sulfonic See Example 5. 1 H NMR (400 MHz, DMSO-d6) d 11.36 (s, 1 H, NH), 10.91 (s, 1 H, NH), 7.74 (d, 1 H), 7.48 (dd, 1 H), 7.25 (c, 1H, NH), 6.99 (d, 1H), 6.02 (s, 1 H), 3.56 (m, 2H), 2.93 ( m, 2H), 2.39 (s, 3H, CH3), 2.37 (d, J = 5 Hz, 3H, NCH3). MS miz 342 [M-1]. Example 5 Acid 2-methyl-6- [5-mephilesulfamoyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -1, 4,5,6-telrahydro-cyclopenia [b] pyrrolidone -3-carboxylic acid A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulphonic acid methylamide (905 mg, 4 mmol) and 2-methyl-6-oxo-1, 4,5,6- tetrahydro-cyclopenia [b] pyrrol-3-carboxylic acid (Example B, 716 mg, 4 mmol) in DMF (50 mL) and piperidine (5 mL) was heated at 110 ° C with stirring for 48 hours. The solvent was removed and the residue was suspended in methanol-ice-water and acidified with 2N HCl. The solid was collected by filtration and then suspended in DCM. The suspension was washed with 2N aqueous NaOH three times. The combined aqueous layer was washed with DCM. The aqueous layer was acidified with 2N HCl and filtered to give a brown solid, which was triturated with MeOH to provide 380 mg of the title compound as a yellow-brown solid. The combined organic layer was dried (Na2SO) and evaporated to give 130 mg of 3- [2-methyl-4,5-dhydro-1H-cyclopenta [b] pyrrole- (6Z) -iI) methylamide. den] -2-oxo-2,3-dihydro-1H-indol-5-sulfonic acid (Example 4) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) d 12.16 (broad s, 1H, COOH), 11, 64 (s, 1 H, NH), 11, 0 (s, 1 H, NH), 7.75 (d, 1 H), 7.52 (dd, J = 2 and 8 Hz, 1 H) , 7.3 (c, 1 H, NH), 7.0 (d, J = 8 Hz, 1H), 3.56 (m, 2H), 3.07 (m, 2H), 2.61 (s) , 3H, CH3), 2.36 (d, J = 5 Hz, 3H, NCH3). MS miz 386 [M-1]. Example 6 Ethyl ester of 2-methyl-6- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -1, 4,5,6-tetrahydro-cyclopenta [b] pyrrole-3-carboxylic acid Procedure similar to that of Example 1 to give 65% of the title compound as a yellow solid. 1HNMR (400 MHz, DMSO-d6) d 11.69 (s, 1H, NH), 11, 09 (s, 1H, NH), 7.82 (s, 1H), 7.66 (d, 1H), 7.05 (d, 1H), 4.19 (c, J = 7 Hz, 2H), 3.64 (m, 2H), 3.18 (s, 3H, CH3), 3.08 (m, 2H) ), 2.62 (s, 3H, CH3), 1.27 (t, J = 7 Hz, 3H). MS miz 399 [M-1]. Example 7 6- [5-Dimethylsulfamoyl! -2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -2-methyl-1,4,6,6-tetrahydro-cyclopenta ethyl ester [b] pyrrole-3-carboxylic acid Procedure similar to that of Example 1 to give 59% of the title compound as a yellow solid. 1HNMR (400 MHz, DMSO-d6) d 11.68 (s, 1H, NH), 11.07 (s, 1H, NH), 7.62 (d, 1H), 7.49 (dd, J = 2 and 8 Hz, 1 H), 7.06 (d, J = 8 Hz, 1H), 4.18 (c, J = 7 Hz, 2H), 3.57 (m, 2H), 3.05 (m , 2H), 2.61 (s, 3H, CH3), 2.59 (s, 6H, N (CH3) 2), 1.26 (t, J = 7 Hz, 3H). MS / 77 / z 428 [M-1]. Example 8 Ethyl 6- [5-isopropyl sulfamoyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -2-methyl-1,4,5,6-teirahydro-cyclopenta ethyl ester [b] pyrrole-3-carboxylic Procedure similar to that of Example 1 to give 65% of the title compound as a yellow solid. 1HNMR (400 MHz, DMSO-d6) d 11.68 (s, 1 H, NH), 10.99 (s, 1H, NH), 7.79 (d, 1H), 7.55 (dd, J = 2 and 8 Hz, 1H), 7.43 (d, J = 7 Hz, 1H, NH), 6.98 (d, J = 8 Hz, 1H), 4.18 (c, J = 7 Hz, 2H ), 3.55 (m, 2H), 3.18 (m, 1 H), 3.07 (m, 2H), 2.61 (s, 3H, CH3), 1.26 (s, 3H, CH3) ), 0.93 (d, J = 6 Hz, 6H, 2xCH3). MS / 77 / z 442 [M-1]. EXAMPLE 9 Ethyl 6- [5-ene-sulfonyl-2-oxo-1,2-dihydro-indoI-3- (3Z) -ylidene] -2-methyl-1, 4,5,6-tetrahydro-cyclopentaphylether [ b) pyrrole-3-carboxylic acid Procedure similar to that of Example 1 to give 40% of the title compound as a yellow solid. 1HNMR (400 MHz, DMSO-d6) d 11.68 (s, 1H, NH), 11.1 (s, 1H, NH), 7.76 (d, 1 H), 7.6 (dd, J = 2 and 8 Hz, 1 H), 7.05 (d, J = 8 Hz, 1 H), 4.18 (c, J = 7 Hz, 2 H), 3.76 (m, 2 H), 3.25 (c, J = 7 Hz, 2H), 3.06 (m, 2H), 2.61 (s, 3H, CH3), 1.27 (t, J = 7 Hz, 3H), 1, 10 (t , J = 7 Hz, 3H). MS /? 7 / z 413 [M-1]. Example 10 2-MethyI-6- [5-methylsulphamoyl-2-oxo-1,2-dihydro-indole- (3Z) - 2-hydroxy-3-pyrrolidin-1-yl-propyl) -amide iIiden] -1,4,5,6-eeryhydro-cyclopenia [b] pyrrole-3-carboxylic acid A mixture of 2-methyl-6- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -1,4,5,6-tetrahydro-cyclopenta [b] pyrrole- 3-carboxylic acid (Example 5. 78 mg, 0.2 mmol), HOBt (27 mg, 0.2 mmol) and EDC (77 mg, 0.4 mmol) in dry DMF (2 mL) was stirred at room temperature for 30 min. min. Then 1-amino-3-pyrrolidin-1-yl-propan-2-ol (0.4 mmol) was added and stirring was continued for 48 hours. The solvent was removed under reduced pressure and the residue was crystallized and purified on a column of silica gel to give 54 mg of the title compound as a yellow solid. 1HNMR (400 MHz, DMSO-d6) d 11.6 (s, 1H, NH), 11.0 (s, 1 H, NH), 7.76 (d, 1H), 7.52 (dd, J = 2 and 8 Hz, 1 H), 7.28 (c, 1H, NH), 7.11 (t, 1H, NH), 7.01 (d, J = 8 Hz, 1H), 4.85 (m , 1H, OH), 3.71 (m, 1H), 3.61 (m, 2H), 3.18 (m, 2H), 3.15 (m, 2H), 3.3-3.4 ( m, 2H), 2.59 (s, 3H, CH3), 2.5 (m, 4H), 2.37 (d, J = 5 Hz, 3H, NCH3), 1.66 (m, 4H). MS m z 512 [M-1]. Example 11: 2-Methyl-6- [5-mephryl-2-fluoro-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -3- (3-cyclopropylamino-2-hydroxy-propyl) -amide. 5,6-Hydro-cyclopenpha [b] pyrrole-3-carboxylic acid Procedure as in Example 10. but 1-amino-3-cyclopropylamino-propan-2-ol was used to give 53 mg of the title compound as a yellow solid. 1HNMR (400 MHz, DMSO-d6) d 11.61 (s, 1 H, NH), 11.01 (s, 1H, NH), 7.77 (d, 1 H), 7.53 (dd, J = 2 and 8 Hz, 1 H), 7.29 (c, 1 H, NH), 7.14 (t, 1 H) , NH), 7.02 (9d, J = 8 Hz, 1H), 4.86 (d, 1H, OH), 3.67 (m, 1H), 3.62 (m, 2H), 3.3 ( m, 2H), 3.22 (m, 1H), 3.17 (m, 2H), 2.6 (m, 2H), 2.59 (s, 3H, CH3), 2.38 (d, J = Hz, 3H, NCH3), 2.09 (m, 1 H), 0.35 (m, 2H), 0.22 (m, 2H). MS m / z 500 [M + 1]. EXAMPLE 12 2-Methylo-6- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -2- (2-Dimethyl-ethyl) -amide. , 5,6-tetrahydro-cyclopenta [b] pyrrole-3-carboxylic acid Procedure as in Example 10, but NN-dimethylethylenediamine was used to give 55 mg of the title compound as an orange solid. 1H? MR (400 MHz, DMSO-d6) d 11.58 (s, 1 H,? H), 11.0 (s, 1 H, ? H), 7.76 (d, 1H), 7.52 (dd, J = 2 and 8 Hz, 1 H), 7.28 (c, 1H,? H), 7.06 (t, 1H, ? H), 7.0 (d, J = 8 Hz, 1H), 3.6 (m, 2H), 3.29 (m, 2H), 3.14 (m, 2H), 2.58 (s) , 3H, CH3), 2.38 (f, 2H), 2.37 (d, J = 5 Hz, 3H,? CH3), 2.18 (s, 3H,? (CH3) 2).

MS / 77 / z 456 [M-1]. Example 13 3- (2-Methyl-3 - ((R) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-carbonyl) -4,5-dihydro-1H-cyclopenta [3-methyl] acid methylamide ] pyrroyl- (6Z) -liden] -2-oxo-2,3-dihydro-1H-indol-5-sulphonic Procedure as in Example 10. but (S) - (+) - 1- (2-pyrroidinylmethyl) pyrrolidine was used to give 54 mg of the title compound as a yellow solid. 1HNMR (400 MHz, DMSO-d6) d 11.56 (broad s, 1H, NH), 10.98 (s, 1H, NH), 7.75 (d, 1 H), 7.51 (dd, J = 2 and 8 Hz, 1H), 7.28 (c, 1H, NH), 7.01 (d, J = 8 Hz, 1 H), 4.22 (broad m, 1H), 3.59 (m, 2H), 3.42 (m, 2H), 2.96 (m, 2H), 2.46 (m, 6H), 2.4 (s, 3H, CH3), 2.37 (d, J = 5 Hz, 3H, NCH3), 2.0 (m, 1 H), 1.84 (m, 3H), 1.62 (m, 4H). Example 14 2-Methyl-6- [2-oxo-5-sufamoyl-1,2-dihydro-indol- (3Z) -ylidene] -1,4,5,6-tetrahydro-cyclopenta [2-methyl] -ethyl ethyl ester ] pyrrole-3-carboxylic acid Procedure similar to that of Example 1 to give 75% of the title compound as a yellow solid. 1HNMR (400 MHz, DMSO-d6) d 11.70 (s, 1 H, NH), 10.97 (s, 1H, NH), 7.85 (s, 1H), 7.58 (d, 1H) , 7.2 (s, 2H, NH2), 6.97 (d, 1H), 4.2 (c, J = 7 Hz, 2H), 3.57 (m, 2H), 3.09 (m, 2H), 2.62 (s, 3H, CH3), 1.27 (t, J = 7 Hz, 3H). MS miz 400 [M-1]. Example 15 3-Cyclopentylidene-2-oxo-2,3-dihydro-1 H-indole-5-sulfonic acid methylamide Procedure similar to that of Example 1 to give 73% of the title compound as a gray solid. 1HNMR (400 MHz, DMSO-d6) d 10.84 (s, 1H, NH), 7.73 (d, 1H), 7.59 (dd, J = 2 and 8 Hz, 1H), 7.31 (d. c, 1H, NH), 6.98 (d, J = 8 Hz, 1H), 2.99 (t, 2H), 2.86 (t, 2H), 2.35 (d, J = 5 Hz, 3H, NCH3), 1.83 (m, 2H), 1.75 (m, 2H). MS m z 291 [M-1]. Example 16 3- [3-Methanesulfonyl-2-methyl-4,5-dihydro-1H-cyclopenta [b] pyrrol- (6Z) -ylidene] -2-oxo-2,3-dihydro-1H-indole acid methylamide -5-sulphonic Procedure similar to that of Example 1 to give 73% of the title compound as a yellow solid. 1HNMR (400 MHz, DMSO-d6) d 11, 82 (s, 1 H, NH), 11, 06 (s, 1 H, NH), 7.76 (d, 1H), 7.55 (dd, J = 2 and 8 Hz, 1H), 7.32 (c, 1 H, NH), 7.02 (d, J = 8 Hz, 1 H), 3.59 (m, 2H), 3.13 (s) , 3H, CH3), 3.10 (m, 2H), 2.6 (s, 3H, CH3), 2.37 (d, J = 5 Hz, 3H, NCH3). MS m / z420 [M-1]. Example 17 Acid. { 6-methoxy-3- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -indan-1-yl} -acetic Procedure similar to that of Example 1 to give 28% of the title compound as a yellow-green solid. 1HNMR (400 MHz, DMSO-d6) d 12.35 (s, 1H, COOH), 10.96 (s, 1H, NH), 9.47 (d, J = 9 Hz, 1H), 7.86 ( s, 1H), 7.6 (d, 1H), 7.29 (c, 1H, NH), 7.12 (d, 1H), 6.99 (d, J = 8 Hz, 1H), 6, 95 (dd, 1H), 3.84 (s, 3H, OCH3), 3.64-3.76 (m, 2H), 3.3 (d, 1H), 2.92 (dd, 1 H), 2.55 (m, 1H), 2.4 (d, J = 5 Hz, 3H, NCH3). MS miz 427 [M-1]. Example 18 5-Fluoro-3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1 -carbonyl) -4,5-dihydro-1 H -cyclopenta [b] pyrrol- (6Z) -ylidene] -1,3-dihydro-indol-2-one Procedure similar to that of Example 1 to give 62% of the title compound as a yellow-green solid. 1HNMR (400 MHz, DMSO-d6) d 11, 62 (s, 1H, NH), 10.57 (s, 1H, NH), 7.2 (dd, 1 H), 6.9 (m, 1H) , 6.83 (dd, 1 H), 4.22 (broad m, 1 H), 3.56 (m, 2H), 3.42 (m, 2H), 2.92 (m, 2H), 2 , 48 (m, 6H), 2.41 (s, 3H, CH3), 2.0 (m, 1H), 1.85 (m, 3H), 1.64 (m, 4H). MS m / z 449 [M + 1]. Example 19 6-Methoxy-3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1 -carbonyl) -4,5-dihydro-1 H-cyclopenia [b] pyrrole- (6Z) -ylidene] -1, 3-dihydro-indoI-2-one Chiral Procedure similar to that of Example 1 to give 70% of the title compound as a yellow solid. 1HNMR (400 MHz, DMSO-d6) d 11, 42 (broad s, 1 H, NH), 10.5 (s, 1H, NH), 7.28 (d, J = 8 Hz, 1 H), 6 , 53 (dd, J = 2 and 8 Hz, 1H), 6.44 (d, J = 2 Hz, 1H), 4.2 (broad m, 1H), 3. 73 (s, 3H, OCH3), 3.46 (m, 2H), 3.41 (m, 2H), 2.9 (m, 2H), 2.48 (m, 6H), 2.36 (s, 3H, CH3), 1.99 (m, 1 H), 1.83 (m, 3H), 1.61 (m, 4H). MS miz 461 [M-1]. Example 20 4-Methoxy-3- [2-methyI-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl) -4,5-dihydro-1H-cyclopenta [b] pyrroK6Z) - ilidene] -1,3-dihydro-indol-2-one Procedure similar to that of Example 1 to give 63% of the title compound as a yellow solid. HNMR (400 MHz, DMSO-d6) d 11.58 (broad s, 1H, NH), 10.55 (s, 1H, NH), 7.41 (d, 1H), 7.29 (m, 2H), 7.0-7.1 (m, 3H), 6.99 (d, 1H), 4, 2 (broad m, 1H), 3.75 (s, 3H, OCH3), 3.55 (m, 2H), 3.42 (m, 2H), 2.92 (m, 2H), 2.45 ( m, 6H), 2.39 (s, 3H, CH 3), 2.0 (m, 1 H), 1.84 (m, 3H), 1.62 (m, 4H). MS m / z 535 [M-1]. Example 21 7-chloro-3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmeryl-pyrroidin-1-carbonyl) -4,5-dihydro-1H-cyclopenia [b] pyrrole - (6Z) -ylidene] -1,3-dihydro-indol-2-one. Procedure similar to that of Example 1 to give 57% of the title compound as a yellow-green solid. 1HNMR (400 MHz, DMSO-d6) d 11.58 (broad s, 1 H, NH), 10.90 (s, 1H, NH), 7.36 (d, J = 8 Hz, 1H), 7, 12 (dd, 1H), 6.97 (t, 1H), 4.22 (broad m, 1 H), 3.55 (m, 2H), 3.41 (m, 2H), 2.91 (m , 2H), 2.46 (rri, 6H), 2.4 (s, 3H, CH3), 1.98 (m, 1 H), 1.84 (m, 3H), 1.62 (m, 4H ). MS miz 463 [M-1]. Example 22 3- [2-Methyl-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-carbonyl) -4,5-dihydro-1 H-cyclopenta [b] pyrrole- (6Z) - ilidene] -1,3-dihydro-pyrrolo [2,3-b] pyridin-2-one Procedure similar to that of Example 1 to give 21% of the title compound as a yellow solid. 1HNMR (400 MHz, DMSO-d6) d 11.46 (broad s, 1H, NH), 11, 08 (s, 1H, NH), 7.95 (dd, 1H), 7.66 (d, 1H) , 6.95 (dd, 1H), 4.2 (broad m, 1H), 3.54 (m, 2H), 3.41 (m, 2H), 2.92 (m, 2H), 2.45 (m, 6H), 2.4 (s, 3H, CH3), 1.98 (m, 1 H), 1.84 (m, 3H), 1.61 (m, 4H). MS miz 430 [M-1]. Example 23 6- (4-Meioxy-phenyl) -3-r2-meityl-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-carbonyl) -4,5-dihydro-1H-cyclopenia [ b] pyrrol- (6Z) -ylidene] -1,3-dihydro-indol-2-one Procedure similar to that of Example 1 to give 63% of the title compound as a yellow solid. 1HNMR (400 MHz, DMSO-d6) d 11.55 (broad s, 1H, NH), 10.61 (s, 1H, NH), 7.55 (m, 2H), 7.43 (d, J = 8 Hz, 1H), 7.21 (dd, J = 2 and 8 Hz, 1H), 7.04 (d, J = 2 Hz, 1H), 7.01 (m, 2H), 4.2 (broad m, 1H), 3.78 (s, 3H, OCH3), 3.55 (m, 2H), 3.42 (m, 2H), 2.92 (m, 2H), 2.5 (m, 6H), 2.39 (s, 3H, CH3), 2.0 (m, 1 H), 1.84 (m, 3H), 1.62 (m, 4H). MS / 77 / z 535 [M-1].

It will be appreciated that, in any given series of compounds, a range of biological activities will be observed. In its presently preferred aspects, this invention relates to new, geometrically restricted, substituted indolinones capable of modulating, regulating and / or inhibiting the protein kinase activity. The following analyzes can be used to select compounds that demonstrate the optimum level of the desired activity. Assay Procedures The following in vitro assays can be used to determine the level of activity and effect of the various compounds of the present invention on one or more of the PKs. Similar analyzes can be designed following the same lines for any PK using techniques well known in the art. Several of the assays described herein are performed in an ELISA format (Sandwich-like Assay of Immunosorbent Substances Linked to Enzymes) (Voller, et al., 1980, "Enzyme-Linked Immunosorbent Assay," Manual of Clinical Immunology, 2nd ed. ., Rose 5 Friedman, Am. Soc. Of Microbiology, Washington, D.C., pp. 359-371). The general procedure is as follows: a compound is introduced into cells expressing the test kinase, either naturally or recombinantly, for a selected period of time after which, if the test kinase is a receptor, a ligand that is known to activate the receptor is added. The cells are lysed and the lysate is transferred to the wells of an ELISA plate previously coated with a specific antibody that recognizes the substrate of the enzymatic phosphorylation reaction. The non-substrates components of the cell lysate are washed and the amount of phosphorylation on the substrate is detected with an antibody that specifically recognizes phosphotyrosine compared to control cells that did not come in contact with the test compound. The currently preferred protocols for carrying out the ELISA experiments for specific PKs are provided below. However, the adaptation of these protocols to determine the activity of the compounds against other RTKs, as well as for CTKs and STKs, is well within the scope of the knowledge of those skilled in the art. Other assays described herein measure the amount of DNA produced in response to the activation of a test kinase, which is a general measure of a proliferative response. The general procedure for this analysis is as follows: a compound is introduced into cells expressing the test kinase, either naturally or recombinantly, for a selected period of time after which, if the test kinase is a receptor , a ligand that is known to activate the receptor is added. After incubation at least overnight, a DNA marker reagent such as 5-bromodeoxyuridine (BrdU) or H3-thymidine is added. The amount of labeled DNA is delected either with an anti-BrdU antibody or by measuring the radioactivity and compared with control cells not contacted with a test compound. BIOASSAY OF GST-FLK-1 This assay analyzes the tyrosine kinase activity of GST-Flk1 on poly (glu-tyr) peptides. Materials and Reagents: 1. 96-well ELISA plates from Corning (Corning Catalog, No. 25805-96). 2. poly (glu-tyr) 4: 1, lyophilized (Sigma Catalog, No. P0275), 1 mg / ml in sterile PBS. 3. PBS buffer: for 1 L, mix 0.2 g of KH2PO4, 1.15 g of Na2HPO4, 0.2 g of KCl and 8 g of NaCl in approx. 900 ml of dH2O. When all reagents have dissolved, adjust the pH to 7.2 with HCl. Bring the total volume to 1 L with dH2O. 4. PBST Buffer: at 1 L of PBS Buffer, add 1.0 mL of Tween-20. 5. Blocking Buffer with TBB: for 1 L, mix 1.21 g of TRIS, 8.77 g of NaCl, 1 ml of TWEEN-20 in approximately 900 ml of dH2O. Adjust the pH to 7.2 with HCl. Add 10 g of BSA, stir to dissolve. Bring the foial volume to 1 L with dH2O. Filtering to eliminate material formed of particles. 6. 1% BSA in PBS: add 10 g of BSA to approx. 990 ml of PBS, shake to dissolve. Adjust the total volume to 1 L with PBS buffer, filter to remove material formed of particles. 7. 50 mM Hepes pH 7.5. 8. GST-Flk1cd purified from the sf9 transformation of recombinant baculovirus (SUGEN, Inc.). 9. 4% DMSO in dH2O. 10. 10 mM ATP in dH2O. 11. MnCl240 mM 12. Kinease Dilution Buffer (KDB): mix 10 ml of Hepes (pH 7.5), 1 ml of 5M NaCl, 40 μL of 100 mM sodium orthovanadate and 0.4 ml of 5% BSA. % in dH2O with 88.56 ml of dH2O. 13. NUNC polypropylene 96-well V-bottom plates, Applied Scientific Catalog, No. AS-72092 14. EDTA: mix 14.12 g of ethylenediaminetetraacetic acid (EDTA) with approx. 70 ml of dH2O. Add 10 N NaOH until the EDTA dissolves. Adjust the pH to 8.0. Adjust the total volume to 100 ml with dH2O. 15. 1st and 2nd Antibody Dilution Buffer: mix 10 ml of 5% BSA in PBS PAMP with 89.5 ml of TBST. 16. Polyclonal rabbit anti-phosphotyrosine antisera (SUGEN, Inc.) 17. HRP amphi-rabbit conjugate prepared in goat. 18. Dissolution of ABST: A approx. 900 ml of dH2O add 19.21 g of cyclic acid and 35.49 g of Na2HPO4. Adjust the pH to 4.0 with phosphoric acid. Add 2,2-Azinobis (3-etl-benzothiazolin-6-sulphonic acid) (ABTS, Sigma, Cat. No. A-1888), keep for approx. 1/2 hour, filter. 19. Hydrogen Peroxide 30%. 20. ABST / H2O2: add 3 μl of H2O2 to 15 ml of ABST solution. 21. 0.2 M HCl Procedure: 1. Coat Corning 96-well ELISA plates with 2 μg of polyEY in 100 μl of PBS / well, keep at room temperature for 2 hours or at 4 ° C overnight. Cover the plates to avoid evaporation. 2. Remove the unbound liquid from the wells by inverting the plate. Wash once with TBST. Slap the plate on a paper foil to remove excess liquid. 3. Add 100 μl of 1% BSA in PBS to each well. Incubate, with shaking, for 1 hr. at room temperature. 4. Repeat step 2. 5. Soak the wells with 50 mM Hepes (pH 7.5, 150 μl / well). 6. Dilute the test compound with 4% dH2O / DMSO to 4 times the desired final assay concentration in 96-well polypropylene plates. 7. Add 25 μl of the diluted test compound to each well of the ELISA plate. In the control wells, place 25 μl of 4% O / DMSO dHO. 8. Dilute GST-Flk1 0.005 μg (5 ngVod in KDB) 9. Add 50 μl of diluted enzyme to each well 10. Add 25 μl 0.5 M EDTA to the negative control wells. 11. Add 25 μl of 40 mM MnCl2 with 4X ATP (2 μM) to all wells (final volume 100 μl, final concentration of 0.5 μM ATP in each well). 12. Incubate, with agitation, for 15 minutes at ambient temperature. 13. Stop the reaction by adding 25 μl of 500 mM EDTA to each well. 14. Wash 3X with TBST and palm the plate on a paper towel to remove excess fluid. 15. Add 100 μl per well of anti-phosphotyrosine antisera, dilution 1: 10,000 in antibody dilution buffer. Incubate, with shaking, for 90 min. at room temperature. 16. Wash as in step 14. 17. Add 100 μl / well of HRP anti-rabbit conjugate prepared in goat (1: 6,000 in antibody dilution buffer). Incubate, with shaking, for 90 minutes at room temperature. 18. Wash as in efapa 14. 19. Add 100 μl of ABST / H2O2 solution at room temperature to each well. 20. Incubate, with agitation for 15 to 30 minutes at room temperature. 21. If necessary, stop the reaction by adding 100 μl of 0.2 M HCl to each well. 22. Read the results in the Dynafech MR7000 ELISA reader with a test filter at 410 nm and with a reference filter at 630 nm. PYK2 BIOASSAY This assay is used to measure the kinase activity in vitro of the full-length pyk2 tagged with HA epitope (FL.pyk2-HA) in an ELISA assay. Materials and Reagents: 1. 96-well ELISA plates from Corning. 2. monoclonal antibody HA-12CA5 (SUGEN, Inc.) 3. PBS (Dulbecco's Phosphate Buffered Saline Solution) (Gibco Catalog, No. 450-1300EB) 4. TBST Buffer: for 1 L, mix 8.766 g of NaCl, 6.057 g of TRIS and 1 ml of 0.1% Triton X-100 in approx. 900 ml dH2O. Adjust the pH to 7.2, bring the volume to 1 L. 5. Blocking Buffer: for 1 L, mix 100 g of 10% BSA, 12.1 g of 100 mM TRIS, 58.44 g of 1 M NaCl and 10 ml of 1% TWEEN-20. 6. FL. pyk2-HA of sf9 cell lysates (SUGEN, Inc.). 7. 4% DMSO in MilliQue H2O. 8. 10 mM ATP in dH2O. 9. MnCl2 1 M. 10. MgCl2 1M. 11. 1M DiTotreiol (DTT). 12. 10X Kinase phosphorylation buffer: mix 5.0 ml of 1M Hepes (pH 7.5), 0.2 ml of 1 M MnCl2, 1.0 ml of 1M MgCl2, 1.0 ml of Triton X- 100 to 10% in 2.8 ml of dH2O. Just before use, add 0.1 ml of DTT 1M. 13. NUNC polypropylene plates with 96 wells in V. 14. EDTA 500 mM in dH2O. 15. Antibody Dilution Buffer: for 100 mL, 1 mL of BSA at % / PBS and 1 mL of 10% Tween-20 in 88 mL of TBS. 16. Anti-Ptyr conjugated with HRP (PY99, Santa Cruz Biotech, Cat. No. SC-7020). 17. ABTS, Moss, No. of Caí. ABST-2000. 18. 10% SDS. Procedure: 1. Coat Corning 96-well ELISA plates with 0.5 μg per well of anti-HA antibody 12CA5 in 100 μl of PBS. Store overnight at 4 ° C. 2. Remove the unbound HA antibody from the wells by inverting the plate. Wash the plate with dH2O. Give the plate a pat on a paper towel to remove excess liquid. 3. Add 150 μL of Blocking Buffer to each well. Incubate, with shaking, for 30 min at room temperature. 4. Wash the plate 4x with TBS-T. 5. Dilute the lysate in PBS (1.5 μg of lysate / 100 μl of PBS). 6. Add 100 μl of diluted lysate to each well. Agifar at room temperature for 1 hr. 7. Wash as in step 4. 8. Add 50 μl of 2X Kinase Buffer to the ELISA plate containing captured pyk2-HA. 9. Add 25 μL of 400 μM test compound in 4% DMSO to each well. For control wells, use 4% DMSO alone. 10. Add 25 μL of 0.5 M EDTA to the negative control wells. 11. Add 25 μl of 20 μM ATP to all wells. Incubate, with shaking, for 10 minutes. 12. Stop the reaction by adding 25 μl of 500 mM EDTA (pH 8.0) to all wells. 13. Wash as in step 4. 14. Add 100 μL Anti-Ptyr conjugated with HRP diluted 1: 6000 in Antibody Dilution Buffer to each well. Incubate, with shaking, for 1 hr. at ambient temperature. 15. Wash the 3X plate with TBST and 1X with PBS. 16. Add 100 μL of ABST solution to each well. 17. If necessary, stop the evolution of the reaction by adding 20 μL of 10% SDS to each well. 18. Read the plate in the ELISA reader with a 410 nm test filter and a reference filter at 630 nm. FGFRT BIOASSAY This assay is used to measure the in vitro kinase activity of FGF1-R in an ELISA assay.

Materials and Reagents: 1. 96-well ELISA plates from Costar (Corning Catalog, No. 3369). 2. PoIi (GIu-Tyr) (Sigma Catalog, No. P0275). 3. PBS (Gibco Catalog, No. 450-1300EB) 4. 50 mM Hepes Buffer Solution. 5. Blocking Buffer (5% BSA / PBS). 6. Purified GST-FGFRT (SUGEN, Inc.) 7. Kinase Dilution Buffer. Mix 500 μl of 1M Hepes (GIBCO), 20 μl of 5% BSA / PBS, 10 μl of 100 mM sodium orthovanadate and 50 μl of 5M NaCl. 8. ATP IO mM 9. ATP / MnCl2 phosphorylation mixture: mix 20 μL of ATP, 400 μL of 1 M MCI2 and 9.56 mL of dH2O. 10. NUNC polypropylene 96-well V-bottom plates (Applied Scientific Catalog, No. AS-72092). 11. EDTA 0.5M. 12. TBST 0.05% Add 500 μL of TWEEN to 1 liter of TBS. 13. Rabbit polyclonal anti-phosphotyrosine serum (SUGEN, Inc.). 14. Anti-rabbit IgG peroxidase conjugate prepared in goat (Biosource, Catalog No. ALI0404). 15. Dissolution of ABTS. - 16. Dissolution of ABTS / H2O2. Procedure: 1. Coat 96-well ELISA plates from Costar with 1 μg per well of Poly (Glu-Tyr) in 100 μl of PBS. Store overnight at 4 ° C. 2. Wash the coated plates once with PBS. 3. Add 150 μL of 5% BSA Blocking Buffer / PBS to each well. Incubate, with shaking, for 1 hr at room temperature. 4. Wash the 2x plate with PBS, then once with 50 mM Hepes. Give the plate a pat on a paper towel to remove excess liquid and bubbles. 5. Add 25 μL of 0.4 mM test compound in 4% DMSO or 4% DMSO alone (conirols) to the plate. 6. Dilute the purified GST-FGFR-i in Kinease Diluent Buffer (5 ng kinase / 50 μl KDB / well). 7. Add 50 μL of diluted kinase to each well. 8. Begin the kinase reaction by adding 25 μl / well of freshly prepared ATP / Mn ++ (0.4 ml of 1M MnCl2, 40 μL of 10 mM ATP, 9.56 ml of dH2?), Freshly prepared. 9. Stop the reaction with 25 μL of 0.5 M EDTA. 10. Wash the 4x plate with fresh TBST. 11. Prepare Antibody Dilution Buffer: For 50 ml, mix 5 ml of 5% BSA, 250 μl of 5% milk and 50 μl of 100 mM sodium vanadate, bring to final volume with 0.05% TBST. 12. Add 100 μl per well of anti-phosphotyrosine (1: 10000 dilution in ADB). Incubate, with agitation for 1 hr. at ambient temperature. 13. Wash as in step 10. 14. Add 100 μl per well of anti-rabbit IgG peroxidase conjugate prepared in Biosource goat (dilution 1: 6000 in ADB). Incubate, with shaking for 1 hr. at room temperature. 15. Wash as in step 10 and then with PBS to remove bubbles and excess TWEEN. 16. Add 100 μl of ABTS / H2O2 solution to each well. 17. Incubate, with shaking, for 10 to 20 minutes. Remove any bubbles. 18. Read the assay on the Dynatech MR7000 ELISA reader: test filter at 410 nm, reference filter at 630 nm. PDGFR BIOASSAY This assay is used for the in vitro kinase activity of PDGFR in an ELISA assay. Materials and Reagents: 1. 96-well ELISA plates from Corning 2. monoclonal anti-PDGFR antibody 28D4C10 (SUGEN, Inc.). 3. PBS. 4. TBST tampon. 5. Blocking buffer (the same as for the EGFR bioassay). 6. Lysate of NIH 3T3 cells expressing PDGFR-β (SUGEN, Inc.). 7. TBS buffer. 8. TBS + 10% DMSO. 9. ATP. 10. MnCl2 11. Kinease buffer phosphorylation mixture: for 10 ml, mix 250 μl of 1 M TRIS, 200 μl of 5 M NaCl, 100 μl of 1 M MnCl 2 and 50 μl of 100 mM Triton X-100 in enough dH 2 O for make 10 ml. 12. NUNC polypropylene plates with 96 wells in V. 13. EDTA. 14. Rabbit polyclonal anti-phosphotyrosine serum (SUGEN, Inc.). 15. Anti-rabbit IgG peroxidase conjugate prepared in goat (Biosource, Cat. No. ALI0404). 16. ABTS. 17. Hydrogen peroxide, 30% solution. 18. ABTS / H2O2. 19. 0.2 M HCl Procedure: 1. Coat Corning 96-well ELISA plates with 0.5 μg of 28D4C10 in 100 μl of PBS per well, keep overnight at 4 ° C. 2. Remove unbound 28D4C10 from the wells by inverting the plate to remove the liquid. Wash 1x with dH2O. Give the plate a pat on a paper towel to remove excess liquid. 3. Add 150 μL of Blocking Buffer to each well. Incubate for 30 min. at room temperature with stirring. 4. Wash the 3x plate with deionized water, then once with TBST. Give the plate a pat on a paper towel to remove excess liquid and bubbles. 5. Dilute the lysate in HNTG (10 μg of ligation / 100 μl of HNTG). 6. Add 100 μl of diluted lysate to each well. Stir at room temperature for 60 min. 7. Wash the plates as described in Step 4. 8. Add 80 μl of working kinase buffer mixture to the ELISA plate containing the captured PDGFR. 9. Dilute the test compound 1:10 in TBS in 96-well polypropylene plates. 10. Add 10 μl of the diluted test compound to the ELISA plate. To the control wells, add 10 μl of TBS + 10% DMSO. Incubate with agitation for 30 minutes at room temperature. 11. Add 10 μl of ATP directly to all wells except the negative control well (the final well volume should be approximately 100 μl with 20 μM ATP in each well.) Incubate 30 minutes with shaking. 12. Stop the reaction by adding 10 μl of EDTA solution to each well. 13. Wash 4x with deionized water, twice with TBST. 14. Add 100 μl anti-phosphotyrosine (dilution 1: 3000 in TBST) per well. Incubate with agitation for 30-45 min. at temperafura environment. 15. Wash as in step 4. 16. Add 100 μl of anti-rabbit IgG peroxidase conjugate prepared in Biosource goat (1: 2000 dilution in TBST) to each well. Incubate with agitation for 30 min. at éemperalura ambienie. 17. Wash as in step 4. 18. Add 100 μl of ABTS / H2O2 solution to each well. 19. Incubate 10 to 30 minutes with shaking. Remove any bubbles. 20. If necessary, stop the reaction with the addition of 100 μl of 0.2 M HCl per well. 21. Read the assay on the Dynatech MR7000 ELISA reader with 410 nm test filter and reference filter at 630 nm. CDK2 / CYCLIN A TEST This assay is used to measure the serine / threonine kinase activity in human cdk2 / cidin A virus in a Proximity Scintillation Assay (SPA). Materials and Reagents. 1. 96-well poly (ethylene terephthalate) (flexible) plates from Wallac (Wallac Catalog, No. 1450-401). 2. Redivue [? 33P] ATP from Amersham (Amersham catalog, No. AH 9968). 3. Polyvinyl toluene SPA beads coated with streptavidin from Amersham (Amersham ca., No. RPNQ0007). The beads should be reconstiluted in PBS without magnesium or calcium, at 20 mg / ml. 4. Enzyme complex cdk2 / activated cyclin A purified from Sf9 cells (SUGEN, Inc.). 5. Biotinylated peptide substrate (Debtide). The peptide biotin-X-PKTPKKAKKL is dissolved in dH2O at a concentration of 5 mg / ml. 6. 20% DMSO in dH2O. 7. Kinease buffer: for 10 ml, mix 9.1 ml of dH2O, 0.5 ml of TRIS (pH 7.4), 0.2 ml of 1 M MgCl2, 0.2 ml of 10% NP40 and 0.02 ml DTT 1M, recently added just before use. 8. 10 mM ATP in dH2O. 9. Tris 1M, pH adjusted to 7.4 with HCl. 10. MgCl 2 1M. 11. DTT 1M. 12. PBS (Gibco Catalog, No. 14190-144). 13. EDTA 0.5M. 14. Stop solution: For 10 ml, mix 9.25 ml of PBS, 0.05 ml of 10 mM ATP, 0.1 ml of 0.5 M EDTA, 0.1 ml of 10% Triton X-100 and 1 ml. , 5 ml of 50 mg / ml SPA beads. Procedure: 1. Prepare solutions of the test compounds at 4x the desired final concentration in 5% DMSO. Add 10 μL to each well. For positive and negative controls, use 10 μL of 20% DMSO alone in the wells. 2. Dilute the peptide substrate (deb-tide) 1: 250 with dH2O to give a final concentration of 0.02 mg / ml. 3. Mix 24 μL of 0.1 mM ATP with 24 μCi of? 33P ATP and enough dH2O to make 600 μL 4. Mix 1: 1 diluted ATP and peptide solutions (600 μL + 600 μL per plate). Add 10 μL of this solution to each well. 5. Dilute 5 μL of cdk2 / cyclin A solution in 2.1 ml 2x kinase buffer (per plate). Add 200 μL of enzyme per well. For negative controls, add 20 μL 2x of kinase tag without enzyme. 6. Mix briefly on a plate stirrer; incubate for 60 minutes. 7. Add 200 μL of stop solution per well. 8. Let it run at rest for at least 10 min. 9. Cenrifuge the plate to approx. 2300 rpm for 10-15 min. 10. Count the plate on a Trilux reader. MET TRANSFOSFORILATION TEST This assay is used to measure the levels of phosphotyrosine on a poly (glutamic acid-firosine, 4: 1) substrate as a means to identify metaphosphorylation agonists / antagonists of the substrate.

Materiales v Reagents: 1. 96-well ELISA plates from Corning, Corning Catalog, No. 25805-96. 2. Poly (glu-tyr), 4: 1, Sigma, Cat. No. P 0275. 3. PBS, Gibco Catalog, No. 450-1300EB 4. 50 mM Hepes 5. Blocking Buffer: Dissolve 25 g Bovine serum albumin, Sigma, Cat. No. A-7888, in 500 ml of PBS, filter through a 4 μm filter. 6. Purified GST fusion protein containing the kinase domain of Met, SUGEN, Inc. 7. TBST buffer. 8. 10% aqueous DMSO (MilliQue H2O). 9. 10 mM Aqueous Adenosine-d-Triphosphate (dH2O), Sigma, Cat. No. A-5394. 10. 2X Kinase Dilution Buffer: For 100 ml, mix 10 mL of 1M HEPES at pH 7.5 with 0.4 mL of 5% BSA / PBS, 0.2 mL of 0.1 M sodium orthovanadate and 1 mL of 5M sodium chloride in 88.4 L dH2O. 11. 4X ATP Reaction Mix: for 10 mL, mix 0.4 mL of 1 M manganese chloride and 0.02 mL of 0.1 M ATP in 9.56 mL of dH2O. 12. 4X Mix of Negative Controls: for 10 mL, mix 0.4 mL of 1 M manganese chloride in 9.6 mL of dH2O. 13. 96-well V-bottom polypropylene NUNC plates, Applied Scientific Catalog, No. S-72092 14. 500 mM EDTA. 15. Antibody Dilution Buffer: for 100 mL, mix 10 mL of 5% BSA / PBS, 0.5 mL of Camatione® 5% Instant Milk in PBS and 0.1 mL of 0.1 M sodium orthovanadate in 88.4 ml of TBST. 16. Polyclonal rabbit antifosifotyrosine antibody, SUGEN, Inc. 17. Antibody conjugated with horseradish peroxidase horseradish prepared in Cabra, Biosource, Inc. 18. Dissolution of ABTS: for 1 L, mix 19.21 g of citric acid , 35.49 g of Na2HPO4 and 500 mg of ABTS with enough dH2O to make 1 L. 19. ABTS / H2O2: mix 15 mL of ABST solution with 2 μL H2O2 five minutes before using it. 20. 0.2 M HCl Procedure: 1. Coat ELISA plates with 2 μg Poly (Glu-Tyr) in 100 μL of PBS, keep overnight at 4 ° C. 2. Block the plate with 150 μL of 5% BSA / PBS for 60 min. 3. Wash the plate twice with PBS then once with 50 mM Hepes buffer pH 7.4. 4. Add 50 μl of the diluted kinase to all wells. (The purified kinase is diluted with Kinase Dilution Buffer.The final concentration should be 10 ng / well.) 5. Add 25 μL of the test compound (in 4% DMSO) or DMSO alone (4% in dH2O) to the controls to the plate. 6. Incubate the kinase / compound mixture for 15 minutes. 7. Add 25 μL of MnCl240 mM to the negative control wells. 8. Add 25 μL of ATP / MnCl2 mixture to all other wells (except negative controls). Incubate for 5 min. 9. Add 25 μL 500 mM EDTA to stop the reaction. 10. Wash the 3x plate with TBST. 11. Add 100 μL of rabbit polyclonal anti-Ptyr diluted 1: 10,000 in Antibody Dilution Buffer to each well. Incubate, with shaking, at room temperature for one hour. 12. Wash the 3x plate with TBST. 13. Dilute the anti-rabbit antibody conjugated with HRP from Biosource 1: 6,000 in Antibody Dilution Buffer. Add 100 μL per well and incubate at room temperature, with shaking, for one hour. 14. Wash the 1X plate with PBS. 15. Add 100 μl of ABTS / H2O2 solution to each well. 16. If necessary, stop the evolution of the reaction with the addition of 100 μl of 0.2 M HCl per well. 17. Read the plate on the Dynatech MR7000 ELISA reader with the test filter at 410 nm and the reference filter at 630 nm. IGF-1 Transphosphorylation Assay This assay is used to measure the level of phosphotyrosine in poly (glutamic acid: tyrosine, 4: 1) for the identification of agonists / antagonists of the transphosphorylation of gst-IGF-1 from a subtraction.

Materials and Reagents: 1. 96-well ELISA plates from Corning. 2. Poly (GIu-Tyr), 4: 1, Sigma, Cat. No. P 0275. 3. PBS, Gibco Catalog, No. 450-1300EB. 4. 50 mM Hepes 5. TBB Blocking Buffer: for 1 L, mix 100 g of BSA, 12.1 g of TRIS (pH 7.5), 58.44 g of sodium chloride and 10 mL of TWEEN-20 at 1%. 6. Purified GST fusion protein containing the IGF-1 kinase domain (SUGEN, Inc.) 7. TBST buffer: for 1 L, mix 6.057 g of Tris, 8.766 g of sodium chloride and 0.5 ml of TWEEN- 20 with enough dH2O to make 1 liter. 8. 4% DMSO in Milli-Q H2O. 9. 10 mM ATP in dH2O. 10. 2X Kinase Dilution Buffer: for 100 mL, mix 10 mL of 1 M HEPES (pH 7.5), 0.4 mL of 5% BSA in dH2O, 0.2 mL of 0.1 M sodium orthovanadate and 1 mL of 5 M sodium chloride with sufficient dH2O to make 100 mL. 11. 4X ATP Reaction Mix: for 10 mL, mix 0.4 mL of 1 M MnCI2 and 0.008 mL of 0.01 M ATP and 9.56 mL of dH2O. 12. 4X Mix of Negative Controls: mix 0.4 mL of 1 M MnCl2 in 9.60 mL of dH2O. 13. NUNC polypropylene plates with 96 bottom V wells. 14. 500 mM EDTA in dH2O. 15. Antibody Dilution Buffer: for 100 mL, mix 10 mL of 5% BSA in PBS, 0.5 mL of 5% Carnation Instant Skim Milk in PBS and 0.1 mL of 0.1 M sodium orthovanadate in 88.4 ml of TBST. 16. Polyclonal rabbit antiphosphotyrosine antibody, SUGEN, Inc. 17. HRP conjugated anti-rabbit antibody prepared in goat, Biosource. 18. Dissolution of ABTS. 20. ABTS / H2O2: mix 15 mL ABTS with 2 μL of H2O2 5 minutes before using it. 21. 0.2 M HCl in dH2O. Procedure: 1. Coat the ELISA plate with 2.0 μg / well of Poly (Glu, Tyr), 4: 1 (Sigma P0275) in 100 μl of PBS. Store the plate overnight at 4 ° C. 2. Wash the plate once with PBS. 3. Add 100 μl of TBB Blocking Buffer to each well. Incubate the plate for 1 hour with shaking at room temperature. 4. Wash the plate once with PBS, then twice with 50 mM Hepes buffer pH 7.5. 5. Add 25 μL of test compound in 4% DMSO (obtained by diluting a storage solution of the 10 mM test compound in 100% DMSO with dH2O) to the plate. 6. Add 10.0 ng of gsi-IGF-1 kinase in 50 μl of Kinase Dilution Buffer to all wells. 7. Begin the kinase reaction by adding 25 μl 4X ATP Reaction Mix to all test wells and positive control wells. Add 25 μ 4X of Negative Controls Mix to all negative control wells. Incubate for 10 minutes, with shaking, at room temperature. 8. Add 25 μl of 0.5 M EDTA (pH 8.0) to all wells. 9. Wash the 4x plate with TBST Buffer. 10. Add polyclonal rabbit anti-phosphotyrosine antisera at a dilution of 1: 10,000 in 100 μl of Antibody Dilution Buffer to all wells. Incubate, with agitation, at room temperature for 1 hour. 11. Wash the plate as in step 9. 12. Add 100 μL of Biosource HRP anti-rabbit at a dilution of 1: 10,000 in Antibody Dilution Buffer at all wells.

Incubate, with agifacíón, at room temperature for 1 hour. 13. Wash the plate as in step 9, follow with a wash with PBS to eliminate bubbles and excess Tween-20. 14. Develop by adding 100 μl / well of ABTS / H2O2 to each well. 15. After approximately 5 minutes, read in the ELISA reader with 410 nm test filter and reference filter at 630 nm. BRdU INCORPORATION TESTING The following assays use cells designed to express a selected receptor and then evaluate the effect of a compound of interest on the DNA synthesis activity induced by the ligand determining the incorporation of BrdU into the DNA. The following materials, reagents and procedures are general for each of the following BrdU incorporation tests. Variations in specific tests are indicated. Materials and General Reagents: 1. The appropriate ligand. 2. The appropriate designed cells. 3. BrdU Marker Reagent: 10 mM, in PBS, pH 7.4 (Roche Molecular Biochemicals, Indianapolis, IN). 4. FixDenat: fixation solution (Roche Molecular Biochemicals, Indianapolis, IN). 5. Anti-BrdU-POD: mouse monoclonal antibody conjugated with peroxidase (Chemicon, Temecula, CA). 6. TMB Substrate Solution: tetramethylbenzidine (TMB, ready to use, Roche Molecular Biochemicals, Indianapolis, IN). 7. Wash Solution of PBS: 1X PBS, pH 7.4. 8. Albumin, Bovine (BSA), fraction V powder (Sigma Chemical Co., USA). General Procedure: 1. The cells are seeded at 8000 cells / well in 10% CS, 2mM Gln in DMEM, in a 96-well plate. The cells are incubated overnight at 37 ° C in 5% CO2. 2. After 24 hours, the cells are washed with PBS, and then deprived of serum in serum-free medium (0% DMEM with 0.1% BSA) for 24 hours. 3. On day 3, the appropriate ligand and the test compound are added simultaneously to the cells. Negative conirol wells receive serum-free DMEM with 0.1% BSA only; the positive conírol cells receive the ligand but not test compound. The test compounds are prepared in DMEM without serum with ligand in a 96 well plate, and serially diluted for 7 test concentrations. 4. After 18 hours of ligand activation, the diluted BrdU label reagent is added (1: 100 in DMEM, 0.1% BSA) and the cells are incubated with BrdU (the final concentration is 10 μM) during 1.5 hours 5. After incubation with marker reagent, the medium is removed by decanting and tapping the inverted plate on a paper towel. The FixDenat solution (50 μl / well) is added and the plates are incubated at room temperature for 45 minutes in a plate agilator. 6. Remove the FixDenat solution by decanting and tapping the inverted plate on a paper towel. Milk (5% dehydrated milk in PBS, 200 μl / well) is added as a blocking solution and the plate is incubated for 30 minutes at room temperature on a plate shaker. 7. The blocking solution is removed by decanting and the wells are washed once with PBS. Anti-BrdU-POD solution is added (1: 200 dilution in PBS), 1% BSA, 50 μl / well) and the plate is incubated for 90 minutes at room temperature on a plate shaker. 8. The antibody conjugate is removed by decanning and the wells are rinsed 5 times with PBS, and the plate is dried by inverting and tapping on a paper towel. 9. Add TMB substrate solution (100 μl / well) and incubate for 20 minutes at room temperature on a plate shaker until color development is sufficient for photometric detection. 10. Measure the absorbance of the samples at 410 nm (in "dual wavelength" mode with a filter reading at 490 nm, as the reference wavelength) on a Dynatech ELISA plate reader. Incorporation Assay of BrdU Induced with EGF Materials and Reagents: 1. Mouse EGF, 201 (Toyobo Co., Lid., Japan). 2. 3T3 / EGFRC7. The rest of the Materials and Reagents and the Procedure, as mentioned above. Assay of Incorporation of BrdU Induced with PDGF Materials v Reagents: 1. Human PDGF B / B (Boehringer Mannheim, Germany). 2. 3T3 / EGFRc7. The rest of the Materials and Reagents and the Procedure, as mentioned above. Assay of BrdU Incorporation Induced with FGF Materials and Reagents: 1. Human FGF2 / bFGF (Gibco BRL, USA). 2. 3T3c7 / EGFr The rest of the Materials and Reagents and the Procedure, as mentioned above. Assay of Incorporation of BrdU Induced with IGF-1 Materials and Reagents: 1. Human, recombinant (G511, Promega Corp., USA) 2. 3T3 / IGF1 r. The rest of the Materials and Reagents and the Procedure, as mentioned above. Src Transphosphorylation Assay This assay is used to systematically detect Src tyrosine kinase inhibitors. Materials and Reagents: 1. Coating buffer: PBS containing sodium azide (0.2mg / ml). 2. BSA aM% p / v in PBS. 3. Wash Buffer: PBS containing 0.05% v / v Tween 20 (PBS-TWEEN) 4. 500mM HEPES pH 7.4. 5. ATP (40 μM) + MgCl 2 (80 mM) in distilled water. 6. MgCl2 (80 mM) in distilled water (for non-ATP targets). 7. Test compounds, 10 mM in DMSO. 8. Assay Buffer: 100 mM HEPES, pH 7.4, containing 2 mM DTT, 0.2 mM sodium orthovanadate and 0.2 mgs / ml BSA. 9. Human partially purified recombinant Src (UBI (14-117) . Anti-phosphotyrosine (rabbit polyclonal anti-PY SUGEN). 11. Anti-rabbit Ig prepared in goat united with HRP (Biosource International, No. 6430) 12. ABTS substrate of HRP or Peroxidase substrate by Pierce. 13. Corning ELISA plates. Procedure: 1. Coat plates with 100 μl of 20 μg / ml poly (Glu-Tyr) (Sigma, No. of Cal. P0275) containing 0.01% sodium azide. Keep overnight at 4 ° C. 2. Block with 1% BSA at 100 μl / well for one hour at room temperature. 3. Prepare the plate with the test compounds (10 mM in DMSO) at 2 μl / well in a Costar plate ready for dilution with dH2? and preparing the reaction plates. 4. Dilute the Src kinase 1: 10,000 in Reaction buffer, for 5 plates prepare 25 ml as follows: 2.5 ml of 1M HEPES pH 7.4 (stored sterile at 4 ° C), 21, 85 ml of distilled water , 0.1 ml of 5% BSA, 0.5 ml of 10 mM sodium orthovanadate (stored sterile at 4 ° C), 50 μl of 1.0M DTT (stored frozen at -20 ° C), and 2.5 μl of Src kinase (stored frozen at -80 ° C). 5. Add 48 μl of distilled water to the 2 μl of each compound in the dilution plate then add 25 μl / well of this to the reaction plate. 6. Add 50 μl of HRP to each well of reaction buffer and then 25 μl of ATP-MgCl2 / well (MgCl2 only to non-ATP targets).

Incubate at room temperature for 15 minutes on the plate shaker. Stop the reaction by adding 25 μl of 0.5 M EDTA to each well. 7. Wash 4X with PBS-TWEEN. 8. Add 100 μl of anti-phosphotyrosine (1: 10,000 of anti-pTyr serum or 1: 3,000 of antibody purified by affinity with PA diluted with glycerol at %) in PBS-TWEEN containing 0.5% BSA, 0.025% skimmed milk powder and 100 μM sodium orthovanadate. Incubate with continuous agitation at room temperature for one hour. 9. Wash the 4X plates with PBS-TWEEN. 10. Add 100 μl of HRP bound Ig (1: 5,000) in PBS-TWEEN containing 0.5% BSA, 0.025% skimmed milk powder and 100 μM sodium orthovanadate. Incubate with agitation at room temperature for one hour. 11. Wash the 4X plates with PBS-TWEEN and then once with PBS. 12. Develop the plate using ABTS or other peroxidase substrate. Cell cycle analysis: A431 cells are exposed in standard culture medium at a desired concentration of a test compound for 20-24 hours at 37 ° C. The cells are then harvested, suspended in PBS, fixed in ice-cold 70% methanol and stained with propidium iodide. The DNA content is then measured using a FACScan flow cytometer. Next, the phase distribution of the cell cycle can be estimated using the CelIFit computer program (Becfon-Dickinson). Test of HUV-EC-C This test is used to measure the activity of a compound against RDF-R, FGF-R, VEGF, aFGF or Flk-1 / KDR, all of which are expressed naturally by HUV-EC cells. DAY O 1. Wash and trypsinize HUV-EC-C cells (human umbilical vein endothelial cells), (American Type Culture Collection, Catalog No. 1730 CRL). Wash with Dulbecco's phosphate buffered saline (D-PBS, obtained from Gibco BRL, catalog number 14190-029) 2 times to approximately 1 ml / 10 cm2 of tissue culture flask. Trysinize with 0.05% trypsin - EDTA in non-enzymatic cell dissociation solution (Sigma Chemical Company, catalog number C-1544). The 0.05% trypsin is made by diluting 0.25% trypsin / 1 mM EDTA (Gibco, catalog no. 25200-049) in the cell dissociation solution. Trypsinize with approximately 1 ml / 25-30 cm2 of tissue culture flask for approximately 5 minutes at 37 ° C. After the cells have separated from the bottle, add an equal volume of assay medium and transfer to a sterile 50 ml centrifuge tube (Fisher Scientific, catalog no. 05-539-6). 2. Wash the cells with approximately 35 ml of assay medium in the sterile 50 ml centrifuge tube by adding the assay medium, centrifuge for 10 minutes at approximately 200 × g, aspirate the supernatant, and resuspend with 35 ml of D-PBS. . Repeat the washing twice more with D-PBS, resuspend the cells in 1 ml of assay medium / 15 cm2 of phial. The test medium consists of F12K medium (Gibco BRL, catalog number 21127-014) and 0.5% heat inactivated fetal bovine serum. Converse the cells with a Coulter Counter® counter (Coulter Electronics, Inc.) and add test medium to the cells to obtain a concentration of 0.8-1.0 x 104 cells / well, incubate ~ 24 h at 37 ° C, 5% CO2 DAY 1 1. Prepare titrations of the test compound by double dilution in separate 96-well plates, generally 50 μM to 0 μM. Use the same test medium as mentioned in step 2 of day 0 above. Titrations are made by adding 90 μl / well of the test compound to 200 μM (4X the final concentration of the well) to the top well of a particular column of the plate. Since the stored test compound is usually 20 mM in DMSO, the 200 μM drug concentration contains 2% DMSO. A diluent prepared at 2% DMSO in assay medium (F12K + 0.5% fetal bovine serum) is used as a diluent for the titrations of the test compound to dilute the test compound but keeping the concentration of DMSO constant. Add this diluent to the remaining wells in the column at 60 μl / well. Take 60 μl of the 120 μl of the dilution of the 200 μM test compound in the upper well of the column and mix with 60 μl in the second well of the column. Take 60 μl of this well and mix with the 60 μl in the third well of the column, and so on until the titrations are completed by double dilution. When mixing the penultimate well, take 60 μl of the 120 μl in this well and discard it. Leave the last well with 60 μl of DMSO / media diluent as a control that does not contain test compound. Make 9 columns of tested test compound, sufficient for triplicate wells each for: (1) VEGF (obtained from Pepro Techlnc, catalog number 100-200), (2) endothelial cell growth factor (ECGF) (also known as growth factor of the acid fibroblast or aFGF) (obtained from Boehringer Mannheim Biochemica, catalog number 1439 600), (3) human PDGF B / B (1276-956, Boehringer Mannheim, Germany) and control of test media . The ECGF comes as a preparation with sodium heparin. 2. Transfer 50 μl / well of the dilutions of the test compound to the 96-well assay plates containing 0.8-1, 0x104 cells / 100 μl / well of the HUV-EC-C cells of day 0 e incubate ~ 2 h at 37 ° C, CO2 at 5%. 3. In triplicate, add 50 μl / well of VEGF to 80 μg / ml, ECGF at 20 ng / ml, or media control at each test compound condition. As with the test compounds, the concentrations of the growth factor are 4X the desired final concentration. Use the assay means of stage 2 of day 0 to make the concentrations of the growth factors, incubate approximately 24 hours at 37 ° C, 5% CO2. Each well will have 50 μl of dilution of the test compound, 50 μl of growth factor or medium, and 100 μl of cells, giving a total of 200 μl / well. Thus the 4X concentrations of the test compound and the growth factors are transformed into 1X once everything has been added to the wells. DAY 2 1. Add 3H-thymidine (Amersham, catalog number TRK-686) at 1 μCi / well (10 μl / well of 100 μCi / ml solution prepared in RPMl medium + 10% heat inactivated fetal bovine serum) ) and incubate -24 h at 37 ° C, 5% CO2. The RPMl is obtained from Gibco BRL, catalog no. 11875-051. DAY 3 1. Freeze plates overnight at -20 ° C. DAY 4 Thaw the plates and collector with a 96-well plate collector (Tomtec Harvester 96®) on filter mats (Wallac, Catalog No. 1205-401), read the counters in a Wallac Beiaplaíe® liquid scintillation conifer. . Animal Models In Vivo XENOINKER ANIMAL MODELS The ability of human tumors to grow as xenografts in athymic mice (eg Balb / c, a / a) provides a useful in vivo model for studying the biological response to treatments for human tumors. Since the first successful xenotransplantation of human tumors in athymic mice (Rygaard and Povisen, 1969, Acta Pathol, Microbial, Scand., 77: 758-760), many different human tumor cell lines have been transplanted (eg, breast, lung, genitourinary, gas-intestinal, head and neck, glioblastoma, bone, and malignant melanomas) and have grown successfully in nude mice. The following assays can be used to determine the level of activity, specificity and effect of the different compounds of the present invention. Three general types of assays are useful for evaluating the compounds: cellular / catalytic, cellular / biological and in vivo. The purpose of cell / catalytic assays is to determine the effect of a compound on the ability of a TK to phosphorylate tyrosines in a known substrate in a cell. The purpose of cell / biological assays is to determine the effect of a compound on the biological response stimulated by a TK in a cell. The object of the in vivo assays is to determine the effect of a compound in an animal model of a particular translohor such as cancer. Suitable cell lines for subcutaneous xenograft experiments include C6 cells (glioma, ATCC # CCL 107), A375 cells (melanoma, ATCC # CRL 1619), A431 cells (squamous cell carcinoma, ATCC # CRL 1555), Calu 6 cells (lung, ATCC # HTB 56), PC3 cells (prostate, ATCC # CRL 1435), SKOV3TP5 cells, S114 (NIH3T3 fibroblast cell line genetically engineered for expressions of cMet and HGF from NCI), U-87MG (human malignant glioma, ATCC HTB 14 ) and NIH 3T3 fibroblasts genetically engineered to overexpress EGFR, PDGFR, IGF-1R or any other test kinase. The following protocol can be used to carry out xenograft experiments: Female nude mice (BALB / c, a / a) are obtained from Simonsen Laboratories (Gilroy, CA). All animals are kept under clean room conditions in Micro-isolator boxes with Alpha-dri bed. They receive sterile food for rodents and water ad libitum. Cell lines are cultured in the appropriate medium (eg, MEM, DMEM, Ham's F10, or Ham's F12 plus 5% -10% fetal bovine serum (FBS) and 2 mM glutamine (GLN). Cell culture, glutamine, and fetal bovine serum are purchased from Gibco Life Technologies (Grand Island, NY) unless otherwise specified. Cells are grown in a humid atmosphere of air at 90-95% and CO2 at 5-10% at 37 ° C. All cell lines are subcultured rufinariamenie twice a week and are negative to mycoplasma as determined by the Mycolecl method (Gibco). The cells are harvested at or near the confluence with Trypsin-EDTA and granulated at 450 x g for 10 min. The granules are resuspended in sterile PBS or sterile media (without FBS) at a particular concentration and the cells are implanted in the rear side of the mice (8-10 mice per group)., 2-10x106 cells / animal). Tumor growth is measured over 3 to 6 weeks using the vernier caliper (vernier). Tumor volumes are calculated as a product of length x width x height unless otherwise indicated. The P values are calculated using the Student t test. The test compounds in 50-100 μL of excipient (DMSO, or VPD: D5W) can be administered by IP injection at different concentrations starting generally on day one after implantation. TUMOR INVASION MODEL The following tumor invasion model has been developed and can be used for the evaluation of the therapeutic value and efficacy of the compounds identified to selectively inhibit the KDR / FLK-1 receptor. Procedure Nude (female) mice of 8 weeks of age (Simonsen Inc.) are used as experimental animals. The implantation of tumor cells can be carried out in a laminar flow cabinet. For the anesthesia, the Xylazine / Ketamine Cocktail is administered intraperitoneally (100 mg / kg ketamine and 5 mg / kg Xylazine). An incision is made in the midline to expose the abdominal cavity (approximately 1.5 cm in length) for injector 107 tumor cells in a volume of 100 μl medium. The cells are injected either into the duodenal lobe of the pancreas or under the serosa of the colon. The peritoneum and muscles are closed with a continuous 6-0 silk suture and the skin is closed using staples. The animals are observed daily. Analysis After 2-6 weeks, depending on the obvious observations of the animals, the roots are sacrificed, and the metastases of the local tumor to various organs (lung, liver, brain, stomach, spleen, heart and muscles) are excised and analyzed. (measurement of tumor size, degree of invasion, immunochemistry, determination of in siii hybridization, etc.). Cell Assay - Phosphorylation of Met Materials and Reagents: 1. Falcon 10 cm culture plates. 2. A549 cells of lung carcinoma. 3. Culture medium F12K (with 2% FBS + 2mM glutamine). 4. Test medium F12K (with 0.1% BSA). 5. Fisher cell scrapers. 6. Lysis buffer (HNTG, 1 mM sodium orthovanadate, 1 mM PMSF and 2mM sodium fluoride). 7. Eppendorf tubes of 1.5 ml. 8. Eppendorf microcentrifuge. 9. BCA assay reagents A and B (No. 23223 and 23224, Pierce). 10. Rotary agitator of test tubes. 11. Rotary agitator of electrotransfer gel containers. 12. 5X sample buffer. 13. Novex prepared gels of 8% acrylamide and tris-glycine. 14. Bio-Rad electrophoresis chamber. 15. SDS-PAGE buffer. 16. TBS (pH 7.6) + 0.1% Triton X-100 (TBST), with or without 5% milk. 17. Immunoblotting buffer. 18. Osmonics nitrocellulose paper. 19. Bio-Rad transfer paper. 20. Gel transfer device. 21. Anti-phosphotyrosine (mouse monoclonal). 22. Pre-Adhered Patterns of Bio-Rad Kaleidoscope (161-0324). 23. Anti-h-met (C-28) polyclonal rabbit, conjugated and unconjugated with agarose (No. sc-161 AC and sc-161, Santa Cruz Biotechnology, Inc.). 24. Donkey Ig and anti-rabbit conjugated with HRP (NA 934, Amersham). 25. Anti-raphon sheep Ig conjugated with HRP (NA 931, Amersham). 26. Chemiluminescent substrate designated SuperSignal West Pico Chemiluminescent Substrate (No. 34080, Pierce). 27. Transparent film Saran Wrap. 28. Kodak BioMax exhibition chassis. 29. Fuji X-ray film. 30. Kodak film developer. Procedure: 1. Seed cells in 10 cm plates with culture medium with 2% FBS + 2mM glutamine. Cultivate near the confluence. 2. Deprive the serum cells overnight in the assay medium with 0.1% BSA. 3. Add the drug to the plates, one dose per plate, usually in a double dilution titration. Add the assay medium (with the same concentration of DMSO as the drugs) to the blank without drug. 4. Incubate the plates 4-5 hours with the drug, then add 50 ng / ml HG for 10 minutes. 5. Wash the plates once with PBS, add 400 μl of lysis buffer, and scrape the cells. Collect in 1, 5 ml Eppendorf tubes. 6. After approximately 10-20 minutes in the lysis buffer, centrifuge the lysates in a microcentrifuge at maximum speed (14,000g) and collect the supernatants in a separate Eppendorf tube. 7. Determine the protein concentration with the BCA assay reagents. 8. Adjust the concentration of the sample to 0.5 mg of protein in 0.4 ml using the lysis buffer. 9. Add 15 μl of anti-h-met AC for immunoprecipitation, run the samples for 2 hours at 4 ° C. 10. Wash the samples 3 times with lysis buffer and resuspend in 35 μl 5X of sample primer. 11. Boil the sample at 100 ° C for 10 minutes and microcentrifuge at the highest setting for 30 minutes to granulate the agarose beads. 12. Load 15 μl of each to 2 gels, one for anti-phosphorylation and the other for anti-h-met. Also load 10 μl of pre-dyed patterns, one lane per gel. 13. Develop the gel at around 100-125 V, then transfer the gel to nitrocellulose or overnight at 70 mA or 1 hour at 500 mAmps. 14. Block the membranes on the rotary shaker for 1 hour in TBS + 0.1% Triton X-100 (TBST) + 5% PBS. All stages from this point are at room temperature unless otherwise indicated. 15. Add 0.8 μg / ml antiphosphotyrosine and 0.25 μg / ml anti-h-met on the rotary shaker or for 2 hours or overnight. 16. Wash the membranes 3 times 5 minutes each in TBST in the roiático agitator. 17. Add antibodies conjugated with HRP (sheep aníi-mouse for antiphosphotyrosine; donkey anti-rabbit for anti-h-met) at 1: 5000 for approximately 45 minutes on the rotary shaker. 18. Wash the membranes 3 times for 5 minutes each in TBST on the rotary shaker. 19. Add the 2 reagents from the SuperSignal kit together in equal volumes (3 ml + 3 ml for each transfer), rotate for 1-2 minutes. 20. Wrap the transfers in transparent film Saran Wrap and close it securely inside the exhibition chassis. 21. In the dark room with only the safety light on, put a sheet of denfro film on the chassis. After the planned time, remove the film and put it in the developing machine for automatic processing. Experiment with the exposure time to get the proper exposure. Proximity Scintillation Assay of ZC1 The Proximity Scintillation Assay (SPA) is used to analyze the activity of serine / threonine kinase protein of ZC1 in vitro for the systematic search for ZC1 inhibitors in a homogeneous assay. The assay described below is favorable for the systematic high-throughput search for ZC1 inhibitors. Materials and solutions: 1. 96-well poly (ethylene terephthalate) (flexible) plates from Wallac (Wallac Catalog, No. 1450-401). 2. Easy-Tide [? 33P] ATP from NEN (NEN cat. NEG. NEG602H). 3. Polyvinyl toluene SPA beads coated with streptavidin from Amersham (Amersham catalog, NIF No. 107). Reconstitute the beads in PBS without magnesium or calcium, at 50 mg / mL. Store the reconstituted beads at 4 ° C. (In order to reach the optimal accounts, it is important that you must be present excess of streptavidin SPA bead to bind all the biotinylated molecules in the assay). Activated ZC1 enzyme purified from Sf9 cells - Final concentration of 300 ng / well. 4. Peptide Substrate No. 902B (Biotin-KRTLRRKRTLRRKRTLRR) - Final Concentration of 0.5 μM / well (2XKm). Procedure: 1. Prepare the inhibitor solutions at 5x the final desired concentration in 5% DMSO. Add 10 μL to each well of the flexible plate. For positive and negative controls, add 10 μL of 5% DMSO. 2. Prepare the ATP mixture as shown above (2.1 ml of ATP mixture is sufficient for a test plate). Add 20 μL to all wells. 3. Add 20 μL of 5M EDTA to the negative control wells. 4. Prepare the enzyme solution in 2.5X kinase buffer (50 mM HEPES pH 7.4, 12.5 mM MnCl2, 500 mM NaCl, and 1 mM DTT). The final enzyme concentration will be 0.30 μg / well (eg, given a storage solution of 0.5 mg / mL, add 302 μL of ZC1 enzyme to 10 mL of Kinase Buffer). Add 20 μL per well to start the reaction. 5. Allow the kinase reaction to proceed at room temperature for 60 minutes. 6. To each well, add 200 μL of stop solution containing 0.05 mM ATP, 5 mM EDTA, 0.1% Tri-ion X-100, and 5 mg per ml streptavidin-coated polyvinyl toluene SPA beads. from Amersham (Cat. No. NIF 1077) on PBS. Incubate for 15 minutes. 7. Centrifuge the plate at 2300 rpm for 15 min. 8. Count the plate on the Trilux reader using the SPA flexible plate protocol (which includes the extinction curve). Aurora2 Proximity Scintillation Assay The Proximity Scintillation Assay (SPA) is used to analyze the activity of serine / Ireonine kinase Aurora2 in vitro to systematically search for Aurora2 inhibitors in a homogeneous assay. The assay described below is favorable for the systematic high-throughput search of Aurora2 inhibitors. Materials and solutions: 1. 96-well poly (ethylene terephthalate) (flexible) plates from Wallac (Wallac Catalog, No. 1450-401). 2. Easy-Tide [? 33P] ATP from NEN (NEN cat. NEG. NEG602H). 3. PE beads of polyvinyloluene coated with streptavidin from Amersham (Amersham catalog, NIF 107). Reconstitute the beads in PBS without magnesium or calcium, at 50 mg / mL. Store the reconstituted beads at 4 ° C. (In order to reach the optimum ranges, it is important that excess of streptavidin SPA beads must be present to bind all the biotinylated molecules in the assay). 4. Enzyme: GST-Aurora2 enzyme purified from BL21 cells. 1.0 mg / ml; aliquots of 500 μl. Use 0.125 mg / well assay.

. Biotinylated peptide substrate: SUGEN peptide No. 800A. Bio-LC-LC-LRRWSLGLRRWSLGLRRWSLGLRRWSLG dissolved in DMSO at a concentration of 10 mg / ml. Stored at -20 ° C in 500 μl aliquots - Final concentration of 0.012 ml / well (2 X Km). Procedure: 1. Prepare the inhibitor solutions at 5x the final desired concentration in 5% DMSO. Add 10 μL to each well of the flexible plate. For positive and negative controls, add 10 μL of 5% DMSO. 2. Prepare the ATP mixture as shown above (2.1 ml of ATP mixture is sufficient for a test plate). Add 20 μL to all wells. 3. Add 20 μL of 5M EDTA to the negative control wells. 4. Prepare the enzyme solution in 2.5X kinase buffer (50 mM HEPES pH 7.4, 12.5 mM MnCl2, 500 mM NaCl, and 1 mM DTT). The final enzyme concentration will be 0.125 μg / well. Add 20 μL per well to start the reaction. 5. Allow the kinase reaction to advance to ambient temperature for 60 minutes. 6. To each well, add 200 μL of a stop solution containing 0.05 mM ATP, 5 mM EDTA, 0.1% Tri-ion X-100, and 5 mg per ml of streptavidin-coated polyvinyloluene SPA beads. from Amersham (N ° de Caí. NIF 1077) in PBS. Incubate for 15 minutes. 7. Centrifuge the plate at 2300 rpm for 15 min. 8. Count the plate on the Trilux reader using the SPA flexible plate protocol. Additional assays Additional assays that can be used to evaluate the compounds of this invention include, without limitation, a bio-flk-1 assay, a test chimeric receptor HER2 - EGF receptor in whole cells, a bio-src assay, a bio-lck assay and an assay that measures the phosphorylation function of raf. The protocols for each of these assays can be found in the U.S. Application Ser. Serial No. 09 / 099,842, which is incorporated by reference, including any drawings, herein. Additionally, U.S. Pat. No. 5,792,783, filed June 5, 1996 and the US Application Ser. Serial No. 09 / 322,297, filed on May 28, 1999, are incorporated by reference as if they were fully disclosed in this report. Table 1, below, shows the IC50 values obtained for various compounds of the preferred embodiments of the invention.

A person skilled in the art would also readily appreciate that the present invention is well adapted to carry out the objectives and to achieve the abovementioned purposes and venies, as well as those inherent in the present memory. The molecular complexes and methods, procedures, fratamienios, molecules, specific compounds described herein are at this time representative of the preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes in these and other uses that will occur to those skilled in the art that are encompassed within the spirit of the invention are defined by the scope of the claims. It will be readily apparent to one skilled in the art that various substitutions and modifications may be made to the invention described herein without departing from the scope and spirit of the invention. All patents and publications mentioned in the specification are indicative of the levels of those skilled in the art to which the invention pertains. All patents and publications are incorporated herein by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated as a reference. The invention described illustratively herein can be practiced in the absence of any element or elements, limitation or limitations that are not specifically described herein. Thus, for example, in each case in the present specification any of the terminologies "comprising", "consisting essentially of" and "consisting of" can be replaced with any of the other two terminologies. The terms and expressions that have been used are used as terms of description and not limitation, and there is no intention that in the use of such terms and expressions to exclude any of the equivalents of the characteristics shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed invention. Thus, it should be understood that although the present invention has been specifically described by preferred embodiments and optional features, it is possible to resort to the modification and variation of the concepts described in the present invention by those skilled in the art, and to make modifications and modifications. variations are considered to be within the scope of this invention as defined by the appended claims.

In addition, while the features and aspects of the invention are described in terms of the Markush groups, those skilled in the art will recognize that the invention is also described as such in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as being selected from the group consisting of bromine, chlorine, and iodine, the claims for X which is bromine and the claims for X which is bromine and chlorine are fully described. Other embodiments are within the following claims.

Claims (5)

CLAIMS A compound of the Formula: wherein A, B, D and E are each independently selected from the group consisting of carbon and nitrogen such that when A is nitrogen, B and E are carbon and when E is nitrogen and A is carbon, then B is carbon or nitrogen; wherein when A, B, D, or E is nitrogen, R2, R3, R4 or R5 do not exist respectively; provided that the ring containing A, B, D and E contains no more than two nylrogens; R2, R3, R4, R5, R7 and Rs are each independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, frihaloalkyl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio , -SOR13, -SO2R? 3, -SO2NR13R14, R14SO2N (R13) -, N-trihalomethanesulfonamido, -C (O) R? 5, -C (O) OR? 5, R? 5C (O) O-, cyano Ni, halo, cyanate, isocyanate, isocyanate, thiocyanate, isothiocyanate, -OC (O) NR? 3R14, R14OC (O) NR13-, -OC (S) NR? 3Ri4, R? OC (S) NR13-, -C (O) NR? 3R14 > R14C (O) NR13- and -NR13R; R2 and R3 or R3 and R4 or R4 and R5 or R7 and R8 together with the atoms to which they are attached may be associated to form a methylenedioxy group, an ethylenedioxy group, an alicyclic ring or a he- loreocyclic ring; R13 and R14 are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, heteroalicyclic, -C (O) R? 5, acetyl, -SO2R15 and - (CH2) nNR? 3Ri4; or R13 and R14 together with the atoms to which they are attached can form a five or six membered heteroalicyclic ring; R15 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl and heteroalicyclic; R9, R10, R11 and R12 are each independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, trihaloalkyl, halo, cyano, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, - SO2R15, -S (O) Ri5, - (CH2) nC (O) ORi5, cyanate, isocyanate, thiocyanate, isothiocyanate, -C (O) NR? 3R, RMC (O) NR? 3- and -NR? 3R14; n is an integer from 0 to 20; X is selected from the group consisting of nitrogen, oxygen, and sulfur; and in which when X is oxygen or sulfur, then R6 does not exist; or a prodrug or pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein A, B, D and E are carbon. 3. The compound of claim 2, wherein X is nitrogen. 4. The compound of claim 1, wherein R2, R3, R4, R5, R7 and Rs are each independently selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, -SOR? 3, - SO2R- | 3, -SO2NR? 3R, -C (O) OR15, halo and -C (O) NR? 3Ri4. 5. The compound of claim 4, wherein A, B, D and E are carbon. 6. The compound of claim 5, wherein X is nitrogen. 7. The compound of claim 1, which is: 2-meityyl-6- [2-oxo-1,2-dihydro-indole- (3Z) -ylidene] -1, 4-ethyl ester , 5,6-tetrahydro-cyclopenta [b] pyrrole-3-carboxylic acid; Ethyl 6- [5- (2,6-dichloro-phenylmethanesulfonyl) -2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -2-methyl-1, 4,5,6- ethyl ester γ-tetrahydro-cyclopenta [b] pyrroi-3-carboxylic acid; 2-methyI-6- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indole- (3Z) -iIden] -1,6,6,6-tetrahydro-cyclopentate [2] ethyl ester pyrrol-3-carboxylic acid; 3- [2-methyl-4,5-dihydro-1H-cyclopenta [b] pyrrole (6Z) -ylidene] -2-oxo-2,3-dihydro-1 H-indole-5-sulfonic acid methyl ester; 2-Methyl-6- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -1,2,5,6-tetrahydro-cyclopenta [b] pyrrole-3-acid carboxylic; 6- [5-methanesulfonyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -2-methyl-1, 4,5,6-tetrahydro-cyclopenpha [b] pyrrol- 3-carboxylic acid; ethyl ester of 6- [5-dimethyl-iso-fluoyl-2-oxo-1,2-dihydro-indol (3Z) -ylidene] -2-methyl-1, 4,5,6-tetrahydro-cyclopenpha [b] pyrrole-3-carboxylic acid; 6- [5-isopropylsulfamoii-2-oxo-1,2-dihydro-indol- (3Z) -iIiden] -2-methyI-1,4,5,6-tetrahydro-cyclopenta [b] ethyl ester ] pyrrole-3-carboxylic acid; ethyl ester of 6- [5-ethanesulfonyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -2-methyl-1,4,5,6-tetrahydro-cyclopenta [b] pyrrol- 3-carboxylic; 2-Methyl-6- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indol- (2-hydroxy-3-pyrrolidin-1-yl-propyl) -amide - Iiden] -1, 4,5,6-teirahydro-cyclopenta [b] pyrrole-3-carboxylic acid; (2-Methyl-6- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indole- (3Z) -ylidene] -1,4,5-cyclopropylamino-2-hydroxy-propyl) -amide. , 6-fefrahydro-cyclopenia [b] pyrrole-3-carboxylic acid; 2-Methyl-6- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indol- (3Z) -iIden] -1,4,5 -amido (2-dimethylamino-eyl) -amide. 6-tetrahydro-cyclopenta [b] pyrrole-3-carboxylic acid; 3- (2-methyl-3 - ((R) -2-pyrrolidin-1-methy1-pyrrolidin-1-carbonyl) -4,5-dihydro-1H-cyclopenta [methyl] acid amide ] pyrrol- (6Z) -ylidene] -2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid; ethyl ester of 2-methyl-6- [2-oxo-5-sulfamoyl-1,2-dihydro-indol- (3Z) -ylidene] -1,4,5,6-feirahydro-cyclopenia [b] pyrrol- 3-carboxylic; 3- [3-methanesulfonyl-2-methyl-4,5-dihydro-1H-cyclopenta [b] pyrrol- (6Z) -ylidene] -2-oxo-2,3-dihydro-1H acid amylamide -Indo-5-sulphonic; acid { 6-methoxy-3- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indoI- (3Z) -ylidene] -indan-1-yl} -acetic; 5-fluoro-3- [2-methyl-3 - ((S) -2-pyrrolidol-1-ylmeryl-pyrrolidin-1-carbonyl) -4,5-dihydro-1H-cyclopenia [b ] pyrrole- (6Z) -lden] -1,3-dihydro-indol-2-one; 6-meioxy-3- [2-methyl-3 - ((S) -2-pyrroidin-1-methyl-1-pyrroidin-1-carbonyl) -4,5-dihydro-1H-cyclopenpha [b] pyrrole - (6Z) -ylidene] -1,3-dihydro-indol-2-one; 4-methoxy-3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-carbonyl) -4,5-dihydro-1H-cyclopenta [b] pyrrole- (6Z) -liden] -1,3-dihydro-indol-2-one; 7-C! Gold-3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl) -4,5-dihydro-1H-cyclopenta [b] pyrrolidone - (6Z) -lden] -1, 3-d1h-dro-indol-2-one; 3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-carbonyl) -4,5-dihydro-1 H-cyclopenta [b] pyrrole- (6Z) ) -ylidene] -1,3-dihydro-pyrrolo [2,3-b] pyridin-2-one; and 6- (4-methoxy-phenyl) -3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-carbonyl) -4, 5-dihydro-1 H-cyclopenia [b] pyrrole- (6Z) -Iden] -1,3-dihydro-indol-2-one; or a prodrug or pharmaceutically acceptable salt thereof. 8.- A compound of Formula: R2, R3, R4, R5, R7 and R8 are each independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, trihaloalkyl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio , -SOR? 3, -SO2R? 3, -SO2NR13Ri4, R? SO2N (Ri3) -, N-ylhalomethanesulfonamido, -C (O) R-? 5, -C (O) OR-? 5, R15C (O) O-, cyano, nitro, halo, cyanate, isocyanate, isocyanate, thiocyanate , isothiocyanate, -OC (O) NR? 3R-? 4, R? 4OC (O) NR? 3-, -OC (S) NR13Ri4, R14OC (S) NR13-, -C (O) NR13R? 4, R14C (O) NR13- and -NR13R14; R2 and R3 or R3 and R4 or R4 and R5 or R7 and R8 together with the atoms to which they are attached may be associated to form a methylenedioxy group, a ylenedioxy group, an alicyclic ring or a heteroalicyclic ring; R13 and Ru are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, heteroalicyclic, -C (O) R? 5, acetyl, -SO2R15 and - (CH2) nNR? 3Ri4; or R-13 and R14 together with the atoms to which they are attached can form a five or six membered heteroalicyclic ring; wherein R15 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, and heteroalicyclic; R9, R10, R11 and R12 are each independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, trihaloalkyl, halo, cyano, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, -SO2R15, -S (O) R-i5, - (CH2) pC (O) ORi5, cyanate, isocyanate, iocyanate, isothiocyanate, -C (O) NR? 3Ri4, Ri4C (O) NR? 3- and -NR13R; and n is an integer from 0 to 20; or a prodrug or pharmaceutically acceptable salt thereof. 9. The compound of claim 8, wherein R2, R3, R4, R5, R7 and Rd are each independently selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, -SOR13, -S? 2R-? 3, -SO2NR-? 3Ri4, -C (O) OR15, halo and -C (O) NR13R14. 10. The compound of claim 8, which is: 2-methyl-6- [2-oxo-1,2-dihydro-indole- (3Z) -ylidene] -1,4,5-ethyl ester , 6-teirahydro-cyclopente [b] pyrrole-3-carboxylic acid; 6- [5- (2,6-Dichloro-phenylmethanesulfonyl) -2-oxo-1,2-d-hydroxy-indol- (3Z) -ylidene] -2-methyl-1,4,5 ethyl ester, 6-η-tetrahydro-cyclopenta [b] pyrrole-3-carboxylic acid; ethyl ester of 2-methyl-6- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indole- (3Z) -ylidene] -1,4,5,6-tetrahydro-cyclopenta [ b] pyrrole-3-carboxylic acid; 3- [2-methyl-4,5-dihydro-1H-cyclopenta [b] pyrrole (6Z) -ylidene] -2-oxo-2,3-dihydro-1 H-indole-5-sulfonic acid methylamide; 2-Methyl-6- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indol- (3Z) -iIiden] -1, 4,5,6-tetrahydro-cyclopenia [b] pyrrol- 3-carboxylic; 6- [5-methanesulfonyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -2-methyl-1,4,5,6-tetrahydro-cyclopenta [b] pyrrol- ethyl ester 3-carboxylic; 6- [5-Dimethylsulfamoyl-2-oxo-1,2-dihydro-indole (3Z) -ylidene] -2-methyl-1, 4,5,6-tetrahydro-cyclopenta [b] pyrrole-3-ethyl ester -carboxylic; ethyl ester of 6- [5-isopropylsulfamoyl-2-oxo-1,2-dihydro-indol- (3Z) -liden] -2-methyl-1, 4,5,6-tetrahydro-cyclopenia [b] pyrrole -3-carboxylic acid; ethyl ester of 6- [5-ethanesulfonyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -2-mephyl-1, 4,5,6-teirahydro-cyclopenpha [b] p R-3-carboxylic acid; 2-Methylo-6- [5-methylsulphamoyl-2-oxo-1,2-dithianediol) (2-hydroxy-3-pyrrolidin-1-yl-propyl) -amide 3Z) -iIiden] -1,4,5,6-tetrahydro-cyclopenpha [b] pyrrole-3-carboxylic acid; 2-Methyl-6- [5-methylsulphamoyl-2-oxo-1,2-dihydro-indol- (3Z) -ylidene] -3-cyclopropylamino-2-hydroxy-propyl) -amide 4,5,6-tetrahydro-cyclopenta [b] pyrrole-3-carboxylic acid; 2-Methyl-6- [5-methylsulfamoyI-2-oxo-1,2-dihydro-indole- (3Z) -ylidene] -2,5,5,6-methoxy-2-dimethylamino] -amide. -tetrahydro-cyclopenia [b] pyrrole-3-carboxylic acid; 3- [2-Methyl-3 - ((R) -2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl) -4,5-dihydro-1H-cyclopenta [b] pyrrole- (6Z) - methylamide - ylidene] -2-oxo-2,3-dihydro-1H-indol-5-sulfonic acid; ethyl ester of 2-methyl-6- [2-oxo-5-sulfamoyl-1,2-dihydro-indole- (3Z) -ylidene] -1, 4,5,6-tetrahydro-cyclopenta [b] pyrrole-3-carboxylic acid; 3- [3-methanesulfonyl-2-methyl-4,5-dihydro-1 H-cyclopenta [b] pyrro] - (6Z) -ylidene] -2-oxo-2,3-dihydro-1H-adolene methylamide -5-sulphonic; acid { 6-methoxy-3- [5-methylsulfamoyl-2-oxo-1,2-dihydro-indoI- (3Z) -liden] -indan-1-yl} -acetic; 5-fluoro-3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-carbonyl) -4,5-dihydro-1H-cyclopenta [b] pyrrole- (6Z) -ylidene] -1,3-dihydro-indol-2-one; 6-methoxy-3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmethyl-pyrrolidin-1-carbonyl) -4,5-dihydro-1 H-cyclopenia [b] pyrrole- (6Z) ) -ylidene] -1,3-dihydro-indol-2-one; 4-meioxy-3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmeryl-pyrrolidin-1 -carbonyl) -4,5-dihydro-1 H -cyclopenta [b] pyrrole- (6Z) ) -liden] -1,3-dihydro-indol-2-one; 7-Chloro-3- [2-methyl-3 - ((S) -2-pyrroidin-1-methyl-pyrrolidin-

1-carbonyl) -4,5-dihydro-1H-cyclopenpha [b] pyrrol- (6Z) -ylidene] -1,3-dihydro-indoI-

2-one;

3- [2-meyyl-3 - ((S) -2-pyrrolidin-1-ylmeryl-pyrrolein-1-carbonyl) -4,5-dihydro-1 H-cyclopenpha [b] pyrrole- (6Z) - ylidene] -1,3-dihydro-pyrrolo [2,3-b] pyridin-2-one; and 6- (

4-methoxy-phenyl) -3- [2-methyl-3 - ((S) -2-pyrrolidin-1-ylmeryl-pyrrolidin-1-carbonyl) -4,

5-dihydro-1H-cyclopenta [ b] pyrrole- (6Z) -ylden] -1,3-dihydro-indol-2-one; or a prodrug or pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition, comprising a compound, prodrug or pharmaceutically acceptable salt of any one of claims 1, 7, 8, or 10 and a pharmaceutically acceptable carrier or excipient. 12. A method for the modulation of the cayalytic activity of a protein kinase comprising contacting said protein kinase with a compound, prodrug or pharmaceutically acceptable salt of any one of claims 1, 7, 8, or 10. 13. The method of claim 12, wherein said protein kinase is selected from the group consisting of a tyrosine kinase receptor, a non-receptor tyrosine kinase and a serine-threonine kinase. 14. A method for treating or preventing a disorder related to protein kinases in an organism, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound, prodrug or pharmaceutically acceptable salt of any one of claims 1, 7, 8, or 10 and a pharmaceutically acceptable carrier or excipient to said organism. 15. The method of claim 14, wherein said protein kinase-related disorder is selected from the group consisting of a receptor tyrosine kinase-related disorder, a disorder related to non-receptor tyrosine kinases and a serine-threonine related disorder. kinases 16. The method of claim 14, wherein said protein kinase related disorder is selected from the group consisting of a PDGFR-related disorder and a flk-related disorder. 17. The method of claim 14, wherein said protein kinase related disorder is a cancer selected from the group consisting of squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung cancer, bladder cancer, head cancer. and neck, melanoma, ovarian cancer, prostate cancer, breast cancer, small cell lung cancer, glioma, colorectal cancer, genitourinary cancer and gastrointestinal cancer. 18. The method of claim 14, wherein said protein kinase related disorder is selected from the group consisting of diabetes, an autoimmune disorder, a hyperproliferation disorder, restenosis, fibrosis, psoriasis, von Heppel-Lindau disease, arthrosis, rheumatoid arthritis, angiogenesis, an inflammatory disorder, an immunological disorder and a cardiovascular disorder. 19. The method of claim 14, wherein said organism is a human being.