MXPA01005934A - 4-alkenyl (and alkynyl) oxindoles as inhibitors of cyclin-dependent kinases, in particular cdk2 - Google Patents

Abstract

Novel 4-alkenyl- and 4-alkynyl oxindoles having formulas (I) and (II) and the pharmaceutically acceptable salts thereof, wherein R1, R2, R3, a, b, and X are as defined herein inhibit cyclin-dependent kinases (CDKs), in particular CDK2 and are useful as anti-proliferative agents in the treatment or control of cell proliferative disorders, in particular breast and colon tumors.

Description

NEW -ALQUENIL (AND ALQUINIL) OXINDOLES COMO INHIBITORS OF CYCLIN DEPENDENT KINASES (CDKs), IN PARTICULAR CDK2 Description of the Invention Uncontrolled cell proliferation is the main characteristic of cancer. Cancer tumor cells usually suffer from certain forms of lesions in genes that directly or indirectly regulate the prolific cell cycle. Cyclin dependent kinases (CDKs) are critical enzymes for cell cycle control. See, for example Coleman et al., "Chemical Inhibitors of Cyclin-dependent Kinases," Annual Reports in Medicinal Chemistry, vol. 32, 1997, pp. 171-179. These enzymes regulate the transitions between the different phases of the cell cycle, such as the progression of the Gi phase to the S phase (the period of active DNA synthesis), or the progression from the G2 phase to the M phase, in which active mitosis and cell division occur. See, for example, the articles on this subject that appeared in Science, vol. 274, December 6, 1996, pp. 1643-1677. The • CDKs are composed of a catalytic subunit CDK and a cyclin regulatory subunit. The cyclin subunit is the key regulator of CDK activity, REF: 129895 so that each CDK interacts with a specific subset of cycles: for example Cyclin A (CDK1, CDK2). The different kinase / cyclin pairs regulate the progression toward specific stages of the cell cycle. See: for example Coleman, upra. Aberrations in cell cycle control have been linked to the uncontrolled growth of cancer cells. See, for example, Kamb, "Cell-Cycle Regulators and Cancer," Trends in Genetics, vol. 11, 1995, pp. 136-140; and Coleman, supra. In addition, changes in the expression of, or in the genes coding for, the CDKs or their regulators have been observed in some tumors. See, for example Webster, "The therapeutic Potential of Targeting the Cell Cycle," Exp. Opin. Invest. Drugs, Vol. 7, pp. 865-887 (1998), and references cited therein. Thus, there is a widespread opinion in the literature that validates the use of inhibitory compounds of CDKs as cellular antiproliferative agents. See, for example, U.S. Patent No. 5,621,082 to Xiong et al., EP O 666 270 A2; WC 97/16447; and the references cited in Coleman, s upra, in particular reference no. 10, Thus, it is desirable to identify chemical inhibitors of CDK kinase activity. It is particularly desirable to identify small molecular compounds that can be easily synthesized and are effective in inhibiting one or more CDKs or CDK / cyclin complexes to treat one or more types of skin. Compounds of the indolinone type (also known as oxindole) postulated as useful in the regulation of cell proliferation through the inhibition of tyrosine kinase are disclosed in WO 96/40116, WO 98/07695, WO 95/01349, WO 96/32380, WO 96/22976, WO 96/16964 (tyrosine kinase inhibitors), and WO 98/50356 (2-indolinone derivatives as modulators of protein kinase activity). The oxindol derivatives have also been described for other therapeutic uses: 5,206,261 (improvement of brain function); WO 92/07830 (peptide antagonists); EP 580 502 Al (antioxidants). There continues to be a need for small easily synthesizable molecular compounds for the treatment of one or more types of tumors, in particular through the regulation of CDKs. It is thus an object of this invention to provide such compounds and compositions containing said compounds. The present invention is directed to novel 4, 5-azolo-oxindoles which inhibit cyclin-dependent kinases (CDKs) in particular CDK2. These compounds and their pharmaceutically acceptable salts, and the prodrugs of said compounds, are useful antiproliferative agents in the treatment or control of cellular proliferative disorders, in particular, of cancer. The invention is also directed to pharmaceutical compositions containing such compounds, and to the use of these compounds in the preparation of medicaments for the treatment and / or prevention of cancer, particularly for the treatment or control of solid tumors. The compounds of the invention are especially useful in the treatment or control of colon and breast tumors. The present invention is also directed to novel compounds useful in the synthesis of the compounds described above. The compounds of the present invention are 4-alkenyl and 4-alkynyl oxindoles having the following formula: and - pharmaceutically active metabolites and prodrugs of the compounds of the formula I; and pharmaceutically acceptable salts of the above compounds; where R1 is hydrogen, -COR4, -COOR4, -CONR6R7, lower alkyl (optionally substituted with one or more of -OR5, -NR6R7, cycloalkyl, heterocycle, -COR4, -COOR4, -CONR6R7, -CN, -N02, - S02R4, halogen, and -S02NR6R7), cycloalkyl (optionally substituted with one or more of -OR5, -NR6R7, lower alkyl, heterocycle, -COR4, -COOR4, -CONR6R7, -CN, -N02, -S02R4, halogen, and -S02NR6R7), heterocycle (optionally substituted with one or more of -OR5, -NR6R7, lower alkyl, cycloalkyl, -COR4, -COOR4, -CONR6R7, -CN, -N02, -S02R4, halogen, and -S02N R6R7); R2 is hydrogen, -OR4, -COOR4, -CONR6R7, -NR6R7, halogen, -N02, -CN, -S02R4, -S02NR6R7, perfluoroalkyl, lower alkyl or lower alkyl substituted by -OR8 and / or -NR6R7; R3 is hydrogen, -OR4, -COR4, -COOR4, -CONR6R7, halogen, -CN, -NR6R7, perfluoroalkyl, lower alkyl or lower alkyl substituted by -OR8 and / or -NR6R7; R4 is hydrogen, lower alkyl (optionally substituted with one or more of -OR5, -COOR3, -COR8, -CONR8R9, -NR6R7, cycloalkyl, heterocycle, -CN, -N02, -S02R8, and -S02NR8R9), cycloalkyl (optionally substituted with one or more of -OR5, -COOR8, -COR8, -CONR8R9, -NR6R7, lower alkyl, heterocycle, -CN, -N02, -S02R8, and -S02NR8R9), or heterocycle (optionally substituted with one or more of -OR5, -COCR3, -COR8, -CONR8R9, -NR6R7, lower alkyl, cycloalkyl, -CN, -N02, -S02R6, and -S02NR8R9); R5 is hydrogen, -OCR8, -CONR8R9, lower alkyl or lower alkyl substituted with one or more of -OR9, -NR9R10, -N (OCR9) R10, -COR9, -CONR9R10, and -COOR9; R6 and R7 are each independently hydrogen, -COR8, -COOR8, -CONR8Rs, S02R3, -S02NR8R9, lower alkyl (optionally substituted with one or more of -OR5, -NR8R9, -COOR8, -COR8, -CONR8R9, - CN, -N02, -S02R8, -S02NR8R9), cycloalkyl (optionally substituted with one or more of -OR5, -COOR8, -COR8, -CONR8R9, -NR8R9, lower alkyl, heterocycle, -CN, -N02, -S02R8, and -S02NR8R9), heterocycle (optionally substituted with one or more of -OR5, -COOR8, -COR8, -CONR8R9, -NR8R9, lower alkyl, cycloalkyl, -CN, -N02, -S02R8, and -S02NR8R9), aryl ( optionally substituted with one or more of -OR5, -COOR8, -COR8, -CONR8R9, -NR8R9, lower alkyl, heterocycle, -CN, -N02, -S02R8, and -S02NR8R9), or heteroaryl (may be optionally substituted with one or more than -OR5, -COOR8, -COR8, -CONR8R9, -NR8R9, lower alkyl, heterocycle, -CN, -N02, -S02R8, and -S02NR8R9:; or R6 and R7 are each independently cycloalkyl (optionally substituted by one or more of -OR5, -COOR8, -COR8, -C ONR8R9, -NR8R9i lower alkyl, heterocycle, -CN, -N02, -S02R8, and -S02NR8R9), heterocycle (optionally substituted by one or more of -OR5, -COOR8, -COR8, -CONR8R9, -NR5R9, lower alkyl , cycloalkyl, -CN, -N02, -S02R8, and -S02NR5R9), aryl (optionally substituted by one or more of -OR5, -COOR8, -COR8, -CONR8R9, -NR8R9, lower alkyl, cycloalkyl, heterocycle, -CN, -N02, -S02R8, and -S02NR8R9), or heteroaryl (may be optionally substituted with one or more of -OR5, -COOR8, -COR8 , -CONR8R9, -NR8R9, lower alkyl, cycloalkyl, heterocycle, -CN, -N02, -302R8, and -S02NR8R9); or alternatively, -NR5R7 forms a ring of 3 to 7 atoms, optionally including said ring one or more additional heteroatoms, and being optionally substituted with one or more of lower alkyl -OR5, -COR8, COOR8, CONR8R9, and -NR5R9; R8 is hydrogen, lower alkyl (optionally substituted with one or more of cycloalkyl, heterocycle, aryl, heteroaryl, -OR9, -NR9R10, and -N (COR9) R10), aryl [optionally substituted with one more than -OR ' -COORX -CORs, -CONRluRs, -NR1UR, lower alkyl, cycloalkyl, heterocycle, -CN, -N02, -S02R9, and -SO2NR10R9), heteroaryl (optionally substituted with one or more of -OR9; -COOR9, -COR9, -CONR10R9, -NR10R9, lower alkyl, cycloalkyl heterocycle, -CN, -N02, -S02R9, and -SO2NR10R9), cycloalkyl (optionally substituted with one or more of -OR9, -COOR9, -COR9, -CONR10R9, -NR10R9, lower alkyl, heterocycle, -CN, -N02, -S02R9, and -SO2NR10R9), or heterocycle (optionally substituted with one or more of -OR9, -COOR9, -COR9, - CONR1 0R9, -NR1 0R9, lower alky, cycloalkyl, - CN, -N02, - S02R9, and - SO2NR1 0R9); R9 and R10 are independently hydrogen or lower alkyl; X is, = N-, = C (R5) -, or = C (COOR8) -; and a is an optional link. The present invention also relates to compounds of formula: wherein R2, R3 and X have the same meanings as mentioned above for formula I, and wherein: b is cycloalkyl (optionally substituted by one or more of -OR5, -NR6R7, lower alkyl, heterocycle, -OCR4 , -COOR4, -CONR6R7, -CN, -N02, -S02R4, halogen, and -S02NR6R7, and b is heterocycle (optionally substituted by one or more of -OR5, -NR6R7, lower alkyl, cycloalkyl, -COR4, -COOR4, -CONR6R7, -CN, -N02, -S02R4, halogen, and -S02NR6R7 The present invention further relates to pharmaceutical compositions comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier or excipient. invention also relates to a method for the treatment of solid tumors, in particular colon or breast tumors, by administering to a human patient in need of said therapy an effective amount of a compound of formula I or II, its salts and / or prodrugs. As used herein, the following terms have the following definitions: "Aryl" means an aromatic group having from 5 to 10 atoms and consisting of 1 or 2 rings. Examples of ar.Llo groups include phenyl and 1- and 2-naphthyl. "Cycloalkyl" means a non-aromatic aliphatic hydrocarbon group containing from 3 to 8 atoms, partially or completely saturated. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexy.Lo. "Effective amount" means an amount of at least one compound of formula I, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, that significantly inhibits proliferation and / or prevents differentiation of a human tamoral cell, including tumor cell lines human "Halogen" means fluorine, chlorine, bromine or iodine. "Heteroaryls" are aromatic groups having 5 to 10 atoms, one or 2 rings, and containing one or more heteroatoms. Examples of heteroaryl groups are 2-3- or 4-pyridyl, tetrazolyl, oxadiazolyl, pyrazinyl, quinolyl, pyrrolyl, and imidazolyl. "Heteroatomo" means an atom chosen from N, O and S. "Heterocycle" means a non-aromatic hydrocarbon group with 3 to 10 members, partially or completely saturated, such as tetrahydroquinolyl, and which contains one or two rings and at least one heteroatom. "IC50" refers to the concentration of a particular 4,5-azolo-oxindole required to inhibit 50% of a measured specific activity. IC50 can be measured, among others, as described in Example 47, see below. "Lower alkyl" denotes a straight or branched chain of an aliphatic hydrocarbon. having 1 to 6, preferably 1 to 4, carbon atoms. Typical lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl, and the like. "Pharmaceutically acceptable salt" refers to covenantal salts of acidic or basic addition which retain the biological effectiveness and properties of the compounds of formula 1 and are formed from. suitable non-toxic organic or inorganic acids or organic or inorganic bases. Samples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid and those derived from organic acids such as p-toluenosu lonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Samples of basic addition salts include those derived from potassium, sodium, ammonium and quaternary ammonium hydroxide, such as for example tetramethylammonium hydroxide. "Pharmaceutically acceptable," such as pharmaceutically acceptable carrier, excipient, prodrug, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered. "Pharmaceutically active methacyolite" means a compound of formula I which is pharmaceutically acceptable: and effective. "Prodrug" refers to a compound that can be converted under physiological conditions or by solvolysis to any of the compounds of formula I or a pharmaceutically acceptable salt of a compound of formula I. A prodrug can be inactive when administered to a subject but is converted into an active compound of formula I. "Substituted," as in substituted alkyls means that the substitution may occur at one or more positions and, if not otherwise indicated, that the substituents are independently chosen from the options specified. In a preferred embodiment of the compounds of formula I, R1 is -COR4, lower alkyl (optionally substituted with one or more of -OR4, -NR6R7, -COR4, -COOR4, -CONR6R7, -N02, cycloalkyl, and heterocycle), cycloalkyl (optionally substituted with one or more of -OR4, -NR6R7, -COR4, -COOR4, -CONR6R7, -N02, lower alkyl, heterocycle), or heterocycle (optionally substituted with one or more of -OR4, -NR6R7, - COR4, -COOR4, -CONR6R7, -N02 lower alkyl, and cycloalkyl). Particularly preferred R1 groups are lower alkyl substituted with one or more of hydroxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkyl-amino, lower dialkylamino, phenylalkyl lower amino, lower alkoxycarbonylamino, lower hydroxyalkyl -amino, lower alkanoylamino, carbamoyloxy, lower alkyl-carbamoyloxy, ureido, morpholinyl, piperidinyl, hydroxypyrrolidinyl, lower alkyl-sulfonylamino, and lower alkyl-phenylsulfonylamino. Other especially preferred R1 groups are hydroxycycloalkyl, hydroxy-tetrahydropyranyl, pyrrolidinyl, hydroxypyrrolidinyl, or hydroxypiperidinyl. In a preferred embodiment of the compounds of formula I, R2 is hydrogen, -OR4, -N02, -NR6R7, halogen, perfluoroalkyl, lower alkyl or lower alkyl substituted by -OR8 and / or NR6R7; In another preferred embodiment of the compounds of formula I, R3 is hydrogen, -OR4, -NR6R7, lower alkyl or lower alkyl substituted by -OR8 and / or -NR6R7; In another preferred embodiment of the compounds of formula I, R 4 is hydrogen, lower alkyl or lower alkyl substituted by -NR 6 R 7, -OR 5, -COOR 8, -COR 8 and / or -CONR 8 R 9; In another preferred embodiment of the compounds of formula I, R5 is hydrogen, -COR8, -CONR8R9, or lower alkyl. In the preferred embodiment of the compounds of the formula ", R6 and R7 are each independently hydrogen, -COR8, -COOR8, -CONR8R9, -S02R8, lower alkyl or lower alkyl substituted by -OR5 and / or -NR8R9; alternatively, -NR6R7 forms a ring of 3 to 7 atoms, said ring optionally including one or more additional heteroatoms, and optionally being substituted by the groups consisting of one or more of -OR5 and -NR5R9. of formula I, R8 is hydrogen, lower alkyl or lower alkyl substituted by aryl, heteroaryl, -OR9, -NR9R10, and / or -N (COR9) R10, In another preferred embodiment of the compounds of formula I, X is = CR5 - o = N-, and "a" is a bond The following are examples of preferred compounds of formula I: (Z) -1,3-dihydro-4- (6-idroxy-1-hexinyl) -3- [ (3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (A), (Z) -I, 3-dihydro-4- (5-hydroxy-1-pentynyl) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (B), (Z) -1,3-dihydro-4- (4-hydroxy-1-butyl) -3- [(3-methoxy-1H-pyrrole-2 -yl) ethylene] -2H-indol-2-one (C), rae- (Z) -1, 3-dihydro-4- (3-hydroxy-3-methyl-1-pentynyl) -3- [(3 -methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (D), (Z) -1, 3-dihydro-4- (3-hydroxy-3-methyl-1-butynyl) -3- (3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (L), (Z) -1, 3-dihi ro- 4- [(l-hydroxycyclohexyl) ethynyl ) -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (M), rac- (Z) -l, 3-dihydro- (3-hydroxy) 3-methyl-1-hexinyl) - [(3-methoxy-1H-pyrrole-2-yl) methylene] -2H-indol-2-one (N), rae- (Z) -1, 3-dihydro- 4- (3, 5-dimethyl-3-hydroxy-1-hexinyl) -3 - [(3-methoxy-1 H -pyrrol-2-yl) methylene] -2H-indol-2-one (O), (R ) - (Z) -1,3-dihydro-4- (3-hydroxy-1-octinyl) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (P), rae- (Z) -1, 3-dihydro- (3-hydroxy-l-octinyl) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole- 2-one (Q), rae- (Z ) -l, 3-dihydro-4- (3-hydroxy-1-pentynyl) -3 - [(3-methoxy-1-pyrrol-2-yl) methylene] -2H-indol-2-one (R ), (Z) -1,3-Dihydro-4- [3- (2-hydroxyethoxy) -1-propynyl] -3- [(3-met oxy-lH-pyrrol-2-yl) methylene] -2H- indole-2-one (S), (S) - (Z) -1, 3-dihydro-4- (3-hydroxy-1-octinyl) -3- [(3-methoxy-lH-pyrrol-2-yl methylene] -2H-indol-2-one (U), (Z) -l, 3-dihydro-4- (3-hydroxy-1-propynyl) -3- [(3-methoxy-lH-pyrrole-2) -yl) methylene-2H-indol-2-one (Y), and (Z) -1,3-dihydro-4- [(1-hydroxycyclopentyl) ethynyl] -3- [(3-methoxy-lH-pyrrol- 2-yl) methylene] -2H-indol-2-one (AA). The following are examples of further preferred compounds of formula I: (Z) -6- [2,3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo- lH-indol-4-yl] -5-hexynoic methyl ester (E), (Z) -5- [2, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] '] -2-oxo-lH-indol-4-yl] -4-pentynoic methyl ester (F), (Z) -6- [2, 3-Dihydro-3- [(3-methoxy-lH-pyrrole -2-yl) -methylene] -2-oxo-lH-indol-4-yl] -5-hexynoic acid (G), acid (Z) -5- [2, 3-Dihydro-3- [(3 -methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo-lH-indol-4-yl] -4-pentynoic acid (H), acid (Z) -5- [2, 3-dihydride -3- [(3-methoxy-lH-pyrrol-2-yl) -methyl ene] -2-oxo-lH-indol-4-yl] -4-pentynoic sodium salt (I), (Z) -5- [2,3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo-lH-indol-4-yl] -4 -pentinamide (J), (Z ) -6- [2, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo-lH-indol-4-yl] -5-hexinamide (K) , (Z) - [3- [2, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] - acid 2-oxo-lH-indol-4-yl] -2-propynyl] propa-nodioic dimethyl ester (V), and (Z) - [3- [2, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo-lH-indol-4-yl] - acid 2-propynyl] propane-dioic (). The following are examples of further preferred compounds of formula I: (Z) -1,3-Dihydro- (3-hydroxy-1-propynyl) -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene ] -5-nitro-2H-indol-2-one (Z), (Z) -5-Amino-l, 3-dihydro-4- (3-hydroxy-l-propinyl) -3- [(3- methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2 -one (BB), (Z) -N- [2, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo-4- (3-hydroxy-l-propynyl) -lH -indol-5-yl] -2-thiopheneacetamide (CC), and (Z) -N- [2, 3-Dihydro- - (3-hydroxy-1-propynyl) -3- [(3-methoxy-1H- pyrrol-2-yl) methylene] -2-oxo-lH-indol-5-yl] -4-pyridinecarboxamide (DD). The following are examples of further preferred compounds of formula I: (Z) -5- [2,3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) ethylene] -5-nitro-2 acid -oxo-lH-indol-4-yl] -4-pentynoic methyl ester (EE), (Z) -5- [5-Amino-2, 3-dihydro-3- [(3-methoxy-lH-pyrrole -2-i 1) methylene] -2-oxo-lH-indol-4-yl] -4-pentynoic methyl ester (FF), (Z) -5- [2, 3-Dihydro-3- [(3 -methoxy-lH-pyrrol-2-yl) methyle or] -2-oxo-5- [(2-thienylacetyl) amino] -IH-indol-4-yl] -4-pentionic methyl ester (GG), and (Z) -5- [2, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-5- [(2-thienylacetyl) amino] -lH- acid indol-4-yl] -4-pent inoic (HH). The following are examples of further preferred compounds of formula I: (Z) -4- (3-Amino-1-propynyl) -1,3-dihydro-3- (3-methoxy-1H-pyrrol-2-yl) methylene ] -2H-Indole-2-one salt trifluoroacetate (II), (Z) -1,3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- [3- ( N-methylamino) -1-propynyl] -2H- indo1-2-one trifluoroacetate salt (JJ), (Z) -1, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene ] -4- [3- (N-Phenylimmethylamino) -1-propynyl] -2H-indole-2-oaa (KK), acid (Z) - [3- [2, 3-Dihydro-3- [( 3-methoxy-lH-pyrrol-2-yl) methylene no] -2-oxo- lH-indol-4-yl] -2-propynyl] carbamic methyl ester (LL), (Z) -carbamic acid 3- [2 , 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -2-propynyl ester (MM), and acid (Z) -N-methylcarbamic 3- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -2-propynyl ester ( NN). The following are examples of further preferred compounds of formula I: rac- (Z) -l, 3-Dihydro-5-fluoro-4- (3-hydroxy-1-pentynyl) -3- [(4-methyl-) imidazole -5- i 1) methylene] -2H-indol-2-one (00), rac- (Z) -l, 3-Dihydro-4- (3-hydroxy-l-pentynyl) -3- [(4 -methyl-lH-imidazol-5-yl) methylene] -5-nitro-2H-indol-2-one (PP), (Z) - :. , 3-Dihydro-5-fluoro-4- (3-hydroxy-l-propynyl) -3- [(4-meth;, l-lH-imidazol-5-yl) methylene] -2H-indol-2-one , trifluoroacetate salt (QQ), (Z) -1, 3-Dihydro-5-fluoro-4- [3- (N-methylamino) -1-propynyl] -3- [(4-methyl-1H-imidazole-5 -yl) methylene] -2H-indole-2-one (RR), rae- (Z) -1, 3-Dihydro-5-fluoro-4- (-hydroxy-l-pentynyl) -3- [(4- methyl-lH-imidazol-5-yl) ethylene] -2H-indol-2-one, trifluoroacetate salt (TT), (Z) -1, 3-Dihydro-4- [3- (N, N-dimethylamino) - 1-propynyl] -5-fluoro-3- [(4-methyl-lH-imidazol-5-yl) methylene] -2H-indol-2-one (UU), (Z) -4- [3-amino- 3-methyl-1-butynyl] -1,3-dihydro-5-fluoro-3- [(-methyl-1H-imidazo1-5-yl) ethylene] -2H-indol-2-one (VV), acid ( Z) -carbamic 3- [2, 3-dihydro-3- [(4-methyl-lH-imidazol-5-yl) methylene] -5-fluoro-2-oxo-lH-indol-4-yl] -2 -propynyl ester (WW), (Z) -1, 3-Dihydro-5-fluoro-3- (4-methyl-lH-imidazol-5-yl) meti le no] -4- [3- (4-morpholinyl ) -1-propynyl) -2H-indol-2-one (XX), (Z) - [3- [2, 3-dihydro-5-fluo] acid ro-3- [(4-methyl-1H-imidazol-5-yl) methylene] -2-oxo-lH-indol-4-yl] -2-propynyl] -carbamic methyl ester (YY), (Z) - [3- [5-fluoro-2, 3-dihydro-3- [(4-met yl-lH-imidazol-5-yl) methylene] -2-oxo-lH-indol-4-yl] -2-propynyl ] area (ZZ), rae- (Z) -2- (acetylamino) -5- [5-fluoro-2,3, dihydro-3 - [(4-meth i -IH-imidazol-5-yl) acid) methylene] -2-oxo-lH-indol-4-yl] -4-pentynoic ethyl ester (AAA), (Z) -4- [3- (N, N-Di-ethylamino) -1-propinyl] -1 , 3-dihydro-5-fluoro-3- [(4-methyl-lH-yl-idazol-5-yl) methylene] -2H-indol-2-one (BBB), (Z) -4- [3- Amino-3-eti1-1-pentynyl] -1,3-dihydro-5-fluoro-3 - [(4-methy1-1H-imidazol-5-yl) methylene] -2H-indol-2-one (CCC ), acid (Z) - [3- [2, 3-dihydro-5-fluoro-3- [(4-methyl-lH-imidazol-5-yl) methylene] -2-oxo-lH-indole-4 -yl] -1, 1-dimethyl-2-propynyl] carbamic methyl ester (DDD), N- [3- [2, 3-Dihydro-5-fluoro-3- (5-methyl-3H-imidazole-4- il-met :. log) -2-oxo-lH-indol-4-yl] -prop-2-ynyl] -acetamide (EEE), and (Z) -1, 3-Dihydro-5-fluoro-3- [(4-met IL-1H-imidazo1-5-yl) methylene] -4- [3- (1-piperidinyl) -1-propynyl-2H-indol-2-one (FFF). The following are examples of additional preferred compounds according to the invention: 3- [2, 3-dihydro- (Z) -3- [(1H-pyrrol-2-yl) methyl) acid; no] -2-oxo-lH-indol-4-yl] - (E) -2-propenoic methyl ester (GGG), 3- [2, 3-dihydro- (Z) -3- [(3- methoxy-lH-pyrrol-2-5 yl) methylene: no] -2-oxo-lH-indol-4-yl] - (E) -2-propenoic methyl ester (HHH), 1,3-Dihydro-4- (3-hydroxy-propenyl) -3- [(3-methoxy-lH-pyrrol-2-yl) met-helene] -indol-2-one (III), 1,3-Dihydro-4- (-hydroxy-but - 1 -enyl) -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -indol-2-one (JJJ), (R) - (Z) -1, 3-Dihydro-5- fluoro- 4- (4-hydroxy-1 -pentinyl) -3- [(4-methyl-1H-imidazol-5-yl) methylene] -2H-indol-2-one (KKK), (S) - (Z ) -1,3-Dihydro-5-fluoro-4- (4-hydroxy-1-pentynyl) -3 - [(4-methyl-1H-imidazol-5-yl) methylene] -2H-indol-2-one (LLL), rae- (Z) -1, 3-Dihydro-5-fluoro-4- (3-hydroxy-l-pentynyl) -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-Indole-2-one (MMM), rae- (Z) -1, 3-Dihydro-5-fluoro-4- (3-hydroxy-l-pentynyl) -3- [(lH-pyrrole-2- il) ethylene] -2H-indol-2-one (NNN), (Z) -1, 3-Dihydro-5-fluoro-4- [3- (N-methylamino) -1-propynyl] -3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (OOO), (Z) -1, 3-Dihydro-5-fluoro-4- [3- (N-methylamino) -1 -propynyl] -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (PPP), hydrochloride salt of (Z) -1, 3-Dihydro-5-fluoro -4- [3- (N-methylamine) -1-propinyl] -3- [< 3-methoxy-lH-pyrrol-2-yl) ethylene] -2H-indol-2-one (QQQ), (R) - (Z) -1, 3-Dihydro-5-fluoro-4- (3-hydroxy -l-butynyl) -3- [(4-methyl-1H-imidazol-5-yl) methyl] -2H-indole-2-or? a (RRR), (R) -IZ) -1, 3 -Dihydro-5-fluoro-4- (4-hydroxy-1 -pentinyl) -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (SSS), acid (Z) -5- [2, 3-Dihydro-5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -4 -pentinoic methyl ester (TTT), (Z) -1, 3-Dihydro-5-fluoro-4- [(1-hydroxy-cyclopentyl) ethynyl] -3- [(3-methoxy-lH-pyrrol-2-yl) ) methylene] -2H-indol-2 -one (UU), (S) - (Z) -1, 3-Dihydro-5-fluoro- - (4-hydroxy-1-pentynyl) -3- [(3 -methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-or.a (VVV), (R) - (Z) -1, 3-Dihydro-5-fluoro- (3-hydroxy) -l-butinyl) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (WWW), (S) - (Z) -1, 3-Dihydro- 5- fluoro-4- (3-hydroxy-1-butynyl) -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (XXX), (S) - (Z) - 1,3-Dihydro-5-fluoro-4- (3-hydroxy-1-butynyl) -3 - [(4-methyl-lH-imidazol-5-yl) methylene] -2H-indol-2-one (YYY ), (Z) -1, 3-Dihydro-5-fluoro-4- [(4-hydroxy-tetrahydro-pyran-4-yl) ethynyl] -3- [(3-methoxy-lH-pyrrole-2-i) 1) methylene] -2H-indol-2-one (ZZZ), (Z) -1, 3-Dihydro-4- [(4-hydroxy-tetrahydro-pyran-4-yl) -etinyl] -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -5-nitro-2H-indol-2-one (AAAA), (S) - (Z) -1, 3-Dihydro-5- fluoro- 3- [(3-methoxy-1H-pyrrol-2-yl) methylene] -4- [(pyrrolidin-2-yl) ethynyl] -2H-indole-2-one (BBBB), hydrochloride salt of (S) - (Z) -1,3-Dihydro-5-fluoro-3- [(3-methox: L-lH-pyrrol-2-yl) methylene] -4 [(pyrrolidin-2-yl) ethynyl; indole-2-one (CCCC), (R) - (Z) -1, 3-Dihydro-5-fluoro-3- [(3-methoxy-1H-pyrrole-2 -: 1) methylene] -4 [ (pyrrolidin-2-yl) ethynyl] -2H-indol-2-one (DDDD), (Z) -3 - [(4-Acetyl-lH-pyrrol-2-yl) methylene) -1,3-dihydro- 5-fluoro-4- [(4-hydroxy-tetrahydro-pyran-4-yl) ethynyl] -2H-indol-2-one (EEEE), (R) - (Z) -4- ( 3-Amino-4-hydroxy-1-butyl) -1,3-dihydro-5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) ethylene] -2H-indole-2- ona (FFFF), (R) - (Z) -1, 3-Dihydro-5-fluoro-4- [3- (3-hydroxy-pyridin-lidin-1-yl) -1-propynyl] -3 [( 3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (GGGG), (S) -i Z) -4- (3-Amino-4-hydroxy-1-butyl) -1,3-dihydro-5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (HHHH), (Z) -2 < - [(4-Acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4- [3- (N-methylamino) -1-propynyl] -2H-indole-2- ona (IIII), hydrochloride salt of (Z) -3 - [(4-acetyl-lH-pyrrol-2-yl) methylene] o] -1,3-dihydro-5-fluoro-4- [3- (N -methylamino) -1-propynyl] -2H-indol-2-one (JJJJ), (S) - (Z) -1, 3-Dihydro-5-fluoro-4- [3- (3-hydroxy-pyrrolidi? -l-yl) -l-propynyl] -3 [(3-methoxy-lH-pyrrol-2-ylmethyl or] -2H-indol-2-one (KKKK), rac- (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4- [(3-hydroxy-pyrrolidin-3-yl) ethynyl] -2H-indol-2-one (LLLL), rae- (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4 - [(3-hydroxy-pyrrolidin-3-yl) ethynyl] -2H-indole-2-one hydrochloride salt of (MMMM), (Z) -1, 3-Dihydro-5-fluoro-4- [(2S, R) - (4-hydroxy-pyrrolidi-2-yl) -etinyl] -3 [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (NNNN), hydrochloride salt of (Z) -1, 3-Dihydro-5-fluoro-4- [(2S, 4R) - (4-hydroxy-pyrrolidin-2-yl) -etinyl] -3 [(3-methoxy-lH-pyrrole-2 -yl) methylene] -2H-indol-2-one (OOOO), hydrochloride salt of (Z) -1,3-dihydro-5-fluoro-4- [(-hydroxy-pLperidin-4-yl) -etinyl ] -3- [(3-methoxy-lH-pyrrol-2-yl) methyne] -2H-indo1-2-one (PPPP), (Z) -4- [(3R, R) -3- Amino- -hydroxy-1 -pentinyl] -1,3-dihydro-5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) ethylene] -2H-indol-2-one (QQQQ), (Z) -1,3-Dihydro-5-fluoro-4- [(2S, 4S) - (-hydroxy-pyrrolidin-2-yl) -etinyl] 3- [ (3-methoxy-lH-pyrro1-2-yl) methylene] -2H-indo1-2-one (RRRR), (R) - (Z) -1, 3-Dihydro-5-fluoro-4- [4- hydroxy-3-methylamino-1-butynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (SSSS), (Z) -4 - [(3S , 4S, 5R) -4-Amino-3,5-dihydroxy-1-hexinyl] -1,3-dihydro-5-fluoro-3 [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H -indol-2-one (TTTT), (Z) -4- [(3R, 45, 5R) -4 -Amino-3,5-dihydroxy-1 -hexinyl] -1, 3-dihic.ro-5- fluoro- 3 [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (UUUU), rae- (Z) -1, 3-Dihydro-5-fluoro- 4- [(3-Hydryloxy-pyrrolidin-3-yl) ethynyl] -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indole-2-one (VVVV), hydrochloride salt of ( Z) -1,3-Dihydro-4- (3-e-tilamino-1-propynyl) -5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2 -one (WWWW), (S) - (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) methylene) -1,3-dihydro-5-fluoro-4 [(pyrrolidin-2- il) ethynyl] -2H-indole-2-one (XXXX), hydrochloride salt of (S) - (Z) -3- [(4-Acetyl-lH-pyrrole-2- il) methylene] -l, 3-dihydro-5-fluoro-4 [(pyrrolidin-2-yl) -etinyl] -2H-indol-2-one (YYYY), (Z) -3- [(4-Acetyl -lH-Pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4- [(2S, 4R) - (-hydroxy-pyrrolidin-2-yl) ethynyl -2H-indole-2- ona (ZZZZ), hydrochloride salt of (Z) -3- [(4-Acetyl-lH-pyrrol-2-illmethylene) -1,3-dihydro-5-fluoro-4- [(2S, 4R) (4- hydroxy-pyrrolidin-2-yl) ethynyl] -2H-indol-2-one (.AAAAA), hydrochloride salt of (Z) -3 - [(4-Acetyl-lH-pyrrol-2-yl) methylene] -1 , 3-dihydro-4- [(3-ethylamino) -i-propynyl) -5-fluoro-2H-indol-2-one (BBBBB), hydrochloride salt of (Z) -3- [(4-Acetyl) lH-pyrrol-2-yl) ethylene] -1,3-dihydro-5-fluoro-4- [(4-hydroxy-piperidin-4-yl) ethynyl] -2H-indo1-2 -one (CCCCC), ( S) -! Z) -1,3-Dihydro-5-fluoro-4- [3-methylamino-4-hydroxy-l-butynyl] -3- [(3-methoxy-lH-pyrrol-2-yl) ethylene] - 2H-indol-2-one (DDDDD), (Z) -5 - [[4- (3-Ethyl-propynyl) -5-fluoro-2-oxo-1,2-d-hydro-indole-3 acid) -ylidene] methyl] -4-methyl-lH-pyrrole-3-o-carboxylic acid ethyl ester hydrochloride salt (EEEEE), (Z) -1, 3-Dihydro-5-fluoro- - [(3R, R) -4-hydroxy-3-methylamino-1-pentynyl] -3 [(3-methoxy-lH-pyrrole-2-yl) methylene] -2H-indol-2-one (FFFFF), hydrochloride salt of (Z) -1, 3-Dihydro-5-fluoro-4- [(3R, 4R) -hydroxy-3-methylamino-l- pentinyl] -3 [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2H-indo1-2 -one (GGGG), (Z) -N- [3- [5- Fluoro-3- [ (3-methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo-2,3-dihydro-lH-indol-4-yl] -prop-2-ynyl] -4-methyl-benzenesulfonamide (HHHHH ), (Z) -N- [3- [5-Fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo-2,3-dihydro-lH-indole 4-yl] -prop-2-ynyl] -methanesulonamide (IIIII), acid (S) - (Z) -5- [[5-Fluoro-2-oxo-4- [(pyrrolidin-2-yl) - etini?] -1, 2-dihydro-indol-3-ylidene] methyl] -4-methyl-lH-pyrrole-3-carboxylic acid ethyl ester (JJJJJ), acid (S) - (Z) -5 - [[ 5-Fluoro-2-oxo-4- [(pyrrolidin-2-yl) -etinyl] -1, 2-dihydro-indol-3-ylidene] methyl] -4-methyl-lH-pyrrole-3-carboxylic ethyl ester, hydrochloride salt (KKKKK), (Z) -1, 3-Dihydro-4- [(3R, S, 5R ) -3,5-dihydroxy-4-ethylamino-1-hexinyl] -5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (LLLLL) , (R) - ..Z) -1, 3-Dihydro-4- [(5-ethylamino-6-methyl) -6H-pyran-2-yl] -5-fluoro-3 [(3-methoxy-lH -pyrrol-2-yl) methylene)] -2H-indo1-2-one (MMMMM), (Z) -1, 3-Dihydro-4- [(3S, 4S, 5R) -3,5-dihydroxy-4 -ethylamino-1-hexinyl] -5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (NNNNN), rae- (Z) hydrochloride salt -1, 3-Dihydro-5-fluoro-4- [3- (2-hydroxy-propylamino) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H -indol-2-one (OOOOO), rae- (Z) -3- [(-acetyl-lH-pyrrol-2-yl) methyl) -1,3-dihydro-5-fluoro-4- hydrochloride salt [3- (2-hydroxypropyl lami. 10) -1-propynyl] -2H-indol-2-one (PPPPP), (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) methylene ] -1,3-dihydro-4- [(3R, 4S, 5R) -3,5-dihydroxy-4-ethyl-lamino-1-hexinyl] -5-fluoro-2H-indol-2-one (QQQQQ), (R) - (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-4- [(5-ethylamino-6-m) ethyl) -6H-pyran-2-yl] -5-fluoro-2H-indol-2-one (RRRRR), (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) methylene] -4- [(3R, S, 5R) -4 -amino-3,5-di-hydroxy-1 -hexinyl] -1,3-dihydro-5-fluoro-2H-indol-2-one (SSSSS), and (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) ethylene] -4- [(3S, 4S, 5R) -4 -amino-3,5-dihydroxy-1-hexinyl] -1 , 3-dihydro-5-fluoro-2H-indol-2-one (TTTTT). The compounds discovered here and defined by the above formulas may show tautomerism or structural isomerism. It is intended that the invention cover any tautomeric or structural isomeric form of these compounds or mixtures of said forms, and will not be limited to any tautomeric or structural isomeric form used in the formulas described above. Synthesis of the compounds according to the invention The compounds of the invention can be prepared by processes known in the art. The appropriate processes; for the synthesis of said compounds are provided by the examples. In general, these compounds can be prepared according to the following: synthesis scheme: GENERAL STAGE 1 GENERAL STAGE 2 where A = Br or I, X = N or C GENERAL STAGE 3 GENERAL STAGE 4 where A = Bro I, X = N or C, Z = H, B (OR9) 2, or SnBu3 GENERAL STAGE 4b The compounds 1, 2, 4, 5 and 6 are either available from commercial distributors or are synthesized, by methods known in the art. Compositions / Formulations In an alternative embodiment, the present invention relates to pharmaceutical compositions comprising at least one compound of formula I or formula XI or a prodrug thereof, or a pharmaceutically acceptable salt of a compound of formula I or formula II or a prodrug of said compound. These pharmaceutical compositions can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard or soft gelatine capsules, solutions, emulsions or suspensions. They can be administered rectally, in the form of suppositories, or parenterally, for example, in the form of injectable solutions. The pharmaceutical compositions of the present invention comprising compounds of formula I or formula II, prodrugs of such compounds, or salts thereof, can be manufactured by methods known in the art, for example by means of mixing, encapsulating, dissolving, conventional granulation, emulsification, entrapment, dragee, or lyophilization. These pharmaceutical preparations can be formulated with therapeutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, spherical acid or its salts can be used as such vehicles for tablets, coated tablets, dragees or hard gelatine capsules. Suitable carriers for soft gelatine capsules are vegetable oils, waxes, fats, semi-solid or liquid polyols. Depending on the nature of the active substance, vehicles are generally not required in the case of soft gelatine capsules. The vehicles suitable for the manufacture of solutions and syrups are water, polyols, sucrose, invert sugar and glucose. The vehicles suitable for injection are water, alcohols, polyols, glycerin, vegetable oils, phospholipids and surfactants. The suitable vehicles for suppositories are natural or hardened oils, waxes, fats and semi-liquid polyols. The pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, humectants, emulsifiers, edulcorant.es, dyes, flavors, salts to vary the osmotic pressure, buffers, coating agents or antioxidants. They may also contain other therapeutically active substances, including other additional active ingredients other than formula I or formula II. Dose As mentioned above, the compounds of formula I or formula II, prodrugs thereof, and their salts, and compositions containing these compounds are useful in the treatment or control of cellular proliferative disorders, in particular oncological disorders. These compounds and formulations containing said compounds are particularly useful in the treatment or control of solid tumors, such as, for example, breast and colon tumors. A therapeutically effective amount of a compound according to this invention represents an amount of compound that is effective to prevent, alleviate or ameliorate the symptoms of the disease or prolong the survival of the subject being treated. The determination of a therapeutically effective amount is within the abilities of experts in the field. The therapeutically effective amount or dose of a compound of formula I can vary within wide limits and will be adjusted to the individual requirements in each particular case. In general, in the case of oral or parenteral administration to adult humans weighing about 70 kg, a daily dose of about 10 mg to 10,000 mg preferably about 200 mg to 1000 mg would be appropriate, although the upper limit may be exceeded when be convenient. The daily dose can be administered as a single or divided dose, or in parenteral administration it can be administered as a continuous infusion. EXAMPLES The compounds of the present invention can be synthesized according to known techniques, such as for example the general schemes provided above. The following examples illustrate the preferred methods in the synthesis of compounds and formulations of the present invention. Example 1: General synthesis steps and starting materials Method A: preparation of l-alkyl-2-propin-1-oles by addition of Grignard over aldehydes OH R-CHO -MGCI THF t R A solution of the appropriate aldehyde (4.0 mmol) in 30 ml of dry tetrahydrofuran under an argon atmosphere was cooled to 0 ° C in an ice bath. Ethynylmagnesium chloride (5 mmol, 0.5 M solution in THF) was added dropwise, and the solution was stirred at a temperature of 0 ° C at room temperature for 1 to 3 h. The reaction was stopped by the addition of saturated ammonium chloride solution in water (15 ml) and the tetrahydrofuran was evaporated in vacuo. The residue was then extracted with ethyl acetate (3 x 30 ml) and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give the desired propargyl alcohol, which was used in the coupling reaction without further purification. Method B: Preparation of l-alkyl-2-propin-l-oles by addition of Grignard over aldehydes OH R-CHO + = -MGCI THF < A solution of the appropriate aldehyde (4.0 mmol) in 30 ml of dry tetrahydrofuran under an argon atmosphere was cooled to 0 ° C in an ice bath. Ethynylmagnesium chloride (10 mmol, 0.5 M solution in THF) was added dropwise, and the solution was stirred at a temperature of 0 ° C at room temperature for 1 to 3 h. The reaction was stopped by the addition of saturated ammonium chloride solution in water (15 ml) and the tetrahydrofuran was evaporated in vacuo. The residue was then extracted with ethyl acetate (3 x 30 ml) and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give the desired propargyl alcohol, which was used in the coupling reaction without further purification. Method C: Preparation of 4-alkynyloxindoles by palladium mediated coupling (0) (where X = I) A solution of the appropriate 4-iodoxindole (4 mmol) and the appropriate alkyne (4.4 mmol) in 3 ml of dimethylformamide and 3 ml of triethylamine was degassed by bubbling argon through the solution for 15 minutes. At this time, copper (I) iodide (16 g, 0.1 mmol) and palladium catalyst (0.04 mmol) were added, and the reaction was heated under argon atmosphere at 60 to 90 ° C for 6 to 96 hours. After cooling, water (20 ml) was added and the precipitate was filtered and dried. The product was purified either by flash column chromatography (Si02, 230-400 mesh with ethyl acetate / hexanes as solvent) or with reverse phase HPLC (using either acetonitrile / water or acetone, trilo / water / trifluoroacetic acid as solvent )., Method D: Preparation of 4-alkynyloxindoles by palladium mediated coupling (0) (where X == Br) A solution of the appropriate 4-bromoxindole (4 mmol) and the appropriate alkyne (4.4 mmol) in 3 ml of dimethylformamide and 3 ml of triethylamine was degassed by bubbling argon through the solution for 15 minutes. At this time copper iodide (I) (16 mg, 0.1 mmol) and palladium catalyst (0.04 mmol) were added, and the reaction was heated under argon atmosphere at 60 to 90 ° C for 6 to 96 hours. After cooling, water (20 ml) was added and the precipitate was filtered and dried. The product was purified either by flash column chromatography (Si02, 230-400 mesh with ethyl acetate / hexanes as solvent) or with reverse phase HPLC (using either acetonitrile / water or acetonitrile / water / trifluoroacetic acid as solvent). Method E: Preparation of methyl esters from carboxylic acids Ether R-C02H + CH2N2 > R-C02CH3 To a solution of the appropriate carboxylic acid (15.3 mmol) in diethyl ether (30 ml) was added a solution of diazomethane (20 mmol, 0.47 M in ether). The reaction was stirred at room temperature for 1 hour, at which time a few drops of acetic acid were added. The solution was washed with saturated sodium bicarbonate (3x25 ml) and the solvent was evaporated to yield the desired methyl ester, which was used without further purification.

Method F: Preparation of carboxylic acids from the methyl ester 1) THF, H20 2) Acid R-CO2CH3 + LiOH R-C02H The appropriate methyl ester (0.14 mmol) was dissolved in a mixture of 2 ml of tetrahydrofuran and 2 ml of water. Lithium hydroxide (2.8 mmol, 20 equiv.) Was added and the reaction was stirred at room temperature for 1 to 24 hours. The tetrahydrofuran was evaporated and 10 ml of water was added. The aqueous phase was extracted with ethyl acetate (2 x 10 ml) and the aqueous phase was then acidified to pH = 2 with 1N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (4 x 20 ml) and the extracts The combined organics were washed with a saturated solution of sodium chloride and then dried over magnesium sulfate. The ethyl acetate was evaporated and the product was recrystallized from ethanol. Method G: Preparation of carboxamides from carboxylic acids HNRR 'R-CO2H + ßuOCOC I + H3C-N O THF R-CONRR' ^ Carboxylic acid (5.1 mmol) was dissolved in 20 ml of dry 10 THF under an argon atmosphere, at which time N-methylmorpholine (7.6 mmol, 0.84 ml) was added, followed by iso-butyl-chloroformate (7.6 mmol, 0.99 ml). ). The reaction was stirred at room temperature for 30 minutes and ammonia gas was bubbled through the reaction mixture for 5 minutes, or the appropriate amine was added. The reaction was then stirred at room temperature for 20 minutes to 24 hours, and then quenched with the addition of water (10 ml). The tetrahydrofuran was evaporated and the aqueous phase was extracted with ethyl acetate (3 x 30 ml) to yield the carboxamide as a white crystalline solid which was coupled without further purification. Method 1: Preparation of (Z) -1,3-dihydro-4- (4-hydroxy-l-butynyl) -3- (3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2 -one and (Z) -1,3-dihydro-4- (5-hydroxy-1-pentynyl) -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indole-2- ona (? H2) nOH n = To a solution of the appropriate alkynol (0.57 mmol) in N, N '-dimethylformamide (20 ml) and triethylamine (10 ml) under an argon atmosphere was added chlorotrimethylsilane (1.0 mmol). The reaction was stirred at room temperature for 1 hour, at which time the bromooxindole (0.38 mmol) was added and the reaction mixture was degassed by bubbling argon through the solution for 15 minutes. Copper (I) iodide (0.038 mmol) and dichloro-bis (triphenylphosphine) palladium (II) 0.019 mmol) were added, and the reaction was heated at 70 ° C for 12 hours. Hydrochloric acid (1U, 5 ml) was then added and the reaction was stirred for 15 minutes. An additional 15 ml of water was added and the precipitate was filtered and dried. The product was purified by flash column chromatography (Si02, 230-400 mesh) with ethyl acetate / hexanes to yield a yellow powder, which was recrystallized from ethyl acetate / hexanes. Method K: Hydrolysis of trimethylsilyl alkyne to alkyne To a solution of the appropriate trimethylsilyl alkyne (4 mmol) in EtOH (80 ml) with addition of THF until complete solution if necessary, a solution of AgN03 (1.46 g, 8.59 mmol) in EtOH (5 ml) and water (15 ml) was added dropwise. . The mixture was stirred at room temperature for 1 h, and then treated with a solution of KCN (2.71 g, 41.6 mmol) in water (10 ml).

After stirring for an additional 20 minutes, the reaction mixture was diluted with water (100 ml) and extracted with EtOAc (3 x 100 ml). The combined EtOAc layers were dried (MgSO 4) and concentrated to dryness under reduced pressure to yield the desired product. Mé to do L: O "Zn, NH4Cl R-N CH 3 OH, H 2 O R-NH; \\ O - > To a solution of a nitro compound in 10% water in methanol was added Zn powder and NH C1. The mixture was heated under reflux for 6 h and then filtered through Celite®. The filtrate was concentrated in vacuo. The product was purified either by flash column chromatography (Si02, 230-400 mesh with ethyl acetate / hexanes as solvent) or by reversed-phase HPLC (using either acetonitrile / water or acetonitrile / water / trifluoroacetic acid as solvents). Method M: To a mixture of an amino compound in THF and saturated aqueous NaHCO 3 was added a THF solution of the acid chloride dropwise. The mixture was stirred for 1 to 10 days at room temperature and then diluted with ethyl acetate. The phases were separated and the organic solution was washed with water and then dried (MgSO4). The product was purified either by flash column chromatography (Si02, 230-400 mesh with ethyl acetate / hexanes as solvent) or by reverse phase HPLC (using either acetonitrile / water or acetonitrile / water / trifluoroacetic acid as solvents).

Method N: Preparation of 3-arylmethyl-substituted oxindoles by coupling with aldehyde A solution or suspension of the appropriate oxindole (1 mmol) and excess aldehyde (1 to 2 mmol) in 2 ml of 1% piperidine in 2-propanol was heated to a temperature of 60 to 90 ° C for 1 to 24 hours . Hot water (2 ml) was added. After cooling, the crystallized or precipitated product was filtered and washed with aqueous 2-propanol and dried. Method X: Procedure to convert aldehydes to alkynes NCHP (0) (OR>, Fl-CHO tBuOK, HF ~ R. (R '= Eto Me) To a suspension of potassium tert-butoxide at -78 ° C under an argon atmosphere in 60 ml of THF was added diazomethylphosphonic acid-diethyl ester or di-azomethyl acid. Phonic-dimethylether. The alkynylaldehyde was added to this mixture in the form of a solution in a small volume of THF. The resulting solution was stirred for 7 hours and then poured onto a mixture of Et20 and H20. The aqueous phase was extracted with Et20 and the combined organic phase was dried over Na2SO4 and concentrated. The desired alkyne product was obtained after silica gel column chromatography (J.C. Gilbert et al., J. Org Chem, 1979, 44, 4997-4998). The diazomethyl phosphonic acid diethyl ester was prepared according to the procedure of M. Regitz et al., Liebigs Ann. Chem., 1971, 748, 207-210. The diazomethyl phosphonic acid dimethyl ester was prepared according to the procedure of S Chira, Syn. Comm, 1989, 19, 561. Method Y: Generic procedure for the N-alkylation of N-Boc alkynes.

A solution of N-Boc alkyne in THF or DMF was added to NaH at 0 ° C to room temperature, and then after vigorous stirring for 2 to 60 min the appropriate alkyl iodide was added. The mixture was stirred for 1 hour overnight and then concentrated. Subsequently CH2C12 was added and the resulting suspension was filtered. The filtrate was concentrated. Alternatively, the reaction mixture was poured into aqueous ammonium chloride solution and extracted with CH2C12. The organic phase was dried over Na2SO4 and concentrated. The desired product was isolated after column chromatography on silica gel. Starting materials Starting material 1: (Z) - -Bromo-1, 3-dihydro-3- [(3-methox: L-lH-pyrrol-2-yl) methylene] -2H-indole-2 -one A mixture of 4-bromo-l, 3-dihydro-2H-indol-2-one (100 mg, 0.47 mmol) (see Kosuge et al., Chem. Harm. Ul. 33 (4): 1414-1418 (1985)) and 3-methoxy-2-pyrrolcarboxyaldehyde excess (70.8 mg, 0.57 mmol) (see Bellami et al., J. Chem. Research (M), 18-19 (1979) and Ch em. Research (M) 0101-0116 (1979)) in 1% piperidine in 2-propanol (1 mL) is heated at 85 C for 2 h. Hot water (1 mL) was added. After cooling, the crystallized product is filtered, washed with aqueous 2-propanol and dried. (Yield 0.13 g, 83%).

Matorial of Part 2: (Z) -1, 3-Dihydro-4-odo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one A mixture of 1,3-dihydro-4-iodo-2H-indol-2-one (0.51 g, 1.97 mmol) (prepared in accordance with T. Fukuyama et al., J. Am. Chem. Soc. 118: 7426-7427 (1996)), and excess 3-methoxy-2-pyrrolcarboxyaldehyde (0.30 g, 2.36 mmol) (prepared according to the method of F. Bellami et al., S upra) in 1% piperidine in 2-propanol (10 mL) is heated at 85 ° C for 4 h. Hot water (10 ml) was added. After cooling, the crystallized product is filtered, washed with aqueous 2-propanol and dried. (Yield 0.46 g, 64%). Starting Material 3: (Z) -1,3-Dihydro-5-fluoro-iodo-3- [(4-methyl-lH-imidazol-5-yl) methylene] -2H-indol-2-one A mixture of 1,3-dihydro-5-fluoro-4-iodo-2H-indole-2-one (0.48 g, 1.7 mmol) (see Example 2A) and excess of 4-methyl-5-imidazolecarboxaldehyde ( 0.40 g, 3.6 mmol) (Aldrich) in 1% piperidine in 2-propanol (10 mL) is heated at 90 ° C for 4 h. Hot water (10 ml) was added. After cooling, the crystallized product is filtered, washed with aqueous 2-propanol and dried. The residue was purified by reverse phase chromatography using trifluoroacetic acid-acetonitrile-water as solvent to yield the product as trifluoroacetate salt. (Yield 0.64 g, 100%).

Starting Material 4: (Z) -1,3-Dihydro-4-iodo-3- [(4-methyl-lH-imidazol-5-yl) methylene] -5-nitro-2H-indol-2-one A mixture of 1,3-dihydro-4-iodo-5-ni tro-2H-indole-2-one (0.41 g, 1.35 mmol) (see Example 2B infra), and excess of 4-methyl-5-imidazolecarboxaldehyde ( 0.18 g, 1. 62 mmol) (Aldrich) in 1% piperidine in 2-propanol (10 mL) is heated at 80 ° C for 4 h. Hot water (10 ml) was added. After cooling, the crystallized product is filtered, washed with aqueous 2-propanol and dried. The residue is purified by reverse phase chromatography using trifluoroacetic acid-acetonitrile-water as solvent to yield the product as the trifluoroacetate salt. (Yield 0.31 g, 58%).

Starting Material 5: (Z) -1, 3-Dihydro-5-fluoro-4-iodo-3- [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one A mixture of 1,3-dihydro-5-fluoro-4-iodo-2H-indole-2-one (1.40 g, 5.05 mmol) (see Example 2A nfra), and excess of 2-pyrrolcarboxyaldehyde (0.60 g, 6.3 mmol) (Aldrich) in 1% piperidine in 2-propanol (20 mL) is heated at 85 ° C for 2.25 h. Hot water (20 mL) was added. After cooling, the crystallized product is filtered, washed with aqueous 2-propanol and dried. (Yield 1.50 g, 84%). Starting Material 6: (Z) -1,3-Dihydro-5-fluoro-4-odo-3- [(-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one A mixture of 1,3-dihydro-5-fluoro-4-iodo-2H-indole-2-one (0.96 g, 3.47 mmol) (see Example 2A infra), and excess of 3-methoxy-2-pyrrolcarboxyaldehyde (0.52) g, 4.16 mmol) (see Bellami et al., J. Chem. Research (S), 18-19 (1979); J. Chem. Research (M), 0101-0116 (1919)) in 1% piperidine in 2-propanol (15 mL) is heated at 85 ° C for 3 h. Hot water (15 L) was added. After cooling, the crystallized product is filtered, washed with aqueous 2-propanol and dried. (Yield 1.24 g, 93%). Starting Material 7: (Z) -4-Bromo-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -5-nitro-2H-indole-2- ona A mixture of 4-bromo-l, 3-dihydro-5-nitro-2H-indol-2-one (0.113 g, 0.44 mmol) (see Example 2C infra), and excess of '3-methoxy-2-pyrrolcarboxyaldehyde ( 66.3 mg, 0.53 mmol) (see Bellami et al., J. Ciiem. Research (S), 18-19 (1979); J. Chem. Research (MJ, 0101-0116 (1979)) in 1% piperidine in 2-propanol (2 mL) is heated at 85 ° C for 3 h, hot water (2 mL) is added, after cooling, the crystallized product is filtered, washed with aqueous 2-propanol and dried (yield 0.136 g). , 85%) Example 2: A. Synthesis of 1, 3-Dihydro-5-fluoro-2-odo-2-indo-2-one A suspension of 1,3-dihydro-l-hydroxy-4-iodo-2H-indol-2-one, (2.43 g, 9 mmol) (see below) is cooled in dry dichloromethane (500 mL) to - 25 ° C under an argon atmosphere with magnetic stirring. A solution of (diethylamino) sulfide trifluoride (DAST, 1.35 L) (Aldrich) in dry dichloromethane (40 L) was added dropwise at a rate such that the temperature of the reaction did not exceed -25 ° C (approx. mm). After stirring for an additional 30 min at -25 ° C, the reaction was stopped by the addition of saturated aqueous sodium bicarbonate solution (180 ml) and allowed to warm to room temperature. The mixture was then filtered through Celite (Fisher Scientific) and the layers were separated. The aqueous phase was extracted with dichloromethane (2 x 300 ml). The dichloromethane phases were washed with saturated aqueous sodium chloride solution, combined, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography on silica gel using ethylodichloromethane acetate (1: 7, V / V) as solvent to yield 1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one. (Yield 1.08 g, 43%). The 1,3-dihydro-l-hydroxy-4-iodo-2H-indol-2-one was prepared according to the method of the procedure of A.S. Kende et al., "Synthesis of 1- Hydroxyoxindoles," Syn th. Commun. , 20 (14) 2133-2138 (1990) . B. Synthesis of 1,3-Dihydro-4-iodo-5-nitro-2H-indol-2-one A mixture of concentrated sulfuric acid (0.73 mL) and concentrated nitric acid (0.14 mL) was slowly added to a solution of 1,3-dihydro-4-iodo-2H-indole-2-one (0.5 g, 1.93 mmol) (see T. Fukuyama, supra, and Kende, supra) in concentrated sulfuric acid (6 mL) at -5 ° C with shaking. The mixture is stirred for an additional 15 min at -5 ° C and then poured onto ice. After allowing to stand for 1 h, the solid was collected by filtration and washed with water, and dried in a vacuum oven to yield 1,3-dihydro-4-iodo-5-ni: ro-2H-indole -2-ona, (Yield 0.46 g 78%). C. Synthesis of 4-Bromo-l, 3-dihydro-5-nitro-2H-indol-2-one A mixture of concentrated sulfuric acid (3.6 ml) and concentrated nitric acid (0.7 L) was slowly added: to a solution of 4-bromo-l, 3-dihydro-2H-indol-2-one (2 g, 9.48 mmol ) (see below) in concentrated sulfuric acid (20 mL) at -5 ° C with stirring. The mixture is stirred for an additional 1 h at -5 ° C, and then poured onto ice. After allowing to stand for 1 h, the formed precipitate was collected by filtration and washed with water, and dried in a vacuum oven to yield 4-bromo-1,3-dihydro-5-nitro-2H-indole-2. -one (Yield 2.33 g, 96%).

The 4-bromo-l, 3-dihydro-2H-indol-2-one was prepared according to the method of the T procedure.

Kosuge et al., "Synthesis and So Reactions of 6- Bromooxindole" Chem. Pharm. Buil, 33 (4): 1414-1418 (1985). Example 3: (Z) -1, 3Dihydro-4 - (6-hydroxy-l -hexinyl) -3- [(3-methoxy-lH-pyrrol-2-yl) methylene) -2H-indol-2-one ( TO) Using General Method D above, 5-hexin-1-ol (56 mg, 0.57 mmol) (Aldrich) was coupled with (Z) -4-bromo-1,3-dihydro-3- [(3-methoxy) lH-pyrrol-2-yl) methylene] -2H-indol-2-one (110 mg, 0.38 mmol) (starting material 1 above) using (Ph3P) 2PdCl2 (13 mg) (Aldrich) and Cul (7 mg) (Aldrich) as a catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70 ° C for 14 h to yield (Z) -l, 3-dihydro-4- (6-hydroxy-1-hexinyl) - 3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. il) methylene] -2H-indol-2-one.

Example 4: (Z) -1,3-Dihydro-4- (5-hydroxy-1-pentynyl) -3 - [(3-methoxy-1 H -pyrrol-2-yl) methylene] -2H-indole-2- ona (B) Using Method I above, 4-pentin-1-ol (40 mg, 0.57 mmol) (Aldrich) was dissolved, under argon, in 3 mL of DMF and 2 mL of triethylamine, and to this solution was added chlorotrimethylsilane ( 0.13 mL, 1 mmol) (Aldrich). The reaction is stirred at room temperature for 1 h, at which time (Z) -4-bromo-1,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] - 2H-indol-2-one (110 mg, 0.38 mmol) (starting material 1 above) and the solution was degassed for 15 min by bubbling argon through the solution. (Ph3P) 2PdCl2 (15 mg) (Aldrich) and Cul (7 mg) (Aldrich) was added and the reaction heated at 70 ° C for 14 h. The reaction mixture was then poured into 25 mL of 1 N HCl and the yellow precipitate was filtered. The product was purified by flash column chromatography to obtain (Z) -l, 3-dihydro-4- (5-hydroxy-l-pentinyl) -3- [[3-methoxy-lH-pyrrol-2-yl] methylene] -2H-indol-2-one in the form of a yellow powder. (Yield 55 mg, 45%). Example 5: (Z) -1,3-Dihydro-4- (4-hydroxy-l-butynyl) -3 - [(3-methoxy-1 H -pyrrol-2-yl) methylene] -2H-indole-2- ona (C) Using Method 1 above, 3-butin-l-ol (40 mg, 0.57 mmol) (Aldrich) was dissolved, under argon, in 3 mL of DMF and 2 mL of triethylamine, and chlorotrimethylsilane (0.13 mL, 1 mmol) was added to this solution. The reaction was stirred at room temperature for 1 h, at which time (Z) -4-bromo-1,3-dihydro-3- [ (3-methoxy-lH-pyrrol-2-yl) -methylene] -2H-indol-2-one (110 mg, 0.38 mmol) (starting material 1 s upra) and the solution was degassed for 15 min by bubbling argon through the solution. They were added (Ph3P) 2PdCl2 (13 mg) and Cul (7 mg) and the reaction is heated at 70 ° C for 14 h. The reaction mixture was then poured into 25 ml of IN HCl and the yellow precipitate is filtered. The product was purified by flash column chromatography to obtain (Z) -1,3-dihydro-4- (4-hydroxy-1-butynyl) -3- (3-methoxy-1H-pyrrol-2-yl) -methylene ] -2H-Indole-2-one as a yellow powder. (Yield 35 mg, 30%). Example 6 Rae- (Z) -1,3-Dihydro-4- (3-hydroxy-3-methyl-1-p-intinyl) -3- [(3-methoxy-1 H -pyrrol-2-yl) methylene] -2H-indol-2-one (D) Using method D above, 3-methyl-1-pentin-3-ol (75 mg, 0.75 mmol) (Aldrich) was coupled with (Z) -4-bromo-1,3-dihydro-3- [(3-) methoxy-lH-pyrrol-2-yl) ethylene] -2H-indol-2-one (Starting material 1 s upra) (200 mg, 0.63 mmol) using (Ph3P) 2PdCl2 (25 mg) and Cul (12 mg) as a catalyst in DMF (3 mL) and Et3N (3 mL) as a solvent at 70 ° C for 17 h to yield rae- (Z) -1, 3-dihydro-4- (3-hydroxy-3-methyl-l- pentinyl) -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 66 mg, 31%).

Example 7: (Z) -6- [2, 3-Dihydro-3- [(3-methoxy-1H-pyrrole-2-yl) ethylene] -2-oxo-1H-indole -4-yl-5- acid Hexinoic methyl ester (E) Using the method D above, methyl 5-hexynoate (109 mg, 0.87 mmol) (see below) was coupled with (Z) -4-bromo-1,3-dihydro-3- [(3-methoxy-1H-) pyrrol-2-yl) methylene] -2H-indol-2-one (179 mg, 0.62 mmol) (starting material 1 s upra) using (Ph3P) 2PdCl2 (30 mg) and Cul (15 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 70 ° C for 15 h to yield (Z) -6- [2, 3-dihydro-3- [(3-methoxy-1H-pyrrole-2-yl) acid. ) meti.'Leno] -2-oxo-lH-indol-4-i 1] -5-hexynoic methyl ester. (Yield 78 mg, 35%). The methyl 5-hexynoate starting material was prepared by the reaction of 5-hexynoic acid with diazomethane in accordance with Method E cited above.

Example 8: (Z) -5- [2,3-Dihydro-3- [(3-methoxy-HH-pyrrole-2-yl) methylene] -2-oxo-lH-indol-4-yl] -4- acid pentinocio methyl ester (F) Using the method D above, methyl 4-pentylate (163 mg, 1.45 mmol) (see below) was coupled with (Z) -4-bromo-1,3-dihydro-3- [(3-methoxy-1H-) pyrrol-2-yl) methylene] -2H-indole-2-one (300 mg, 1.03 mmol) (Starting material 1 s upra) using (Ph3P) 2PdCl2 (30 mg) and Cul (15 mg) as catalyst in DMF (5 mL) and Et 3 N (5 L) as solvent at 70 ° C for 14 h to yield (Z) -5- [2,3-dihydro-3- [(3-methoxy-1 H -pyrrol-2-yl) acid. ethylene] -2-oxo-lH-indol-4-yl] -4-pentynoic methyl ester. (Yield 120 mg, 33%). The methyl 4-pentynoate starting material was prepared by the reaction of 4-pentynoic acid with diazomethane in accordance with Method E cited above.

Example 9: (Z) -6- [2, 3-Dihydro-3- (3-methoxy-iH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -5- acid Hexinoic (G) Using Method F cited above, lo (Z) -6- [2,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indole- 4-yl] -5-hexynoic methyl ester (40 mg, 0.11 mmol) (from Example 7 cited above) was hydrolyzed with LiOH.H20 (92 mg, 2.19 mmol) in THF (3 mL) and water (3 L) during 22 h to yield (Z) -6- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] acid. 5-Hexynoic. (Yield 31 mg, 81%). Example 10: (Z) -5- [2, 3-Dihydro-3- [(3-methoxy-1H-pyrrole-2-yl) methylene] -2-oxo-1H-indole-1] -4- acid pentinoic (H) Using Method F cited above, (Z) -5- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indole-4 acid -yl] -4-pentynoic methyl ester (50 mg, 0.14 mmol) (from Example 8 cited above) was hydrolyzed with LiOH.H20 (118 mg, 2.8 mmol) in THF (3 mL) and water (3 mL) for 22 hours. h. (Yield 40 mg, 85%). Example 11: (Z) -5- [2,3-Dihydro-3- [(3-methoxy-1H-pyrrole-2-yl) methylene] -2-oxo-lH-indole-4-yl] -4- pentinoic sodium salt (I) Na "Acid (Z) -5- [2,3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo-lH-indol-4-yl] -4 -pentinoic acid (100 mg, 3 mmol) (from Example 10 cited above) was dissolved in tetrahydrofuran (1 mL), and 1N sodium hydroxide (3 mL) was added.The resulting product, (Z) -5- [2] acid. , 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -4-pentynoic sodium salt, was purified by phase HPLC Reverse (acetonitrile-water for 15 minutes) Example 12: (Z) -5- [2, 3-Dihydro-3- [(3-methoxy-1H-pyrrol-2-jl) methylene] -2-oxo-lH -indol-4-yl] -4-pentinamide (J) Using Method C cited above, 4-pentyline (49 mg, 0.5 mmol) (prepared from 4-pentionic acid in accordance with Method G cited above) was coupled with (Z) -1, 3- Dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (Starting Material 2 s upra) (120 mg, 0.32 mmol) using (Ph3P ) 2PdCl2 (12 mg) and Cul (6 mg) as a catalyst in DMF (1 mL) and Et3N (1 mL) as solvent at 70 ° C for 22 h to yield (Z) -5- [2,3-dihydro- 3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -4-pentinamide. (Yield 45 mg, 42%). Example 13: (Z) -6- [2, 3-Dihydro-3- [(3-methoxy-1 H -pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -5- hexinamide (K) Using Method C cited above, 5-hexyne ida (46 mg, 0.4 mmol) • (prepared from 5-hexynoic acid by Method G cited above) was coupled with (Z) -1,3-dihydro-4- iodo-3- [(3-methox.L-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (Starting material 2 s upra) (113 mg, 0.31 mmol) using (Ph3P) 2PdCl2 (12 mg) and Cul (6 mg) as a catalyst in DMF (1 mL) and Et3N (1 mL) as solvent at 70 ° C for 22 h to yield (Z) -6- [2,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -5-hexinamide. (Yield 52 mg, 48%).

Example 14: (Z) -1,3-Dihydro-4- (3-hydroxy-3-methyl-l-Butynyl) -3- [3-methoxy-lH-pyrrol-2-yl) methylene) -2H-indole 2-one (L) Using method D above, 3-methyl-l-but-in-3-ol (150 mg, 1.78 mmol) (Aldrich) was coupled with (Z) -4-bromo-1,3-dihydro-3- [(3 -methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (101 mg, 0.32 mmol) (starting material 1 above) using (Ph3P) 2PdCl2 (30 mg) and Cul (16 mg) as a catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70 ° C for 18 h to yield (Z) -l, 3-dihydro-4- (3-hydroxy-3-methyl-1-butynyl) -3- [(3-methoxy-lH-pyrrol-2-yl) et ylene] -2H-indol-2-one. (Yield 43 mg, 38%). Example 15: (Z) -1, 3-Dihydro-4- [(1-hydroxyle-hexyl) -et: Lnyl] -3- [(3-methoxy-lH-pyrrole-2-yl) methylene] -2H- indole-2-one (M) Using Method C cited above, 1-ethynyl-1-cyclohexanol (60 mg, 0.48 mmol) (Aldrich) was coupled with (Z) -1,3-dihydro-4-iodo-3- [(3-methoxy-1H -pyrrol-2-yl) -methylene] -2H-indole-2-one (146 mg, 0.4 mmol) (Material from 5 batch 2 s upra) using (Ph3P) 2PdC. ".2 (20 mg) and Cul ( 10 mg) as a catalyst in DMF (2 L; and Et 3 N (2 mL) as solvent at 70 ° C for 15 h to yield (Z) -1,3-dihydro-4- [(1-hydroxycyclohexyl) ethynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2H-indol-2-one. (Yield 94 mg, 65%) Example 16: Rae- (Z) -1, 3-Dihydro -4- (3-hydroxy-3-methyl-1-hexinyl) -3 - [(3-methoxy-lH-pyrrole-2-yl) methylene] -2H-indol-2-one (N) Using method D above, 3-methyl-1-hexin-3-ol (98 mg, 0.87 mmol) (Aldrich) was coupled with (Z) -4-bromo-1,3-dihydro-3- [(3-) methoxy-lH-pyrrol-2-yl) ethylene] -2H-indole-2-one (Starting Material 1 s upra) (127 mg, 0.4 mmol) using (Ph3P) 2PdCl2 (46 mg) and Cul (22 mg) as a catalyst in DMF (3 mL) and Et3N (3 mL) as a solvent at 70 ° C for 22 h to give ra e - (Z) -1,3-dihydro-4- (3-hydroxy-3-methyl-1) hexyl) -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 92 mg, 66%). Example 17: Rae- (Z) -1, 3-Dihydro-4- (3,5-dimethyl-3-hydroxy-1-hexinyl) -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene ] -2H-Indole -2 -one (O) Using Method C cited above, 3,5-dimethyl-1-hexin-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z) -1,3-dihydro-4-iodo-3- [ (3-methoxy-lH-pyrrole-2-yl) -methylene] -2H-indole-2-one (starting material 2 s upra) (146 mg, 0.4 mmol) using (Ph3P) 2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70 ° C for 15 h to yield ra e - (Z) -l, 3- dihydro-4- (3, 5-dimethyl-3-hydroxy-1-hexinyl) -3 - [(3-methoxy-1 H -pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 87 mg, 60%). Example 18: (R) (Z) -1,3-Dihydro-4- (3-hydroxy-l-octynyl) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole -2-ona (P) Using Method C cited above, (R) - (+) - 1-octin-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z) -1,3-dihydro-4-iodo-3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] 2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 s upra) using (Ph3P) 2PdCl2 (20 mg) and (10 mg) as a catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70 ° C for 15 h to yield (R) - (Z) -l, 3-dihydro-4- (3-hydroxy). loctinyl) -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 91 mg, 62%). Example 19: Rae- (Z) -1,3-Dihydro-4- (3-hydroxy-1-octynyl) -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indole 2-one (Q) Using Method C cited above, rac-1-oct-in-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z) -l-3-dihydro-4-iodo-3 - [(3- methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 Supra) using (Ph3P) 2PdCl2 (20 mg) and Cul (10 mg) as a catalyst in DMF (2 L) and Et 3 N (2 L) as solvent at 70 ° C for 15 h to yield rae- (Z) -1,3-dihydro-4- ( 3-hydroxy-l-octynyl) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 88 mg, 60%). Example 20: Rae- (Z) -1, 3-Dihydro- (3-hydroxy-1-pentynyl) -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indole-2 -one (R) Using Method C cited above, 1-pentin-3-ol (40 mg, 0.48 mmol) (Aldrich) was coupled with (Z) -l, 3-dihydro-4-iodo-3- [( 3-methoxy-lH-pyrrol-2-yl) ethylene] -2H-indol-2-one (146 mg, 0.4 mmol) (starting material 2 supra) using (Ph3P) 2PdCl2 (20 mg) and Cul (10 mg ) as a catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70 ° C for 15 h to yield .rae- (Z) -1, 3-dihydro-4- (3-hydroxy-l-pentynyl) -3- [(3-methoxy-lH-pyrrol-2-yl) ethylene] -2H-indol-2-one. (Yield 78 mg, 60%). Example 21: 3- (2-Hydroxyethoxy) -1-propine Sodium metal (2.3 g, 0.1 mol) was added to 60 mL of ethylene glycol over a period of 4 h. Propargyl bromide (80% solution in toluene, 11.1 mL, 0.1 mol) (Aldrich) was then added dropwise during 2. 5 h while maintaining the reaction temperature at -40 ° C. When the addition was complete, the reaction mixture was heated to 70-80 ° C for 1.5 h. The reaction mixture was then cooled and added to 50 ml of water and 40 ml of diethyl ether. The phases were separated, and the aqueous phase was extracted with diethyl ether (4x15 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield 3- (2-hydroxyethoxy) -1-propyne. Example 22: (Z) -1, 3-Dihydro-4 - [3- (2-hydroxyethoxy) -1-propynyl] -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H- indole-2-one (S) Using Method C cited above, 3- (2-hydroxyethoxy) -1-propyne (53 mg, 0.53 mmol) (from Example 21 cited above) was coupled with (Z) -l, 3-dihydro-4-iodo-3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (150 mg, 0.41 mmol) (Starting Material 2 s upra) using (Ph3P) 2PdCl2 (20 mg) and Cul (10 mg) as cataLizador in DMF (2 mL) and Et3N (2 mL) as solvent at 70 ° C for 18 h to yield (Z) -l, 3-dihydro-4- [3- (2-hydroxyethoxy) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 68 mg, 49%).

Example 23: rac-3- [(2,2-Dimethyl-l, 3-dioxolan-4-yl) methoxy] -1-propine Sodium hydride (1.32 g, 55 mmol) was added to a solution of 2.2 -d: .methyl-l, 3-dioxolan-4-methanol (Aldrich) in THF (60 mL), and the resulting mixture is refluxed for 90 min and then cooled to 0 ° C. Tetrabutylammonium iodide (370 mg), and propargyl bromide (80% in toluene, 6.22 mL, 50 mmol) (Aldrich) were successively added. After stirring for 150 min. at room temperature, 20 ml of water were added and the THF was evaporated in vacuo. The aqueous phase was then extracted with diethyl ether (4 x 50 ml) and the combined organic phases were dried over magnesium sulfate and concentrated in vacuo to yield rac-3- [(2,2-dimethyl-l, 3-dioxolan -4-yl) methoxy] -1-propine. Example 24: Rae- (Z) -4- [3- [(2,2-dimethyl-l, 3-dioxolan-4-yl) methoxy] -1-propynyl] -1,3-dihydro-3- [( 3-methoxy-lH-pyrrol-2-yl) methylene > ] -2H-indol-2 Using Method C cited above, 3- [(2, 2-dimethyl-1, 3-dioxolan-4-yl) methoxy] -1-propyne (90 mg, 0.53 mmol) (from Example 23 cited above) was coupled with ( Z) -1,3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2H-indol-2-one (starting material 2 s upra) ( 150 mg, 0.41 mmol) using (Ph3P) 2PdCl2 (20 mg) and Cul (10 mg) as a catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70 ° C for 18 h at rae (Z) -4 - [3- [(2, 2-dimethyl-l, 3-dioxolan-4-yl) methoxy. ] -1-propynyl] -1,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 97 mg, 58%). Example 25: (S) - (Z) -1,3-Dihydro-4- (3-hydroxy-1-octinyl) -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H- Indole-2-one (U) Using Method C cited above, (S) - (-) -l-octin-3-ol (61 mg, 0.53 mmol) (Aldrich) was coupled with (Z) 1,3-dihydro-4-iodo-3 [(3-methoxy-lH-pyrro1-2-yl) methylene] -2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 s upra) using (Ph3P) 2PdCl2 (20 mg) and (10 mg) as a catalyst in DMF (2 L) and Et 3 N (2 mL) as solvent at 70 ° C for 18 h to yield (S) - (Z) -1,3-dihydro-4- (3-hydroxy). l-octynyl) -3- [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 101 mg, 68%). Example 26: (Z) - (3- (2,3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] acid - 2-propynyl] -propanedioic dimethyl ester (V) Using Method C cited above, dLmethyl propargyl malonate (83 mg, 0.49 mmol) was coupled.

(Fluka) with (Z) -1,3-dihydro-4-iodo-3- (3-methoxy-lH-pyrrol-2-yl) -methylene] -2H-indol-2-one (150 mg, 0.41 mmol ) (Starting material 2 s upra) using (Ph3P) 2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70 ° C for 18 h to yield acid (Z) - [3- [2, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -2-propynyl] propanedioic dimethyl ester. (Yield 82 mg, 49%) Example 27: (Z) - [3- [2, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methyl] -2-oxo- acid lH-indol-4-yl] -2-propynyl] -propanedioic acid () Using Method F cited above, the acid (Z) - [3- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indole- 4-yl] -2-propynyl] propanedioic dimethyl ester (68 mg, 0.16 mmol) (from Example 26 cited above) was hydrolyzed with LiOH.H 0 (140 mg, 3.32 mmol) in THF (1 mL) and water (1 mL) at room temperature for 20 h to yield acid (Z) - [3- [2,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo-lH -indol-4-yl] -2-propynyl] propanedioic acid. (Yield 49 mg, 82%). Example 28 (Z) -1,3-Dihydro-4- (3-methoxy-1-propynyl) -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indol-2-one (X) 0 Using Method C cited above, methyl propargyl ether (34 mg, 0.49 mmol) (Aldrich) was coupled with (Z) -1,3-dihydro-4-iodo-3- (3-methoxy-1H-pyrrole-2). -yl) methylene] -2H-indol-2-one (150 mg, 0.41 5 mmol) (starting material 2 s upra) using (Ph3P) 2Pdc: -2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70 ° C for 18 h to yield (Z) -1, 3- dihydro-4- (3-methoxy-1-propynyl) -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-0-indol-2-one. (Yield 69 mg, 55%). Example 29: (Z) -1, 3-Dihydro-4- (3-hydroxy-1-propynyl) -3 - [(3-methoxy-lH-pyrrole-2-yl) methyl] -2H-indole-2- ona (Y) Using method D above, propargyl alcohol (43.9 mg, 0.78 mmol) (Aldrich) was coupled with (Z) -4-bromo-1,3-dihydro-3- [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indole-2-one (100 mg, 0.31 mmol) (Starting material 1 s upra) using (Ph3P) 2PdCl2 (12.8 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et 3 N (3 riL) as a solvent at 85 ° C for 18 h to yield (2) -1,3-dihydro-4- (3-hydroxy-1-propynyl) -3- [(3-methoxy-1H-pyrrole -2-yl) methylene] -2H-indol-2-one. (Yield 42 mg, 5.46%) Example 30: (Z) -1, 3-Dihydro-4- (3-hydroxy-1-propynyl) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene ] -5-nitro-2H-indol-2-one (Z) Using Method C cited above, propargyl alcohol (0.11 g, 1.95 mmol) (Aldrich) was coupled with (Z) -1,3-dihydro-4-iodo-3- [(3-methoxy-1H-pyrrole-2 il) methylene] -5-nitro-2H-indol-2-one (0.32 g, 0.78 mmo.L) (starting material 2 cited above) using (Ph3P) 2PdCl2 (27.4 mg) and Cul (7.4 mg) as catalyst in DMF (3 mL) and Et3N (3 L) as solvent at 85 ° C for 18 h to yield (Z) -1, 3-dihydro-4- (3-hydroxy-1-propinyl) 3- [(3- methoxy-lH-pyrrol-2-yl) methylene] -5-nitro-2H-indol-2-one. (Yield 0.12 g, 46%). Example 31: (Z) -1,3-Dihydro-4- [(1-hydroxycyclopentyl) et.inyl] -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2 -one (AA) Using method D above, 1-ethynyl-cyclopentyl (86.3 mg, 0.78 mmol) (Aldrich) was coupled with (Z) -4-bromo-1,3-dihydro-3- [(3-methoxy-1H-pyrrole -2-yl) methylene] -2H-indole-2-one (0.1 g, 0.31 mmol) (starting material 1 cited above) using (Ph3P) 2PdCL2 (12.6 mg) and Cul (3 mg) as catalyst in DMF ( 3 mL) and Et 3 N (3 mL) as solvent at 85 ° C for 2 days to yield (Z) -1,3-dihydro-4- [(1-hydroxycyclopentyl) ethynyl] -3- [(3-methoxy-1H) -pyrrol-2-yl) -methylene] -2H-indol-2-one. (Yield 43 mg, 40%). Example 32: j Z) -5-Amino-l, 3-dihydro-4- (3-hydroxy-l-propynyl) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H- indole-2-one (BB) Using Method L cited above, (Z) -l, 3-dihydro-4- (3-hydroxy-l-propynyl) -3- (3-methoxy-lH-pyrrol-2-yl) methylene] -5-nitro -2H-indol-2-one (63 mg, 0.19 mmol) (from Example 30 cited above) was reduced with zinc (0.11 g, 1.67 mmol) and ammonium chloride (22.4 mg, 0.42 mmol) in 10% water in methanol (10 mL) with heating under reflux for 2 h to yield (Z) -5-amino-1,3-dihydro-4- (3-hydroxy-1-propynyl) 3- [(3-methoxy-1 H-pyrrol- 2-yl) methylene] -2H-indo 1-2-one.

(Yield 18 mg, 40%). Example 33: (Z) -N- [2, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-l) methylene] -2-oxo-4- (3-hydroxy-1-propynyl) -1H-indol-5-iL] -2-thiopheneacetamide (CC) Using Method M cited above, (Z) -5-amino-1,3-dihydro-4- (3-hydroxy-1-propynyl) 3- [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indol-2-one (20 mg, 0.065 mmol) (from Example 32 cited above) was acylated with 2-thiopheneacetyl chloride (21 mg, 0.13 mmol) (Aldrich) in THF (2 mL) at RT for 2 h. h to yield (Z) -N- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-4- (3-hydroxy-l-propynyl) -lH-indol-5-yl] 2-thiopheneacetamide. (Yield 18.2 mg, 65%). Example 34: (Z) -N- (2, 3-Dihydro-4- (3-hydroxy-1-propynyl) -3 - [(3-methoxy-1 H -pyrrol-2-yl) methylene] -2-oxo -lH-indol-5-yl] -4-pyridinecarboxamide (DD) Using Method M cited above, (Z) -5-amino-1,3-dihydro-4- (3-hydroxy-1-propynyl) 3- [(3-methoxy-lH-pyrrol-2, -yl) methylene ] -2H-Indole-2-one (20 mg, 0.065 mmol) (from Example 32 cited above) was acylated with isonicotinyl chloride (23 mg, 0.13 mmol) (Aldrich) in THF (2 mL) at room temperature for 10 minutes. days to yield (Z) -N- [2, 3-dihydro-4- (3-hydroxy-1-propynyl) -3 - [(3-methoxy-1 H -pyrrol-2-yl) methylene] -2-oxo -IH-indol-5-yl] -4-pyridinecarboxamide. (Yield 10 mg, 37). Example 35: (Z) -5- [2, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -5-nitro-2-oxo-lH-indole-4 acid -yl] -4-pentynoic methyl ester (EE) Using method D above, methyl 4-pentynoate (0.18 g, 1.65 mmol) was coupled with (Z) -4-bromo-1, -dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -5-nitro-2H-indol-2-one (starting material 1 s upra) (0.3 g, 0.82 mmol) using (Ph3P) 2PdCl2 (28.8 mg) and Cul (7.8 mg) as catalyst in DMF (8 mL) and Et3N (8 mL) as solvent at 8500 for 18 h to yield (Z) -5- [2,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene]] - 5-Nitro-2-oxo-lH-indol-4-yl] -4-pentynoic methyl ester. (Yield 0.23 g, 72%). Example 36: (Z) -5- (5-Amino-2,3-dihydro-3- [(3-methoxy-lH-pyrrole-2-yl) methylene] -2-oxo-lH-indole-4- acid il] -4-pentynoic methyl ester (FF) Using Method L cited above, (Z) -5- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -5-nitro-2-oxo-lH- acid indol-4-yl] -4-pentynoic methyl ester (0.22 g, 0.57 mmol) (from Example 35 cited above) was reduced with zinc (0.33 g, 5.1 mmol) and ammonium chloride (67.1 mg, 1.25 mmol) in water 10% in methanol (20 mL) with heating under reflux for 4 h to yield (Z) -5- [5-amino-2, 3-dihydro-3- [(3-methoxy-1H-pyrrole-2-yl) acid] methylene] -2-oxo-lH-indol-4-i. '. ] -4-pentynoic methyl ester (Yield 0.1 g, 48). Example 37: (Z) -5- [2, 3-Dihydro-3- [(3-methoxy-l-pyrrol-2-yl) methylene] -2-oxo-5- [(2-thienylacetyl) amino] acid ] -lH-indol-4-yl] - -pentinoic methyl ester Using Method M cited above, (Z) -5- [5-amino-2,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo-lH acid -indol-4-yl] -4-pentynoic methyl ester (82.7 mg, 0.23 mmol) (from Example 36 cited 0 above) was acylated with 2-thiopheneacetyl chloride (72.7 mg, 0.45 mmol) (Aldrich) in THF (8 mL) at room temperature for 18-20h to yield (Z) -5- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-5- acid. [(2-thienylacetyl) -amino] -lH-indol-5-yl] -4-pentynoic methyl ester. (Yield 90 mg, 65%) Example 38: (Z) -5- (2,3-Dihydro-3- [(3-methoxy-1H-pyrrole-2-yl) methylene] -2-oxo-5- [ (2-thienylacetyl) amino] -lH-inclol-4-yl-4-pentynoic acid (HH) Using Method F cited above, (Z) -5- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-OXO-5- [(2- thienylacetyl) amino] -lH-indol-4-yl] -4-penthionic methyl ester (from Example 37) (70 mg, 0.14 mmol) was hydrolyzed with LiOH.H20 (21 mg, 0.50 mmol) in a THF-water mixture (5 mL, V / V 2: 1) at room temperature for 3 days to yield (Z) -5- [2,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl)] acid. methylene] -2-oxo-5 [(2-thienylacetyl) amino] -lH-indol-4-yl] -4-pentynoic acid. (Yield 56 mg, 82%). Example 39: (Z) -4 - (3-Amino-1-propynyl) -1,3-dihydro-3- [(3-methoxy-1 H -pyrrol-2-yl) methylene] -2H-indole-2- ona trifluoroacetate salt (II) Using the method D above, propargylamine (34.5 mg, 0.63 mmol) (Aldrich) was coupled with (Z) -4-bromo-1,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (0.1 g, 0.31 mmol) (Starting material 1 s upra) using (Ph3P) 2PdCl2 (11 mg) and Cul (3 mg) as a catalyst in DMF (2 mL) and Et3N (3 mL) as solvent at 80 ° C for 20 h to yield (Z) -4- (3-amino-1-propynyl) -1,3-dihydro-3- [(3-methoxy-1H-pyrrole-2 -yl) methylene] -2H-indol-2-one trifluoroacetate salt after purification by reverse phase chromatography. (Yield 14 mg, 15%). Example 40: (Z) -1,3-Dihydro-3- [(3-methoxy-1H-pyrrol-2-yl) methyl enol -4- [3 (N-methylamino) -1-propynyl] -2H-indole -2-one, trifluoroacetate salt (JJ) Using method D above, N-methyl-propargylamine (43.5 mg, 0.63 mmol) (Aldrich) was coupled with (Z) -4-bromo-1,3-dihydro-3- [(3-methoxy-1H-pyrrol- 2-yl) methylene] -2H-indole-2-one (Starting material 1 s upra) (0.1 g, 0.31 mmol) using (Ph3P) Pd (18 mg) and Cul (3 mg) as a catalyst in DMF (3 mg). mL) and Et3N (3 L) as a solvent at 80 ° C for 3 days to yield (Z) -l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -4 - [3- (N-methylamino) -1-propynyl] -2H-indol-2-one trifluoroacetate salt after purification by reverse phase chromatography. (Yield 15 mg, 15%). Example 41: (Z) -1, 3-Dihydro-3- [(3-methoxy-1H-pyrrol-2-y1) methylene] -4- [3- (N-phenylmethylamino) -1 -propinyl] -2H- Indole-2-one (KK) Using Method C cited above, N-benzyl-3-propylamine (45 mg, 0.3 mmol) (prepared in accordance with B. Henque et al., J. Org. Ch., 57: 7056-7066 (1992) ) was coupled with (Z) -1,3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (0.11 g, 0.3 mmol ) (Starting material 2 s upra) using (Ph3P) 2PdCl (11 mg) and Cul (3 mg) as a catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80 ° C for 6 h to yield ( Z) -1, 3-dihydro-3- [(3-metho-lH-pyrrol-2-yl) ethylene] -4- [3- (N-phenyl-methylamir or) -l-propynyl] -2H- Indole-2-one. (Yield 78 mg, 66%). Example 42: (Z) - [3- [2, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] acid - 2-propynyl] -carbamic methyl ester (LL) Using Method C cited above, 2-propynyl carbamic acid methyl ester (71.3 mg, 0.63 mmol) (see below) was coupled with (Z) -1,3-dihydro-4-iodo-3- [(3-methoxy -lH-pyrrol-2-yl) methylcell] -2H-indole-2-one (110 mg-, 0.3 mmol) (starting material 2 s upra) using (Ph3P) 2PdCl2 (11 mg) and Cul (3 mg ) as a catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80 ° C for 6 h to yield (Z) - [3- [2, 3-dihydro-3- [(3-methoxy-1H) acid. -pyrrol-2-yl) -methylene] -methyl ester. (Yield 25 mg, 23%). Mastyl ester of 2-propynyl carbamic acid was prepared by the reaction of propargylamine with methyl chloroformate in dichloromethane and saturated aqueous sodium bicarbonate solution. Example 43: (Z) -carbamic acid 3- [2,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) ethylene] -2-oxo-lH-indol-4-yl] - 2-propynyl ester (MM) Using Method C cited above, propargyl carbamate (62.4 mg, 0.63 mmol) (see below) was coupled with (Z) -1,3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol- 2-yl) methylene] -2H-indole-2-one (110 g, D.3 mmol) (starting material 2 s upra) using (Ph3P) 2PdCl2 (11 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as a solvent at 80 ° C will last 6 hours to yield (Z) -carbamic acid 3- [2,3-dihydro-3- [(3-methoxy-1H-pyrrole-2) i 1) methylene] -2-oxo-lH-indol-4-yl] -2-propynyl ester. (Yield 43 mg, 43%). The starting compound propargyl carbamate was prepared by the reaction of propargyl alcohol with sodium cyanate in trifluoroacetic acid and diethyl ether at room temperature for 18 h. Example 44: (Z) -N-Methylcarbamic acid 3- [2,3-dihydro-3"[(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl ] -2-propynyl ester (NN) Using Method C cited above, N-methyl prop »argyl carbamate (71.3 mg, 0.63 mmol) (see below) was coupled with (Z) -1,3-dihydro-4-iodo-3- [(3-methoxy -lH-pyrrol-2-yl) methylene] -2H-indole-2-one (110 mg, 0.3 mmol) (Starting Material 2 s upra) using (Ph3P) 2PdCl2 (11 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80 ° C for 6 h to yield (Z) -N-methylcarbamic acid 3- [2,3-dihydro-3- [(3-methoxy-1H) -pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -2-propynyl ester. (Yield 32 mg, 29%). The N-methyl propargyl carbamate was prepared by the reaction of propargyl alcohol with methyl isocyanate in trifluoroacetic acid and diethyl ether at room temperature for 18 h. Example 45: Rae- (Z) -1,3-Dihydro-5-fluoro-4- (3-hydroxy-1-pentynyl) -3 - [(4-methyl-1H-imidazol-5-yl) methylene] - 2H-iridol-2-one (00) Using Method C cited above, 1-pentin-3-cl (28.5 mg, 0.34 mmol) (Aldrich) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [(4 -methyl-lH-imidazol-5-yl) -methylene] -2H-indol-2-one (50 mg, 0.135 mmol) (starting material 3 s upra) using (Ph3P) 2PdCl2 (9.5 mg) and Cul (2.6 mg) as a catalyst in DMF (3 L) and Et 3 N (3 mL) as a solvent at 80 ° C for 6 h to yield e - (Z) -l, 3-dihydro-5-fluoro-4- (3-hydroxy) -l-pentynyl) -3- [(4-methyl-lH-imidazol-5-yl) methylene] -2H-indol-2-one. (Yield 17 mg, 39%).

Example 46: Rae- (Z) -1,3-Dihydro- (3-hydroxy-1-pentynyl) -3 - [(4-methyl-1H-imidazol-5-yl) methylene] -5-nitro-2H - indole-2-one (PP) Using Method C cited above, 1-pentin-3-ol (52.6 mg, 0.63 mmol) (Aldrich) was coupled with (Z) -l, 3-dihydro-4-iodo-3- [(4-methyl-lH -imidazol-5-yl) methylene] -5-nitro-2H-indole-2-one (100 mg, 0.25 mmol) (Starting Material 4 s upra) using (Ph3P) 2PdCl2 (17.5 mg) and Cul (4.8 mg) ) as a catalyst in DMF (3 mL) and Et3N (3 mL) as a solvent at 80 ° C for 6 h to yield rae- (Z) -1, 3-dihydro-4- (3-hydroxy-l-pentil) -3- [(4-Methyl-lH-imidazol-5-yl) -methylene] -5-nitro-2H-indol-2-one. (Yield 12 mg, 14%). Example 47: (Z) -1,3-Dihydro-5-fluoro-4- (3-hydroxy-1-propynyl) -3- (4-methyl-1H-imidazol-5-yl) methylene] -2H-indole -2-one, salt trifluoroacetate (QQ) Using Method C cited above, propargyl alcohol (38 mg, 0.68 mmol) was coupled with (Z) -l, 3-dihydro-5-fluoro-4-iodo-3- [(-methyl-1H-imidazole-5- il) ethyler.o] -2H-indol-2-one (100 mg, 0.27 mmol) (Starting material 3 sec.) using (Ph3P) 2PdCl2 (19 mg) and Cul (5.2 mg) as a catalyst in DMF (3 mg). mL) and Et3N (3 mL) as solvent at "80 ° C for 1 day to yield (Z) -1,3-dihydro-5-fluoro-4- (3-hydroxy-1-propynyl) -3- [( 4-methyl-lH-imidazol-5-yl) methylene] -2H-indol-2-one trifluoroacetate salt after purification by reverse phase chromatography (Yield 37 mg, 46%) Example 48: (Z) -1 , 3-Dihydro-5-fluoro-4- [3- (N-methylamino) -1-p-ropinyl] -3- [(-methyl-lH-imidazol-S-yl) methylether] -2H-indole -2 -one (RR) Using Method C cited above, N-methyl propargyl amine (23.3 mg, 0.34 mmol) (Aldrich) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [(4-methyl) -lH-imidazol-5-yl) methylene] -2H-indole-2-one (50 mg, 0.135 mmol) (starting material 3 s upra) using (Ph3P) 4Pd (15.6 mg) and Cul (3 mg) as catalyst in DMF (3 mL; and Et3N (3 mL) as solvent at 80 ° C for 8 h to yield (Z) -1,3-dihydro-5-fluoro-4- [3- (N-methylamino) -l -propynyl] -3- [(-methyl-lH-imidazol-5-yl) methylene] -2H-indol-2-one. (Yield 17 mg, 41%) Example 49: (Z) -1, 3- Dihydro-4-ethynyl-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (SS) Step 1: (Z) -1, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- (2-trimethylsilyl-ethynyl) -2H-indol-2-one Using method D above, tri-ethylsilacetylene (0.94 g, 9.63 mmol) (Aldrich) was coupled with (Z) 4-bromo-1,3-dihydro-3- (3-methoxy-1H-pyrrole-2-yl) methylene] -2H-indole-2-one (2.05 g, 6.42 mmol) (starting material 1 s upra) using (Ph3P) 2PdCl2 (0.23 g) and Cul (61 mg) as a catalyst in DMF (15 mL) and Et 3 N (15 mL) as a solvent at 80 ° C for 2 days to yield (Z) -1,3-dihydro-3- [(3-methoxy-1 H -pyrrol-2-yl) ethylene] - 4- (2-trimethylsilyl-ethynyl) -2H-indol-2-one. (Yield 1.3 g, 60%).

Step 2: (Z) -1, 3-Dihydro-4-ethynyl-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (SS) Using Method K cited above, a solution of (Z) -1,3-dihydro-3- [(3-methoxy-lH-pyrro1-2- i 1) -methylene] -4- (2-trimethylsilyl-ethynyl) -2H-Indole-2-one (1.3 g, 3.86 mmol) (from Step 1 above) in EtOH (80 mL) is treated with AgN03 (1.46 g, 8.59 mmol) in ethanol (5 mL) and water (15 mL). mL) at room temperature for 1 h followed by KCN (2.71 g, 41.6 mmol) in water (10 mL) to yield (Z) -1,3-dihydro-4-ethynyl-3 [(3-methoxy-1H-pyrrole). -2-yl) methylene] -2H-indol-2-one. (Yield 1.02 g, 100%). Example 50: Rae- (Z) -1,3-Dihydro-5-fluoro-4- (4-hydroxy-1-pentynyl) -3- [(4-methyl-1H-imidazol-5-yl) methylene ] -2H-Indole-2-one, trifluoroacetate salt (TT) Using Method C cited above, 1-pentin-4-ol (28.5 mg, 0.34 mmol) (Aldrich) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3 [(4 -methyl-lH-imidazol-5-yl) -methylene] -2H-indole-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P) 2PdCl2 (9.5 mg) and Cul (3 mg ) as a catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80 ° C for 8 h to yield rae- (Z) -1, 3-dihydro-5-fluoro-4- (-hydroxyl-pentynyl) -3- [(4-Methyl-lH-imidazol-5-yl) -methylene] -2H-indol-2-one, trifluoroacetate salt, after purification by reverse phase chromatography. (Yield 26 mg, 59%). Example 51: (Z) -1, 3-Dihydro-4 - [3- (, N-dimethylamino) -1-propynyl] -5-fluoro-3 [(-methyl-lH-imidazol-S-il) methylene] -2H-indol-2-one (UU) Using Method C cited above, N, N-dimethylpropropylamine (42.2 mg, 0.51 mmol) (Aldrich) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [(4- methyl-lH-imidazol-5-yl) methylene] -2H-indol-2-one (75 mg, 0.203 mmol) (Starting Material 3 supra) using (Ph3P) 4Pd (23.5 mg) and Cul (4 mg) as catalyst in DMF (3 mL) and Et3N (3 L) as solvent at 80 ° C for 6 h to yield (Z) -1, 3-dihydro-4- [3- (N, N-dimethylamino) -1-propynyl ] -5-fluoro-3- [(4-methyl-1H-imidazol-5-yl) methylene] -2H-indol-2-one. (Yield 40 mg, 61%). Example 52: (Z) -4- [3-Amino-3-methyl-l-butynyl] -1,3-dihydro-5-fluoro-3- [(4-methyl-lH-imidazol-5-yl) methylene ] -2H-indol-2-one (W) Using Method C cited above, 3-amino-3-methyl-1-butine (42.2 mg, 0.51 mmol) (Aldrich) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3 - [(4-Methyl-lH-imidazol-5-yl) methylene] -2H-indole-2-one (Starting Material 3 s upra) (75 mg, 0.203 mmol) using (Ph3P) 4Pd (23.5 mg) and Cul (4 mg) as a catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80 ° C for 18 h to yield (Z) -4- [3-amino-3-methyl-1-butynyl] -1,3-dihydro-5-fluoro-3- [(-methyl-lH-imidazol-5-yl) methylether] -2H-indol-2-one. (Yield 44 mg, 67%). Example 53: (Z) -carbamic acid 3- [2,3-dihydro-3- [(4-methyl-lH-imidazol-5-yl) methylene] -5-fluoro-2-oxo-lH-indole-4 -yl] -2-propynyl ester (WW) Using Method C cited above, propargyl carbamate (50.3 mg, 0.51 mmol) (see Example 43 upra) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [(4-metho) 1-1H-imidazol-5-yl) methylene] -2H-indole-2-one (Starting Material 3 supra) (75 mg, 0.203 mmol) using (Ph3P) 4Pd (23.5 mg) and Cul (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80 ° C for 1 day to yield (Z) -carbamic acid 3- [2,3-dihydro-3- [(4-methyl-1H-imidazole)] -5-yl) -methylene] -5-fluoro-2-oxo-lH-indol-4-yl] -2-propynyl ester.

(Yield 10 mg, 15%). Example 54: (Z) -1,3-Dihydro-5-fluoro-3- [(4-methyl-lH-imidazol-5-yl) methylene] -4- [3- (4-morpholinyl) -1-propynyl ] -2H-indol-2-one (XX) Using Method C cited above, 3- (4-morpholinyl) -1-propine (63.6 mg, 0.51 mmol) (prepared according to the method of H. Kano et al. ., J. Med. Ch., 10: 411-418 (1967)) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [(4-methyl-1H-imidazole. - 5-yl) methylene] -2H-indol-2-one (75 mg, 0.203 mmol) (Starting material 3 s upra) using (Ph3P) 4Pd (23.5 mg) and Cul (4 mg) as a catalyst in DMF (3 mL) and Et 3 N (3 mL) as a solvent at 80 ° C for 18 h to yield (Z) -1,3-dihydro-5-fluoro-3- [(4-methyl-lH-imidazol-5-yl) methylene] -4 - [3- (4-morpholinyl) -1-propynyl] -2H-indol-2-one. (Yield 40 mg, 54%). Example 55: Acid (Z) - [3- [2, 3-Dihydro-5-fluoro-3- [(4-methyl-lH-imidazol-5-yl) methylene] -2-oxo-lH-indole-4 -yl] -2-propynyl] carbamic methyl ester Using Method C cited above, 2-propynyl-carbamic acid methyl ester (57.5 mg, 0.51 mmol) (see Example 42 upra) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodine -3- [(-methyl-lH-imidazol-5-yl) methylene] -2H-indol-2-one (Starting material 3 s upra) (75 mg, 0.203 mmol) using (Ph3P) 4Pd (23.5 mg) (Aldrich) and Cul (4 mg) as a catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80 ° C for 18 h to yield acid (Z) [3- [2, 3-dihydro-5- fluoro-3- [(4-methyl-lH-imidazol-5-yl) methylene] -2-oxo-lH-indol-4-yl] -2-propynyl] carbamic methyl ester. (Yield 15 mg, 21%). Example 56: (Z) - (3- [5-fluoro-2,3-dihydro-3- [(-methyl-1H-imidazol-5-yl) methylene] -2-oxo-lH-indol-4-yl ] -2-propinyl] urea (ZZ) Using Method C cited above, 2-propynylurea (50 mg, 0.51 mmol) (see below) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [(4 -methyl-lH-imidazol-5-yl) methylene] -2H-indole-2-one (starting material 3 s upra) (75 mg, 0.203 mmol) using (Ph3P) 4Pd (23.5 mg) and Cul (4 mg ) as a catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80 ° C for 18 h to yield (Z) - (3- [5-fluoro-2,3-dihydro-3- [(-methyl) -lH-imidazol-5-yl) methylene] -2-oxo-lH-indol-4-yl] -2-propynyl] urea. (Yield 11 mg, 16%) The starting material 2-propynylurea was prepared by reaction of propargylamine (Aldrich) with sodium cyanate in a mixture of concentrated hydrochloric acid and water (3: 2) at room temperature during min . Example 57: Rae- (Z) -2- (acetylamino) -5- [5-fluoro-2, -dihydro-3- [(4-methyl-lH-imidazol-5-yl) methylene] -2] acid -oxo-lH-indol-4-yl] -4 -pentinoic ethyl ester (AAA) Using Method C cited above, 2 - (acetylamino) -4-pentynoic acid ethyl ester (92.6 mg0.51 mmol) (Bachem) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [(4-methyl-1H-imidazol-5-yl) methylene] -2H-indole -2-one (starting material 3 supra) (75 mg, 0.203 mmol) using (Ph3P) 4Pd (23.5 mg) and Cul (4 mg) as a catalyst in DMF (3 mL) and Et3N (3 mL) as solvent 80 ° C for 5 h to yield acid rae- (Z) -2- (acetylamino) -5- [5-fluoro-2,3-dihydro-3- [(-methyl-1H-imidazol-5-yl) methylene] ] -2-oxo-lH-indol-4-yl] -4-pentynoic ethyl ester. (Yield 70 mg, 81%). Example 58: (Z) -4- [3- (N, N-Diethylamino) -1-propynyl] -1,3-dihydro-5-fluoro-3 [(4-methyl-lH-imidazol-5-yl) methylene] -2H-indol-2-one (BBB) Using Method C cited above, N, N-diethyl Lpropargyl amine (38 mg, 0.34 mmol) (Aldrich) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [(4- methyl-lH-imidazol-5-yl) ethylene] -2H-indo1-2-one (starting material 3 s upra) (50 mg, 0.135 mmol) using (Ph3P) 4Pd (16 mg) and Cul (3 mg) as a catalyst in DMF (3 mL) and Et3N (3 mL) as a solvent at 80 ° C for 18 h to yield (Z) -4- [3- (N, N-diethylamino) -1-propynyl] -3, -dihydro-5-fluoro-3- [(4-methyl-1H-imidazol-5-yl) ethylene] -2H-indol-2-one. (Yield 20 mg, 42%). Example 59: (Z) -4- [3-Amino-3-ethyl-l-pentynyl] -1,3-dihydro-5-fluoro-3- [(4-methyl-lH-imidazol-5-yl) ethylene ] -2H-Indole-2-one (CCC) Using Method C cited above, 3-amino-3-ethyl-1-pentyne (37.6 mg, 0.34 mmol) (Aldrich) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3. - [(4-methyl-lH-imide zol-5-yl) mephylene] -2H-indole-2-one (Starting material 3 s upra) (50 mg, 0.135 mmol) using (Ph3P) 4Pd (16 mg) and Cul (3 mg) as a catalyst in DMF (3 L) and Et 3 N (3 mL) as solvent at 80 ° C for 6 h to yield (Z) -4- [3-amino-3-ethyl-1-pentynyl] -1, 3-dihydr: o -5-fluoro-3- (4-methyl-1H-imidazol-5-yl) methylene] -2H-indol-2-one. (Yield 45 mg, 95%). Example 60: (Z) - [3- (2, 3-Dihydro-5-fluoro-3- [(4-methyl-lH-imidazol-5-yl) methylene] -2-oxo-lH-indole-4 acid -yl] -1, l-dimethyl-2-propynyl] carbamic methyl ester (DDD) Using Method C cited above, (1,1-dimethyl-2-propynyl) -carbamic acid methyl ester (47.7 mg, 0.34 mmol) (see below) was coupled with (Z) -1,3-dihydro-5- fluoro-4-iodo-3- [(4-methyl-lH-imidazol-5-yl) -methylene] -2H-indole-2-one (Starting Material 2- s upra) (50 mg, 0.135 mmol) using (Ph3P) 4Pd (16 mg) and Cul (3 mg) as a catalyst in DMF (3 mg) and Et3N (3 mL) as solvent at 80 ° C for 5 h to yield acid (Z) - [3 [2, 3 -dihydro-5-fluoro-3- [(4-methyl-lH-Lmidazol-5-yl) methylene] -2 -oxo-lH-indol-4-i 1] -1, 1-dimethyl-2-propynyl ] carbamic methyl ester. (Yield 40 mg, 77%). The starting acidic compound (1/1-dimethyl-2-propynyl) -carbamic methyl ester was prepared by the reaction of 3-amino-3-met il-1-butine (Aldrich) with methyl chloroformate (Aldrich) in dichloromethane and saturated aqueous sodium bicarbonate solution.

Example 61: N- [3- [2, 3-Dihydro-5-fluoro-3- [(5-methyl-3H-imidazol-4-yl) methylene] -2-oxo-lH-indol-4-yl] -prop-2-inyl] -acet.amide (EEE) Using Method C cited above, N-propargyl acetamide (32.8 mg, 0.34 mmol) (prepared from the reaction of propargylamine (Aldrich) with acetyl chloride and triethylamine in dichloromethane a 0 ° C during coupling with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [(4-methyl-lH-imidazol-5-yl) methylene] -2H-indole-2- Ona (starting material 3 supra) (50 mg, 0.135 mmol) using (Ph3P) Pd (16 mg) and Cul (3 mg) as a catalyst in DMF (3 mL) and Et3N (3 mL) as a solvent at 80 ° C. for 5 h to yield N- [3- [2, 3-dihydro-5-fluoro-3- [(5-methyl-3H-imidazol-4-yl) methylene] -2-oxo-lH-indole-4- il] -prop-2-ynyl] -acetamide. (Yield 35 mg, 77%). Example 62: (Z) -1,3-Dihydro-5-fluoro-3- [(-methyl-lH-imidazol-5-yl) methylene] -4- [3- (1-piperidinyl) -1-propynyl] -2H-indol-2-one (FFF) Using Method C cited above, 1- (2-propynyl) -piperidine (41.3 mg, 0.34 mmol) (prepared according to the method of Kano et al., Upra) was coupled with (Z) -1,3-dihydro -5-fluoro-4-iodo-3- [(4-methyl-lH-imidazol-5-yl) methylene] -2H-indole-2-one (Starting Material 3 s upra) (50 mg, 0.135 mmol) using (Ph3P) 4Pd (16 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 L) as solvent at 80 ° C for 5 h to yield (Z) -1, 3-dihydro- 5-fluoro-3- [(4-methyl-lH-imidazol-5-yl) methylene] -4- [3- (1-piperidinyl) -1-propynyl] -2H-indol-2-one. (Yield 15 mg, 31%). Example 63: (Z) -4-Iodo-3- [(lH-pyrrol-2-yl) methylene] -1,3-dihydro-indol-2-one A mixture of 1, 3-dihydro-4-iodo-2H-indol-2-one (404.1 mg, 1.56 mmol) (prepared according to the method of T. Fukuya et al., Upra) and pyrrole-2-carboxaldehyde (163.2) mg, 1.72 mmol) (Aldrich) in 2-propanol (6.2 mL) is treated with 2 drops of piperidine (Aldrich). The reaction mixture is heated to reflux for 2-1 h and then allowed to cool to 23 ° C, at which time the reaction mixture is filtered. The solid is washed several times with sterile distilled water and then allowed to air dry to give (Z) -1,3-dihydro-4-iodo-3- [(1H-pyrrol-2-yl) ethylene] -indole- 2-one pure. (Yield 341.8 mg, 65%) in the form of a yellow solid, which was used without further purification. Ejep lo 64: 3- [2, 3-dihydro- (Z) -3- [(lH-pyrrol-2-y1) methylene] -2-oxo-lH-indol-4-yl] - (E) - acid 2-propenoic methyl ester.r (GGG) To a stirred solution of (Z) -1,3-dihydro-4-iodo-3 - [(1H-pyrrol-2-yl) methylene] indol-2-one (from Example 63) (500 mg, 1.49 mmol) DMF (8 mL) and TEA (3 mL) were added with methyl acrylate (0.26 L, 2.98 mmol) (Aldrich), tri-otolylphosphine (361 mg, 1.19 mmol) (Aldrich) and Pd (OAc) 2 (67 mg 0.30 mmol) (Aldrich). The reaction mixture is stirred at 85 ° C overnight in a pressure tube. The solvent was removed in vacuo, and the residue was purified by chromatography on silica gel (Hex: EtOAc = 5: 1) to provide 3- [2,3-di-1-dihydroxy] -3- [(1H-) acid. pyrrol-2-yl) ethylene] -2-oxo-lH-indol-yl) - (E) -2-propenoic methyl ester in the form of a yellow solid. (Yield 363 mg, 83%). Example 65: 3- acid. { 2, 3-dihydro- (Z) -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] - (E) -2- propenoic methyl ester (HHH) 5 To a stirred solution of (Z) -1,3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indo1-2-one (545 mg, 1.49 mmol) (Starting Material 2 s)) in 5 DMF (8 mL) and TEA (3 mL) was added methylacrylate (0.26 mL, 2.98 mmol) (Aldrich), tri-o-tolyl fos fine (361 mg, 1.19 mmol ) (Aldrich) and Pd (0Ac) 2 (67 mg, 0.39 mmol) (Aldrich). The reaction mixture is stirred at 85 ° C overnight in a pressure tube. The solvent was removed in vacuo, and the residue was purified by chromatography on silica gel (Hex: EtOAc = 5: 1) to provide 3- [2,3-dihydro- (Z) -3- [(3-methoxy) acid. -lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] - (E) -2-propenoic methyl ester in the form of a yellow solid. (Yield 371 mg, 77%). Example 66: 3-hydroxy-l-propenyl-boric acid To a stirred solution of propargylalcohol (0.584 mL, 10 mmol) (Aldrich) in THF (3 mL) was added dropwise catecholborane (20 mL, 1.0 M solution in THF) , 20 mmol) (Aldrich) at room temperature. After the gas evolution has ended, the mixture is heated to reflux for 5 h and allowed to cool to room temperature. To the cooled reaction mixture was added water (10 ml). The mixture was then stirred for 2 h at 20 ° C. The solvent was evaporated and the aqueous phase was washed with ether (3 x 15 ml). The water was lyophilized and the resulting 3-hydroxy-1-propenylboric acid was used without further purification. Example 67: 1,3-Dihydro-4- (3-hydroxy-propenyl) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -indol-2-one (III) To a stirred solution of (Z) -1,3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indo1-2-one (50 mg, 0.14 mmol) (Starting material 2 s)) in dimethoxyethane (5 L) was added 3-hydroxy-1-propenyl-boric acid (from Example 66 cited above) (42 mg, 0.418 mmol), tetrakis (triphenylphosphine) palladium (0) (39 mg, 0.034 mmol) (Aldrich) and 2 M solution of Na > C03 in H20 (0.34 L). The reaction mixture is stirred at 85 ° C overnight in a pressure tube. . The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (Hex: EtOAc = 5: 1) to provide 1,3-dihydro-4- (3-hydroxy-propenyl) 3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -indol-2 -one like a yellow solid. (Yield 22 mg, 53%). Example 68: 4-hydroxy-1-butenyl-boric acid To a stirred solution of 3-butyn-1-ol (0.748 mL, 10 mmol) (Aldrich) in THF (3 mL) was added dropwise catecholborane (20 mL , 1.0 M solution in THF, 20 mmol) (Aldrich) at room temperature. After the gas evolution has ended, the mixture is heated to reflux for 5 h and allowed to cool to room temperature. To the cooled reaction mixture was added water (10 ml). The mixture was then stirred for 2 h at 20 ° C. The solvent was evaporated and the aqueous phase was washed with ether (3 x 15 ml). The water was lyophilized and 4-hydroxy-1-butenylboric acid was used without further purification. Example 69: 1,3-Dihydro-4- (4-hydroxy-but-1-enyl) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -indol-2-one (JJJ) To a stirred solution of (Z) -1,3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (50 mg) 0.14 mmol) (Starting Material 2) in dimethoxyethane (5 mL) was added 4-hydroxy-1-butenyl-boric acid (48 mg, 0.418 mmol) (from Example 68 cited above), tetrakis (triphenylphosphine) palladium (0) (39 mg, 0.034 mmol) (Aldrich) and 2M solution of Na 2 CO 3 in H 2 O (0.34 L). The reaction mixture is stirred at 85 ° C overnight in a pressure tube. The solvent was removed in vacuo, and the residue was purified by chromatography on silica gel (Hex: EtOAc = 5: 1) to give 1,3-dihydro-4- (4-hydroxy-but-1-enyl) -3- [(3-methoxy-lH-pyrrol-2-yl) mephylene] -indo1-2-one as a yellow solid. (Yield 21 mg, 50%). Example 70: (R) - (Z) -1,3-Dihydro-5-fluoro-4- (4-hydroxy-1 -pentinyl) -3 - [(4-methyl-1H-imidazol-5-yl) methylene ] -2H-indole -2 -one (KKK) Using Method C cited above, (R) -pent-4-in-2-ol (68 mg, 0.82 mmol) (see Example 78 below) was coupled with (Z) -1, 3-dihydro-5-fluoro -4-iodo-3- [(4-methyl-lH-imidazol-5-yl) methylene] -2H-indo 1-2-one (100 mg, 0.27 mmol) (Starting Material 3 supra) using (Ph3P) 4Pd (31 mg, 0.03 mmol) and Cul (6 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80 ° C for 4 hours. After completion, the reaction mixture was concentrated and the residue was chromatographed on a column of silica gel with pure CH 3 CN, then THF and finally MeOH as elution solvent. (R) - (Z) -1,3-Dihydro-5-fluoro-4- (4-hydroxy-1-pentynyl) -3- [(4-methyl-lH-imidazol-5-yl) methylene] - The resulting 2H-indol-2-one was triturated with Et20 and then recrystallized from superheated EtOH. (Yield 18 mg, 20%). Example 71: (S) - (Z) -1,3-Di- hydro-5-fluoro-4- (4-hydroxy-1 -pentinyl) -3- [(4-methyl-1H-imidazol-5-yl) methylene ] -2H-indole -2 -one (LLL) Using Method C cited above, (S) -pent-4-in-2-ol (68 mg, 0.82 mmol) (see Example 81 below) was coupled with (Z) -1, 3-dihydro-5-fluoro -4-iodo-3- [(-methyl-1H-imidazol-5-yl) methylene] -2H-indo 1-2-one (100 mg, 0.27 mmol) (starting material 3 s upra) epleting (Ph3P 4Pd (31 mg, 0.03 mmol) and Cul (6 mg) in a mixture of DMF (5 L) and Et3N (5 mL) as solvent at 80 ° C for 4 hours. After completion, the reaction mixture was concentrated and the residue was chromatographed on a column of silica gel with pure CH 3 CN, then THF and finally MeOH as elution solvent. (S) - (Z) -1,3-Dihydro-5-fluoro-4- (4-hydroxy-1-pentynyl) -3 - [(4-methyl-1H-imidazol-5-yl) ethylene] - The resulting 2H-indol-2-one was triturated with Et20 and then recrystallized from supercalated EtOH. (Yield 57 mg, 65%). Exempyl 72: Rae- (Z) -1,3-Dihydro-5-fluoro-4- (3-hydroxy-1-pentynyl) -3- [(3-methoxy-1H-pyrrol-2-yl) methylene] - 2 H -incol-2-one (MMM) Using Method C cited above, 1-pentin-3-ol (54.5 mg, 0.65 mmol) (Aldrich) was coupled with Z) -1, 3-dihydro-5-fluoro-4-iodo-3- [(3 -methoxy-lH-pyrrol-2-yl) -methylene] -2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, see above) using (Ph3P) 4Pd (30 mg) and Cul (5 mg) as a catalyst in DMF (5 L) and Et 3 N (5 L) as solvent at 85 ° C for 18 h to yield rae- (Z) -1,3-dihydro-5-fluoro-4- (3-hydroxyl-pentynyl) -3- [(3-methoxy) lH-pyrrol-2-yl) -methylene] -2H-indol-2-one. (Yield 56 mg, 64%). Example 73: Rae- (Z) -1,3-Dihydro-5-fluoro-4- (3-hydroxy-1-pentynyl) -3- [(1H-pyrrol-2-yl) methylene] -2H-indole 2-one (NNN) Using Method C cited above, 1-pentin-3-ol (58.9 mg, 0.7 mmol) (Aldrich) was coupled with (Z) -l, 3-d: Lhydro-5-fluoro-4-iodo-3- [ (lH-pyrrol-2-yl) methylene] -2H-indol-2-one (100 mg, 0.28 mmol) (Starting Material 5, supra) using (Ph3P) 4Pd (32 mg) and Cul (5.3 mg) as a catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85 ° C for 10 h to yield rae- (Z) -1, 3-Dihydro-5-fluoro-4- (3-hydroxy-l- pentynyl) -3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 64 mg, 70%). Example 74: (Z) -1, 3-Dihydro-5-fluoro-4 - [3- (N-methylamino) -1-propynyl] -3 [(lH-pyrrole-2-y1) methylene] -2H-indole -2-one (000) Using Method C cited above, N-methylpropargylamine (48.4 mg, 0.7 mmol) was coupled with (Z) -1, 3-dihydro-5-fluoro-4-odo-3- [(1H-pyrrole-2-methylene] -2H-indol-2-one (100 mg, 0.28 mmol) (Starting Material 5, supra) employing ( Ph3P) 4Pd (32 mg) and Cul (5.3 mg) as a catalyst in DMF (5 mL) and Et3N (5 L) as a solvent at 85 ° C for 18 h to yield (Z) -1,3-dihydro-5- fluoro-4- [3- (N-methylamino) -1-propynyl] -3 [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 10 mg, 12%). 75: (Z) -1, 3-Dihydro-5-fluoro-4- [3- (N-methylamino) -1-ropinyl] -3- (3-methoxy-lH-pyrrol-2-yl) methylene] - 2H-indol-2-one (PPP) Using Method C cited above, N-methylpropargylamine (44.9 mg, 0.65 mmol) was coupled with (Z) -l, 3-dihydro-5-fluoro-4-iodo-3- [(3-methoxy-1H-pyrrol- 2-yl) -methylene] -2H-indole-2-one (100 mg, 0.26 mmol) (Starting Material 6, supra) using (Ph3P) 4Pd (32 mg) and Cul (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85 ° C for 18 h to yield (Z) -1, 3-Dihydro-5-fluoro-4- [3- (N-methylamino) -1-propynyl] - 3 -) (3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 10 mg, 12%). Example 76: hydrochloride salt of (Z) -1,3-dihydro-5-fluoro-4- [3- (N-methyl-amino) -1-propynyl] -3 - [(3-methoxy-1H-pyrrol- 2-yl) methylene] -2H-indol-2-one (QQQ) Using Method C cited above, N-methyl-propargylamine (45 mg, 0.66 mmol) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [(3-methoxy-1H-) pyrrol-2-yl) -methylene] -2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, see above) using (Ph3P) 4Pd (30.1 mg) and Cul (6.0 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 80 ° C for 5 h to yield saL hydrochloride of (Z) -1, 3-dihydro-5-fluoro-4- [3- (N-methylamino ) -1-propynyl] -3 - [(3-methoxy-1H-pyrro 1-2 -yl) methylene] -2H-indole-2-Ona. (Yield 30 mg, 32%). To this free base in methanol was added 4N HCl (2 ml) in dioxane (0.02 ml) (Aldrich). The mixture was evaporated to dryness to yield the hydrochloride salt. Example 77: (R) - (Z) -1,3-Dihydro-5-fluoro-4- (3-hydroxy-1-butynyl) -3- (4-methyl-lH-imidazol-5-yl) methylene] -2H-indol-2-one (RRR) Using Method C cited above, (R) - But-3-in-2-ol (189 mg, 2.71 mmol) (Aldrich) was coupled with (Z) -1, 3-dihydro-5-fluoro-4-iodine -3- [(-methyl-lH-imidazol-5-yl) -methylene] -2H-indol-2-one (100 mg 0.27 mmol) (Starting Material 3 supra) using (Ph3P) 4Pd (30 mg, 0.03 mmol) and Cul (2 mg) in a mixture of DMF (5 mL) and Et3N (5 L) as solvent at 80 ° C for 4 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4 and concentrated. (R) - (Z) -l, 3-DihydrD-5-fluoro-4- (3-hydroxy-l-butynyl) -3 - [(4-methyl-lH-yl-idazol-5-yl) methylene was obtained ] -2H-indol-2-one after chromatography on silica gel with 0-10% MeOH in a CH2C12 gradient and trituration with Et2Q. (Performance 40 mg, 47%). Example 78: (R) - (Z) -1,3-Dihydro-5-fluoro-4- (4-hydroxy-1 -pentinyl) -3 - [(3-methoxy-1H-pyrrole-2-yl) methylene ] -2H-indol -2-one (SSS) Using Method C cited above, (R) -pent-4-in-2-ol (44 mg, 0.52 mmol) (see below) was coupled with (Z) -1,3-dihydro-5-fluoro- 4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) ethylene] -2H-indol-2-one (50 mg, 0. 13 mmol) (Starting Material 6) using (Ph3P) 4Pd (15 mg, 0.01 mol) and Cul (2 mg) in a mixture of DMF (5mL) and E; 3N (5L) as a solvent at 80 ° C for 7 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na.'SO4 and concentrated. (R) - (Z) -1,3-Dihydro-5-fluoro-4- (4-hydroxy-1-pentini 1) -3 [(3-methoxy-lH-pyrrole-2-yl) methylene was obtained ] -2H-indol-2-one after chromatography on silica gel with 0-70% EtOAc in a gradient of hexanes and trituration with Et20. (Rendimie:.? To 20 mg, 45%). The optically active () -pent-4-in-2-ol was prepared according to the method of C. Dimitriadis, Tetrahedron Asymme try, 1 997, 8, 2153. Example 79: acid (Z) -5 - ^ 2, 3-dihydro-5-fluoro-3- [(3-methoxy-1H-pyrrol-2-yl) methylene] -2-oxo-1H-indol-4-yl] -4-pentynoic methyl ester ( TTT) Using Method C cited above, 4-pentynoic acid methyl ester (75.7 mg, 0.68 mmol) (see Example 8, s upra) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3 - [(3-methoxy-lH-pyrrol-2-y1) methylene] -2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, supra) using (Ph3P) 4Pd (31.2 mg ) and Cul (5.0 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 80 ° C for 7 h to yield acid (Z) -5- [2, 3-Dihydro-5-fluoro-3- [(3-methoxy-l-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -4 -pentinoic methyl ester. (Yield 86 mg, 90%). Example 80: (Z) -1,3-Dihydro-5-fluoro-4 - [(1-hydroxy-cyclopentyl) ethynyl] -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H -indol-2-ona (UUU) Using Method C cited above, 1-ethynyl-1-cyclopentanol (35.8 mg, 0.33 mmol) (Aldrich) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3 [(3- methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (50 mg, 0.13 mmol) (starting material 6) using (Ph3P) 4Pd (15 mg) and Cul (2.5 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 80 ° C for 5 h to yield (Z) -l, 3-Dihydro-5-fluoro-4 - [(1-hydroxycyclopentyl) ethynyl] -3- (3-methoxy-lH-pyrrol-2-yl) -methylene] -2H-indol-2-one. (Yield 32 mg, 67%). Example 81: (S) - (Z) -1,3-Dihydro-5-fluoro-4- (4-hydroxy-1-pentynyl) -3- (3-methoxy-1H-pyrrole-2-yl) methylene. ] -2H-indole -2 -one (VW) Using Method C cited above, (S) -pent-4-in-2-ol (44 mg, 0.52 mmol) (see below) was coupled with (Z) -1, 3-dihydro-5-fluoro-4 -iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (50 mg, 0. 13 mmol) (Starting Material 6) using (Ph3P) 4Pd (15 mg, 0.01 mmol) and Cul (2 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80 ° C for 7 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4 and concentrated. (S) - (Z) -1,3-Dihydro-5-fluoro-4- (4-hydroxy-1 -pentinyl) 3- [(3-methoxy-1 H -pyrrol-2-yl) methylene] - 2H-indol-2-one after chromatography on silica gel with 0-70% EtOAc in a gradient of hexanes and trituration with Et20.

(Yield 30 mg, 65%). The optically active (S) -pent-4-in-2-ol was prepared according to the method of C. Dimitriadis, Tetrahedron Asymrn et ry, 1 997, 8, 2153. Example 82: (R) - ( Z) -1,3-Dihydro-5-fluoro-4- (3-hydroxy-1-butynyl) -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indole-2- ona (WWW) Using Method C cited above, (R) -but-3-in- 2-ol (37 mg, 0.53 mmol) (Aldrich) was coupled with (Z) -l, 3-dihydro-5-fluoro-4-iodine -3 [(3-methoxy-1H-pyrrol-2-yl) -methylene] -2H-indol-2-one (50 mg, 0.13 mmol) (starting material 6) using (Ph3P) 4Pd (15 mg, 0.01 mmol) and Cul (2 mg) in a mixture of DMF (3 mL) and Et3N (3 mL) as solvent at 80 ° C for 6 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4 and concentrated. (R) - (Z) -1,3-Dihydro -5-fluoro-4- (3-hydroxy-l-butynyl) -3 [(3-methoxy-lH-pyrrole-2-yl) methylene] - 2H-indol-2-one after chromatography on silica gel with 0-70% EtOAc in a gradient of hexanes and trituration with petroleum ether. (Yield 21 mg, 48%). Example 83: (S) - (Z) -1,3-Dihydro-5-fluoro-4- (3-hydroxy-1-butynyl) -3- [(3-methoxy-1H-pyrrol-2-yl) methylene ] -2H-Indole-2-one (XXX) Using Method C cited above, (S) -but-3-in-2-ol (36 mg, 0.53 mmol) (Aldrich) was coupled with (Z) -1, 3-dihydro-5-fluoro-4-iodine -3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (ph3P) 4Pd (15 mg, 0.01 mmol) and Cul (2 mg) in a mixture of DMF (3-mL) and Et3N (3 mL) as solvent at 80 ° C for 5 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4 and concentrated. (S) - (Z) -1,3-Dihydro-5-fluoro-4- (3-hydroxy-1-butynyl) -3 [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-Indole-2-one after chromatography on silica gel with 0-70% EtOAc in a gradient of hexanes and trituration with petroleum ether. (Yield 32 mg, 75%). Example 84: (S) - (Z) -1,3-Dihydro-5-fluoro-4- (3-hydroxy-1-butynyl) -3- [(4-methyl-1H-imidazol-5-yl) methylene ? o] -2H-indole -2-one (YYY) Using Method C cited above, (S) -but-3-in- 2-ol (38 mg, 0.54 mmol) (Aldrich) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [(4-methyl-lH-imidazol-5-yl) -methylene] -2H- indole-2-one (50 mg, 0.14 mmol) (starting material 3 s upra) using (Ph3P) 4Pd (16 mg, 0.01 mmol) and Cul (2 mg) in a mixture of DMF (3 mL) and Et3N ( 3 mL) as solvent at 80 ° C for 5 hours After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4 and concentrated. (S) - (Z) -1,3-Dihydro-5-fluoro-4- (3-hydroxy-1-butynyl) -3 [(4-methyl-lH-imidazol-5-yl) methylene] - 2 H -indole-2-one after a column in silica gel with a gradient of 0-10% MeOH in CH2C1 and trituration with Et20. (Yield 21 mg, 50%). Example 85A: 4-Ethynyl-tetrahydro-pyran-4-ol A solution of ethynylmagnesium chloride in THF (0.5 M, 120 mL, 60 mmol) was added with cooling in an ice-water bath to a solution of tetrahydro-4H-pyran-4-one (4.96 g, 50 mmol) ( Aldrich) in diethyl ether (300 mL) dropwise for 15 min. The mixture is stirred under refrigeration for 3 h. Aqueous ammonium chloride solution (100 mL, 15% WN) was then added and the mixture extracted with ether (2 X 200 mL). The ether phases were washed with saturated aqueous sodium chloride solution (200 mL), then combined, dried (MgSO 4), filtered and concentrated to yield 4-ethynyl-tetrahydro-pyran-4-ol as an oil. colorless that solidified at rest. (Yield 6.01 g, 96.%).

Example 85B: (Z) -l, 3-Dihydro-5-fluoro-4- [(4-hydroxy-tetrahydro-pyran-4-yl) ethynyl] -3- [(3-methoxy-1H-pyrrol- 2-yl) methylene] -2H-indol-2-one (ZZZ) Using Method C cited above, 4-ethynyl-tetrahydro-pyran-4-ol (41.1 mg, 0.33 mmol) (Example 85A) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo- 3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) employing (Ph3P) 4Pd (15 mg) and (2.5 mg) as a catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 85 ° C for 7 h to yield (Z) -1,3-Dihydro-5-fluoro-4- (4-hydroxy). tetrahydro-pyran-4-yl) ethynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] 2H-indol-2-one. (Yield 36 mg, 75%). Example 86: (Z) -1,3-Dihydro-4- [(-hydroxy-te rahydro-pyran-4-yl) ethynyl] -3 [(3-methoxy-lH-pyrrol-2-yl) methylene] - 5-ni tro-2H-indol-2-one (AAAA) Using Method C cited above, 4-ethynyl-te trahydro-pyran-4-ol (43.3 mg, 0.34 mmol) (Example 85A) was coupled with (Z) -1,3-dihydro-4-bromo-3- [ (3-methoxy-lH-pyrrol-2-yl) methylene] -5-nitro-2H-indol-2-one (50 mg, 0.14 mmol) (Starting Material 7) using (Ph3P) 4Pd (16 mg) and Cul (3.0 mg) as a catalyst in DMF (4 mL) and Et3N (4 mL) as a solvent at 85 ° C for 18 h to yield (Z) -1,3-Dihydro-4- [(4-hydroxytetrahydro-pyran- 4-yl) ethynyl] -3- (3-methoxy-1H-pyrrol-2-yl) methylene] -5-nitro-2H-indo1-2-one. (Yield 30 mg, 53%). Example 87A: (S) -N-Boc-2-Formyl-pyrrolidine (S) -N-Boc-2-Formyl-pyrrolidine was prepared by Swern oxidation of (S) -N-Boc-prolinol (Fluque) in accordance with the conditions described by M.G.B. Drew et al., J. Ch em. Soc. Pergui n 1, 1998, 1627, during the 1st oxidation of CBZ-prolinol. Example 87B: (S) -N-Boc-2-Ethinyl-pyrrolidine (S) -Sf-Boc-2-Ethynyl-pyrrolidine was prepared according to Method X cited above by the treatment of (S) -N-Boc-2-formyl-pyrrolidine (470 mg, 2.36 mmol) (Example 87A cited above) with potassium tert-butoxide (340 mg, 3.07 mmol) and diazomethophosphonicodiethyl ester acid (550 mg, 3.07 mmol) (also prepared according to Method X) The product was obtained after gel column chromatography. silica with 10% Et20 in hexanes. (Yield 200 mg, 43%). Example 87C: (S) - (Z) -1,3-Dihydro-5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- [(pyrrolidin-2-yl) -etinyl] -2H-indol-2-one (BBBB) Using Method C cited above, (S) -N-Boc-2-ethynyl-pyrrolidine (100 mg, 0.52 mmol) (Example 87B) was coupled with (Z) -1,3-dihydro-5-fluoro-4 -iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P) 4Pd (15 mg , 0.01 mmol) and a catalytic amount of Cul in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80 ° C for 4 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4, concentrated and the residue is chromatographed on a silica gel column with gradient 40-70% EtOAc in hexanes. The intermediate obtained from this operation was dissolved directly at 0 ° C in 5 ml of a solution of tri-fluoroacetic acid 50% in CH2C12 containing 0.2 ml of H20 and stirred for 2.5 hours. After the completionThe reaction mixture is diluted with EtOAc and extracted with ammonium hydroxide. The organic phase is dried over Na 2 SO 4 and concentrated. (S) - (Z) -1,3-Dihydro-5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- [(pyrrolidin-2-yl) - ethynyl] -2H-indole-2-one after reversed-phase column chromatography with a gradient of 0-90% MeOH in H20, a column chromatography on silica gel with pure THF and a precipitation of THF with excess hexanes . (Yield 8 mg, 18%). Example 88: Hydrochloride salt of (S) - (Z) -1,3-dihydro-5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- [(pyrrolidin-2 -yl) ethynyl] -2H-indol-2-one (CCCC) A solution of (S) - (Z) -1,3-dihydro-5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- [(pyrrolidin-2-yl) -etinyl] -2H-indole-2-one (20 mg, 0.06 mmol) (Compound BBBB) in dioxane (2 mL) is treated with aqueous HCl under vigorous stirring. The hydrochloride salt was obtained after lyophilization. (Yield 20 mg, 86%).

E xemployment 89A: (R) -N-Boc-2 -Formil -pi rrolidine (R) -N-Boc-2-Formyl-pyrrolidine was prepared by Swern oxidation of (R) -NBoc prolinol (Fluka) using the procedure for the oxidation of CBZ-prolinol described in M.G.B. Drew and cois., Supra. Example 89B: (R) -N-Boc-2-E tínil-pirrolidina (R) -N-Boc-2-Ethynyl-pyrrolidine was prepared according to Method X cited above by the treatment of (R) -N-Boc-2-formyl-pyrrolidine (700 mg, 3.51 mmol) (Example 89A ) with potassium tert-butoxide (510 mg, 4.56 mmol) and diazomethylphosphonic acid diethyl ester (820 mg, 4.56 mmol) (also prepared in accordance with Method X). (R) -N-Boc-2-Ethynyl-pyrrolidine was obtained after chromatography on silica gel with Et20 in hexanes. (Yield 150 mg, 25%).

Example 89C: (R) - (Z) -1,3-Dihydro-5-fluoro-3-f (3-methoxy-lH-pyrrol-2-yl) methylene-4 - [(pyrrolidin-2-yl) ethynyl] -2H-Indole-2-one (DDDD) Using Method C cited above, (R) -N-Boc2-ethynyl-pyrrolidine (100 mg, 0.52 mmol) (Example 89B) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo- 3 - [(3-methoxy-lH-pyrrol-2-yl) mephylene] -2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P) 4Pd (15 mg, 0.01 mmol) and a catalytic amount of Cul (2 mg) in a mixture of DMF (4 L) and Et 3 N (4 L) as solvent at 80 ° C for 6 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4, concentrated and the residue chromatographed on a silica gel column with a gradient of 40-70% EtOAc in hexanes. The intermediate obtained from this operation is dissolved directly at 0 ° C, in 5 ml of a 50% solution of trifluoroacetic acid in CH2C12 containing 0.3 ml of H20 and stirred for 2 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with ammonium hydroxide. The organic phase is dried over Na 2 SO 4 and concentrated. (R) - (Z) -1,3-Dihydro-5-fluoro-3- [(3-methoxy-1H-pyrrol-2-yl) methylene] -4- [(pyrrolidin-2-yl) ethynyl was obtained ] -2H-indol-2-one after reverse phase column chromatography with 0-90% MeOH in a gradient of H20, a column chromatography on silica gel with pure THF and a precipitation of THF with excess hexanes. (Yield 14 mg, 31%). Example 90A: 4-Acetyl-2-formylpyrrole 4 - . 4-Acetyl-2-formylpyrrole was prepared according to the method of the D.O. Cheng et al., Synthesis of Substituted Porfirins. Te trahedron Le t t ers, 1 977, 1469-1472. Example 90B: (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) -methylene] -1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one 1,3-Dihydro-5-fluoro-4-iodo-2H-indol-2-one (0.77 g, 2.8 mmol) (see Example 2A, see above) and 4-acetyl-2-formylpyrrole (0.42 g, 3.06 mmol) ) (Example 90A cited above) was suspended in 1% piperidine in 2-propanol (12 mL) and THF (5 mL) and heated at 85 ° C for 2 h. A yellow precipitate formed. After cooling to room temperature, the product was collected by filtration and washed with aqueous 2-propanol and dried in a vacuum oven to yield (Z) -3 - [(4-acetyl-lH-pyrrol-2-yl. methylene] -1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one. (Yield 0.89 g, 80.8%). Example 90C: (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) -methylene] -1,3-dihydro-5-fluoro-4- [(4-hydroxy-tetrahydro-pyran-4) -i 1) ethynyl] -2H-indole-2-one (EEEE) Using Method C cited above, 4- Ethinyl-tetrahydro-pyran-4-ol (0.16 g, 1.26 mmol) (Example 85A) was coupled with (Z) -3- [(-acetyl-1H-pyrrole-2) -yl) methylene] -1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (0.2 g, 0.50 mmol) (Example 90B cited above) employing (Ph3P) 4Pd (58.4 mg) and Cul (9.6 mg) as a catalyst in DMF (15 mL) and Et3N (15 mL) as solvent at 85 ° C for 18 h. (Yield 102 mg, 52%). Example 9IA: (R) -N-Boc-2, 2-dimethyl-4-ethanol-1-oxazolidine (R) -N-Boc-2, 2-dimethyl-4-ethynyl-oxazolidine was prepared according to the method X cited above by the treatment of tert-butyl- (S) -4-formyl-2,2-dimethyl 3-oxazolidine carboxylate (1.00 g, 4.36 mmol L) (Aldrich) with potassium tert-butoxide (730 mg 6.54 mmol) and diazomethylphosphonic acid diethyl ester (1.20 9, 6.54 mmol) (see Method X, supra). The reaction was allowed to warm slowly to room temperature and stirred for a total of 12 hours. The product was obtained after column chromatography on silica gel with 20% Et20 in hexanes. (Yield 600 mg, 61%). Example 91 B: (R) - (Z) -4- (3-.Amino-4-hydroxy-1-butyne-1) -1, 3-dihydro-5-fluoro-3 [(3-methoxy-1H-pyrrole -2 -yl) methylene] -2 H-indol-2-one (FFFF) Using Method C cited above, (R) -N-Boc-2, 2-d: Lmethyl-4-ethynyloxazolidine (141 mg, 0.62 mmol) (Example 91A cited above) was coupled with dihydro-5-fluoro -4-iodo-3 - [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P) 4Pd (24 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80 ° C for 8.5 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4, concentrated and the residue is chromatographed on a column of silica gel with a gradient of 0-50% THF in hexanes. The intermediate resulting from this operation was dissolved directly in 6 mL of a 50% solution of trifluoroacetic acid in CH2C12 containing 0.6 L of H20 at 0 ° C and stirred for 2 hours .. After completion, the reaction mixture is diluted with EtOAc and extracted with ammonium hydroxide. The organic phase is dried over Na 2 SO 4 and concentrated. (R) - (Z) -4- (3-Amino-4-hydroxy-1-butynyl) -1,3-dihydro-5-fluoro-3- [(3-methoxy-1H-pyrrole-2-yl) was obtained il) methylene] -2H-indol-2-one after column chromatography on silica gel with a gradient of 0-20% MeOH in CH2C12 and precipitation of THF with excess pentane. (Yield 10 mg, 14%). Example 92A: (R) -3-Hydroxy-l-prop-2-ynyl-pyrrolidi aa To a solution of (R) -3-hydroxy-pyrrole idine (2.00 g, 22.95 mmol) (Aldrich) and Et3N (9.00 g, 88.93 mmol) in 45 mL of CH2C12 at 0 ° C was added propargyl bromide (3.00 g). , 25.21 mmol) dropwise. After completion of the addition, the reaction mixture is filtered and the filtrate is washed with saline, dried over Na 2 SO 4 and concentrated. (R) -3-Hydroxy-1-prop-2-ynyl-pyrrolidine was obtained after Krugerhor distillation. (Yield 700 mg, 24%). Example 92B: (R) - (Z) -1,3-Dihydro-5-fluoro-4 - [3- (3-hydroxy-pyrrolidin-1-yl) -1-propynyl] -3- [(3 -methoxy-1H-pyrrol-2-yl) methylene] -2H-indol-2-one (GGGG) Using Method C cited above, (R) -3-hydroxy-l-prop-2-ynyl-pyrrolidine (60 mg, 0.48 mmol) (Example 92A) was coupled with (Z) -1,3-dihydro-5- fluoro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (60 mg, 0.16 mmol) (Starting Material 6) using (Ph3P) 4Pd (18 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80 ° C for 6 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20, the organic phase is dried over Na2SO4 and concentrated. (R) - (Z) -1,3-Dihydro-5-fluoro-4- [3- (3-hydroxy-pyrrolidin-1-yl) -1-propynyl] -3- [(3-methoxy) 1H-pyrrol-2-yl) ethylene] -2H-indole-2-one after column chromatography on silica gel with a gradient of 0-20% MeOH in CH2C12 and a precipitation of THF with excess pentane. (Yield 45 mg, 76%). Example 93A: (S) -N-Boc-2, 2-dimethyl-4-etinyl-oxazolidine (S) -N-Boc-2,2-dimethyl-4-ethynyl-oxazolidine was prepared according to the method X cited above by the treatment of tert-butyl- (R) -4-formyl-, 2-dimethyl 3-oxazolidine carboxylate (1.00 g, 4.36 mmol) (Aldrich) with potassium tert-butoxide (730 mg, 6.54 mmol) and diazomethyl phosphonic acid diethyl ester (1.20 g, 6.54 mmol) (Method X cited above). The reaction was allowed to warm slowly to room temperature and stirred for a total of 12 hours. (S) -N-Boc-2, 2-dimethyl-4-ethanol-oxazolidine was obtained after column chromatography on silica gel with 20% Et20 in hexanes. (Yield 420 mg, 43%).

Example 93B: (S) - (Z) -4 - (3 -Ami non-4-hydroxy-1-butyl) -1,3-dihydro-5 -f luoro-3 [(3-methoxy-lH- pyrrole -2 -iP methylene] -2H-indole -2-on a (HHHH) Using Method C cited above, (S) -N-Boc-2, 2-d Lmethyl-4-ethynyl-oxazolidine (140 mg, 0.62 mmol) (Example 93A cited above) was coupled with (Z) -1, 3 -dihydro-5-fluoro-4- iodo-3- [(3-methoxy-lH-pyrrol-2-yl) -metheno] -2H-indole-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P) Pd (24 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80 ° C for 6 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4, concentrated and the residue chromatographed on a column of silica gel with 0-5.)% THF in hexanes gradient. The termite meal obtained from this operation was directly dissolved in 5 ml of a 50% solution of trifluoroacetic acid in CH2C1 containing 0.5 ml of H20 at 0 ° C and stirred for 2 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with ammonium hydroxide. The organic phase is dried over Na 2 SO and concentrated. (S) - (Z) -4- (3-Amin-4-hydroxy-1-butynyl) -1,3-dihydro-5-fluoro-3- [(3-methoxy-1H-pyrrole-2- il) ethylene] -2H-indol-2-one after column chromatography on silica gel with a gradient of 0-20% MeOH in CH2C12 and precipitation of THF with excess pentane. (Yield 22 mg, 31%). Example 94: (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4 [3- (N-methylamino) -1-propynyl] -2H-indol-2-one (IIII) Using Method C cited above, N-methylpropargyl amine (43.6 mg, 0.66 mmol) was coupled with (Z) -3 - [(4-acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro- 5-fluoro-4-iodo-2H-indol-2 -one (100 mg, 0.25 mmol) (Example 90B) using (Ph3P) Pd (30.1 mg) and Cul (6.0 mg) as catalyst in DMF (6 mL) and Et 3 N (6 mL) as solvent at 89 ° C for 5 h to yield (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4 [3- (N-methylamino) -1-propynyl] -2H-indo 1-2 -one. (Yield 10 mg, 12%). Example 95A: N-Boc-N-methylpropargylamine Di-tert-butyl dicarbonate (2.27 g, 10.4 mmol) in dichloromethane (10 mL) was added dropwise to a solution of N-methylpropargylamine (0.72 g, 10.4 mmol) in dichloromethane (25 mL) at room temperature with stirring magnetic After 1 h, the reaction mixture is diluted with dichloromethane and washed with 1 N aqueous hydrochloric acid (30 mL) and saturated aqueous sodium bicarbonate solution (30 L). The aqueous phases were washed with dichloromethane (50 mL). The dichloromethane solutions were combined, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (Biotage 40S, EtOAc-hexanes v / v 1: 9 as solvent) to yield N-Boc-N-methylpropargiiamine. (Yield 1.54 g,: 7.4 'Example 95B: hydrochloride salt of (Z) -3-1 (4-acetyl-lH-pyrrol-2-yl) -methylene] -1,3-dihydro-5-luoro-4 - [ 3- (N-methylamino) -1-propynyl] -2H-indol-2-one (JJJJ) Using Method C cited above, N-Boc-N-methylpr opargyl-amine (0.12 g, 0.70 mmol) (Example 95A cited above) was coupled with (Z) -3- [(4-acetyl-lH-pyrrole-2 -yl) methylene] -1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (0.1 g, 0.25 mmol) (Example 90B) using (Ph3P) 4Pd (40 mg) and Cul ( 8.0 mg) as a catalyst in DMF (6 mL) and Et3N (6 mL) as a solvent at 85 ° C for 5 h. To the resulting compound was added a 1: 1 mixture of trifluoroacetic acid / CH2C12 (5 ml) and 3 drops of water at 0 ° C and the mixture was stirred at 0 ° C for 2 h. The mixture was then quenched with concentrated NH OH (5 mL) and diluted with EtOAc. The organic phase is washed with saline and dried with MgSO4. The product was purified by flash column chromatography (10% MeOH in CH2C12). To the free base in methanol (2 mL) was added 4N HCl in dioxane (0.02 mL). The evaporation of the solvent to dryness yielded the hydrochloride salt. (Yield 30 mg, 32%). Example 96A: (S) -3-Hydroxy-l-prop-2-ynyl-pyrrolidine HQ.

To a solution of (R) -3-hydroxy-l-prop-2-ynyl-pyrrolidine (200 mg, 1.59 mmol) (see Example 92A), benzoic acid (230 mg, 1.91 mmol) (Aldrich) and triphenylphosphine (628 mg, 2.39 mmol) (Aldrich) in 25 L of THF, diisopropyl azodicarboxylate (485 g, 2.39 mmol) (Aldrich) was added at 0 ° C. The mixture is stirred for 1.25 hr and then partitioned between EtOAc and saturated aqueous Na 2 CO 3. The organic phase is dried over Na 2 SO 4, concentrated, and the residue is passed through a column of silica gel with a gradient of 0-50% EtOAc in hexanes. The resulting benzoate ester intermediate was then dissolved in 15 mL of MeOH, and K2CO3 (439 mg, 3.18 mmol) was added. After stirring for 36 hr the reaction mixture is filtered and concentrated. (S) -3-Hydroxy-1-prop-2-inylpyrrolidine was obtained after column chromatography on silica gel with pure THF and trituration with pentane. (Yield 102 mg, 51%).

Example 96B: (S) - (Z) -1,3-Dihydro-5-f luoro-4- (3- (3-hydroxy-p.Lrrolidin-1-yl) -1-propynyl] -3- [( 3-methoxy-1H-pyrrole-2-.L1) methylene] -2H-indol-2-one (KKKK) Using Method C cited above, (S) -3-hydroxy-l-prop-2-ynyl-pyrrolidine (60 mg, 0.48 mmol) (Example 96A) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (60 mg, 0.16 mmol) (starting material 6) using (Ph3P) 4Pd (18 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80 ° C for 6 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4 and concentrated. (S) - (Z) -1,3-Dihydro-5-fluoro-4- [3- (3-hydroxy-pyrrolidin-1-yl) -1-propynyl] -3- [(3-methoxy) 1H-pyrrol-2-yl) methylene] -2H-indole-2-one, then column chromatography on silica gel with a gradient of 0-20% MeOH in CH2C12 and precipitation of THF with excess pentane. (Yield 42 mg, 71%).

Example 97A: N-Boc-3-p irol i dinona N-Boc-3-pyrrolidinone was prepared according to the procedure method of Y. Narukawa et al., "General and Efficient Synthesis of 2-Alkylcarbapenems: Synthesis of Dethiacarba Analogs of Clinically Useful Carbapenems Via Paladium-Catalyzed Cross-Coupling Reaction ", Te trah edron, 1997, 53, 539-556. Example 97B: Rae-N-Boc-3-hydroxy-3-etini-1-pyrrolidine Ethinyl magnesium chloride (0.5 M in THF, 210 mL, 105 mmol) is diluted with THF (100 L) and cooled in an ice-water bath. A solution of N-Boc-3-pyrrolidinone (9.21 g, 50 mmol) (Example 97A cited above) in THF (100 mL) was added dropwise after cooling. The mixture is stirred for 2 h and then aqueous ammonium chloride solution (100 mL, 15% w / v) is added. The mixture is then extracted with ether (2 X 400 mL). The ester layers are washed with saturated aqueous sodium chloride solution (200 ml), combined, and dried, filtered and concentrated. The residue was chromatographed (Biotage Flash 40S, EtOAc-hexanes as solvent) to yield rac-N-Boc-3-hydroxy-3-etiine-1-pyrrolidine as a pale yellow oil which crystallized on standing. (Yield 10.13 g, 96.4%). Example 97C: rac-3-Hydroxy-3-ethynyl-pyrrolidine Rae- N.-Boc-3-hydroxy-3-ethynyl-pyrrolidine (2.02 g, 9.56 mmol) (Example 97B cited above) was dissolved in H 3 CN (20 mL). P-Toluenesulfonic acid monohydrate (3.64 g, 19.12 mmol) was added and the mixture was stirred at room temperature. The reaction was followed by TLC until no more starting material was observed. Excess sodium potassium carbonate was added to remove the acid and neutralize the salt. The suspension is filtered and the residue is washed with 10% methanol in dichloromethane. The filtrate and the washing of the residue are combined and concentrated to yield the crude product. The crude product is then filtered through silica gel and eluted with a mixture of triethylamine-methanol-dichloromethane (1: 3: 16, v / v). The combined eluate was concentrated and crystallized) from methanol-dichloromethane-hexanes to yield pure rac-3-hydroxy-3-ethynyl pyrrolidine as prisms. (0.24 g, yield 22.6%). Example 97D: Rae- (Z) -3- [(Acetyl-lH-pyrrol-2-yl) -methylene] -1,3-dihydro-5-fluoro-4- (3-hydroxy-pyrrolidin-3-yl) ethynyl] -2H-indol-2-one (LLLL) Using Method C cited above, rac-3-hydroxy-3-ethynyl-pyrrolidine (35.1 mg, 0.32 mmol) (Example 97C) was coupled with (Z) -3- [(4-acetyl-lH-pyrrole-2- il) -methylene] -1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (50 mg, 0.13 mmol) (see Example 90B) using (Ph3P) 4Pd (15 mg) and (3.0 mg) as a catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85 ° C for 5 h. (Yield 10 mg, 21%).

Example 98: Rae- (Z) -3 - [(4-Acetyl-IH-pyrrole-2-yl) -methylene) -1,3-dihydro-5-fluoro-4 - [(3-hydroxy-) hydrochloride salt pyrrolidin-3-i1) ethynyl] -2H-indol-2-one Using Method C cited above, N-Boc-3-hydroxy-3-ethynyl-pyrrolidine (0.2 g, 0.95 mmol) (Example 97B) was coupled with (Z) -3- [(4-aceti L-lH-pyrrole -2-yl) ethylene] -1,3-dihydro-5-fluoro-4- Lodo-2H-indol-2-one (0.15 g, 0.38 mmol) (Example 90B) using (Ph3P) 4Pd (60 mg) and Cul (13.5 mg) as catalyst in DMF (8 mL) and Et3N (8 mL) as solvent at 85 ° C for 8 h. To the resulting compound in CH2C12 (6 mL) was added a 1: 1 mixture of trifluoroacetic acid / CH2C12 (6 mL) and 3 drops of water at 0 ° C and the mixture was stirred at 0 ° C for 3 h. Quench with concentrated NH40H solution (6 mL) and dilute with EtOAc. The organic phase was washed with saline and dried with MgSO4. The product was purified by flash column chromatography (10% MeOH in CH2C12). To the free base in methanol (2 mL) was added 4N HCl in dioxane (0.04 mL). The evaporation of the solvent to dryness yielded the hydrochloride salt. (Yield 65.6 mg, 41%). Example 99A: (3R, 5S) -N-Boc-3- (tert-Butyldimethylsiloxy) -5-hydroxymethylene pyrrolidine A solution of trans-1-hydroxy proline (2.00 g, 15.24 mmol) (Aldrich) and imidazole (2.20 g, 32.01 mmol) (Aldrich) in CH2C12 (60 mL) is treated with tertbutyl chloride ldimet ilsili lo (4.60 g). , 30.48 mmol) (Aldrich). After stirring overnight the mixture was poured into saline and extracted with CH2C12. The organic phase is dried over Na 2 SO 4 and concentrated. The residue was then directly dissolved in 50 ml of MeOH and the resulting solution was heated to reflux for 4.5 hours and then stirred at room temperature for another 17 h. The solvent is then evaporated in vacuo and the resulting interme diary is diluted in 60 mL of THF, cooled to 0 ° C and BF3"Et20 (15.30 mmol, 1.92 mL) (Aldrich) and BH3-DMS (22, 90 mmol, 2.30 mL) (Aldrich) The resulting mixture is then refluxed for 1.5 hours, cooled to room temperature, quenched with MeOH, and concentrated.The residue was partitioned between CH2C12 and ammonium hydroxide. After 4 hours of vigorous stirring, the two layers were separated and the aqueous phase was extracted again with CH2C12 and the combined organic phases were dried over Na2SO4 and concentrated, the residue was dissolved directly in 35 mL of CH2C12 and then added. Et 3 N (3.08 g, 30.60 mmol), a catalytic amount of DMAP (Fluka) and diterc-butyl-dicarbonate (3.30 g, 15.30 mmol) (Fluka) at 0 ° C. The reaction was allowed to warm slowly to room temperature, stirred for 2.5 hours, and then poured over H20.The aqueous phase is separated and ex bring twice more with CH2C12 and the combined organic layer is dried over Na2SO and concentrated. (3R, 5S) -N-Boc-3- (tert-Buti 1dimeti Isi loxi) -5-hydroxymethylene-pyrrolidine was obtained after column chromatography on silica gel with 0-50% EtOAc in hexanes gradient. (Yield 2.10 g, 42% overall). Example 99B: (3R, 5S) -N-Boc-3-tert-Butyldimethyl-siloxy-5-ethynyl-pyrrolidine (3R, 5S) -N-Boc-3- (tert-Butyldimethylsiloxy) -5-hydroxy-methylene-pyrrolidine (1.30 g, 3.92 mmol) (Example 99A cited above), as a solution in a small volume of CH2C12 was transferred via a cannula under argon to a solution of oxalyl chloride (0.65 g, 5.09 mmol) (Aldrich), DMSO (0.92 g, 11.76 mmol) and Et3N (1.59 g, 15.68 mmol) in 60 mL of CH2C12 a -78 ° C. After 10 min the mixture was poured over H20. The aqueous layer is extracted twice more with CH2C12 and the combined CH2C12 layer is extracted with saturated aqueous NaHCO3 solution, dried over Na2SO4 and evaporated in vacuo. The residue is treated directly according to the X method with potassium tert-butoxide (660 mg, 5.88 mmol) and diazomet ilphos phonicodimethyl ester (880 mg, 5.88 mmol) in 60 mL of THF. The reaction was allowed to warm to room temperature slowly and stirred for a total of 17.5 hours. (3R, 5S) -N-Boc-3-tert-Butyldimethylsilyoxy-5-ethynyl-pyrrolidine was obtained after column chromatography on silica gel with a gradient 0-20% Et20 in hexanes. (Yield 720 mg, 56%). Example 99C: (3R, 5S) -N-Boc-3-Hydroxy-5-etinyl-pyrrolidine H (3R, 5S) -N-Boc-3-tert-Butyldimethylsiloxy-5-ethynyl-pyrrolidine: (700 mg, 2.15 mmol) (Example 99B cited above) was dissolved in a mixture of THF (20 mL) and H20 ( lmL). TBAF (1 M in TF) (Aldrich) was added (2.15 mL, 2.15 mmol) at 0 ° C and the reaction mixture was allowed to warm slowly to room temperature. After 21 hr at room temperature and 2 hrs at 50 ° C the mixture was concentrated in a small volume diluted with EtOAc and washed with saline. The organic phase is dried over Na 2 SO 4 and concentrated. (3R, 5S) -N-Boc-3-Hydroxy-5-ethynylpyrrolidine was obtained after column chromatography on silica gel with a gradient of 0-100% EtOAc in hexanes. (Yield 390 mg, 81%).

Example 99D: (Z) -1,3-Dihydro-5-fluoro-4 - [(2S, 4R) (4-hydroxy-pyrrolidin-2-yl) ethynyl] -3- (3-methoxy-1H-pyrrol- 2-yl) methyleneol-2H-indol-2-one (NNNN) Using Method C cited above, (3R, 5S) -N-Boc-3-Hydroxy-5-ethynyl-pyrrolidine (98 mg, 0.47 mmol) (Example 99C cited above) was coupled cen (Z) -1, 3- dihydro-5-fluoro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2H-indol-2-one (60 mg, 0.16 mmol) (Starting Material 6) using (Ph3P) 4Pd (18 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 L) as solvent at 80 ° C for 6 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4, concentrated and the residue is chromatographed < on a column of silica gel with 0-100% EtOAc in hexanes gradient. The intermediate resulting from this operation was directly dissolved in 5 mL of a 50% trifluoroacetic acid solution in CH2C12 containing 0.2 mL of H20 at 0 ° C and stirred for 2 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with ammonium hydroxide. The organic phase is dried over Na 2 SO and concentrated. (Z) -1, 3-Dihydro-5-fluoro-4- [(2S, 4R) - (4-hydroxy-pyrrolidin-2-yl) -etinyl] -3- [(3-methoxy-lH-pyrrol- 2-yl) methylene] -2H-indol-2-one was obtained after column chromatography on silica gel with gradient 0-20% MeOH in CH2C12 and precipitation of THF with excess pentane. (Yield 12 mg, 31%). Example 100: Hydrochloride salt of (Z) -1,3-Dihydro-5-fluoro-4- [(2S, 4R) - (4-hydroxy-pyrrolidin-2-yl) ethynyl] -3- [(3-methoxy -lH-pyrrol-2-yl) methylene] -2H-indol-2-one (OOOO) A solution of (Z) -1,3-dihydro-5-fluoro-4- [(2S, 4R) - (4-hydroxy-pyrrolidin-2-yl) ethynyl] -3- [(3-methoxy-lH- pyrrol-2-yl) methylene] -2H-indol-2-one (30 mg, 0.06 mmol) (Example 99D cited above) in DMF (3 mL) is treated with aqueous HCl with vigorous stirring.

The solution was lyophilized and the residue was precipitated from a mixture of CH2Cl2 / MeOH (3: 1) with excess pentanes. (Yield 30 mg, 91%) Example 101A: N-Boc-4-hydroxy-4-etinyl-piperidine A solution of ethynylmagnesium chloride in THF (100 mL, 50 mmol) is diluted with THF (50 mL) and cooled in a water and ice bath. A solution of Boc-4-piperidone (5.06 g, 25.4 mmol) (Aldrich) in THF (50 mL) was added dropwise over 15 min. The mixture is stirred after cooling for 3 h. Aqueous ammonium chloride solution (100 mL, 15% w / v) is added, and the resulting mixture is extracted with ether (2 X 200 mL). The ether layers were washed with saturated aqueous sodium chloride solution (200 ml), then combined, dried (MgSO 4), filtered and concentrated. The residue was purified by chromatography (Biotage 40M, ethyl acetate-hexanes 1: 3, v / v as solvent) to yield N-Boc-4-hydroxy-4-ethynyl-piperidine as a colorless oil that solidified, resting . (Yield 5.39 g, 94.2%).

Example 1Q1B: (Z) -1,3-Dihydro-5-fluoro-4- [(4-hydroxy-piperidin-4-yl) ethynyl] -3 - [(3-methoxy-lH-pyrrole-2) hydrochloride salt -yl) -methylene] -2H-indol-2-one (PPPP) Using Method C cited above, N-Boc-4-hydroxy-4-ethynyl-piperidine (74.3 mg, 0.33 mmol) (Example 101A cited above) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole- 2-one (50 mg, 0.13 mmol) (starting material 6) using (Ph3P) Pd (15 mg) and Cul (3 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 85 ° C for 5 h. To the resulting compound in CH2C12 (5 mL) was added a 1: 1 mixture of trifluoroacetic acid / CH2C12 (5 mL) and 2 drops of water at 0 ° C and the mixture was stirred at 0 ° C for 1.5 h. The mixture is then quenched with concentrated NH OH (5 mL) and diluted with EtOAc. The organic phase is washed with saline and dried with MgSO4. The product was purified by flash column chromatography (20% MeOH in CH2C12). The 4N HCl in dioxane (0.01 mL) was added to the free base in methanol (2 mL). The evaporation of the solvent to dryness yielded the hydrochloride salt. (Yield 12 mg, 24%). Example 102A: (4S, 5R) -N-Boc-2, 2, 5-trimethyl-oxazo-1-idine-4-carbaldehyde (4S, 5R) -N-Boc-2,2,5-trimethyl-oxazole idine-4-carbaldehyde was prepared according to the method of P. Garne ::, The Synthesis and Configuratioal Stability of Differently Protected ß- Hydroxy-a-amino Aldehides. J. Org. Chem. 1987, 52, 2361-2364. Example 102B: (R, 5R) -N-Boc-2, 2,5-Trimethyl-4-etinyl-oxazolidine To a solution of (45.5R) -N-Boc-2, 2, 5-trimethyl-oxazolidine-4-carbaldehyde (1.52 g, 5.43 mmol) (Example 102A cited above) and dimethyl (1-diazo-2-oxopropyl) -phosphonate (1.57g, 8.15 mmol) in dry MeOH (30 L) was added K2CO3 at 0 ° C. The mixture is stirred at 0 ° C for 30 mm and at room temperature for 20 h. After addition of saturated aqueous NH 4 Cl and EtOAc, the organic phase is separated and the aqueous phase is extracted with EtOAc (3X). The ethyl acetate phases were combined and dried with MgSO4.

The crude material was purified by flash column chromatography eluting with EtOAc / hexanes (1: 6) to yield (R, 5R) -N-Boc-2, 2, -Trimethyl-4-etyl-oxazolidine.

(Yield 0.97 g, 65%). Example 102C: (Z) -4 - [(3R, 4R) -3-Amino-4-hydroxy-1-pentynyl] -1,3-dihydro-5-fluoro-3- [(3-methoxy-1H-pyrrole -2-i P metile no] -2H-indole -2 -one (QQQQ) Using Method C cited above, (4R, 5R) -N-Boc-2, 2, 5-trimeti 1- -eti-ene loxazole idine (0.18 g, 0. 65 mmol) (Example 102B) was coupled with (Z) -l, 3-dihydro-5-fluoro-4-iodo-3- [(0.1 g, 0.26 mmol) (Starting Material 6) using (Ph3P) 4Pd ( 30 mg) and Cul (6 mg) as a catalyst in DMF (6 mL) and Et3N (6 mL) as solvent at 85 ° C for 1 day. To the resulting compound in CH2C12 (6 mL) was added a 1: 1 mixture of tri-luoroacetic acid / CH2C12 (6 mL) and 3 drops of water at 0 ° C and the. The mixture is stirred at 0 ° C for 1.5 h. The mixture is then quenched with concentrated NH OH (6 mL) and diluted co? EtOAc. The organic phase is washed with saline and dried with MgSO4. (Z) -4- [(3R, 4R) -3-Amino-4-h: .droxy-1-pentynyl] -1, 3-dihydro-5-fluoro-3- [(3-methoxy-1H- pyrrol-2-yl) methylene] -2H-indo1-2 -one was purified by flash column chromatography (10% MeOH in CH2C12). (Yield 44 mg, 48%). Example 103A: (3S, 5S) N-Boc-5-ethynyl-3-hydroxy-pyrrolidine A solution of (3R, 5S) -N-Boc-3-Hydroxy-5-ethynyl-pyrrolidine (200 mg, 0.95 mmol) (Example 99C), benzoic acid (138 mg, 0.11 mmol) and triphenylphosphine (373 mg, 1.42 mmol) in 15 mL of THF was added diisopropylazodicarboxylate (287 mg, 1.42 mmol) at 0 ° C.

The mixture was allowed to warm slowly to room temperature and stirred for 18 hours. The reaction mixture was then concentrated and the residue was directly passed through a column of silica gel with a gradient of 0-30% EtOAc in hexanes. The intermediate benzoate ester was dissolved in 6 mL of MeOH and then K2C03 (260 mg1.89 mmol). The mixture, after stirring overnight, is filtered and concentrated in the form of a residue which after column chromatography on silica gel with a gradient of 0-70% EtOAc in hexanes yielded (3S, 5S) -N -Boc-5-eti nil-3-hydroxy-pyrrolidine. (Yield 170 mg, 85%). EXAMPLE 103B: (Z) -1,3-Dihydro-5-fluoro-4 - [(2S, 4S) - (-hydroxy-pyrrolidin-2-yl) ethynyl] -3- [(3-methoxy-1H-pyrrole -2-yl) methylene] -2H-indol-2-one (RRRR) Using Method C cited above, (3S, 5S) -N- (132 mg, 0.62 mmol) (Example 103A cited above) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3 [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P) 4Pd (24 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80 ° C for 5.5 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4, concentrated, and the residue chromatographed on a column of silica gel with a gradient of 0-100% EtOAc in hexanes. The resulting intermediate was dissolved in 4 L of a 50% solution of trifluoroacetic acid in CH2C12 containing 0.2 mL of H20 at 0 ° C and stirred for 2 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with ammonium hydroxide. The organic phase is dried over Na 2 SO 4 and concentrated. (Z) -1,3-Dihydro-5-fluoro-4 - [(2S, 4S) - (4-hydroxypyrrolidin-2-yl) -etinyl] -3- [(3-methoxy-1H-pyrrole -2-yl) methylene] -2H-indole-2-one after column chromatography on silica gel with a gradient of 0-20% MeOH in CH2C12 and precipitation of THF with excess pentane. (Yield 45 mg, 58%). Example 104A: (R) -N-Boc-2-amino-but-3-in-l-ol A solution of (R) -N-Boc-2, 2-dimethyl-4-ethynyl-oxazolidine (200 mg, 0.89 mmol) (Example 91A cited above) in a mixture of MeOH (10 L) and water (1 mL) it is treated with p-toluenosulonic acid monohydrate (16 mg, 0.09 mmol). After stirring at reflux overnight there was obtained a thermodynamic mixture of starting material and product (approximately 1: 1). The solvent was concentrated and the product separated from the material starting material by column chromatography on silica gel with a gradient of 0-60-100% EtOAc in hexanes. The recovered Partition Material was subjected to the above process for two more times to yield (R) -N-Boc-2-aminobut-3-in-1-ol. (Yield 150 mg, 91%). Example 104B: (R) -N-BOC-2-amino-l- (-tere-butyl-di-1-yl-silyloxy) -but-3-yne To a solution of (R) -N-Boc-2-amino-but-B-in-l-ol (150 mg, 0.81 mmol) (Example 104B) and imidazole (110 mg, 1.62 mmol) (Aldrich) in CH 2 Cl 12 (10 mL) was added at 0 ° C tert-butyldimethylsilyl chloride (146 mg, 0.97 mmol) (Fluka). After 5 min the reaction mixture was poured over H20 and extracted with CH2C12. The CH2C12 phase is dried over Na2SO and concentrated as a residue which after column chromatography on silica gel with a gradient of 0-30% Et20 in hexanes yielded the product. (Yield 210 mg, 83%). Example 104C: (R) -2- (N-Boc-N-methylamino) -1- (tert-but:? Ldimeti l si l i loxi) but-3-ina (R) -2- (N-Boc-N-methylamino) -1- (tert-butyldimethylsilyloxy) -but-3-na was synthesized in accordance with Method Y cited above by the treatment of (R) -N -Boc-2-amino-l- (-tert-butyldimethylsilyloxy) -but-3-nane (200 mg, 0.67 mmol) (Example 104B) with NaH (21 mg, 0.87 mmol, and Mel (189 mg, 1.34 mmol) in THF (12 mL) The product was obtained after column chromatography on silica gel with a gradient of 0-10% EtOAc in hexanes (Yield 200 mg, 95%).

Example 104D: (R) - (Z) -1,3-Dihydro-5-fluoro-4 - [4-hydroxy-3-methylamino- [butynyl] -3- [(3-methoxy-1H-pyrrole-2-yl) methylene] -2H-indol-2-one (SSSS) Using Method C cited above, (R) -2- (N-Boc-N-methylamino) -1- (tert-butyldimethylsilyloxy) -but-3-ina (130 mg, 0.42 mmol) (Example 104C) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P) 4Pd (24 mg, 0.02 mmol.) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80 ° C for 5 hours. hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na2SO4, concentrated, and the residue was chromatographed on a column of silica gel with a gradient of 40-100% EtOAc in hexanes. The intermediate resulting from the operation was dissolved directly in 10 mL of a 50% trifluoroacetic acid solution in CH2C12 containing 0.5 L of H20 at 0 ° C and stirred for 2.5 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with ammonium hydroxide. The organic phase is dried over Na2SO and concentrated. (R) - (Z) -1,3-Dihydro-5-fluoro-4- [4-hydroxy-3-methyl-1-amino-1-butyl] -3- [(3-methoxy-1H- pyrrol-2-yl) -methylene] -2H-indole-2-one after column chromatography on silica gel with a gradient of 0-10% MeOH in CH2C12 and precipitation of THF with excess pentane. (Yield 28 g, 38%). Example 105A: 4R- (ÍR-Hydroxy-prop-2-ynyl) -2,2,5-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester 4R- (lS-Hydroxy-prop-2-ynyl) -2,2,5R-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester To a solution of ethynylmagnesium chloride (130.8 mL, 0.5M in THF solution, 65.4 mmol) was added (4R, 5R) -N-boc-2, 2, 5-trimeti-1-ethyloxazole idine (3.0 g, LOX mmol) (Example 102A) in THF (20 ml). The mixture is stirred at room temperature for 4.5 h. The reaction is quenched with EtOH (11 mL) and saturated aqueous NH4C1 (18.4 mL) and stirred at room temperature overnight. The resulting mixture was acidified with 2N aqueous HCl (16 mL). The aqueous layer is extracted with CH2C12 (3X) and the combined organic phases are washed with saturated aqueous NaHC03, saline and dried with MgSO4. The crude material was purified by flash column chromatography eluting with EtOAc / hexanes (1: 6) to give 4R- (lS-hydroxy-prop-2-ynyl) -2,5,5-R-tert-butyl ester. trimethyloxazolidine-3-carboxylic acid (yield 0.86 g, 26%) and tert-butyl ester of 4R- (lR-hydroxy-prop-2-in: .l) -2, 2, 5R-trimethyl-oxazo-lidina-3 -carboxylic (yield 1.7 g, 52%). Example 1Q5B: (Z) -4- [(3S, 4S, 5R) -4 -Amino-3,5-dihydroxy-1-hexinyl] -1,3-dihydro-5-fluoro-3- [(3- methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (TTTT) Using Method C cited above, 4R- (lS-hydroxy-prop-2-ynyl) -2,5,5-tr-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (0.2 g, 0.65 mmol) (Example 105A cited above) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) meti Leño) -2H-indole-2- Ona (0.1 g, 0.26 mmol) (Starting Material 6) using (Ph3P) 4Pd (30 mg) (Aldrich) and Cul (6 mg) as a catalyst in DMF (5 mL) and Et3N (5 L) as a solvent at 85 ° C for 18 h. To the resulting compound in CH2C12 (10 mL) was added a 1: 1 mixture of trifluoroacetic acid / CH2C12 (10 mL) and 5 drops of water at 0 ° C and the mixture was stirred at 0 ° C for 1.5 h. The mixture is then quenched with concentrated NH 4 OH (10 mL) and diluted with EtOAc. The organic phase is washed with saline and dried with MgSO4. The product was purified by flash column chromatography (10% MeOH in CH2C12). (Yield 30 mg, 30%). Example 106: (Z) -4 - [(3R, 4S, 5R) -4-Amino-3,5-dihydroxy-1 -hexy and 1] -1, 3-dihydro-5-f luoro-3- [ (3-methoxy-lH-pyrrole-2-yl) methylene] -2H-indole-2 -one (UUUU) Using Method C cited above, 4R- (1R-Hydroxy-prop-2-ynyl) -2,2,5R-trimethyloxazolidine-3-carboxylic acid tert-butyl ester (0.2 g, 0.65 mmol) (Example 1 05A cited above) it was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methyl. or] -2H-indole-2-one (0.1 g, 0.26 mmol) (Starting Material 6) using (Ph3P) 4P (30 mg) and Cul (6 mg) co or catalyst in DMF (5 mL) and Et3N ( 5 L) as solvent at 85 ° C for 18 h. To the above-mentioned compound in CH2C12 (10 mL) was added a 1: 1 mixture of trifluoroacetic acid / CH2C12 (10 L) and 5 drops of water at 0 ° C and the mixture was stirred at 0 ° C for 1.5 h. The mixture is then quenched with concentrated NH OH (10 mL) and diluted with EtOAc. The organic ase is washed with saline and dried with MgSO4. The product was purified by flash column chromatography (10% MeOH in CH2C12). (Yield 35 mg, 35%). Example 107: rac- (Z) -l, 3-Dihydro-5-fluoro-4 - [(3-hydroxy-pyrrolidin-3-y1) ethynyl] -3- [(3-methoxy-lH-pyrrole) hydrochloride salt -2-yl) methylene] -2H-indol-2-one (WW) Using Method C cited above, rac-N-boc-3-hydyloxy-3-ethynyl-pyrrolidine (70.7 mg, 0.33 mmol) (see Example 97B) was coupled with (Z) -1,3-dihydro- 5-Fluoro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (0.10 g, 0.26 mmol) (Starting Material 6) using (Ph3P 4Pd (31 mg) and Cul (6.0 mg) as a catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85 ° C for 1 day. To compound 25 resulting in CH2C12 (5 mL) was added a 1: 1 mixture of tri-luoroacetic acid / CH2C12 (5 mL) and 2 drops of water at 0 ° C and the mixture was stirred at 0 ° C for 1.5 h., NH NH concentrated (10 mL) is added and diluted with EtOAc. The organic phase is washed with saline and dried with MgSO4. The product was purified by flash column chromatography (10% MeOH in CH2C12). To a free base in methanol (3 mL) was added 4N HCl in dioxane (0.03 mL). The evaporation of the solvent to dryness yielded the hydrochloride salt. (Yield 54.5 mg, 55%). Example 108A: N-Boc-N-ethylpropargylamine Di-tert-butyl dicarbonate (42.8 g, 196 mmol) in dichloromethane (100 mL) was added dropwise to a solution of propargylamine (11.02 g, 200 mmol) in dichloromethane (200 mL) at room temperature with magnetic stirring. After 2 h, the reaction mixture is washed with 1 N aqueous hydrochloric acid (300 mL) and saturated aqueous sodium bicarbonate solution (300 mL). The aqueous layer is washed with dichloromethane (300 mL). The dichloromethane solutions were combined, dried (MgSO 4), filtered and concentrated. The residue was purified by flash chromatography (Biotage 40S, EtOAc-hexanes v / v 1: 9 as solvent) to yield crude N-Boc-propargylamine (32.32 g). The crude N-Boc-propargylamine (3.1 g, 20 mmol) was dissolved in dry dimethylformamide (20 mL) with magnetic stirring and cooled in an ice-water bath. Sodium hydride (0.61 g, 24 mmol) was added in small portions. After stirring for 15 min, iodoethane (3.74 g, 24 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 3 h, then diluted with ether and extracted with water and saturated saline. The aqueous layer was washed again with ether and the ether phases were combined, dried (MgSO 4), filtered and concentrated. The residue was purified by flash chromatography (Biotage 4M, ethyl acetate-hexanes as solvent to yield N-Boc-N-ethylpropargyl amine. (Yield 3.19 g, 87%) Example 108B: hydrochloride salt of (Z) -1, 3-Dihydro-4- (3-ethylarnino-l-propynyl) -5-fluoro-3- [(3-methoxy-lH-pyrrole-2-: Ll) methylene] -2H-indol-2-one (WWWW) Using Method C cited above, N-Boc-N-ethylpropargyl amine (0.12 g, 0.63 mmol) (Example 108A cited above) was coupled with (Z) -l, 3-dihydro-5-fluoro-4-iodine -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (0.1 g, 0.26 mmol) (Starting Material 6) using (Ph3P) 4Pd (40.0 mg ) and Cul (9.0 mg) as a catalyst in DMF (5 mL) and Et3N (5 mL) with solvent at 85 ° C for 1 day. To the resulting compound in CH2C12 (6 mL) was added a 1: 1 mixture of trifluoroacetic acid. / CH2C12 (6 mL) and 3 drops of water at 0 ° C and la. The mixture is stirred at 0 ° C for 1 h. The mixture is quenched with concentrated NH40H (10 mL) and diluted with EtOAc. The organic phase is washed with saline and dried with MgSO4. The product was purified by flash column chromatography (10% MeOH in CH2C12) • To the base, free in methanol (2 mL) was added 4N HCl in dioxane (0.04 mL). The evaporation of the solvent to dryness yielded the hydrochloride salt. (Yield 49 mg, 50%). Example 109: (S) - (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) -methylene] -1,3-dihydro-5-fluoro-4- (pyrrolidin-2-yl) ethynyl] -2H-indol-2-one (XXXX) Using Method C cited above, (S) -N-Boc-2-Ethynyl-pyrrolidine (220 mg, 1.13 mmol) (Example 87B) was coupled with (Z) -3- [(4-acetyl-lH-pyrrol- 2-yl) methylene] -1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (150 mg, 0.38 mmol) (Example 90B) using (Ph3P) 4Pd (44 mg, 0.04 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80 ° C. for 7 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4, concentrated and the residue chromatographed on a column of silica gel with a gradient of 0-5% MeOH in CH 2 C 12. The intermediate that escapes from the process was dissolved in 6 mL of a 50% solution of trifluoroacetic acid in CH2C12 containing 0.3 mL of H20 at 0 ° C and stirred for 2 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with ammonium hydroxide. The organic phase is dried over Na 2 SO 4 and concentrated. (S) - (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4- (pyrrolidin-2-yl) ethynyl] - 2H-indol-2-one was obtained after column on silica gel with a gradient of 0-10% MeOH in CH2C12 and precipitation of THF with excess pentane. (Yield 56 mg, 41%). Example 110: (S) - (Z) -3 - [(4-Acetyl-lH-pyrrol-2-yl) -methylene] -1,3-dihydro-5-fluoro-4 - (pyrrolidin-2) hydrochloride salt -yl) ethynyl] -2H-indole -2-one (YYYY) A solution of (S) - (Z) -3- [(4-acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4- [(pyrrolidin-2-yl ) -etinyl] -2H-indole-2-one (25 mg, 0.07 mmol) (Example 109 cited above) in dioxane (3 mL) is treated with aqueous HCl with vigorous stirring. Hydrochloride salt of (S) - (Z) -3- [(-Aceti 1-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4- (pyrrolid.Ln-2 was obtained -yl) ethynyl] -2H-indole-2-one after lyophilization of the solution. (Yield 24 mg, 76%). Example 111: (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) -methylene] -1,3-dihydro-5-fluoro-4- [(2S, 4R) - (4-hydroxy -pyrrolidi -2-yl) ethynyl] -2H-indole -2 -one (ZZZZ) Using Method C cited above, (3R, 5S) -N-Boc-3-Hydroxy-5-ethynyl-pyrrolidine (240 mg, 1.13 mmol) (Example 99C cited above) was coupled with (Z) -3 - [( 4-acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (150 mg, 0.38 mmol) (Example 90B) using (Ph3P 4Pd (43 mg, 0.04 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80 ° C for 5 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4, concentrated and the residue is chromatographed on a column of silica gel with a gradient of 0-100% EtOAc in hexanes. The resulting intermediate was dissolved in 6 mL of a 50% solution of trifluoroacetic acid in CH2C12 containing 0.4 mL of H20 at 0 ° C and stirred for 2 hours. After completion, the solution was poured onto ammonium hydroxide and extracted with a 5: 1 (v / v) mixture of EtOAc and DMF. The organic phase is dried over Na 2 SO 4 and concentrated. (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) mephylene] -l, 3-dihydro-5-fluoro-4- [(2S, 4R) - (4-hydroxy-pyrrolidin was obtained -2-yl) ethynyl] -2H-indole-2-one after column chromatography on silica gel with a gradient of 0-10% MeOH in CH2C12 and trituration with CH2C12, (Yield 50 mg, 35%). Example 112: (Z) -3 - [(4-Acetyl-1H- [(2S, 4R) - (4-hydroxy-pyrrolidin-2-y1) ethynyl] -2H-indole-2-one hydrochloride salt (AAAAA ) A solution of (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4 - [(2S, 4R) - (4-hydroxy) pyrrolidin-2-yl) ethynyl] -2H-indole-2-one (20 mg, 0.06 mmol) (Example 111 cited above) in a mixture of DMF / dioxane (2/7 mL respectively) is treated with aqueous HCl with stirring vigorous Hydrochloride salt of (Z) -3 - [(4-Acetyl-lH-pyrrol-2-yl) methylene] -!, 3-dihydro-5-fluoro-4- [(2S, 4R) - (4 - hydroxy-pyrrolidi-2-yl) ethynyl] -2H-indole-2-one after lyophilization and treatment with THF and pentane. (Yield 20 mg, 91%). Example 113: (Z) -3 - [(4-Acetyl-1H-pyrrol-2-yl) -methylene] -1,3-dihydro-4- [(3-ethylamino) -1-propynyl] hydrochloride salt 5-fluoro-2H-indol-2-one (BBBBB) Using Method C cited above, N-Boc-N-ethylpropargylamine (0.12 g, 0.63 mmol) (Example 1 03A cited above) was coupled with (Z) -3- [(4-acetyl-1H-pyrrole-2- il) methylene] -1,3-dihydro-5-fluoro-4-iodo-2H-indole-2-o:? a (0.1 g, 0.25 mmol) (Example 90B) using (Ph3P) 4Pd (40.0 mg) and Cul (9.0 mg) as a catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85 ° C for 12 h. To the resulting co-column in CH2C12 (6 mL) was added a 1: 1 mixture of trifluoroacetic acid / CH2C12 (6 mL) and 3 drops of water at 0 ° C and the mixture was stirred at 0 ° C for 1 h. The mixture is quenched with concentrated NH40H (10 mL) and diluted with EtOAc. The organic phase is washed with saline and dried with MgSO4. The product was purified by chromatography: lash in column (10% MeOH in CH2C12). To the free base in methanol (2 mL) was added 4N HCl in dioxane (0.05 mL). Evaporation of the solvent to dryness yielded the desired hydrochloride salt.

(Yield 41 mg, 42%). Example 114: (Z) -3 - [(4-Acetyl-1H-pyrrol-2-yl) -methylene] -1,3-dihydro-5-fluoro-4 - [(4-hydroxy-pLperidin-) hydrochloride salt 4-yl) ethynyl) -2H-indol-2-one (CCCCC) Using Method C cited above, N-Boc-4-hydroxy-4-ethynyl-piperidine (0.21 g, 0.95 mmol (Example 101 A cited above) was coupled with (Z) -3- [(4-acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4 .-. Mud-2H-indol-2-one (0.15 g, 0.38 mmol) (Example 90B) using (Ph3P) 4Pd (60 mg) and Cul (13.5 mg) as a catalyst in DMF (8 mL) and Et3N (8 mL) as solvent at 85 ° C for 5 h.To the resulting compound in CH2C12 (6 mL) was added a 1: 1 mixture of trifluoroacetic acid / CH2C12 (6 mL ) and 3 drops of water at 0 ° C and the mixture is stirred at 0 ° C for 3 h.The mixture is then quenched with concentrated NH 4 OH (10 L) and diluted with EtOAc.The precipitated product is filtered and washed with Methanol: To the free base in methanol (2 mL) was added 4N HCl in dioxane (0.04 mL) The evaporation of the solvent to dryness yielded the desired hydrochloride salt (Yield 57 mg, 36%) Example 115A: (S) N-Boc-2-amino-but-3-in-l-ol A solution of (S) -N-Boc-2, 2-dimethyl-4-ethanol 1-oxazolidine (200 mg, 0.89 mmol) (Example 93A cited above) in a mixture of MeOH (25 mL) and water (2 mL) ) is treated with p-toluenesulfonic acid monohydrate (16 mg, 0.09 mmol) in accordance with the procedure cited above in Example 104A. (Yield 120 mg, 73%). Example 115B: (S) -N-Boc-2-amino-l- (-tert-butyl-dimethylsilyloxy) -but-3-ina (S) - -Boc-2-amino-1- (-tert-butyldimethylsilyloxy) -but-3-na was prepared by the treatment of (S) -N-Boc-2-amino-but-3-in-1 -ol (120 mg, 0.65 mmol) (Example 115A cited above) with imidazole (110 mg, 1.29 mmol) (Aldrich) and tert-butyldimethylsilyl chloride (120 mg, 0.77 mmol) (Fluka) in CH2C12 (10 L ) in accordance with the procedure cited above in Example 104B. (Yield 190 mg, 98%). Example 115C: (S) -2- (N-Boc-N-Methylamino) -1- (terebutyldimethylsilyloxy) but-3-ina (S) -2- (N-Boc-N-Methylamino) -1- (-tert-butyldimethylsilyloxy) -but-3-na was synthesized in accordance with Method Y cited above by the treatment of (S) -N- Boc-2-amino-l- (-tert-butyldimethylsilyloxy) -but-3-nane (190 mg, 0.64 mmol) (Example 115B) with NaH (18 mg, 0.76 mmol) and Mel (180 mg 1.27 mmol) in THF (5 mL). The product was obtained after column chromatography on silica gel with a gradient of 0-10% EtOAc in hexanes. (Yield 190 mg, 95%). Example 115 D: (S) - (Z) -1,3-Dihydro-5-fluoro-4- [3-methylamino- -hydroxy-1-butyne] -3- [(3-methoxy-lH-pyrrole-2 -yl) methylene] -2H-indol-2-one (DDDDD) Using Method C cited above, (S) -2- (N-Boc-N-methylamino) -1- (tert-butyldimethylsilyloxy) -but-3-nane (19C mg, 0.61 mmol) (Example 115C cited above) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P) 4Pd (24 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80 ° C for 5.5 hours . After completion, the reaction mixture is diluted with EtQAc and extracted with H20, the organic phase is dried over Na2SO, concentrated and the residue chromatographed on a column of silica gel with 40-100% EtOAc in gradient hexanes. The resulting intermediate: was dissolved directly in 6 L of a 50% solution of trifluoroacetic acid in CH2C12 containing 0.5 mL of H20 at 0 ° C and stirred for 2 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with ammonium hydroxide. The organic phase is dried over Na 2 SO 4 and concentrated. (S) - (Z) -1,3-Dihydro-5-fluoro-4- [3-methylamino-4-hydroxy-1-butynyl] 3- [(3-methoxy-lH-pyrrol-2-yl Methyleneol-2H-indole-2-or? a after column chromatography on silica gel with a gradient of 0-10% MeOH in CH2C12 and precipitation of THF with excess pentane. (Yield 32 mg, 42%). Example 116A: 5-Formyl-4-methyl-lH-pyrrole-3-carboxylic acid ethyl ester -Formyl-4-methyl-lH-pyrrole-3-carboxylic acid ethyl ester was prepared according to the method of the method of J.B. Paine 111 / et al., 5-Unsubstituted 2-pyrrolcarboxaldehydes during Porfirin Synthesys and the Cyanovinyl Protecting Group. J. Org. Ohem. 1988, 53, 2787-2795. Example 116B: (Z) -5- (5-Fluoro-4-iodo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl) -4-methyl-lH-pyrrole-3-carboxylic acid ethyl ester A suspension of 1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (0.5 g, 1.8 mmol) (Example 2A) and 5-formyl-4-methyl-lH-pyrrole-3 acid. Carboxylic ethyl ester (0.39 g, 2.17 mmol) (Example 116A cited above) in 1% piperidine in 2-propanol (6 mL) is heated at 80 ° C for 3 h. The precipitate is collected and washed with water to yield (Z) -5- (5-Fluoro-4-iodo-2-oxo-l, 2-dihydro-indol-3-ylidene-methyl) -4-methyl-1H- acid. pyrrole-3-carboxylic acid ethyl ester. (Yield 0.67 g, 5%) Example 116C: (Z) -5 - [(4- (3-Etylamino-prop-1-ynyl) -5-fluoro-2-oxo-1, 2- hydrochloride salt dihydro-indol-3-i lead] methyl] -4-methi1-1H-pyrrole-3-carboxylic acid ethyl ester (EEEEE) Using Method C cited above, N-Boc-N-ethylpropargylamine (0.16 g, 0.85 mmol) (Example 108A cited above) was coupled with 5- (5-fluoro-4-iodo-2-oxo-l, 2- dihydroindol-3-y1 idenomethyl) -4-methyl-lH-pyrrole-3-carboxylic acid ethyl ester (Example 116B cited above) (0.15 g, 0.34 mmol) using (Ph3P) 4Pd (60.0 mg) and Cul (13.5 mg) as a catalyst in DMF (8 mL) and Et3N (8 L) as solvent at 81 ° C for 6 h. To the resulting compound in CH2C12 (8 mL) was added a 1: 1 mixture of trifluoroacetic acid / CH2C12 (8 mL) and 4 drops of water at 0 ° C and the mixture was stirred at 0 ° C for 1 h. The mixture is quenched with concentrated NH4OH (10 mL) and diluted with EtOAc. The precipitated product is filtered and washed with methanol. To the free base in methanol (3 mL) was added 4N HCl in dioxane (0.03 mL). The evaporation of the solvent - to dryness yielded the hydrochloride salt. (Yield 50 mg, 33%). Example 117A: (2R, 3R) -N-Boc-3-amino-pent-4-in-2 -ol.

A solution of (4R, 5R) -N-boc-4-ethynyl-2,2,5-trimethyl-oxazolidine (1.60 g 6.69 mmol) (Example 102B) and p-toluenesulfonic acid monohydrate (130 mg 0.67 mmol) in MeOH (70 mL) is heated to reflux. After stirring overnight the solvent was concentrated and the residue was chromatographed directly on a column of silica gel with a gradient of 0-40% EtOAc in hexanes. The product was obtained (yield 1.10 g, 83%) as well as recovered starting material (220 mg, 14%). Example 117B: (2R, 3R) -N-Boc-3-amino-2- (-tert-butyl-dimethylsi.Lyloxy) -pent-4-ina (2R, 3R) -N-Boc-3-amino-2- (-tetra-but-1-dimethylsilyloxy) -pen; -4-ina was prepared by the treatment of (2R, 3R) -N-Boc-3-amino -pent-4-in-2-ol (1.10 g, 5.02 mmol) (Example 117A cited above) with imidazole (680 mg, 10.04 mmol) and tert-butyldimethylsilyl chloride (800 mg, 5.52 mmol) in 35 mL of CH2C12. After stirring at room temperature for 24 h, the mixture was concentrated to a residue which, after column chromatography on silica gel with gradient 0-20% EtOAc in hexanes yielded (2R, 3R) -N-Boc-3 -amino-2- (-tert-butyldimethylsilyloxy) -pent-4-ina. (Yield 1.30 g, 83%). Example 117C: (2R, 3R) -3- (N-Boc-N-methylamino) -2- (-tert-butyldimethylsilyloxy) -pent-4-ino (2R, 3R) -3- (N-Boc-N-methylamino) -2- (-tert-butyldimethylsilyloxy) -pent-4-ina was synthesized in accordance with Method Y above cited by the treatment of (2R) , 3R) -N-Boc-3-amino-2- (-tert-butyldimethylsilyloxy) -pent-4-ina (400 mg, 1.27 mmol) (Example 117B) with NaH (36 mg, 1.52 mmol) and Mel (360 mg, 2.54 mmol) in THF (30 mL). The product was obtained after column chromatography on silica gel with 0-10% Et20 in hexanes gradient.

(Yield 370 mg, 89%). Example 117D: (Z) -1, 3-Dihydro-5-fluoro-4 - [(3R, R) -4-hydroxy-3-methylamino-1 -pentinyl] -3- [(3-methoxy-1H-pyrrole -2- il) methyleneol -2H-indole -2-one (FFFFF) Using Method C cited above, (2R, 3R) -3- (N-Boc-N-methylamino) -2- (tert-butyldimethylsilyloxy) -pen t-4-nane (370 mg, 1.13 mmol) (Example 117C quoted above) ) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-o? a (150 mg, 0.39 mmol) (starting material 6) using (Ph3P) 4Pd (45 mg, 0.04 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80 ° C for 5 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4, concentrated and the residue chromatographed on a silica gel column with gradient 0-40% EtOAc in hexanes. The resulting intermediate was dissolved in 5 mL of a 50% solution of trifluoroacetic acid in CH2C12 containing 0.5 mL of H20 at 0 ° C and stirred for 2 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with ammonium hydroxide. The organic phase is dried over Na 2 SO 4 and concentrated. (Z) -1,3-Dihydro-5-fluoro-4- (3R, 4R) -4-hydroxy-3-methylamino-1-pentynyl] -3- [(3-methoxy L-1H-pyrrole-2 -yl) methylene] -2H-indol-2-one was obtained after column chromatography on silica gel with gradient 0-10% MeOH in CH2C12 and precipitation of THF with excess pentane. (Yield 53 mg, 37%). Example 118: (Z) -1,3-Dihydro-5-fluoro-4- (3R, 4R) -4-hydroxy-3-methylamino-l-pentynyl) -3- [(3-methox: L) hydrochloride salt -lH-pyrrol-2-yl) methyleneol-2H-indol-2-one (GGGGG) A solution of (Z) -1,3-dihydro-5-fluoro-4- [(3R, 4R) -4-hydroxy-3-methylamino-1-pentynyl] -3- [(3-methoxy-1H-pyrrole -2-yl) ethylene] -2H-indol-2-one (35 mg, 0.07 mmol) (Example 117C) in dioxane (5 mL) is treated with aqueous HCl with vigorous stirring. Hydrochloride salt of (Z) -1,3-Dihydro-5-fluoro-4- [(3R, R) -4-hydroxy-3-methylamino-pentynyl] -3- [(3-methoxy-lH -pyrrol-2-yl) methylene] -2H-indole-2-one after lyophilization and precipitation of a mixture (1: 3, v / v) of MeOH / CH2Cl2 with excess hexanes. (Yield 32 mg, 83%). Example 119A: 4 -Methyl-N- (prop-2-ynyl) -benzene-sul-onamide To a solution of propargylamine (2.00 g, 36.29 mmol) and E, t3N (7.30 g, 72.59 mmol) in CH2C12, p-toluenesulfonyl chloride was added in small portions. (6.90 g, 36.29 mmol) (J.T. Baker) at 0 ° C. After 5 min the mixture was filtered and the filtrate was concentrated to a residue that after direct application on a column of silica gel with a gradient of 0-40% EtOAc in hexanes gradient yielded 4-Methyl-N- (prop -2-inyl) benzenesulfonamide. (Yield 7.30 g, 96%). Example 119B: (Z) -N- [3- [5-Fluoro-3- [(3-methoxy-lH-pyrrole-2-yl) methylene] -2-oxo-2,3-dihydro-lH- indol-4-yl] -prop-2-in:? l] -4-methyl-benzenesulfonamide (HHHHH) Using Method C cited above, 4-Methyl-N- (prop-2-ynyl) -benzenesulfonamide (130 mg, 0.62 mmol) (Example 119A cited above) was coupled with (Z) -1,3-dihydro-5- fluoro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P) 4Pd (24 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80 ° C for 5 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4 and concentrated. (Z) -N- [3- [5-Fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-OXO-2,3-dihydro-lH-indole-4 was obtained -yl] -prop-2-ynyl] -4-methyl-benzenesulfonamide after purification with HPLC with 40% EtOAc in hexanes and precipitation of THF with excess hexanes. (Yield 42 mg, 44%). Example 120A: N- (Prop-2-ynyl) -methanesulfonamide To a solution of propargylamine (2.00 g, 36.29 mmol) and Et3N (7.30 g, 72.59 mmol) in dichloromethane was added dropwise methanesulfonyl chloride (4.10 g, 36.29 mmol) at 0 ° C. After 5 min the mixture was filtered and the filtrate was concentrated to a residue that after direct application on a column of silica gel with a gradient of 0-40% EtOAc in hexanes yielded N- (Prop-2-ynyl) methanesulfonamide . (Yield 2.00 g, 42%). Example 120B: (Z) -N- [3- [5-Fluoro-3- [(3-methoxy-1 H -pyrrol-2-yl) methylene] -2-oxo 2, 3-dihydro-1H-indole -4- il] -prop-2-in: .l] -methanesulfonamide (IIIII) Using Method C cited above, N- (Prop-2-ynyl) -methanesulfonamide (80 mg, 0.62 mmol) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodo-3- [ (3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (80 mg, 0.21 mmol) (starting material 6) using (Ph3P) 4Pd (24 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80 ° C for 5 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4 and concentrated. (Z) -N- [3- [5-Fluoro-3- [(3-methoxy-l-pyrrol-2-yl) ethylene] -2-oxo-2,3-dihydro-lH-indole-4 was obtained -yl] -prop-2-ynyl] methanesulfonamide after purification by HPLC with 40% EtOAc in hexanes and precipitation of THF with excess pentane. (Yield 48 mg, 59%). Example 121: (S) - (Z) -5- [[5-Fluoro-2-oxo-4- (pyrrolidin-2-yl) ethynyl] -!, 2-dihydro-indol-3-ylidene] -methyl acid ] - -methyl-lH-pyrrole-3-carboxylic acid ethyl ester (JJJJJ) Using Method C cited above, (S) -N-Boc-2-Ethynyl-pyrrolidine (106 mg, 0.55 mmol) (Example 87B) was coupled with (Z) -5- (5-fluoro-4-iodo- 2-oxo-1,2-dihydro-indol-3-ylidene-methyl) -4-methyl-lH-pyrrole-3-carboxylic acid ethyl ester (80 mg, 0.18 mmol) (Example 116B) using (Ph3P) 4Pd (21 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80 ° C for 5 hours . After completion, the reaction mixture is diluted with EtOAc and extracted with H20. The organic phase is dried over Na 2 SO 4, concentrated and the residue chromatographed on a column of silica gel with a gradient of 0-40% EtOAc in hexanes. The resulting intermediate was dissolved in 5 mL of a 50% solution of trifluoroacetic acid in CH2C12 containing 0.5 mL of H20 at 0 ° C and stirred for 2 hours. After completion, the reaction mixture is diluted with EtOAc and extracted with ammonium hydroxide. The organic phase is dried over Na2SO and concentrated. (S) - (Z) -5- [[5-Fluoro-2-oxo-4- [(pyrrolidin-2-yl) ethynyl] -1,2-dihydro-indol-3-ylidene] - methyl] -4-methyl-lH-pyrrole-3-carboxylic acid ethyl ester after column chromatography on silica gel with gradient 0-100% EtOAc in hexanes-30% THF in EtOAc and precipitation of THF with excess hexanes . (Yield 21 mg, 28%). Example 122: (S) - (Z) -5- [[5-Fluor-2-oxo-4- [(pyrrolidin-2-yl) ethynyl] -!, 2-dihydro-i-dol acid hydrochloride salt -3-ylidene] methyl] -4-methyl-! H-pyrrole-3-carboxylic acid ethyl ester (KKKKK) A solution of (S) - (Z) -5- [[5-Fluoro-2-oxo-4- (pi rolidin-2-yl) ethynyl] -1,2-dihydro-indol-3-i lead] -ethyl] -4-met i-lH-pyrrole-3-carboxylic acid ethyl ester (14 mg, 0.03 mmol) (from Example 121 cited above) in dioxane (10 L) is treated with aqueous HCl under vigorous stirring. Hydrochloride salt of (S) - (Z) -5- [[5-Fluoro-2-oxo-4- [(pyrrolidin-2-yl) ethynyl] -1,2-dihydro-indol-3-ylidene was obtained ] methyl] -4-methyl-lH-pyrrole-3-carboxylic acid ethyl ester after lyophilization. (Yield 12 mg, 79%). Example 123A: (2R-Hydroxy-S- (lR-hydroxy-ethyl) but- -inyl] -carbamic acid tert-butyl ester To a solution of 4R- (1R-hydro-1-prop-2-ynyl) -2,5,5-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.02 g, 3.79 mmol) (Example 105A cited above) ) in MeOH (20 mL) was added BC13 (1.0 M in CH2C12, 2.6 mL, 2.6 mmol) by injection. The reaction mixture is stirred at room temperature for 2 h. The reaction is stopped by the addition of AcOEt (150 mL) and washed with H20, saline, and dried over Na2SO4. After concentrating, [2R-hydroxy-lS- (lR-hydroxy-ethyl) -but-3-ynyl] -carbamic acid tert-butyl ester was obtained as a colorless oil which was used in the next step without further purification. (Yield 0.85 g, 98.1%).

Example 123B: (4R-Ethynyl-2, 2, 6R-trimethyl [1, 3] diox n-5S-yl) -carbamic acid tert-butyl ester To a solution of [2R-hydroxy-lS- (IR-hydroxy-ethyl) -but-3-ynyl] -carbamic acid tert-butyl ester (0.80 g, 3.5 mmol) (Example 123A cited above) in a mixture of acetone (20 mL) and 2,2-dimethoxypropane (5 mL) (Aldrich) was added camphor sulphonic acid (50 mg) (Aldrich). The reaction mixture is stirred at room temperature for 2 h. The reaction is stopped by addition of AcOEt (150 mL) and washed with H20, saline, and dried over Na2SO4. After concentration, the crude product was purified by flash column chromatography (25% AcOEt in hexanes) to yield (4R-ethynyl-2, 2, 6R-trimethyl- [1, 3] dioxan- tert -butyl ester. 5S-il) -carbamic (yield 0.52 g, 55.3%) and tert-butyl ester of 4R- (lS-hydroxy-prop-2-ynyl) -2,2, 5R-trimeti-1-oxazolidine-3-carboxylic acid in the form of a colorless oil. (Yield 0.22 g 23.4%).

Example 123C: ethyl- (4R, 5S, 6R-4-ethynyl-2, 2,6-trimethyl- [1, 3] -dioxan-5-yl) carbamic acid tert-butyl ester To a solution of (4R-ethynyl-2,2,6R-trimethyl- [1, 3] dioxan-5S-yl) -carbamic acid tert-butyl ester (0.50 g, 1.86 mmol) (Example 123C) in DMF ( 5 mL) was added NaH (95%, 56.3 mg, 2.23 mmol). The reaction mixture is stirred at room temperature for 15 min followed by the addition of EtI (0.35 g, 2.23 mmol). After stirring at room temperature for 2 h, the reaction is stopped by saturated NH4C1. The organic phase is extracted with AcOEt (150 mL) and washed with H20, saline, and dried over Na2SO4. After concentration, tert-butyl ester of ethyl- (4R, 5S, 6R-4- ethynyl-2, 2,6-trimethyl- [1,3] -dioxan-5-yl) carbamic acid as a colorless oil which was used in the next step without further purification. (Yield 0.53 g, 95.9%).

Example 123D: (Z) -1, 3-Dihydro-4- [(3R, S, 5R) -3,5-dihydroxy-4-ethylamino-1-hexinyl] -5-fluoro-3- [(3-methoxy) lH-pyrrol-2-yl) methylene] -2H-indol-2-one (LLLLL) Example 123E: (R) - (Z) -1,3-Dihydro-4 - [(5-ethylamino-6-. {(3-methoxy-lH-pyrrol-2-yl) methylene)] -2H-indole -2-one (MMMMM) Using Method C cited above, tert-butyl ester of ethyl acid [(3R, 4S, 5R) -4-ethynyl-2, 2,6-trimethyl- [1, 3] dioxan-5-yl] - Carbamic acid (148.5 mg, 0.50 mmo!) (Example 123C cited above) was coupled with (Z) -1,3-dihydro-5-fluoro-4-iodO-3- (3-methoxy-1H-pyrrole-2) -yl) methylene] -2H-indol-2-one (96 mg, 0.25 mmol) (Starting Material 6) using (Ph3P) 4Pd (23.1 mg, 8 ol) and Cul (5 mg) as a catalyst in DMF (5 mg). mL) and Et3N (5 mL) as solvent at 85 ° C for 5 h to yield the coupling product (137.2 mg, 99.2% after purification in flash column). This coupling product (125 mg) is then treated with 50% trifluoroacetic acid 1 CH2CI2 (5 mL) and 0.5 mL of water at room temperature for 1 h. The reaction mixture was concentrated to approximately 2 mL and diluted with AcOEt (50 mL) and then quenched with 2 N NaOH. The organic phase is washed with saline and dried with Na 2 SO 4. After concentration, the crude product (: .13.6 mg) is triturated with AcOEt / hexanes and the precipitate is collected by filtration to give (Z) -l, 3-Dihydro-4 - [(3R, 4S, 5R) - 3, 5-dihydroxy-4-ethylamino-l-hexinyl] -5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (LLLLL) as a solid brown-orange. (Yield 29.5 mg, 31.6%). The filtrate is then purified by flash column chromatography (5% -10% MeOH in CH2C12) to yield (R) - (Z) -l, 3-dihydro-4- [(5-ethylamino-6-methyl) - 6H-pyran-2-yl] -5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene)] -2H-indol-2-one (MMMMM). (Yield 33.6 mg, 37.6%).

Example 124A: [2S-Hydroxy-lS- (lR-hydroxyethyl) -but-3-ynyl] -carbamic acid tert-butyl ester To a solution of 4R- (lS-Hydro-i-prop-2-ynyl) -2,5,5-trimethyl-1-oxazolidine-3-carboxylic acid tert-butyl ester (1.40 g, 5.20 mmol) (Example 105A cited above) in MeOH (30 mL) was added BC13 (1.0 M in CH2C12, 4.6 mL, 4.6 mmol) by injection. The reaction mixture is stirred at room temperature for 1.5 h. The reaction is stopped by the addition of AcOEt (150 mL) and washed with H20, saline, and dried over Na2SO4. After concentration, [2S-hydroxy-lS- (lR-hydroxy-ethyl) -but-3-ynyl] -carbamic acid tert-butyl ester was obtained as a colorless oil which was used in the next step without further purification . (Yield 0.90 g, 75.0%). Examol 124B: [2S- (tert-Butyl-dimethyl-silanyloxy) -IS- [IR- (tert -butyldimethyl-silanyloxy) -ethyl] -but-3-inyl] -carbamic acid tert-butyl ester (TBDMS = tert-butyl-dimethyl-silanyl) To a solution of [2S-hydro i-lS- (lR-hydroxy-ethyl) -but-3-ynyl] -carbamic acid tert-butyl ester (0.90 g, 3.9 mmol) (Example 124A cited above) in DMF (3 L) were added imidazole (1.6 g, 23.6 mmol) and tert-butyl-dimethyl-silanyl chloride (1.42 g, 9.4 mmol). The reaction mixture is stirred at room temperature for 2 h. The reaction is stopped by the addition of ice-water and extracted by AcOEt (150 mL), washed with H20, saline, and dried over Na2SO4. After concentration, the crude product was purified by flash column chromatography (2.5% AcOEt in hexanes) to yield [2S (tert-butyl-1-dimethylsilanyloxy) tert-butyl ester -IS- [IR- (tert- butyl-dimethyl-s Llynyloxy) -ethyl] -but-3-ynyl] -carbamic acid in the form of a colorless oil. (Yield 1.34 g, 78.8%). Example 124C: [2S- (tert-Butyl-dimethyl-silanyloxy) -IS- [IR- (tert-butyldimethyl-silanyloxy) -ethyl-but-3-yn-L] -eti -carbamic acid tert-butyl ester To a solution of [2S- (tere-butyl-dimethyl-silanyloxy) -IS- [IR- (tere-butyldimethyl-1-yl-loxi) -ethyl] -but-3-ynyl] -carbamic acid tert-butyl ester ( 0.39 g, 0.85 mmol) (Example 124B cited above) in DMF (3 L) was added NaH (95%, 32.0 mg, 1.28 mmol). The reaction mixture is stirred at room temperature for 15 min followed by the addition of EtI (0.26 g, 1.70 mmol). After stirring at room temperature for 3.5 h, the reaction is stopped by saturated NH4C1. The organic phase is extracted by AcOEt (150 mL) and washed with H20, saline, and dried over Na2SO4. After concentration, the crude product was purified by flash column chromatography (2.5% AcOEt in hexanes) to yield [2S- (tert-butyl-dimethylsilanyloxy) tert-butyl ester) -1S- [IR- (tere -butyldimeti 1-silanyloxy) -ethyl] -but-3-ynyl] -ethyl-carbenic acid (0.2 g, 48.5%) as a colorless oil.

Example 124D: (Z) -1, 3-Dihydro-4 - [(3S, 4S, 5R) -3,5-dihydroxy-4-ethylamino-l -hexinyl] -5-fluoro-3- [(3-) methoxy-lH-pyrrole-2-yl) methylene] -2H-indole-2-one (NNNNN) Using Method C cited above, [2S- (tert-butyl-dimethylsilanyloxy) -IS- [IR (tertbutyl-1-dimethyl-sih-lanyloxy) -ethyl] -but-3-ini-tert -butyl ester] ethylcarbamic acid (200 mg, 0.40 mmol) (Example 124C cited above) was coupled with (Z) -l, 3-dihydro-5-fluoro-4-iodo-3- [(3-methoxy-1H-pyrrole-2-yl) il) methylene] -2H-indol-2-one (77 mg, 0.20 mmol) (Starting Material 6) using (Ph3P) 4Pd (23 mg, mol%) and Cul (3 mg) as a catalyst in DMF (5.5 mL) and Et3N (5.! ML) as solvent at 85 ° C for 5 h to yield the coupling product (147 mg, 99.3% after purification by flash chromatography). This coupling product (146 mg) is then treated with 50% trifluoroacetic acid / CH2C12 (5 mL) at room temperature for 1 h. The reaction mixture was concentrated to approximately 2 mL and diluted with AcOEt (50 mL) and then quenched with saturated NaHCO 3. The organic phase is washed with saline and dried with Na2SO4. After the concentration, the crude product (130 mg) is then dissolved in 1.6 mL of THF. To this solution was added 0.19 mL of 1 M tetrabutylammonium fluoride / THF and the reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture is diluted with AcOEt, washed with saline and dried with Na2SO4. After concentration, the crude product is then purified by flash column chromatography (10% MeOH in CH2C12) to yield (Z) -1,3-dihydro-4- [(3S, 4S, 5) -3.5- dihydroxy-4-propiolamino-1 -hexinyl] -5-fluoro-3- [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 17 mg, 22%). Example 125A: N-Boc-l-prop-2-inylamino-propan-2-ol Propylene oxide (4.80 g, 82 mmol) (Aldrich) was added to a solution of propargylamine (9.06 g, 164 mmol) in methanol (30 mL) at room temperature. The mixture is stirred for 16 h and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (60 mL). A solution of di-tert-butyl dicarbonate (16.16 g, 74 mmol) in dichloromethane (10 mL) was added dropwise at room temperature with magnetic stirring. After 4 h, the mixture is diluted with ether (200 mL) and extracted with 1 N aqueous hydrochloric acid (2 X 100 L) and saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layers were washed with ether (200 mL). The organic phases are combined, dried (MgSO 4), filtered, and concentrated. The residue was purified by flash chromatography (Biotage 40M, ethyl acetate-hexanes, 1: 3, v / v, as solvent, 25 mL / fraction) to yield N-Boc-1-prop-2-ynylamino-propan- 2-ol pure. (Yield 5.25 g, 30%). Example 125B: rac- (Z) -1,3-Dihydro-5-fluoro-4- [3- (2-hydroxy-propylamino) -lpropinyl] -3- [(3-methoxy-lH-pyrrol-) hydrochloride salt 2-yl) methylene] -2H-indol-2-one (OOOOO) Using Method C cited above, N-Boc-1-prop-2-inylamino-propan-2-ol (0.14 g, 0.65 mmol) (Example 125A cited above) was coupled with (Z) -1,3-dihydro -5-fluoro-4-iodo-3- [(methoxy-lH-pyrrole-2-methylene] -2H-indol-2-one (0.1 g, 0.26 mmol) (Starting Material 6) using (Ph3P) 4Pd ( 30.0 mg) and Cul (5.0 mg) as a catalyst in DMF (5 mL) and Et3N (5 mL) cone solvent at 85 ° C for 5 h.To the resulting compound in CH2C12 (6 mL) was added a 1: 1 mixture of acid trifluoroacetic acid / CH2C12 (6 mL) and 3 drops of water at 0 ° C and the mixture is stirred at 0 ° C for 2 h, then the mixture is quenched with concentrated NH4OH (6 mL) and diluted with EtOAc. it is washed with saline and dried with MgSO.The resulting product was purified by flash column chromatography (10% MeOH in CH2C12). To the free base in methanol (3 mL) was added 4N HOI in dioxane (0.04 mL). Evaporation of the solvent to dryness yielded rae- (Z) -1,3 hydrochloride salt -Dihydro-5-fluoro-4- [3- (2-hydroxy-propylamino) -1-propynyl] -3- [(3-methoxy-lH-pyrrol-2-yl) methy] -2H-indole-2 -one (Yield 39 mg, 35%). Example 126: Rae- (Z) -3- [(Acetyl-lH-pyrrol-2-yl) -methylene] -1,3-dihydro-5-fluoro-4- [3- (2-hydroxy hydrochloride salt -propylamino) -1-propynyl] -2H-indol-2-one (PPPPP) Using Method C cited above, N-Boc-1-prop-2-ynylamino-propan-2-ol (0.13 g, 0.63 mmol) (Example I.25A cited above) was coupled with (Z) -3 - [( 4-acetyl-lH-pyrrol-2-yl) ethylene] -1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (0.1 g, 0.25 mmol) (Example 90B) using (Ph3P 4Pd (30.0 mg) and Cul (5.0 mg) as a catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85 ° C for 5 h. To the resulting compound in CH2C12 (6 mL) was added a 1: 1 mixture of trifluoroacetic acid / CH2C12 (6 mL) and 3 drops of water at 0 ° C and the mixture was stirred at 0 ° C for 2 h. The mixture is then quenched with concentrated NH 4 OH (6 mL) and diluted with EtOAc. The organic phase is washed with saline and dried with MgSO4. The resulting product is purified by flash column chromatography (10% MeO in CH2C12). To the free base in methanol (2 L) is added 4N HCl in dioxane (0.06). mL). Evaporation of the solvent to dryness yielded rac- (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4- [3- hydrochloride salt (2-hydroxy-propylamino) -1-propynyl] -2H-indol-2-one. (Yield 39 mg, 35%). Example 127A: (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) -methylene] -1,3-dihydro-4- [(3R, S, 5R) -3,5-dihydroxy- 4-ethylamino-1-hexynyl] -5-fluoro-2H-indole -2 -one Example 127B: (R) - (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) methyleneol -1,3-dihydro-4- [(5-ethylamino-6-methyl) -6H- piran-2-yl] -5-fluoro-2H-indol-2-one (RRRRR) Using Method C cited above, tert-butylester of Ethyl- (4R, 5S, 6R-4-ethynyl-2),, 6-trimethyl- [1, 3] dioxan-5-yl) -carbamic acid (165 mg, 0.56 mmol) (Example 123C) was coupled with (Z) -3- [(4-acetyl-lH-pyrrole-2 -yl) methylene] -1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (122 mg, 0.31 mmol) (Example 90B) using (Ph3P) 4Pd (28.7 mg, 8mol%) and Cul (5 mg) as a catalyst in DMF (6 mL) and Et3N (6 mL) as solvent at 85 ° C for 5 h to yield the coupling product (161.2 mg, 92.0% after flash column purification). This coupling product (150 mg) is then treated with 50% trifluoroacetic acid / CH2C12 (5 mL) and 0.5 mL of water at room temperature for 1 h. The reaction mixture was concentrated to approximately 2 mL and diluted with AcOEt (50 mL) and then quenched with 2 N NaOH. The organic phase is washed with saline solution and dried with Na2S04. After the concentration, the raw product (136.5 mg) was triturated with AcOEt / hexanes and the precipitate was collected by filtration to yield (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-4- (3R, 4S, 5R) -3,5-dihydroxy-4-ethylamino-l-hexinyl] -5-fluoro-2H-indol-2-one (QQQQQ) as a brown-orange solid. (Yield 63.0 mg, 55.9%) The filtrate cited above is then punctured by flash column chromatography (5% -10% MeOH in CH2C12) to yield (R) - (Z) -3- [(4-Acetyl-1H- pyrrol-2-yl) methylene] -1,3-dihydro-4- [(5-e thyl-lamino-6-methyl) -6H-pyran-2-yl] -5-f-luoro-2H-indole-2- ona (RRRRR) (Rendimierito 36.5 mg, 33.8%). Example 128: (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) -methylene] -4 - [(3R, 4S, 5R) -4 -ami no- 3, 5 -dihydroxy -1 -hexinyl] -1,3-dihicyl-5-fluoro-2H-indol-2-one (SSSSS) Using Method C cited above, 4R- (1R-Hydroxy-prop-2-ynyl) -2,2,5-methyl-3-carboxylic acid tert-butyl ester (151mg, 0.56 mmol) (Example 105A cited above) was coupled with (Z) -3- (4-acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4-.L-do-2H-indole-2- ona (122 mg, 0.31 mmol) (Example 90B) using (Ph3P) 4Pd (28.7 mg, 8 mol) and Cul (3 mg) as a catalyst in DMF (6 mL) and Et3N (6 mL) as a solvent at 85 ° C. for 5 h to yield the coupling product (108 mg, 65%) after purification on a flash column. This coupling product (108 mg) is then treated with 50% trifluoroacetic acid / CH2C12 (5 mL) and 0.5 mL of water at room temperature for 1 h. The reaction mixture was concentrated to approximately 2 mL and diluted with AcOEt (50 mL) and then quenched with 2 N NaOH. The organic phase is washed with saline and dried with Na 2 SO 4. After concentration, the crude product was purified by flash column chromatography (10% MeOH in CH2C12) to yield (Z) -3- [(-Aceti 1-1H-pyrrole-2-a: 1) methylene] -4 - [(3R, 4S, 5R) -4-amino-3, 5-dihydroxy-1-hexinyl] -1,3-dihydro-5-fluoro-2H-indol-2-one as a yellow solid. (16.0 mg, 20.2%). Example 129: (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) -methylene] -4 - [(3S, 4S, 5R) -4-amino-3,5-dihydroxy -1- Hexylin] -1,3-dihydro-5-fluoro-2H-indol-2-one (TTTTT) Using Method C cited above, 4R- (lS-Hydroxy-prop-2-ynyl) -2,2,5-tr-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (151 mg, 0.56 muley) (Example 105A cited above) was coupled with (Z) -3- [(4-acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4-iodo-2H-indole-2- ona (122 mg, 0.31 mmol) (Example 90B) using (Ph3P) 4Pd (28.7 mg, 8 mol) and Cul (3 mg) as a catalyst in DMF (6 mL) and Et3N (6 mL) as solvent at 85 ° C. C for 5 h to yield the coupling product (136 mg, 80.0%) after purification on a flash column. This coupling product (135 mg) is then treated with 50% trifluoroacetic acid / CH2Cl2 (5 mL) and 0.5 mL of water at room temperature for 1 h. The reaction mixture was concentrated to approximately 2 mL and diluted with AcOEt (50 mL) and then quenched with 2 N NaOH. The organic phase is washed with saline and dried with Na 2 SO 4. After concentration, the crude product (136.5 mg) was triturated with AcOEt / hexanes and the precipitate was collected by filtration to yield (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) methylene] - 4 - [(3S, 4S, 5R) -4-amino-3,5-dihydroxy-1-hexinyl] -1,3-dihydro-5-fluoro-2H-indol-2-one as a yellow solid. (Yield 88.0 mg, 88.0%). Example 130: Antiproliferative Activity The antiproliferative activity of the compounds of the invention is demonstrated below. These effects indicate that the compounds of the present invention are valuable in the treatment of cancer, in particular for solid tumors, such as breast and colon tumors.

Flash Card CDK2 Assay To determine the inhibition of CDK2 activity, 96-well Flash plates (New England Nuclear, Boston, MA) were coated with recombinant purified retinoblastoma (Rb) protein. Rb is a natural substrate for phosphorylation by CDK2 (Herwig and Strauss Eur. J. Bi ochem., Vol. 246 (1997) pp. 581-601 and references contained therein). The human active recombinant complexes Cyclin E / CDK2 are added to the Flash plates covered with Rb together with 32 P-ATP and dilutions of the test compounds. The plates are incubated for 25 minutes at room temperature with shaking, washed and counted in the Topcount scintillation counter (Packard Instrument Co., Downers Grove, IL). The dilutions of the test compounds are tested in duplicate in each test. The percentage of inhibition of Rb phosphorylation, which is a measure of the inhibition of CDK2 activity, is determined according to the following formula: 100 x [1- (test compound - non-specific) / (total - non-specific )] where "test compound" refers to the average of counts per minute in the duplicates of the test, "non-specific" refers to the average of counts per minute when Cycline E / CDK2 is not added, and "total" refers to the average accounts per minute when compound is not added. The results of the above in vitro experiments are presented in Table I below. TABLE 1 Table IB Cell-Based Assays The 1 line of estrogen receptor negative breast epithelial carcinoma (MDA-MB435) was purchased from the American Type Culture Cell Collection (ATCC, Rockville, MD) and grown on the medium recommended by ATCC. For analysis of the effect of the test compounds on the growth of these cells, the cells are plated at 2000 cells per well in a 96-well tissue culture plate and incubated overnight at 37 ° C with 5% C02 • The next day, the test compounds are dissolved in 100% dimethylsulfoxide (DMSO) to give a stock solution of 10 mM. Each compound is diluted with sterile medium at 1 mM in an amount sufficient to give a final concentration of 120 μM. The compounds are then serially diluted in medium with 1.2% DMSO. A quarter of the final volume of the diluted compounds is transferred to the 96-well plates. The test compounds are tested in duplicate. DMSO is added to a cell of "control cells" so that the final concentration of DMSO in each cell is 0.3%. Cells in which no cells are added serve as "targets". The cells to which no inhibitor is added serve as "control without inhibitor". The plates are returned to the incubator, and 5 days after the addition of the test compound, they are analyzed as described below. 3- (4,5-Dimethylthiazol-2-yl) -2,5-diphenyl-2H-tetrazolium bromide (thiazolyl blue; MTT) is added to each well to give a final concentration of 1 mg / ml. The plates are incubated at 37 ° C for 3 hours. The plates are centrifuged at 1000 rpm for 5 minutes before aspiration of the medium containing MTT. The medium containing MTT is then removed and 100 μl of 100% ethanol is added to each cell to dissolve the resulting formazan metabolite. To ensure complete dissolution, the plates are stirred for 15 minutes at room temperature. The absorbances are read in a microfitration plate reader (Molecular Dynamics) at a wavelength of 570 nm with a reference of 650 nm. The percentage of inhibition is calculated by subtracting the absorbance of the white cells (without cells) from all the cells, and subtracting the division of the average absorbance of each assay doubled by the average of controls of 1.00. The inhibitory concentrations (IC50) are determined from the linear regression of a plot of the logarithm of the concentration versus the percentage of inhibition. The SW480 colon carcinoma line is also obtained from ATCC and is tested according to the same protocol provided above with the following modification: the S 480 cell line is plated at 1000 cells per cell and analyzed at 4 days after the addition of the test compound. The results of the foregoing in vitro tests are advanced below in Tables II and III TABLE II Antiproliferative Activity in the Cell Line MDA-MB435 * * Most data reflect the results of an experiment. In those cases where an experiment is repeated, the data above is an average of the results of the separate experiments.

TABLE III Antiproliferative Activity in the SW480 Cell Line Example 131: Formulation of Tablets The compiue s to represent a compound of the invention Manufacturing procedure: 1. Mix items 1, 2 and 3 in a suitable mixer for 15 minutes. 2. Granulate the powdery mixture from Step 1 with a 20% Povidone K30 Solution (item 4). 3. Dry the granulation from Step 2 at 50 ° C. 4. Pass the granulation from Step 3 through a suitable grinding equipment. 5. Add item 5 to the ground granulation from Step 4 and mix for 3 minutes. 6. Compress the granulation from Step 5 in a suitable press. Example 55: Capsule Formulation * Compound 1 represents a compound of the invention Manufacturing Procedure 1. Mix items 1, 2 and 3 in a suitable mixer for 15 minutes. 2. Add items 4 and 5 and mix for 3 minutes. 3. Fill a suitable capsule.

E n g lis 133: Preparing a Solution for Injection / emulsion * The compound represents a compound of the invention Manufacturing Procedure: 1. Dissolve item 1 in item 2 2. Add items: items 3, 4 and 5 to item 6 and mix until dispersion, then homogenize. 3. Add the solution from step 1 to the mixture from step 2 and homogenize until the dispersion is translucent. 4. Filter sterile through 0.2 Dm filters and fill vials.

Example 134: Preparation of solution Injection / Emulsion * Compound 1 represents a compound of the invention. Manufacturing Procedure: 1. Dissolve item in item 2 2. Add items 3, 4 and 5 to item 6 and mix until dispersion, then homogenize. 3. Add the solution from step 1 to the mixture from step 2 and homogenize until the dispersion is translucent. 4. Filter sterile through 0.2 Dm filters and fill vials. While the invention has been described and illustrated with reference to specific and preferred embodiments, those skilled in the art will know that variations and modifications can be made by the usual experimentation and practice of the invention. Thus, the invention is not intended to be limited by the foregoing description, but is defined by the following claims and their equivalents. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Claims (33)

1. R E I V I N D I C A C I O N E Having described the above, the property contained in the following claims is claimed as property: 1. Compounds of formula I: and pharmaceutically active prodrugs and metabolites of the compounds of the formula I; and pharmaceutically acceptable salts of the above compounds; characterized in that R1 is hydrogen, -COR4, -COOR4, -CONR6R7, lower alkyl (optionally substituted with one or more of -OR5, -NRbR,: icloalkyl, heterocycle, -COR -COOR4, -CONR6R7, -CN, -N02, -S02R4, halogen, and -S02NR6R7), cycloalkyl (optionally substituted with one or more of -OR5, -NR6R7, lower alkyl, heterocycle, -COR4, -COOR4, -CONR6R7, -CN , -N02, -S02R4, halogen, and -S02NR6R7), heterocycle (optionally substituted with one or more of -OR5, -NR6R7, lower alkyl, cycloalkyl, -COR4, -COOR4, -CONR6R7, -CN, -N02, - S02R4, halogen, and -S02N R6R7); R2 is hydrogen, -OR4, -COOR4, -CONR6R7, -NR6R7, halogen, -N02, -CN, -S02R4, -S02NR6R7, perfluoroalkyl, lower alkyl or lower alkyl substituted by -OR8 and / or -NR6R7; R3 is hydrogen, -OR4, -COR4, -COOR4, -CONR6R7, halogen, -CN, -NR6R7, perfluoroalkyl, lower alkyl or lower alkyl substituted by -OR8 and / or -NR6R7; R4 is hydrogen, lower alkyl (optionally substituted with one or more of -OR5, -COOR8, -COR8, -CONR8R9, -NR6R7, cycloalkyl, heterocyclic, -CN, -N02, -S02R8, and -S02NR8R9), cycloalkyl (optionally substituted with one or more of -OR5, -COOR8, -COR8, -CONR8R9, -NR6R7, lower alkyl, heterocyclic, -CN, -N02, -S02R8, and -S02NR8R9), or heterocyclic (optionally substituted with one or more of -OR5, -COOR3, -COR8, -CONR8R9, -NR6R7, lower alkyl, cycloalkyl, -CN, -N02, -S02R6, and -S02NR8R9); R5 is hydrogen, -OCR8, -CONR8R9, lower alkyl or lower alkyl substituted with one or more of -OR9, -NR9R10, -N (OCR9) R10, -COR9, -CONR9R10, and -COOR9; R6 and R7 are each independently hydrogen, -COR8, -COOR8, -CONR8R9, S02R8, -S02NR8R9, lower alkyl (optionally substituted with one or more of -OR5, -NR8R9, -COOR8, -COR8, -CONR8R9, -CN , -N02, -S02R8, -S02NR8R9), cycloalkyl (optionally substituted with one or more of -OR5, -COOR8, -COR8, -CONR8R9, -NR8R9, lower alkyl, heterocycle, -CN, -N02, -S02R8, and -S02NR8R9), heterocycle (optionally substituted with one or more of -OR5, -COOR8, -COR8, -CONR8R9, -NR8R9, lower alkyl, cycloalkyl, -CN, -N02, -S02R8, and -S02NR8R9), aryl (optionally substituted with one or more of -OR5, -COOR8, -COR8, -CONR8R9, -NR8R9, lower alkyl, heterocycle, -CN, -N02, -S02R8, and -S02NR8R9), or heteroari Lo (may be optionally substituted with one or more than -OR5, -COOR8, -COR8, -CONR8R9, -NR8R9, lower alkyl, heterocycle, -CN, -N02, -S02R8, and -S02NR8R9); or R6 and R7 are each independently cycloalkyl (optionally substituted by one or more of -OR5, -COOR8, -COR8, -CONR8R9, -NR8R9, lower alkyl, heterocycle, -CN, -N02, -S02R8, and -S02NR8R9), heterocycle (optionally substituted by one or more of -OR5, -COOR8, -COR8, -CONR8R9, -NR5R9, lower alkyl, cycloalkyl, -CN, -N02, -S02R8, and -S02NR5R9), aryl (optionally substituted by one or more of -OR5, -COOR8, -COR8, -CONR8R9, -NR8R9, lower alkyl, cycloalkyl, heterocycle, -CN, -N02, -S02R8, and -S02NR8R9), or heteroaryl (may optionally be substituted with one or more of -OR5, -COOR8, -COR8, -CONR8R9, -NR8R9, lower alkyl, cycloalkyl, heterocycle, -CN, -N02, -S02R8, and -S02NR8R9); or alternatively, -NR5R7 forms a ring of from 3 to 7 atoms, optionally including said ring one or more additional heteroatoms, and is optionally substituted with one or more of lower alkyl -OR5, -COR8, COOR8, CONR8R9, and -NR5R9; R8 is hydrogen, lower alkyl (optionally substituted with one or more of cycloalkyl, heterocycle, aryl, heteroaryl, -OR9, -NR9R10, and -N (COR9) R10), aryl (optionally substituted with one or more of -OR9, - COOR9, -COR9, -CONR10R9, -NR10R9, lower alkyl, cycloalkyl, heterocycle, -CN, -N02 / -S02R9, and -SO2NR10R9i, heteroaryl (optionally substituted with one or more of -OR9; -COOR9, -COR9, -CONR10R9, -NR10R9, lower alkyl, cycloalkyl heterocycle, -CN, -N02, -S02R9, and -SO2NR10R9), cycloalkyl (optionally substituted with one or more of -OR9, -COOR9, -COR9, -CONR10R9, -NR10R9, lower alkyl, heterocycle, -CN, -N02 / -SO > R9, and -SO2NR10R9), or heterocycle (optionally substituted with one or more of -OR9, -COOR9, -COR9, -CONR10R9, -NR10R9, lower alkyl, cycloalkyl, -CN, -NO, -S02R9, and -SO2NR10R9); R9 and R10 are independently hydrogen or lower alkyl; X is = N-, = C (R5) -, or = C (COOR8) -; and a is an optional link.
2. 2. The compounds of claim 1, characterized in that R1 is hydrogen, -COR4, -COOR4. -C0NR6R7, lower alkyl (optionally substituted with one or more of -OR4, -NR6R7, cycloalkyl, heterocycle, -COR4, -COOR4, -CONR6R7, -CN, -N02, -S02R4, halogen, and -S02NR6R7) cycloalkyl (optionally substituted with one or more of -OR4, -NR6R7, lower alkyl, heterocycle, -COR4, -COOR4, -CONR6R7, -CN, -N02, -S02R4, halogen, and -S02NR6R7), heterocycle (optionally substituted with one or more of -OR5, -NR6R7, lower alkyl, cycloalkyl, -COR4, -COOR4, -CONR6R7, -CN, -N02, -S02R4, halogen, and -S02N R6R7); x is = N- or = OH-; and from R2 to R10 are as in claim 1.
3. 3. The compounds of claim 1 or 2 wherein R1 is -COR4, lower alkyl (optionally substituted with one or more of -OR4, -NR6R7, -COR4, - COOR4, -CONR6R7, -N02, cycloalkyl, and heterocycle), cycloalkyl (optionally substituted with one or more of -OR4, -NR6R7, -COR4, -COOR4, -CONR6R7, -N02, lower alkyl, heterocycle), or heterocycle ( optionally substituted with one or more of -OR4, -NR6R7, -COR4, -COOR4, -CONR6R7, -N02, lower alkyl, and cycloalkyl); R2 is hydrogen, -OR4, -N02, -NR6R7, halogen, perfluoroalkyl, lower alkyl or lower alkyl substituted by -OR8 and / or NR6R7; R3 is hydrogen, -OR4, -NR6R7, lower alkyl or lower alkyl substituted by -OR8 and / or -NR6R7.
4. 4. The compounds of any one of claims 1 to 3, characterized in that R4 is hydrogen, lower alkyl or lower alkyl substituted by -NR6R7, -OR5, -COOR8, -COR8 and / or -CONR8R9; R5 is hydrogen, -COR8, -CONR8R9, or lower alkyl; R6 and R7 are each independently hydrogen, -COR8, -COOR8, -CONR8R9, -S02R8, lower alkyl or lower alkyl substituted by -OR5 and / or -NR8R9; or alternatively, -NR6R 'forms a ring of 3 to 7 atoms, said ring optionally including one or more additional heteroatoms, and being optionally substituted by the groups consisting of one or more of -OR5 and -NR5R9: R8 is: hydrogen, lower alkyl or lower alkyl substituted by aryl, heteroaryl, -OR9, -NR9R10, and / or -N (COR9) R: °.
5. 5. The compounds of any one of claims 1 to 4, characterized in that R2 is fluoro or -N02.
6. 6. The compounds of any of claims 1 to 5, characterized in that X is = CR5- or = N-.
7. The compounds of any of claims 1 to 6, characterized in that R1 is lower alkyl substituted with one or more of hydroxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, lower alkyl-amino, lower-dialkylamino, phenyl -alkyl ihferior-amino, lower alkoxycarbonylamino, lower hydroxyalkyl-amino, lower alkanoylamino, carbamoyloxy, lower alkylcarbamoyloxy, ureido, morpholinyl, piperidinyl, hydroxypyrrolidinyl, lower alkyl-sulfonylamino, and lower alkyl-phenylsulfonylamino, or in which R1 is hydroxycycloalkyl , hydroxy-tetrahydropyranyl, pyrrolidinyl, hydroxypyrrolidinyl, or hydroxypiperidinyl.
8. 8. The compounds of any of claims 1 to 1, characterized in that the dotted link designated "a" is present.
9. 9. The compounds of claim 8, (Z) -l, 3-dihydro-4- (6-hydroxy-l-hexinyl) -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene] - 2H-indol-2-one (A), (Z) -1, 3-dihydro-4- (5-hydroxy-l-pentynyl) -3- [(3-methoxy-lH-pyrrol-2-yl) methylene ] -2H-indol-2-one (B), (Z) -1, 3-dihydro-4- (4-hydroxy-1-butyl) -3- [(3-methoxy-1H-pyrrole-2 il) methylene] -2H-indol-2-one (C), rae-Z) -1, 3-dihydro-4- (3-hydroxy-3-methyl-1-pentynyl) -3- [(3-methoxy -lH-pyrrol-2-yl) methylene] -2H-indol-2-one (D), (Z) -1, 3-dihydro-4- (3-hydroxy-3-methyl-1-butynyl) - 3- (3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (L), (Z) -1, 3-dihydro-4- [(1-hydroxycyclohexyl) ethynyl) - 3- [(3-Methoxy>: i-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (M), rae- (Z) -1, 3-dihydro-4- (3 -hydroxy-3-methyl-1-hexinyl) - [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indo1-2-one (N), rae- (Z) -1, 3 dihydro-4- (3, 5-dimethyl-3-hydroxy-1-hexinyl) -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indol-2-one (O), (R) - (Z) -1, 3-dihydro-4- (3-hydroxy-1-octinyl) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole- 2-one (P), rae- (Z) -1, 3-dihydro-4- (3-hydroxy-1-octinyl) -3- [(3-methoxy-1H-pyrrol-2-yl) methylene] - 2H-indol-2-one (Q), rae- (Z) -1, 3-dihydro-4- (3-hydroxy-l -pentinyl) -3- [(3-methoxy-lH-pyrrol-2-yl methylene] -2H-indol-2-one (R), (Z) -1,3-dihydro-4- [3- (2-hydroxyethoxy) -1-propynyl] -3- [(3-methoxy-1H) -pyrrol-2-yl) methylene] -2H-indo1-2-one (S), (S) - (Z) -1, 3-dihydro-4- (3-hydroxy-1-octinyl) -3- [ (3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (U), (Z) -1, 3-dihydro-4- (3-hydroxy-1-propinyl) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene-2H-indol-2-one (Y), and (Z) -1, 3-dihydro-4- [(1-hydroxycyclopentyl) ethynyl] - 3- [(3-methox: - lH-pyrrol-2-yl) methylene] -2H-indol-2-one (AA).
10. 10. The compounds of claim 8, (Z) -6- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo-lH-indole -4-yl] -5-hexinoic methyl ester (E),. (Z) -5- [2, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) -methyl] -2-oxo-lH-indol-4-yl] -4- acid pentinoic methyl ester (F), (Z) -6- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) -methyl] -2-oxo-lH-indole -4-yl] -5-hexynoic acid (G), (Z) -5- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo acid -lH-indol-4-yl] -4-pentynoic acid (H), (Z) -5- [2, 3-dihydrO-3- [(3-methoxy-lH-pyrro1-2-yl) -methyl ene] ] -2-oxo-lH-indol-4-yl] -4-pentynoic sodium salt (I), (Z) -5- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrole-2 -yl) -methylene] -2-oxo-lH-indol-4-yl] -4-pentinamide (J), (Z) -6- [2,3-dihydro-3- [(3-methoxy-H-) pyrrol-2-yl) -methylene] -2-oxo-lH-indol-4-yl] -5-hexinamide (K), (Z) - [3- [2,3-dihydro-3- [(3)] -methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo-lH-indol-4-yl] -2-propynyl] propane-nodioxy dimethyl ester (V), and acid (Z) - [3- [2,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo-lH-indol-4-yl] -2-propynyl] propanedioic acid (W).
11. 11. The compounds of claim 8, (Z) -1, 3-dihydro-4- (3-hydroxy-1-propynyl) -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene] - 5-nitro-2H-indol-2-one (Z), (Z) -5-amino-l, 3-dihydro-4- (3-hydroxy-l-propynyl) -3- [(3-methoxy-lH -pyrrol-2-yl) methylene] -2H-indol-2-one (BB), (Z) -N- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo-4- (3-hydroxy-l-propynyl) -IH-indol-5-yl] -2-thiopheneacetamide (CC), and (Z) -N- [2, 3 -dihydro- 4- (3-hydroxy-1-propynyl) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-5-yl] -4-pyridinecarboxamide (DD) .
12. The compounds of claim 8, (Z) -5- [2,3-dihydro-3- [(3-methoxy-1H-pyrro 1-2-yl) methylene] -5-nitro-2-oxo acid -lH-indol-4-yl] -4-pentynoic methyl ester (EE), (Z) -5- [5-amino-2,3-dihydro-3- [(3-methoxy-lH-pyrrole-2)] -yl) methylene] -2-oxo-lH-indol-4-yl] -4-pentynoic methyl ester (FF), (Z) -5- [2,3-dihydro-3- [(3-methoxy) lH-pyrrol-2-yl) methylene] -2-oxo-5- [(2-thienylacetyl) amino] -IH-indol-4-yl] -4-pentionic methyl ester (GG), and acid (Z) - 5- [2,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-5- [(2-thienylacetyl) amino] -lH-indol-4-yl ] -4-pen tinoico (HH).
13. 13. The compounds of claim 8, (Z) -4- (3-amino-1-propynyl) -1,3-dihydro-3- (3-methoxy-1H-pyrrol-2-yl) methylene] -2H -indole-2-one salt trifluoroacetate (II), (Z) -L, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- [3- (N- methylamino) -1-propynyl] -2H-indol-2-one trifluoroacetate salt (JJ), (Z) -1, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] - 4- [3- (N-Phenylmethylamino) -1-propynyl] -2H-indole-2-one (KK), (Z) - [3- [2,3-dihydro-3- [(3-methoxy)] lH-pyrrol-2-yl) methylene or] -2-oxo-lH-indol-4-yl] -2-propynyl] carbamic methyl ést sr (LL), (Z) -carbamic acid 3- [2, 3- dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -2-propynyl ester (MM), and acid (Z) -N- methylcarbamic 3- [2, 3-dihydro-3- [(3-methoxy-1H-pyrrol-2-yl) methylene] -2 -oxo-1H-indol-4-yl] -2-propynyl ester (NN).
14. 14. The compounds of claim 8, rae- (Z) -1, 3-dihydro-5-fluoro-4- (3-hydroxy-l-pentynyl) -3- [(4-methyl-lH-imidazol-5-yl) methylene] -2H- indo l- 2 -one (00), rae- (Z) -1, 3-dihydro-4- (3-hydroxy-l-pentynyl) -3- [(4-methyl-1H-imidazol-5-yl) methylene] -5-nitro-2H-indol-2-one (PP), (Z) -L, 3-dihydro-5-fluoro-4- (3-hydroxy-l-propynyl) -3- [(-met Ll-lH-imidazo1-5-yl) methylene] -2H-indol-2-one, trifluoroacetate salt (QQ) (Z) -L, 3-dihydro-5-fluoro-4- [3- (N-methylamino ) -1-propynyl] -3- [(-methyl-1H-imidazol-5-yl) methylene] -2H-indol-2-one (RR), rae- (Z) -1, 3-dihydro-5 -fluoro-4- (4-hydroxy-l-pentynyl) -3- [(-methyl-lH-imidazol-5-yl) methylene] -2H-indole-2-o? a, trifluoroacetate salt (TT), ( Z) -L, 3-dihydro-4- [3- (N, N-dimethylamino) -1-propynyl] -5-fluoro-3 - [(4-meth i 1-lH-imidazo-1-5-yl) methylene] -2H-indol-2-one (UU), (Z) -4- [3-amino-3-methyl-1-butynyl] -1, 3-dihydro-5-fluoro-3- [(4- methyl-lH-imide zol-5-yl) methylene] -2H-indol-2-one (VV), (Z) -carbamic acid 3- [2,3-dihydro-3- [(4-m)] ethyl-lH-imidazol-5-yl) methylene] -5-fluoro-2-oxo-lH-indol-4-yl] -2-propynyl ester (WW), (Z) -I, 3-dihydro-5- fluoro-3- (4-methyl-lH-imidazo-l, 5-yl) methylene] -4- [3- (4-morpholinyl) -1-propynyl) -2H-indol-2-one (XX), acid ( Z) - [3- [2, 3-dihydro-5-fluoro-3- [(4-methyl-1H-imidazol- -yl) methylene] -2-oxo-lH-indol-4-yl] -2 - propynyl] -carbamic methyl ester (YY), (Z) - [3- [5-fluoro-2,3-dihydro-3- [(4-methyl-lH-imidazol-yl) methylene] -2-oxo- lH-indol-4-yl] -2-propynyl] urea (ZZ), rae- (Z) -2- (acetylamino) -5- [5-fluoro- 2, 3, dihydro-3- [(4- methyl-lH-imidazol-5-yl) methylene] -2-oxo-lH-indol-4-yl] -4-pentynoic ethyl ester (AAA), (Z) -A- [3- (N, N-Diethylamino ) -1-propynyl] -1,3-dihydro-5-fluoro-3- [(4-methyl-1H-imidazol-5-yl) methylene] -2H-indol-2-one (BBB), (Z ) - - [3-amino-3-ethyl-l-pentynyl] -1,3-dihydro-5-fluoro-3- | (4-methyl-1H-imidazol-5-yl) ethylene] -2H-indole-2-one (CCC), (Z) - [3- [2, 3-dihydro-5-f-3-chloro]) [(4-methyl-lH-imidazol-5-yl) ethylene] -2-oxo-lH-indol-4-yl] -1,1-dimethyl-2-propynyl] carbamic methyl ester (DDD), N- [3- [2, 3-dihydro-5-fluoro-3- (5-methyl-1H-imide zol-4-yl-methylene) -2-oxo-lH-indol-4-yl] -prop-2 -inyl] -acetamide (EEE), and (Z) -1, 3-dihydro-5-fluoro-3- [(4-methyl-lH-imidazo1-5-yl) methyl or] -4- [3- ( 1-piperidinyl) -1-propynyl-2H-indol-2-one (FFF).
15. 15. The compounds of any one of claims 1 to 7, characterized in that the dotted link designated "a" is absent.
16. 16. The compounds of claim 15, 3- [2, 3-dihydro- (Z) -3- [(lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] acid] - (E) -2-propenoic methyl ester (GGG), 3- [2, 3-dihydro- (Z) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2- oxo-lH-indol-4-yl] - (E) -2-propenoic methyl ester (HHH), 1,3-dihydro-4- (3-hydroxy-propenyl) -3- [(3-methoxy-lH- pyrrole-2-i 1) mephylene] -indo1-2-one (III), 1,3-dihydro-4- (4-hydroxy-but-l-enyl) -3- [(3-methoxy-1H-pyrrole -2-yl) methylene] -indol-2-one (JJJ).
17. 17. The compounds of claim 8, (R) - (Z) -1, 3-dihydro-5-fluoro-4- (-hydroxy-1-pentynyl) -3- [(4-methyl-1H-imidazole- 5-yl) methylene] -2H-indol-2-one (KKK), (S) - (Z) -1, 3-dihydro-5-fluoro-4- (4-hydroxy-1-pentynyl) -3- [(4-methyl-lH-imidazol-5-yl) methylene] -2H-indol-2-one (LLL), rae- (Z) -1, 3-dihydro-5-fluoro-4- (3-hydroxy -l-pentynyl) -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (MMM), rae- (Z) -1, 3-dihydro-5- fluoro-4- (3-hydroxy-l-pentynyl) -3- [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one (NNN), (Z) -L, 3-dihydro- 5-fluoro-4- [3- (N-methylamino) -1-propynyl] -3- [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one (OOO), (Z) - L, 3-Dihydro-5-fluoro-4- [3- (N-methylamino) -1-propynyl] -3 - [(3-methoxy-1 H -pyrrol-2-yl) methylene] -2H-indole-2 -one (PPP), hydrochloride salt of (Z) -1, 3-dihydro-5-fluoro-4- [3- (N-methylamino) -1-propynyl] -3- [(3-methoxy-lH-pyrrole -2-iDmethyleium] -2H-indol-2-one (QQQ), (R) - (Z) -1, 3-dihydro-5-fluoro-4- (3-hid roxy-1-butynyl) -3- [(4-methyl-lH-imidazol-5-yl) methylene] -2H-indol-2-one (RRR), (R) - (Z) -1, 3-dihydro - 5-fluoro-4- (-hydroxy-1-pentynyl) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (SSS), acid (Z) -5- [2,3-dihydro-5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -4-pentynoic methyl ester (TTT).
18. 18. The compounds of claim 8, (Z) -1, 3-dihydro-5-fluoro-4- [(1-hydroxy-cyclopentyl) ethynyl] -3 - [(3-methoxy-1H-pyrrole-2-yl) il) methylene] -2H-indol-2-one (UUU), (S) - (Z) -1, 3-dihydro-5-fluoro-4- (4-hydroxy-1-pentynyl) -3- [( 3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (VVV), (R) - (Z) -1, 3-dihydro-5-fluoro-4- (3-hydroxy) - 1-butynyl) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (WWW), (S) - (Z) -1, 3-dihydro- 5-fluoro-4- (3-hydroxy-1-butynyl) -3- [(3-methoxy-1 H -pyrrol-2-yl) methylene] -2H-indol-2-one (XXX), (S) - (Z) -1,3-dihydro-5-fluoro-4- (3-hydroxy-1-butynyl) -3- [(4-methyl-lH-imidazol-5-yl) methylene] -2H-indole-2 -one (YYY), (Z) -L, 3-dihydro-5-fluoro-4- [(4-hydroxy-tetrahydro-pyran-4-yL) ethynyl] -3- [(3-methoxy-lH-pyrrole -2-yl) methylene] -2H-indol-2-one (ZZZ), (Z) -L, 3-dihydro-4- [(4-hydroxy-tetrahydro-pyran-4-yl) -etini 1] - 3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -5-nitro-2H-indol-2-one (.AAAA).
19. 19. The compounds of claim 8, (S) - (Z) -1, 3-dihydro-5-fluoro-3- [(3-methoxy-1H-pyrrol-2-yl) methylene] -4- [( pyrrolidin-2-yl) ethynyl] -2H-indol-2-one (BBBB), hydrochloride salt of (S) - (Z) -1,3-dihydro-5-fluoro-3- [(3-methoxy-1H -pyrrol-2-yl) methylene] -4 [(pyrrolidin-2-yl) ethynyl] -2H-indole-2-one (CCCC), (R) - (Z) -1, 3-dihydro-5-fluoro -3- [(3-methoxy-lH-pyrrol-2-yl) ethylene] - [(pyrrolidin-2-yl) ethynyl] -2H-indol-2-one (DDDD), (Z) -3- [( 4-acetyl-lH-pyrrol-2-yl) methylene) -1,3-dihydro-5-fluoro-4- [(4-hydroxy-tetrahydro-pyran-4-yl) ethynyl | -2H-indol-2-one (EEEE), (R) - (Z) -4- (3-amino-4-hydroxy-1-butyl) -1,3-dihydro-5-fluoro-3- [ (3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (FFFF).
20. 20. The compounds of claim 8, (R) - (Z) -1, 3-dihydro-5-fluoro-4- [3- (3-hydroxy-pyrro-1-idinyl-L) -1-propynyl] -3 [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (GGGG), (S) - (Z) -4- (3-amino-4-hydroxy-1) butyl) -1,3-dihydro-5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (HHHH), (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4- [3- (N-methylamino) -1-propynyl] -2H-Indole-2-one (III), hydrochloride salt of (Z) -3 - [(4-acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4- [3- (N-methylamino) -1-propynyl] -2H-indol-2-one (JJJJ), (S) - (Z) -1, 3-dihydro-5-fluoro- 4- [3- (3 -hydroxy-pyrrolidin-1-yl) -1-propynyl] -3 [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (KKKK).
21. 21. The compounds of claim 8, rae- (Z) -3- [(4-acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4- [(3-hydroxy -pyrrolidin-3-yl) ethynyl] -2H-indole-2-one (LLLL), rac- (Z) -3- [(4-acetyl-lH-pyrrol-2-yl) methylene] -1, 3- dihydro-5-fluoro-4- [(3-hydroxy-pyrrolidin-3-yl) ethynyl] -2H-indole-2-one hydrochloride salt of (MMMM), (Z) -1, 3-dihydro-5-fluoro -4- [(2S, 4R) - (4-Hydroxy-pyrrolidin-2-yl) -etinyl] -3 [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (NNNN), hydrochloride salt of (Z) -1, 3-dihydro-5-fluoro-4- [(2S, 4R) -I 4-hydroxy-pyrrolidin-2-yl) -etinyl] -3 [(3- methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (OOOO).
22. 22. The compounds of claim 8, (Z) -1,3-dihydro-5-fluoro-4- [(4-hydroxy-piperidin-4-yl) -etinyl] -3- [(3-methoxy) hydrochloride salt. lH-pyrrol-2-yl) methylene] -2H-indol-2-one (PPPP), (Z) -X [(3R, 4R) -3-amino-hydroxy-1 -pentinyl] -1,3- dihydro-5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (QQQQ), (Z) -1, 3-dihydro-5-fluoro- 4- [(2S, 4S) - (-hydroxy-pyrrolidin-2-yl) -etinyl] 3- [(3-methoxy-1H-pyrro1-2-yl) methylene] -2H-indol-2-one (RRRR ).
23. 23. The compounds of claim 8, (R) -l Z) -1,3-dihydro-5-fluoro-4- [4-hydroxy-3-methylamino-1-butynyl] -3- [(3-methoxy -lH-pyrrol-2-yl) methylene] -2H-indol-2-one (SSSS), (Z) -4- [(3S, 4S, 5R) -4-amino-3,5-dihydroxy-l- Hexylin] -1,3-dihydro-5-fluoro-3 [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (TTTT), (Z) -4- [( 3R, 45, 5R) -4-amino-3,5-dihydroxy-1-hexinyl] -1,3-dihydro-5-fluoro-3 [(3-methoxy-lH-pyrrol-2-yl) methylene] - 2H-indol-2-one (UUUU), rae- (Z) -1, 3-dihydro-5-fluoro-4- [(3-hydroxy-pyrrolidin-3-yl) ethynyl] -3- [ (3-methoxy-lH pyrro1-2-: L1) methylene] -2H-indo1-2-one (VVVV), hydrochloride salt of (Z) -1, 3-dihydro-4- (3-ethylamino-1 -propini .L) -5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (WWWW), (S) - (Z) -3- [( 4-acetyl-lH-pyrrol-2-yl) methylene) -1,3-dihydro-5-fluoro-4 [(pyrrolidin-2-yl) ethynyl] -2H-indol-2-one (XXXX), hydrochloride salt of (S) - (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) methylene] -1, 3-dihi dro-5-fluoro-4 [(pyrrolidin-2-yl) -etinyl] -2H-indol-2-one (YYYY), (Z) -3- [(4-acetyl-lH-pyrrol-2-yl methylene] -1,3-dihydro-5-fluoro-4- [(2S, 4R) - (4-hydroxy-pyrrolidin-2-yl) ethynyl I -2H-indol-2-one (ZZZZ).
24. 24. The compounds of claim 8, (Z) -3 - [(4-acetyl-lH-pyrrol-2-yl) methylene o) -1,3-dihydro-5-fluoro-4- [(hydrochloride salt. 2S, 4R) (4-hydroxy-pyrrolidi-2-yl) ethynyl] -2H-indol-2-one (AA? AR), hydrochloride salt of (Z) -3- [(4-acetyl-lH-pyrrol- 2-yl) methylene] -1,3-dihydro-4- [(3-ethylamino) -i-propynyl) -5-fluoro-2H-indol-2-one (BBBBB), hydrochloride salt of (Z) -3 - [(4-acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-5-fluoro-4- [(4-hydroxy-piperidin-4-yl) ethynyl] -2H-indole-2 -one (CCCCC), (S) - [Z) -l, 3-dihydro-5-fluoro-4- [3-methylamino-4-hydroxy-1-butynyl] -3- [(3-methoxy) lH-pyrrole-2-illmethylene] -2H-indol-2-one (DDDDD)
25. 25. The compounds of claim 8, (Z) -5- [[4- (3-ethylamino-propynyl) -5- acid] fluoro-2-oxo-1,2-dihydro-indol-3-ylidene] methyl] -4-methyl-lH-pyrrole-3-carboxylic acid ethyl ester hydrochloride salt (EEEEE), (Z) -1, 3-dihydro- 5-fluoro-4- [(3R, 4R) - -hydroxy-3-methylamino-1-pentynyl] -3 [(3-methoxy-1 H -pyrrol-2-yl) methylene] - 2H-Indole-2-one (FFFFF), hydrochloride salt of (Z) -1, 3-Dihydro-5-fluoro-4- [(3R, 4R) -4-hydroxy-3-methylamino-1 -pentinyl ] -3 [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2H-indo 1-2 -one (GGGG), (Z) -N- [3- [5-fluoro- 3- [ (3-methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo-2,3-dihydro-lH-indol-4-yl] -prop-2-ynyl] -4-methyl-benzenesul-fonamide ( HHHHH), (Z) -N- [3- [5-fluoro-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2-oxo-2,3-dihydro-lH-indole -4-yl] -prop-2-ynyl] -methanesulonamide (IIIII), (S) - (Z) -5- [[5-fluoro-2 -oxo-4- [(pyrrol-idin-2-yl)] acid ) -etiniL] -l, 2-dihydro-indo1-3-i lead] methyl] -4-methyl-lH-pyrrole -3-carboxylic acid ethyl ester (JJJJJ).
26. 26. The compounds of claim 8, acid; S) - (Z) -5- [[5-fluoro-2-oxo-4- [(pyrrolidin-2-yl) -etinyl] -1,2-dihydro-indol-3-ylidene] methyl] -4 -methyl-lH-pyrrole-3-carboxylic acid ethyl ester, hydrochloride salt (KKKKK), (Z) -1, 3-dihydro- - [(3R, 4S, 5R) -3,5-dihydroxy-4-ethylamino-1 -hexinyl] -5-fluoro-3- [(3-methoxy-1H-pyrro 1-2 -yl) methylene] -2H-indol-2-one (LLLLL), (R) - (Z) -1, 3 -dihydro-4- [(5-etylamino-6-methyl) -6H-pyran-2-yl] -5-fluoro-3 [(3-methoxy-lH-pyrrol-2-yl) methylene]] -2H -indol-2-one (MMMMM), (Z) -1, 3-dihydro-4- [(3S, 4S, 5R) -3,5-dihydroxy-4-ethylamino-1-hexinyl] -5-fluoro- 3- [(3-methoxy-1H-pyrro 1-2-methylene] -2H-indol-2-one (NNNNN)
27. 27. The compounds of claim 8, rae- (Z) -1,3 hydrochloride salt. -Dihydro-5-fluoro-4- [3- (2-hydroxy-propylamino) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2- ona (OOOOO), rae- (Z) -3- [(4-acetyl-lH-pyrrol-2-yl) methylene] -!, hydrochloride salt, 3-dihydro-5-fluoro-4- [3- (2 -hydroxy-propylamino) -1-propynyl] -2H-indol-2-one (PP PPP), (Z) -3- [(4-acetyl-lH-pyrrol-2-yl) ethylene] -1,3-dihydro-4- [(3R, 4S, 5R) -3,5-dihydroxy-4 -ethylamino-1-hexynyl] -5-fluoro-2H-indol-2-one (QQQQQ), (R) - (Z) -3- [(4-acetyl-lH-pyrrol-2-yl) methylene] - 1,3-dihydro-4- [(5-ethylamino-6-methyl) -6H-pyran-2-yl] -5-fluoro-2H-indol-2-one (RRRRR), (Z) -3- [ (4-acetyl-lH-pyrrol-2-yl) methylene] -4- [(3R, 4S, 5R) -4-amino-3, 5-dihydroxy-1-hexinyl] -1,3-dihydro-5- fluoro-2H-indol-2-one (SSSSS), and (Z) -3 - [(4-acetyl-lH-pyrrol-2-yl) methylene] -4- [(3S, 4S, 5R) -4- amino-3, 5-dihydroxy-1-hexinyl] -1,3-dihydro-5-fluoro-2H-indol-2-one (TTTTT).
28. 28. A compound having the formula II characterized in that b is cycloalkyl (optionally substituted by one or more of -OR5, -NR6R7, lower alkyl, heterocycle, -OCR4, -COOR4, -CONR6R7, -CN, -N02, -S02R4, halogen, and -S02NR6R7; and b is heterocycle (optionally substituted by one or more of -OR5, -NR6R7, lower alkyl, cycloalkyl, -COR4, -COOR4, -CONR6R7, -CN, -N02, -S02R4, halogen, and -S02NR6R7, and wherein R2, R3 and X have the same meaning as stated in claim 1 of formula I.
29. 29. The compounds of claim 28, (R) - (Z) -1, 3-dihydro-4- [(5-ethylamino- 6-met yl) -6H-pyran-2-yl] -5-fluoro-3- [(3-methoxy-lH-pyrroi-2-yl) methylene]] -2H-indol-2-one (MMMMM), (R) - (Z) -3- [(4-Acetyl-lH-pyrrol-2-yl) methylene] -1,3-dihydro-4- [(5-ethylamino-6-methyl) -6H-pyran- 2-yl] -5-fluoro-2H-indol-2-one (RRRRR)
30. 30. Compounds (Z) -3- [(4-acetyl-lH-pyrrol-2-yl) methylene] -1, 3 -dihydro-5-fluoro-4- lodo-2H-indo 1-2-one, rac-N-Boc-3-hydroxy-3-ethynyl-pyrrolidine, (3R, 5S) -N-boc-3-hydrox i-5-ethynyl-pyrrolidine, N-Boc-4-hydroxy-4-ethynyl-piperidine, (4R, 5R) -N-boc-2, 2, 5-Trimeti 1-4-ynyl-oxazolidine, (3S , 5S) -N-boc-5-ethynyl-3-hydroxy-pyrrole idine, (R) -N-boc-2-amino-l- (-tert-butyldimethylsilyloxy) -but-3-ina. (R) -2- (N-Boc-N-methylamino) -1- (tert-buty-ldimethylsilyl-yloxy) -but-3-nane, tert-butyl ester of 4R- (lR-hydroxy-prop-2-) inyl) - 2,2,5R-tr: Lmethyl-oxazolidine-3-carboxylic acid, 4R- (lS-hydroxy-prop-2-ynyl) -2,2, 5R-trimethyl-oxazolidine-3-carboxylic acid tert-butyl acid ester, N-boc-Ne: ilpropargyl amine, (S) -N-boc-2-amino-but-3-in-l-ol, (S) -N-boc-2-amino-1- ( -tert-butyldimeti Isyloxy) -but-3-ina, (S) -2- (N- or -N-methylamino) -1- (-tert-butyldimethylsilyloxy) -but-3-na, acid (Z ) -5- (5-Fluoro-4-iodo-2-oxo-l, 2-dihydro-indol-3-ylidene-methyl) -4-methyl-lH-pyrrole-3-carboxylic acid ethyl ester, (2R, 3R) -N-boc-3-amino-2- (-tert-butyldimethylsilyloxy) -pent-4-ina, (2R, 3R) -3- (N-boc-N-methylamino) -2- ( butyldimeti 1-silyloxy) -pent-4-ina, [2R-hydroxy-lS- (lR-hydroxy-ethyl) -but-3-ynyl] -carbamic acid tert-butyl ester, (4R-ethynyl-2,2) , 6R-trimethyl- [1,3] dioxan-5S-yl) -carbamic acid tert-butyl ester, tert-butyl ester of ethyl- (4R, 5S, 6R-4) -ethyl-2-, 2-, 6-trimethyl- [1, 3] -dioxan-5-yl) -carbamic acid, tert-butyl ester of [2S-hydroxy-lS- (lR-hydroxy-ethyl) -but-- 3-inyl] -carbamic acid, tert-butyl ester. [2S- (tert-butyl-dimethyl-silanyloxy :.) -IS- [IR- (tert-butyl-1-dimethyl-si-lanyl-loxi) ethyl] - but-3-ini] -carbamic acid, tert-butyl ester of [2S- (tert-butyl-dimethyl-silanyloxy:) -IS- [IR- (tert-butyl-dimethyl-silanyloxy) ethyl] -but-3 acid -inyl] -ethyl-carbamic acid, N-boc-1-prop-2-ynylamino-propan-2-o1, (Z -4-bro? ao-l, 3-dihydro-3- [(3-methoxy-lH -pyrrol-2-yl methylene] -2H-indole-2-one, (Z -1, 3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-ylmethyl) -2H -indol-2-one, (Z -1, 3-dihydro-5-fluoro-4-iodo-3- [(4-methyl-lH-imidazol-5-yl) methylene] 2H- indo 1-2 -one , (Z -1, 3-d: Lhydro-4-iodo-3- [(4-methyl-lH-imidazol-5-ylmethyl)] -5-nitro-2H-indo1-2-one, (Z- 4-bromo- 1, 3-dihydro-5-fluoro-3- [(3-methoxy-1H-pyrrol-2-yl) methylene] 2H-indol-2-one, (Z 1, 3-d: L-hydroxy) 5-fluoro-4-iodo-3- [(3-methoxy-1) H-pyrrol-2-yl) methylene] 2H-indo 1-2 -one, (Z-4-bromo-1,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl methylene] - 5-nitro-2H-indol-2-one, (Z -1, 3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-ylmethylene] -5-nitro-2H-indo1 -2-one, 1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one, 1,3-dihydro-4-iodo-5-nitro-2H-indol-2-one, - bromo- 1, 3-dihydro-5-nitro-2H-indol-2-one, and (Z) -1, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] - 4- (2-trimethylsilylethynyl) -2H-indo1-2 -one.
31. 31. A pharmaceutical composition, characterized in that it contains as an active ingredient a compound of claim 1-29 and a pharmaceutically acceptable carrier or excipient.
32. 32. The compounds of claims 1 to 29 for use as medicaments.
33. 33. The use of a compound of formula I or II of any of claims 1 to 29 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament, characterized in that it contains the compound for the treatment or control of proliferative disorders of the cells , in particular breast or colon tumors. INHIBITORS OF CYCLIN DEPENDENT KINASES (CDKs), IN PARTICULAR CDK2 SUMMARY OF THE INVENTION New 4-alkenyl (and alkynyl) oxmdoles that present the formula and pharmaceutically acceptable salts thereof in which R ", R", R, a, b, and X are as defined herein, inhibit cyclin-dependent kinases (CDKs), in particular CDK2, and are useful as anticancer agents. Fertility iprol in the treatment or control of disorders of cell proliferation, in particular colon or breast tumors.