MXPA01006049A

MXPA01006049A - 4- and 5-alkynyloxindoles and 4- and 5-alkenyloxindoles

Info

Publication number: MXPA01006049A
Application number: MXPA/A/2001/006049A
Authority: MX
Inventors: Luk Kinchun; E Mahaney Paige; Gregory Mischke Steven
Original assignee: F Hoffmannla Roche Ag
Priority date: 1998-12-17
Filing date: 2001-06-14
Publication date: 2001-12-13

Abstract

4- and 5-alkynyloxindoles as well as 4- and 5-alkenyloxindoles having formula (I) and (II), wherein R1, R2, R3, R11, R12, X and z have the meaning indicated in the specification, inhibit or modulate protein kinases, in particular JNK protein kinases and are useful as anti-inflammatory agents, particularly in the treatment of rheumatoid arthritis.

Description

4- and 5-Alkynyloxyindoles and 4- and 5-Alkenyloxyindoles Field of the Invention The present invention relates to novel 4- and 5-Alkynyloxyindoles as well as 4- and 5-Alkenyloxindoles which inhibit or modulate protein kinases, in particular JNK protein kinases. These compounds and their pharmaceutically acceptable salts, and the prodrugs of such compounds, are useful as anti-inflammatory agents, particularly useful in the treatment of rheumatoid arthritis. The invention also relates to pharmaceutical compositions containing such compounds, and to methods for the treatment and / or control of inflammation, particularly in the treatment or control of rheumatoid arthritis. This invention also relates to intermediates useful for the preparation of the above compounds. Protein kinases are a class of proteins that regulate a variety of cellular functions. This is achieved by the phosphorylation of specific amino acids of protein substrates that result in a conformational alteration of the substrate protein. The conformational change modulates substrate activity or its ability to interact with other binding partners. The Ref: 129922 Enzymatic activity of the protein kinase refers to the speed with which the kinase adds phosphate groups to a substrate. It can be measured, for example, by determining the amount of a substrate that is converted into a product as a function of time. The phosphorylation of a substrate takes place in the active center of a protein kinase. JNK protein kinases (Jun N-terminal kinase) (also known as "stress-activated protein kinases", "stress-activated protein kinases" or "SPAK") are members of mitogen-activated kinases (MAPs). See, p. e. S. Gupta et al., EMBO J., vol. 15 no. 11 (1996) pp. 2760-2770; and Yang et al., Nature, vol. 389 (October 23, 1997) pp. 865-870. At least ten JNK isoforms are currently known. See, Gupta, id. As its name suggests, one of the JNK substates is c-Jun. JNK phosphorylates the activation domain NH ^ -terminal of c-Jun in Ser63 and Ser73, causing a transcriptional activation of c-Jun higher. See, Gupta, id. In turn, c-Jun is an AP-1 transcription factor that acts as an intermediate in immediate-early gene expression. See, p. e., A. Minden et al., Biochimica et Biophysica Acta 1333 (1997) F85-F104; and P. Agel et al., Biochimica et Biophysica Acta, vol. 1072 (1991) pp.129-157.

JNK protein kinase is strongly activated in response to treatment of cells with pro-inflammatory cytokines or exposure to environmental stress. Thus, JNK acts as an intermediary to the effect of extracellular stimuli on c-Jun. See, Gupta, supra; and Minden, supra. Accordingly, JNK is a physiological regulator of AP-1 transcriptional activity. Thus, inhibition of JNK activity will inhibit AP-1-dependent transcription of inflammatory and immune intermediates that are involved in proliferative pathological conditions, for example inflammatory diseases and neurodegenerative diseases, in particular rheumatoid arthritis. See, e.g. S antek et al., Molecular and Cellular Biology, vol. 17 (1997) pp. 6274-6282; Maroney et al., J. Neuroscience, vol. 18 (January 01, 1998) pp. 104-111; and Minden, supra, in F92. The rat JNK homolog is also referred to as SAPK (stress-activated protein kinase). The SAPK isoforms share a significant identity (> 90%) of sequence with the corresponding JNK isoforms [compare Kyriakis et al., Nature Vol. 369 (May 12, 1994) pp. 156-160 and Gupta et al., Supra]. Both JNK and SAPK are capable of phosphorylating the c-Jun substrate and therefore have a very similar enzymatic activity. JNK and SAPK are part of a protein kinase cascade that is activated by several extracellular stimuli. See p. and. Minden supra; and Kyriakis et al., BioEssays Vol. 18 (1996) pp. 567-577. Both JNK and SAPK can be activated by phosphorylation at specific threonine and tyrosine residues by MAP kinase dual-specific kinases such as MKK4, SEK-1, or MKK7. See Kyriakis et al., Supra; and Tournier et al., Proceedings of the National Academy of Sciences USA Vol. 94 (July 1997), p. 7337-7342). The MAP kinase kinases of dual specificity can be activated by phosphorylation in serine and / or threonine residues by MAP kinase kinase kinases such as MEKK-1. In this way, the measurement of the enzymatic activity of JNK or SAPK can be increased by activation by the upstream or preceding kinases. In addition, the measure of inhibition of SAPK correlates closely with the inhibition of JUNK. Inhibitors of the catalytic activity of protein kinases are known in the art. See WO 98/24432 (indolinic compounds that inhibit FLK protein kinase); WO 97/45409 (substituted analogs of tetralylmethylene oxindole which inhibit tyrosine kinase). In particular, small molecule inhibitors typically block the binding of substrates by strongly interacting with the ATP binding site of the protein kinase (or "active site").

See WO 98/24432. It is desirable to identify small molecule compounds that can be easily synthesized and effective in inhibiting the catalytic activity of protein kinases, in particular of the JNK protein kinases. Indolinone compounds (also known as oxindole) which are said to be useful in the regulation of abnormal cell proliferation through inhibition of tyrosine kinase are described, for example, in WO 96/40116, WO 98/07695, WO 95 / 01349, WO 96/32380, WO 96/22976, WO 96/16964, WO 98/50356 (2-indolinone derivatives as modulators of protein kinase activity); Mohammadi et. al, Science, Vol. 276, May 9, 1997, pp. 955-960.-Oxindol derivatives have also been described for several other therapeutic uses: 5,206,261 (improvement of brain function); WO 92/07830 (peptide antagonists); EP 580 502 Al (antioxidants).

Summary of the Invention There remains a need for small molecule compounds, easily synthesized, that are effective in inhibiting JNK protein kinases and therefore useful in the treatment or control of proliferative disease states, such as inflammatory diseases and neurodegenerative diseases. , in particular, rheumatoid arthritis. It is therefore an object of this invention to provide these compounds and compositions containing these compounds. In one embodiment, the present invention relates to 4-alkynyloxyindoles and 4-alkenyloxyindoles of formula: and pharmaceutically acceptable salts thereof, wherein: R1 is lower alkyl which is substituted by aryl, aryloxy, heteroaryl, heteroaryloxy, substituted aryl, substituted aryloxy, substituted heteroaryl, and / or substituted heteroaryloxy, and optionally may also be substituted by R13, perfluoroalkyl, cycloalkyl (or cycloalkyl substituted by lower alkyl and / or R1j), or heterocycle (or heterocycle substituted by lower alkyl and / or R13), and wherein the substituents on the substituted aryl, substituted aryloxy, substituted heteroaryl, and substituted heteroaryloxy are one or more of R, lower alkyl (optionally substituted by R "), cycloalkyl (optionally substituted by RiJ), heterocycle (optionally substituted by R1), aryl (optionally substituted by R13, perfluoroalkyl, lower alkyl, lower alkyl substituted by R13, cycloalkyl, cycloalkyl substituted by R13, heterocycle (optionally substituted by R13), or heteroaryl (op. optionally substituted by R13, perfluoroalkyl, lower alkyl, lower alkyl substituted by R13, cycloalkyl, cycloalkyl substituted by R13, or heterocycle or heterocycle substituted by R13); R- is hydrogen, -OR4, -OCOR4, -COR ", -COOR- -CONR 6e" R7 ', -NR, 6DnR7', halogen, -N02, -CN, -S02R, -S02NR 6Rp7 ', perfluoroalkyl, alkyl lower or lower alkyl substituted by -OR8 or -NR6R7; R3 is hydrogen, -OR4, -COR4, -COOR4, -CONR6R7, halogen, -CN, -NR6 R7, perfluoroalkyl, lower alkyl or lower alkyl substituted by -ORs or - NR6R7; R4 is hydrogen, lower alkyl (optionally substituted by (a), cycloalkyl and / or heterocycle), cycloalkyl (optionally substituted by (a), lower alkyl and / or heterocycle), heterocycle (optionally substituted by (a), alkyl lower and / or cycloalkyl), aryl (optionally substituted by (a), cycloalkyl, heterocycle and / or halogen), heteroaryl (optionally substituted by (a), cycloalkyl, heterocycle, and / or halogen, where (a) is -OR5 , -COOR8, -COR8, -CONR8R9, -NR6R ", -CN, -NO;, -S02R8, and / or -S02NR8R9; R ° is hydrogen, -COR, -CONR8R9 lower alkyl (optionally substituted by OR9, -NR9R10, -N (COR9) R10, -COR9, -CONR R, -SR9 and / or -COOR9; R6 and R7 are each hydrogen, -COR8, -COOR8, -CONR8R9, -S02Re8, S02NR3R9, lower alkyl, lower alkyl substituted by (b), cycloalkyl (optionally substituted by (b), lower alkyl, and / or heterocycle), heterocycle, heterocycle substituted by (b), lower alkyl and / or cycloalkyl) , aryl, aryl substituted by (b), lower alkyl, cycloalkyl and / or heterocycle), heteroaryl, heteroaryl substituted by (b), lower alkyl, cycloalkyl and / or heterocycle); or R6 and R7 are each cycloalkyl (optionally substituted by (b), lower alkyl and / or heterocycle; (optionally substituted by (b), lower alkyl and / or cycloalkyl, aryl (optionally substituted by (b), lower alkyl, cycloalkyl and / or heterocycle, or heteroaryl (optionally substituted by (b), lower alkyl, cycloalkyl and / or heterocycle, where (b) is OR5, -NR8 R9 -CO0RB, -CORB, -CONReR- -CN, -NO- -S02Re -S02NR8R9; alternatively, -NR6R7 can form a ring of 3 to 7 atoms, said ring optionally includes one or more additional heteroatoms and is optionally substituted by one or more of lower alkyl, -OR5, -COR8, -C00R, -CONR8R9, and -NR5R9; R8 is hydrogen, lower alkyl (optionally substituted by cycloalkyl, heterocycle, aryl, heteroaryl, -0Rq, -NR9R10, and / or -N (COR9) R10), aryl (optionally substituted by (c), lower alkyl, cycloalkyl and / or heterocycle), heteroaryl (optionally substituted by (c), lower alkyl, cycloalkyl and / or heterocycle), cycloalkyl (optionally substituted by (c), lower alkyl and / or heterocycle), heterocycle (optionally substituted by (c), lower alkyl and / or cycloalkyl); where (c) is -OR9, -COOR9, -COR9, -CONR10R9, -NR10R9, -CN, -N02.

-S02R9, -SO2NR10R9; R9 and R10 are each independently hydrogen or lower alkyl; R13 is halogen, -OR4, -OCOR4, -COR4 -COOR4, -CONR6R7, -N02, -NR5R7, -CN, -SO2R4, or -S02NR6R7; X is = N- or -CH-; and the dotted line link represented by z is optional. In another embodiment, the invention relates to -alkynyloxyindoles and 5-alkenyloxyindoles having the formula: and pharmaceutically acceptable salts thereof, wherein: R11 is hydrogen, -COR *, -C00R% -C0NR6DtR,, lower alkyl (optionally substituted by -OR5, -NR6R7, hologenic, -N02, -S02R4, -S02NR6R7 , -CN, -COR4, -COOR4, -CONR6R7, cycloalkyl, heterocycle, aryl, and / or heteroaryl), cycloalkyl (optionally substituted by -OR5, -NR5R7, halogen, -N02, -S02R4, -S02N R6R7, -CN , -COR4, -COOR4, -CONR6R7, lower alkyl, heterocycle, aryl, and / or heteroaryl) heterocycle (optionally substituted by -OR5, -NR6R7, halogen, -OR5, -NR6R7, hologenic, -N02, -S02R4, - S02NR6R7, -CN, -COR4, -COOR4, -CONR6R ", lower alkyl, cycloalkyl, aryl, and / or heteroaryl), aryl (optionally substituted by -OR3, -NRDR, hologenic, -N02, ~ S02R4, -CN, -COR4, -COOR4, -CONRdR7, lower alkyl, and / or perfluoroalkyl) or heteroaryl (optionally substituted by -OR5, -NR6R7, hologenic, -N02, -S02R4, -S02NR6R7, -CN, -COR4, -COOR4, - CONR6R7, lower alkyl, and / or perfluoroalkyl); R12 is hydrogen, -OR4, -OCOR4, -COR4, -COOR4, -CONR6R7, -NR5R7 halogen, -N0, -CN, -S02R4, -S02NRdR7, perfluoroalkyl, lower alkyl (optionally substituted by OR4, -NR6R7, cycloalkyl, heterocycle , -COR4, -COOR4, CONR6R7, -CN, -N02, -SO: R4, -S02NR6R7, and / or halogen), cycloalkyl (optionally substituted by OR4, -NR6R7, lower alkyl, heterocycle, -COR4, -COOR4 , CONR6R7, -CN, -NOi, -S02R \ -S02NR 6tonRl ', and / or halogen), or heterocycle (optionally substituted -OR, -NR 6pR7, lower alkyl, cycloalkyl, -COR4, -COOR4, CONR6R7, -CN, -N02 , -S02R4, -S02NR6R7, and / or halogen), and R3 to R7, X and z are as defined for formula I above. The present invention further relates to pharmaceutical compositions comprising a pharmaceutically effective amount of one or more of any of the compounds described above and a pharmaceutically acceptable carrier or excipient. The present invention also relates to the use of a compound of claim 1 or 13 or pharmaceutically active prodrugs and etabolites of these compounds in the preparation of a medicament for the treatment or control of inflammatory diseases, in particular of rheumatoid arthritis. The present invention also relates to intermediates useful for the preparation of the 4- and 5-alkynyloxyindoles and 4- and 5-alkenyloxindoles described above. As used herein, the following terms will have the following definitions. "Aryl" means an aromatic group having 5 to 10 atoms and consisting of 1 or 2 rings. "Aryloxy" means an aryl radical that includes at least one oxygen and that is attached to the rest of the molecule via the oxygen atom. "Cycloalkyl" means a non-aromatic, partially or fully saturated cyclic aliphatic hydrocarbon group containing from 3 to 8 atoms. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl. "Effective amount" means an amount of at least one compound of formula I and / or II, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, which inhibits the development or proliferation of (1) a disease or inflammatory response and / or (2) a neurodegenerative disease or response, such as, for example, and not as a limitation, rheumatoid arthritis. "Halogen" means fluorine, chlorine, bromine or iodine. "Heteroaryl" groups 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 and quinolyl. "Heteroaryloxy" means a heteroaryl radical that includes at least one oxygen and that is attached to the rest of the molecule via the oxygen atom. "Heteroatom" means an atom selected from N, O and S. "Heterocycle" means a non-aromatic, partially or fully saturated, non-aromatic, 3- to 10-membered hydrocarbon group, such as tetrahydroquinolyl, which contains one or two rings and at least one heteroetam. "IC50" refers to the concentration of a particular 4- or 5-alkynyloxyindole or 4- or 5-alkenyloxyindole necessary to inhibit 50% of the phosphorylation of cJun, which constitutes a measure of inhibition of SAPK activity. The IC 50 can be measured, inter alia, using the assay described herein in Example 102. "Lower alkyl" denotes a straight or branched chain saturated aliphatic hydrocarbon having 1 to 6, preferably 1 to 4, carbon atoms. The lower-typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl and the like. "Pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts that retain the biological effectiveness and properties of the compounds of formula I or II and are formed from non-toxic acids or organic or inorganic bases adequate. Examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, iodhydric acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Examples of base addition salts include those derived from sodium, potassium, 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 metabolite" means a metabolic product of a compound of formula I or II that is pharmaceutically acceptable and effective. "Prodrug" refers to a compound that can be converted by solvolysis or under physiological conditions to any of the compounds of formula I or II or a pharmaceutically acceptable salt of a compound of formula I or II. A prodrug may be inactive when administered to a subject but converted into an active compound formula I or II.

"Substituted," as in substituted alkyl means that the substitution may take place in one or more positions, that one or more substituents may be selected, and, unless otherwise indicated, that the substituents are independently selected from the specified options. In one embodiment, the invention relates to compounds of formulas I and II, wherein R 4 is hydrogen, lower alkyl (optionally substituted by (a), cycloalkyl and / or heterocycle), cycloalkyl (optionally substituted by (a), lower alkyl and / or heterocycle), or heterocycle (optionally substituted by (a) I lower alkyl and / or cycloalkyl) I where (a) is -OR5, -COOR8, -COR8, -CONR8R9, -NR6R7, -CN, -N02, -S02R8, and / or -S02NR8R9; and R5 is hydrogen, -COR8, -CONR8R9 or lower alkyl (optionally substituted by -OR9, -NR9R10, -N (COR9) R10, -COR9, CONR9R10 and / or -COOR °, and R1 to R10, X and z are as defined above In a preferred embodiment, the invention is refers to compounds of formula I wherein R1 is lower alkyl which is substituted by aryl or substituted aryl, and optionally also substituted by halogen, -OR4, -COR4, -COOR4, -CONR6R7, cycloalkyl, heterocycle, -COOR4, C0NR6R7, cycloalkyl which is substituted by OR =, -NR6R7, COOR4, CONR6R7, and / or heterocycle which is substituted by OR5, -NR ^ 7, COOR4, CONR6R7; and wherein the substituents of the substituted aryl are selected from halogen, -OR4, -COR4, -COOR4, -C0NR6R7, -N02, NR5R7, -S02R4, -S02NR6R ', -CN, perfluoroalkyl, lower alkyl, cycloalkyl, heterocycle, alkyl lower which is substituted by -OR5, and -NR6R7, COOR4, C0NR6R7, cycloalkyl substituted by OR5, and -NR6R7, COOR4, CONR6R7, or heterocycle substituted by OR5, -NR6R7, COOR4, CONRdR7; lower alkyl which is substituted by heteroaryl or substituted heteroaryl, and optionally also substituted by halogen, -OR4, -COR4, -COOR4, -CONRdR7, cycloalkyl, heterocycle, cycloalkyl which is substituted by OR5, COOR4, CONR6R7, and / or -NR6R7, and / or heterocycle which is substituted by -OR5, COOR4, CONR6R7, and / or -NRdR7; and wherein the substituents of the substituted heteroaryl are selected from halogen, -OR4, -COR4, -COOR4, NR6R7, -S02R4, -S02NR6R7, -NO_, -CN, -CONR6R7, lower alkyl, cycloalkyl, heterocycle, lower alkyl which is substituted by -OR5, -NR6R7, COOR4, CONR6R7, cycloalkyl which is substituted by -OR5, -NR6R7, COOR4, CONR6R7, and / or heterocycle which is substituted by -OR3, -NRdbrR > 7 ', COOR * and / or CONR ^ R' aryl (optionally substituted by halogen, -OR4, -COR4, -COOR4, -CONR6R7, lower alkyl, cycloalkyl, heterocycle, lower alkyl which is substituted by -OR5, -NR R, COOR4, CONR6R7, cycloalkyl which is substituted by -OR5, COOR4, CONR6R7, and / or -NReR7, and heterocycle which is substituted by -OR5, COOR4, C0NRdR7, and / or -NR5R7, or heteroaryl (optionally substituted by halogen, -OR4, -COR4, -COOR4, -CONR6R7, lower alkyl, cycloalkyl, heterocycle, lower alkyl which is substituted by -OR5, COOR4, CONR6R7, and / or -NR6R7, cycloalkyl which is substituted by - OR5, COOR4, CONR6R7, and / or -NR5R7, and / or heterocycle which is substituted by -OR5, COOR4, CONR6R7, and / or -NR6R7.) In another preferred embodiment, the invention relates to compounds of formulas I and II, wherein X is CH and R3 is lower alkoxy, furthermore, wherein R1 is lower alkyl substituted by phenyl which is substituted by one to three substituents of between the hydroxyl group, lower alkoxy, di- (lower alkyl) -amino, di- (lower alkyl) amino-lower alkoxy, morpholino-lower alkyl, carboxy-lower alkoxy and lower alkanoylamino; or R1 is lower alkyl substituted as above and additionally by hydroxyl; or wherein R1 is lower alkyl substituted by pyridyl, pyrrolyl, N-lower alkyl-pyrolyl, thienyl, thienyl substituted by lower alkoxy, furyl, 1,3-benzodioxolyl, or 1,3-benzodioxolyl substituted by lower alkoxy; or wherein R1 is lower alkyl substituted as above and additionally by hydroxyl; or wherein Rx is pyridyl. Also preferred are those of formula I wherein the optional z bond is present. Preferred compounds of formula II are those in which R3 is hydrogen, -OR4, -NRdR7, and / or lower alkyl (optionally substituted by -OR8, -NR6R7); R4 is hydrogen, lower alkyl (optionally substituted by one or more -OR5, -COOR8, -COR8, -CONR8R9), cycloalkyl (optionally substituted by one or more -OR5, -COOR8, -COR8, and -CONR8R9), or heterocycle (optionally substituted by one or more -OR5, -COOR8, -COR8, and -CONR8R9); R5 is hydrogen, -COR8, -CONR8R9, or lower alkyl; R6 and R7 are each independently hydrogen, -COR8, -COOR8, -CONR8R9, or lower alkyl (optionally substituted by one or more of -OR9, -NR8R9, COOR8, and CONR8R9) or alternatively, -NR6R7 optionally forms a ring having from 3 to 7 atoms, optionally including said ring one or more additional heteroatoms and being optionally substituted by one or more lower alkyl, -OR, -COOR, -CONR8R9, and -NR5R9; R8 is hydrogen or lower alkyl (optionally substituted by one or more of aryl, heteroaryl, -OR9, COOR8, CONRqR10, and -NR9R10); Ru is aryl (optionally substituted by -OR5, and / or -NR5R7); R12 is hydrogen, -COR4, -COOR4, and -C0NRdR7, lower alkyl (optionally substituted by one or more of -OR4, -NR6R7, cycloalkyl, heterocycle, -COR4, -COOR4, and -CONR6R7, -CN, -N02, -S02R4, -S02, NR6R7, and halogen), cycloalkyl (optionally substituted by one or more of -OR4, -NRdR7, lower alkyl, heterocycle, -COR4, -COOR4, and -CONR6R7, -CN, -N02, -S02R4, -S02, NRdR7, and halogen), heterocycle (optionally substituted by one or more of -OR4, -NR6R7, lower alkyl, cycloalkyl, -COR4, -COOR4, and -CONR6R7, -CN, -N02, -S02R4, -S02, NR6R7, and halogen); and the optional link z is present. The invention further relates to intermediates useful for the preparation of compounds of formula I: 1,3-Dihydro-5-fluoro-4-iodo-2H-indol-2-one, (Z) -1,3-Dihydro-3 - [(lH-pyrrol-2-yl) methylene] -5- (trimethylsilyl) ethynyl-2H-indol-2-one, (Z) -5-Bromo-l, 3-dihydro-3- [(3-methoxy -lH-pyrrol-2-yl) methylene] -2H-indol-2-one, (Z) -1, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -5 - (trimethylsilyl) ethynyl-2H-indol-2-one, (Z) -5-Bromo-l, 3-dihydro-3- [(4-methyl-lH-imidazol-5-yl) methylene] -2H-indole -2-one, (Z) -1, 3-Dihydro-3- [(4-methyl-lH-imidazol-5-yl) methylene] -5- (trimethylsilyl) ethynyl-2H-indol-2-one. The compounds described herein and covered by the above formulas may show tautomerism or structural isomerism. It is understood that the invention encompasses any tautomeric or structural isomeric form of these compounds, or mixtures of these forms, and is not limited to a tautomeric or isomeric structural form used in the formulas outlined above.

General Synthesis Schemes The compounds of formulas I and II can be prepared by processes known in the art. Suitable processes for synthesizing these compounds are provided in the examples. In general, these compounds can be prepared according to the following synthesis schemes.

Compounds of Formula I: Scheme I P Where A = Br or I, X = N or C Where A = Br or I, X = N or C General Step 2b General Step 2s where A = Br or I, Ar = Aryl or heteroaryl, X = N or C Compounds 1 and 2 are available from commercial sources or are synthesized by methods known in the art. Compounds 1 and 2 are reacted in piperidine to provide compound 3. When R1 of the compound to be synthesized is different from Ar, compound 3 is then reacted with compound 4, which is also available from commercial sources or is synthesized by methods known in the art, to give compound 1. See, General Step 2a. When R1 of the compound to be synthesized is Ar, then compound I wherein R is trimethylsilyl is then reacted with AgN03 and KCN according to General Step 2b to give compound 5. In accordance with General Step 2c, the compound 5 is then reacted with compound 6, which is available from commercial sources or is synthesized by methods known in the art, to give compound 7. Compounds of Formula II: Scheme II The compounds of formula 8 and 9 are available from commercial sources. These compounds are reacted in piperidine in an appropriate solvent to give a compound of formula 10. The compounds of formula 10 are then reacted with a compound of formula 11, which is also commercially available, to give a compound of formula II. In an alternative embodiment, the present invention relates to pharmaceutical compositions comprising at least one compound of formula I or II or a prodrug thereof, or a pharmaceutically acceptable salt of a compound of formula I or II or a prodrug thereof. 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 also be administered rectally, for example, in the form of suppositories, or parenterally, for example, in the form of injection solutions. Pharmaceutical compositions of the present invention comprising compounds of formula I or II, prodrugs of these compounds, or salts thereof, can be manufactured in a manner known in the art, e.g. e. by conventional means of mixing, encapsulating, dissolving, granulating, emulsifying, entrapping, making dragees, or lyophilizing processes. These pharmaceutical preparations can be formulated with therapeutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable vehicles 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 necessary in the case of soft gelatine capsules. Suitable vehicles for the manufacture of solutions and syrups are water, polyols, sucrose, invert sugar and glucose. Suitable vehicles for injection are water, alcohols, polyols, glycerin, vegetable oils, phospholipids and surfactants. Suitable carriers for suppositories are natural or hardened oils, waxes, fats and semi-liquid polyols. The pharmaceutical preparations may also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They may also contain other substances of therapeutic value, including additional active ingredients other than those of formula I or II. As mentioned above, the compounds of formula I or II, prodrugs thereof, and their salts, and compositions containing these compounds are useful in the treatment or control of inflammatory diseases and neurodegenerative diseases, in particular, in the treatment or control of rheumatoid arthritis. A therapeutically effective amount of a compound according to this invention means an amount of compound that is effective to prevent, alleviate or ameliorate disease symptoms of the subject being treated. The determination of a therapeutically effective amount is within the skill of the art. The therapeutically effective amount or dosage of a compound of formula I or II can vary within wide limits and will be adjusted to the particular requirements of each particular case. In general, in the case of oral or parenteral administration to adult humans weighing about 70 kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg should be appropriate, although the upper limit can be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, can be given as a continuous infusion. The compounds of the present invention can be synthesized according to known techniques, such as for example those of the General Reaction Scheme I provided above. The following examples illustrate the preferred methods for synthesizing the compounds and formulations of the present invention. Example 1; General synthesis methods and starting materials Method A: Preparation of 1-alkyl or l-aryl-2-propin-l-oles via addition of Grignard to aldehydes OH R-CHO + -MgCI THF < R A solution of the appropriate aldehyde (4.0 mmol) in 30 mL of dry tetrahydrofuran, under argon, was cooled to 0 ° C with an ice bath. Ethynyl magnesium chloride (5 mmol, 0.5 M solution in THF) was added dropwise, and the solution was stirred at 0 ° C or room temperature for 1 to 3 h. The reaction was stopped by the addition of a saturated solution of ammonium chloride in water (15 mL), and the tetrahydrofuran was evaporated in vacuo. The residue was then extracted with ethyl acetate (3x30 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 1-alkyl or l-aryl-2-propin-l-oles via addition of Grignard to aldehydes OH R-CHO + = _-- MgCl THF < R A solution of the appropriate aldehyde (4.0 mmol) in 30 mL of dry tetrahydrofuran, under argon, was cooled to 0 ° C with an ice bath. Ethynyl magnesium chloride (10 mmol, 0.5 M solution in THF) was added dropwise, and the solution was stirred at 0 ° C or room temperature for 1 to 3 h. The reaction was stopped by the addition of a saturated solution of ammonium chloride in water (15 mL), and the tetrahydrofuran was evaporated in vacuo. The residue was then extracted with ethyl acetate (3x30 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 via palladium mediated coupling (O) A solution of the appropriate 4-iodooxindole (4 mmol), and the appropriate alkyne (4.4 mmol) in 3 mL of dimethylformamide and 3 L of triethylamine was degassed by bubbling argon through the solution for 15 minutes. At this time, copper (I) iodide (16 mg, 0.1 mmol) and palladium (0) catalyst (see Examples) (0.04 mmol) were added, and the reaction was heated, under argon, to a temperature between 60 to 90 ° C, for 6 to 96 hours. After allowing to cool, water (20 L) was added and the precipitate was filtered and dried. The product was purified either with flash column chromatography (Si02, 230-400 mesh with ethyl acetate / hexane as solvent) or with reverse phase HPLC (using either acetonitrile / water or acetonitrile / water / trifluoroacetic acid as solvent) . Method D: Preparation of 4-alkynyloxindoles via palladium-mediated coupling (0) A solution of the appropriate 4-bromooxindole (4 mmol), and the appropriate alkyne (4.4 mmol) in 3 mL of dimethylformamide and 3 L of triethylamine was degassed by bubbling argon through the solution for 15 minutes. At this time, copper (I) iodide (16 mg, 0.1 mmol) and catalyst (0.04 mmol) were added, and the reaction was heated, under argon, to between 60 to 90 ° C for 6 to 96 hours. After allowing to cool, water (20 L) was added and the precipitate was filtered and dried. The product was purified via either flash column chromatography (SiO_, 230-400 esh with ethyl acetate / hexane as solvent) or with reverse phase HPLC (using either acetonitrile / water, or with acetonitrile / water / trifluoroacetic acid). as solvent). Method E: Preparation of methyl esters from carboxylic acids Ete: R-COH CH2N2 R-COoC 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 point a few drops of acetic acid were added The solution was washed with saturated sodium bicarbonate (3x25 mL) and the solvent was evaporated to give the desired methyl ester which was used without further purification Method F: Preparation of carboxylic acids from the methyl esters i -HF, H20 R-CO-CH, L_I 1 I 2: acid R-COH 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 96 hours. The tetrahydrofuran was then evaporated and 10 mL of water was added. The aqueous phase was then extracted with ethyl acetate (2x10 mL) and the aqueous phase was then acidified to pH = 2 with 1N hydrochloric acid. The aqueous phase was then extracted with ethyl acetate (4x20 mL), and the combined organic extracts 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 H: Mitsunobu coupling of N- (2-hydroxyethyl) morpholine to phenols To a solution of the appropriate phenol (3.3 mmol), N- (2-hydroxyethyl) morpholine (4.9 mmmol), and triphenylphosphine (5, mmol) in tetrahydrofuran (30 L), under argon, was added via a funnel of addition a solution of diethyl azodicarboxylate (5.0 mmol, 0.863 g) in 15 mL of tetrahydrofuran. The reaction was stirred at room temperature for 14 hours at which time water (15 mL) was added and tetrahydrofuran was evaporated. The aqueous phase was extracted with ethyl acetate (4x30 mL), and the combined organic extracts were washed with a saturated solution of sodium chloride, dried over magnesium sulfate and the solvent was evaporated. The product was purified by flash column chromatography (Si02, 230-400 mesh) with ethyl acetate / hexane. Method J: Preparation of 4-alkynyloxindoles via palladium mediated coupling (O) A solution of the appropriate 4-ethynyl oxindole (4 mmol), and the appropriate aryl halide (4.4 mmol) in 3 mL of dimethylformamide and 3 L of triethylamine was degassed by bubbling argon through the solution for 15 minutes . At this time, copper (I) iodide (16 mg, 0.1 mmol) and palladium (0) catalyst (0.04 mmol) were added, and the reaction was heated, under argon, to between 60 to 90 °. C for 12 to 96 hours. After allowing to cool, water (20 mL) was added and the precipitate was filtered and dried. The product was purified by either flash column chromatography (Si02, 230-400 mesh with ethyl acetate / hexane as solvent) or with reverse phase HPLC (using either acetonitrile / water or acetonitrile / water / trifluoroacetic acid as solvent). 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 dissolution if necessary, a solution of AgN03 (1.46 g, 8.59 mmol) in EtOH (5 mL) and water (15 mL). The mixture was stirred at room temperature for 1 h, then treated with a solution of KCN (2.71 g, 41.6 mmol) in water (10 mL). After stirring for a further 20 min, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3X 100 L). The combined EtOAc layers were dried (MgSO 4) and concentrated to dryness under reduced pressure to give the product identified above. Method L: O "Zn, NH4CI R-N + CH 3 OH, H20 R-NHc ^ To a solution of nitro compound in 10% water in methanol was added Zn powder and NH ^ Cl. The mixture was heated to reflux for 6 h and then filtered through Celite® (Fisher Scientific). The filtrate was concentrated in vacuo. The product was purified either by flash column chromatography (Si02, 230-400 mesh with ethyl acetate / hexane as solvent) or with reverse phase HPLC (using either acetonitrile / water or acetonitrile / water / trifluoroacetic acid as solvent). Method M: To a mixture of the amino compound in THF and saturated aqueous NaHCO 3 was added dropwise a THF solution of the acid chloride. The mixture was stirred for 3 h at 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 by either flash column chromatography (Si02 / 230-400 mesh with ethyl acetate / hexane as solvent) or reverse phase HPLC (using either acetonitrile / water or acetonitrile / water / trifluoroacetic acid as solvent ). Method N: Preparation of 3-arylmethylene-substituted oxindoles via coupling with aldehyde A solution or suspension of the appropriate oxindole (1 mmol), and excess aldehyde (1 to 2 mmol) in 2 L of 1% piperidine in 2-propanol was heated to between 60 to 90 ° C for i to 48 hours. Hot water (2 mL) was added. Upon cooling, the crystallized product was filtered, washed with aqueous 2-propanol, and dried.

Starting Material 1: (Z) -4-Bromo-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one A mixture of 4-bromo-l, 3-dihydro-2H-indol-2-one (100 mg, 0.47 mmol) (prepared according to T. Kosuge et al., Chem. Pharm. Bull. 33 (4): 1414-1418 (1985)), and 3-methoxy-2-pyrrol-carboxyaldehyde (70.8 mg, 0.57 mmol) in excess (prepared according to F. Bellamy, J. Chem. Research (S) (1979) 18 -19; J. Chem. Research (M) (1979) 0106-0116) in 1% piperidine in 2-propanol (1 mL) was heated at 85 ° C for 2 h. Hot water (1 mL) was added. Upon cooling, the crystallized product was filtered, washed with aqueous 2-propanol and dried. (Yield 0.13 g, 83%). Starting Material 2: (Z) -1, 3-Dihydro-4-iodo-3-l (3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one A mixture of 1,3-dihydro-4-iodo-2H-indol-2-one (prepared according to T. Fukuyama et al., JA Chem. Soc. 118: 7426-7427 (1996)) (0.51 g, 1.97 mmol), and 3-methoxy-2-pyrrol-carboxyaldehyde (0.30 g, 2.36 mmol) in excess (see Bellamy, supra) in 1% piperidine in 2-propanol (10 mL) was heated to 85 ° C for 4 h. Hot water (10 mL) was added. Upon cooling, the crystallized product was filtered, washed with aqueous 2-propanol and dried. (Yield 0.46 g, 64%). Starting material 3: (Z) -4-bromo-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) ethylene] -5-nitro-2H-indol-2-one A mixture of 4-bromo-l, 3-dihydro-5-nitro-2H-indol-2-one (from Example 4 below). { 0,113 g. 0.44 mmol), and excess 3-methoxy-2-pyrrolcarboxyaldehyde (66.3 mg, 0.53 mmol) (see Bellamy, supra) in 1% piperidine in 2-propanol (2 mL) was heated to 85 °. C for 3 h. Hot water (2 mL) was added. Upon cooling, the crystallized product was filtered, washed with aqueous 2-propanol and dried. (Yield 0. 136 g, 85%). Starting Material 4: (Z) -1, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene-4- (2-trimethylsilyl-ethynyl) -2H-indal-2-one Trimethylsilyl acetylene (0.94 g, 9.63 mmol) (Aldrich) was coupled with (Z) -4-bromo-1,3-dihydro-3- [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indol-2-one (2.05 g, 6.42 mmol) (Starting Material 1) using (Ph3P) PdCl2 (0.23 g) (Aldrich) and Cul (61 mg) (Aldrich) as catalyst in DMF (15 mL) and Et3N (15 mL) as solvent at 80 ° C for 2 days according to method D described above. (Yield 1.3 g, 60%). Starting Material 5: (Z) -l, 3-Dihydro-4-ethynyl-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one A solution of (Z) -1,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- (2-trimethylsilyl-ethynyl) -2H-indol-2-one ( 1.3 g, 3.86 mmol) (starting material 4) in EtOH (80 mL) was treated with AgN03 (1.46 g, 8.59 mmol) in ethanol (5 mL) and water (15 L) at room temperature for 1 h followed by KCN (2.71 g, 41.6 mmol) in water (10 L) according to the K method described above. (Yield 1.02 g, 100%). Starting Material 6: 5-Bromo-l, 3-dihydro-2H-indol-2-one 1,3-Dihydro-2H-indol-2-one (5.25 g, 39.43 mmol) (Aldrich) was treated with a 1: 1 solution of glacial acetic acid and distilled water (246 mL). The resulting reaction mixture was cooled to 0 ° C and then slowly treated with N-bromosuccinimide (14.03 g, 78.85 mmol) (J.T. Baker). After the complete addition of N-bromosuccinimide, the cooling bath was removed, and the reaction mixture was stirred at 23 ° C for 1 h. Upon stirring at 23 ° C, the reaction mixture became viscous and a white solid precipitated. The reaction mixture was poured into 500 mL of distilled water and filtered to give a crude white solid. Recrystallization from methanol gave pure 5-bromo-1,3-dihydro-2H-indol-2-one as a pink solid. (Yield 5.28 g, 63%; mp 219-220 ° C). Starting Material 7: (Z) -5-Bromo-l, 3-dihydro-3- [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one A mixture of 5-bromo-l, 3-dihydro-2H-indol-2-one (3.10 g, 14.62 mmol) (starting material 6) and pyrrole-2-carboxaldehyde (1.46 g, 15.35 mmol) (Aldrich) in 2-propanol (73 mL) was treated with 10- 12 drops of piperidine. The reaction mixture was heated to reflux for 20 h and then allowed to cool to 23 ° C, at which time the reaction mixture was filtered. The resulting solid was washed well with hexanes, followed by petroleum ether, and then allowed to air dry to yield (Z) -5-bromo-1,3-dihydro-3- [(1H-pyrrol-2-yl) methylene. ] -2H-indol-2-one pure as a yellow solid which was used without further purification. (Yield 4.01 g, 95%; mp 267-268 ° C).

Starting material 8: (Z) -1,3-Dihydro-5-iodo-3- [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one To a solution of iodide of [[1- ([(1,1-dimethyl-ethyl) -oxy] carbonyl] -lH-pyrrol-2-yl] methyl] triphenylphosphonium (2.3 g, 4.0 mmol) (prepared according to the procedure of: VH Rawal et al., J. Org. Chem. 1987, 52 (1), 19-28) in 36 mL of DMF at 0 ° C under argon, NaH (0.13 g) was slowly added. 5.4 mmol) The mixture was stirred at 0 ° C for 45 min, the solution was then allowed to warm to room temperature, and 5-iodoisatin (1.0 g, 3.66 mmol) was added. The mixture was heated to reflux for 15 h, at which time acetone (1 L) was added and the solvent mixture was evaporated, then the residue was purified by flash column chromatography (25% EtOAc / hex) to give (Z ) -1,3-dihydro-5-iodo-3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (Yield 1.05 g, 83%).

Starting Material 9: (Z) -4-Bromo-l, 3-dihydro-3- [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one A mixture of 4-bromo-1,3-dihydro-2H-indol-2-one (0.2 g, 0.94 mmol) (see T. Kosuge et al., Chem. Pharm. Bull. ): 1414-1418 (1985)), and excess pyrrole-2-carboxaldehyde (0.11 g, 1.13 mmol) (Aldrich) in 1% piperidine in 2-propanol (2 mL) was heated to 85 ° C. for 2 h. Hot water (2 mL) was added. Upon cooling, the crystallized product was filtered, washed with aqueous 2-propanol and dried. (Yield 0.26 g, 96%) Example 2: Synthesis of 1,3-Dihydro-5-fluoro-4-iodo-2H-indol-2-one (A) A suspension of 1,3-dihydro-l-hydroxy-4-iodo-2H-indol-2-one (2.43 g, 9 mmol) (prepared according to Kende et al., Synth Commun. 20 (14, 2133 -2138 (1990)) in dry dichloromethane (500 mL) was cooled to -25 ° C under an argon atmosphere with magnetic stirring, a solution of diethylaminosulfur trifluoride (DAST, 1.35 mL) (Aldrich) was added dropwise. in dry dichloromethane (40 mL) at a rate such that the temperature of the reaction did not rise above -25 ° C (about 15 min.) After stirring for 30 min more at -25 ° C, the reaction was The mixture was then filtered through Celite® (Fisher) and the phases were separated, The aqueous phase was extracted with dichloromethane (10 ml) and the mixture was filtered off with saturated aqueous sodium bicarbonate solution (180 mL) and allowed to warm to room temperature. 2 X 300 mL) The dichloromethane phases were washed with saturated aqueous sodium chloride solution (200 mL), combined, dried (magnesium sulfate) and concentrated. The resulting residue was purified by flash chromatography on silica gel using ethyl acetate-dichloromethane (1: 7, V / V) as solvent to give 1,3-dihydro-5-fluoro-4-iodo-2H- indole-2-one (Yield 1.08 g, 43%). Example 3: Synthesis of l, 3-Dihydro-4-iodo-5-nitro-2H-indol-2-one (B) A mixture of concentrated sulfuric acid (0.73 mL) and concentrated nitric acid (0.14 L) was slowly added to a solution of 1,3-dihydro-4-iodo-2H-indol-2-one (0, 5 g, 1.93 mmol) (see Fukuyama, supra) in concentrated sulfuric acid (6 mL) at -5 ° C, with stirring. The mixture was stirred for 15 min., More at -5 ° C, then poured on ice. After allowing to stand for 1 h, the solid was collected by filtration, washed with water, and dried in a vacuum oven to give 1,3-dihydro-4-iodo-5-nitro-2H-indol-2-one . (Yield 0.46 g, 78%). Example 4: Synthesis of 4-Bromo-l, 3-dihydro-5-nitro-2H-indol-2-one (C) A mixture of concentrated sulfuric acid (3.6 mL) and concentrated nitric acid (0.7 mmL) was added slowly to a solution of 4-bromo-1,3-dihydro-2H-indol-2-one (2 g, 9.48 mmol) (prepared according to T. Kosuge et al., Chem. Pharm. Bull. 33 (4): 1414-1418 (1985)) in concentrated sulfuric acid (20 mL) at -5 ° C, with stirring. The mixture was stirred for a further 1 h at -5 ° C, then poured onto ice. After allowing to stand for 1 h, the formed precipitate was collected by filtration, washed with water, and dried in a vacuum oven to give 4-bromo-1,3-dihydro-5-nitro-2H-indole-2-. ona (Yield 2.33 g, 96%). Example 5: Synthesis of (Z) -1,3-Dihydro-4- (phenylethynyl) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (D) Using General Method D described above, phenyl acetylene (32 mg, 0.31 mmol) (Aldrich) was coupled with (Z) -4-bromo-1,3-dihydro-3- [(3-methoxy-1H-pyrrole -2-yl) methylene] -2H-indol-2-one (50 mg, 0.16 mmol) (Starting Material 1) using DPPFPdCl2 (6.5 mg) (Aldrich) and Cul (1.5 mg) ( Aldrich) as a catalyst in DMF (2 mL) and EtN (3 mL) as solvent, at 85 ° C for 18 h, to give (2) -1,3-dihydro-4- (phenylethynyl) -3- [(3 -methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 20 mg, 37%) Example 6: Synthesis of (Z) -1,3-Dihydro-4- (phenylethynyl) -3-t (lH-pyrrol-2-yl) methylene] -2H-indole-2- ona (E) Using General Method D described above, phenyl acetylene (32 mg, 0.31 mmol) (Aldrich) was coupled with (2) -4-bromo-1,3-dihydro-3- [(1H-pyrrol-2-yl) methylene] -2H-indole-2-one (Starting Material 9) (46.3 mg, 0.16 mmol) using (Ph3P) Pd (8 mg) (Aldrich) and Cul (1.5 mg) (Aldrich) ) as catalyst, in DMF (2 mL) and Et3N (3 mL) as solvent, at 85 ° C for 18 h, providing (2) -1.3 dihydro-4- (phenylethynyl) -3- [(IH-pyrrole -2-il) methylene] -2H-indol-2-one. (Yield 41 mg, 83%). Example 7: Synthesis of (Z) -5- [3- [2, 3-dihydro-2-oxo-3- (1H-pyrrol-2-ylmethylene) -lH-indol-4-yl] -2-propinyl] -6 (5H) phenanthridinone (F) A solution of (Z) -1,3-dihydro-4-iodo-3- [(1H-pyrrol-2-yl) ethylene] -2H-indol-2-one (from Example 71, infra) (50 mg, 0.15 mmol), and 5- (2-propynyl) -6 (5H) -phenanthridinone (45 mg, 0.19 mmol) (prepared according to Walser et al., J. Med. Chem. 34 ( 3), 1209-1221 (1991)) in 1 mL of tetrahydrofuran and 1 mL of triethylamine was degassed by bubbling argon through the solution for 10 minutes. Copper (I) iodide (11 mg, 0.06 mmol) and tetrakis (triphenylphosphine) palladium (O) (3 mg, 0.03 mmol) were then added, and the reaction was stirred at room temperature for 72 hours. Then water (10 mL) was added and the precipitate was filtered and dried. The product was purified by flash column chromatography (Si02, 230-400 mesh) with ethyl acetate / hexane, to give a yellow powder which was recrystallized from ethyl acetate / hexane, to give (2) -5- [ 3 [2, 3-dihydro-2-oxo-3- (lH-pyrrol-2-ylmethylene) -lH-indol-4-yl] -2-propinyl] -6 (5H) -phenanthridinone. (Yield 25 mg, 38%).

Example 8: Synthesis of (Z) -l, 3-Dihydro-4- [(4-methoxyphenyl) ethynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2 -one (G) Step A: 4-Methoxyphenyl acetylene Using the D method described above, 4-bromoanisole (Aldrich) was coupled with trimethylsilylacetylene (Aldrich) using (Ph3P) 2PdCl2 and Cul as catalyst, in DMF and Et3N as solvent, and heated to reflux for 1 day. The resulting trimethylsilyl derivative was hydrolyzed with aqueous potassium hydroxide to give 4-methoxyphenyl acetylene. Step B: Using General Method D described above, 4-methoxyphenyl acetylene (0.49 g, 3.68 mmol) (from Step A described above) was coupled with (Z) -4-bromo-1,3-dihydro- 3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (Starting Material 1) (0.47 g, 1.47 mmol) using DPPFPdCl2 (0.129) (Aldrich) and Cul. { 28 mg) (Aldrich) as catalyst, in DMF (10 mL) and Et3N (15 mL) as solvent, and heated to reflux for 1 day, yielding (Z) -l, 3-dihydro-4- [(4- methoxyphenyl) ethynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 0.31 g, 57%). Example 9: Synthesis of rae- (Z) -l, 3-Dihydro-4- [3-hydroxy-3- (4-methoxyphenyl) -1-propynyl] -3- [(3-methoxy-lH-pyrrole-2 -yl) methylene-2H-indol-2-one (H) Using Method D described above, 3-hydroxy-3- (4-methoxyphenyl) -1-propyne (115 mg, 0.70 mmol) (prepared by the addition of ethylmagnesium chloride (Aldrich) to 4-methoxybenzaldehyde (Aldrich) was coupled. ) according to Method A described above), with (Z) -4-bromo-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (Starting material 1) (174 mg, 0.55 mmol) using (Ph3P) 2PdCl2 (18 mg) (Aldrich) and Cul (10 mg) (Aldrich) as a catalyst, in DMF (2.5 L) and Et3N ( 2.5 mL) as solvent, at 70 ° C for 15 h, yielding rac- (Z) -1, 3-dihydro-4- [3-hydroxy-3- (4-methoxyphenyl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 32 mg, 32%). Example 10: Synthesis of rae- (Z) -1,3-Dihydro-4- [3-hydroxy-3- (3-hydroxyphenyl) -1-propynyl] -3- [(3-methoxy-lH-pyrrole-2 -yl) methylene] -2H-indol-2-one (I) Using Method D described above, 3-hydroxy-3- (3-hydroxyphenyl) -1-propyne (140 mg, 0.94 mmol) (prepared by addition of ethynyl agnesium chloride (Aldrich) to 3-hydroxybenzaldehyde (Aldrich) by method B described above) was coupled to (Z) -4-bromo-1,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (Starting material 1 (200 mg, 0.63 mmol) using (Ph3P) 2PdCl2 (68 mg) (Aldrich) and Cul (32 mg) (Aldrich) as a catalyst, in DMF (4mL) and Et3N (4mL) as solvent, at 80 ° C for 15 h, yielding rae- (Z) -1,3-dihydro-4- [3-hydroxy-3- (3-hydroxyphenyl) -1-propynyl] -3- [(3-methoxy) lH-pyrrol-2-yl) methylene] -2H-indol-2-one (Yield 82 mg, 31%) Example 11: Synthesis of rae- (Z) -l, 3-Dihydro-4- [3- hydroxy-3- (3-methoxyphenyl) -l-propynyl-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (J) Using Method D described above, 3-hydroxy-3- (3-methoxyphenyl) -1-propyne (151 mg, 1.0 mmol) (prepared by addition of ethynylmagnesium chloride (Aldrich) to 3-methoxybenzaldehyde (Aldrich) according to Method A described above) was coupled to (Z) -4-brsmo-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one ( Starting Material 1) (220 mg, 0.69 mmol) using (Ph3P) 2PdCl2 (100 mg) (Aldrich) and Cul (55 mg) (Aldrich) as a catalyst, in DMF (5 L) and Et3N (5 mL) as solvent, at 70 ° C for 18 h, yielding rae- (Z) -1, 3-dihydro-4- [3-hydroxy-3- (3-methoxyphenyl) -1-propynyl] -3- [(3- methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 66 mg, 24%). Example 12: Synthesis of rae- (Z) -4- [3- [2,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indole -4-yl] -1-hydroxy-2-propynyl] benzoic methyl ester (K) Using Method D described above, the 4- (l-hydroxy-2-propynyl) -benzoic acid methyl ester (137 mg, 0.72 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to 4-carboxybenzaldehyde ( Aldrich) using Method B described above to give the acid which was converted to its methyl ester by Method E described above), was coupled to (Z) -4-bromo-1,3-dihydro-3- [(3 -methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (Starting Material 1 (221 mg, 0.69 mmol) using (Ph3P) 2PdCl; (37 mg) (Aldrich) and (18 mg) (Aldrich) as a catalyst, in DMF (4mL) and Et M (4 mL) as solvent, at 70 ° C for 18 h, yielding rae- (Z) -4- [3- [2, 3-dihydro-3-. { (3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -l-hydroxy-2-propynyl] benzoic methyl ester. (Yield 52 mg, 18%). Example 13: Synthesis of Rae- (Z) -4- [3- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indole -4-yl] -1-hydroxy-2-propynyl] benzoic acid (L) Using Method F described above, 4- [l-hydroxy-3- [3- (3-methoxy-lH-pyrrol-2-ylmethylene) -2-oxo-2,3-dihydro-lH-indole was hydrolyzed. 4-yl] -prop-2-ynyl] -benzoic acid methyl ester (30 mg, 0.07 mmol) (from Example 12 described above) with LiOH.H20 (13 mg, 2.7 mmol) in THF (1 mL) and water (1 mL) at room temperature for 18 h, to give rac- (Z) -4- [3- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrole-2-yl) acid) methylene] -2-oxo-lH-indol-4-yl] -l-hydroxy-2-propynyl] benzoic acid. (Yield 21 mg, 72%). Example 14: Synthesis of rae- (Z) -1,3-Dihydro- [3-hydroxy-3- (2-methoxyphenyl) -1-propynyl] -3- [(3-methoxy-lH-pyrrol-2-yl Methylene-2H-indol-2-one (M) Using Method D described above, 3-hydroxy-3- (2-methoxyphenyl) -1-propyne (150 mg, 0.92 mmol) was coupled. (prepared by addition of ethynylmagnesium chloride (Aldrich) to 2-methoxybenzaldehyde (Aldrich) according to Method A described above), a (Z) -4-bromo-1,3-dihydro-3- [(3-methoxy-1H -pyrrol-2-yl) methylene] -2H-indole-2-one (Starting Material 1) (200 mg, 0.63 mmol) using (Ph3P) 2PdCl2 (70 mg) (Aldrich) and Cul (40 mg) (Aldrich) as catalyst, in DMF (3 mL) and Et3N (3 mL) as solvent, at 70 ° C for 18 h, yielding rae- (Z) -1,3-dihydro-4- (3-hydroxy-3) - (2-methoxyphenyl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) ethylene] -2H-indol-2-one. (Yield 71 mg, 28%) Example 15 : Synthesis of rae- (Z) -4- [3- (1, 3-benzodioxol-5-yl) 3-hydroxy-l-propynyl] -1,3-dihydro-3- [(3-methoxy-lH- pyrrol-2-yl) methylene] -2H-indol-2-one (N) Using Method D described above, 3- (1,3-benzodioxol-5-yl) -3-hydroxy-1-propyne (110 mg, 0.62 mmol) (prepared by the addition of ethynylmagnesium chloride) was coupled.

(Aldrich) to piperonal (Aldrich) according to Method A described above) to (Z) -4-bromo-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H -indole-2-one (100 mg, 0.34 mmol) (starting material 1) using (Ph3P) 2PdCl (30 mg) (Aldrich) and Cul (16 mg) (Aldrich) as catalyst, in DMF (3 mL ) and Et3N (3 mL) as solvent, at 70 ° C for 16 h, yielding rae- (Z) -4- [3- (1,3-benzodioxol-5-yl) -3-hydroxy-l-propynyl] -1, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 46 mg, 33%). Example 16: Synthesis of rae- (Z) -1,3-Dihydro-4- [3-hydroxy-3- (4-hydroxy-3-methoxyphenyl) -1-propynyl] -3- [(3-methoxy-lH -pyrrol-2-yl) methylene] -2H-indol-2-one (O) Using Method D described above, 3-hydroxy-3- (4-hydroxy-3-methoxyphenyl) -1-propyne (197 mg, 1.1 mmol) (prepared by the addition of ethynylmagnesium chloride) was coupled.

(Aldrich) to vanillin (Aldrich) according to Method B described above) to (Z) -4-bromo-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H -indole-2-one (Starting Material 1) (116 mg, 0.36 mmol) using (Ph3P) 2PdCl2 (33 mg) (Aldrich) and Cul (18 mg) (Aldrich) as a catalyst, in DMF (3 mL ) and Et3N (3 mL) as solvent, at 70 ° C for 16 h, yielding rae- (Z) -1,3-dihydro-4- [3-hydroxy-3- (4-hydroxy-3-methoxyphenyl) - 1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 31 mg, 21%). Example 17: Synthesis of 3-hydroxy-3- (4-hydroxyphenyl) -1-propyne (P) To a solution of trimethylsilylacetylene (1.00 g, 10 mmol) (Aldrich) in dry THF (100 mL) under argon a -78 ° C n-butyl lithium (4.4 mL, 11 mmol, 2.5 M solution in hexanes) (Aldrich) was added dropwise. The reaction was stirred for 30 min. at -78 ° C, after which 4-hydroxybenzaldehyde (0.50 g, 4 mmol) (Aldrich) was added and the reaction was allowed to warm slowly to room temperature. A saturated solution of ammonium chloride (5 mL) was then added and the reaction was stirred at room temperature for 2 h. The solution was then diluted by adding 30 L of water, and the THF was removed in vacuo. The product was extracted with ethyl acetate (3 x 50 mL) and the combined organic phases were dried over magnesium sulfate and concentrated in vacuo to give pure 3-hydroxy-3- (4-hydroxyphenyl) -1-propyne which was used directly, without further purification. (Yield 501 mg, 84%).

Example 18: Synthesis of rae- (Z) -1,3-Dihydro-4- [3-hydroxy-3- (4-hydroxy-enyl) -1-propynyl] -3- [(3-methoxy-1H-pyrrol- 2-yl) methylene] -2H-indol-2-one (Q) Using Method D described above, 3-hydroxy-3- (4-hydroxyphenyl) -1-propyne (120 mg, 0.84 mmol) (from Example 17 described above) was coupled to (Z) -4-bromo-1 , 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (110 mg, 0.34 mmol) (starting material 1) using (Ph3P) 2PdCl2 (30 mg) (Aldrich) and Cul (15 mg) (Aldrich) as catalyst, in DMF (3 mL) and Et3N (3 mL) as solvent, at 70 ° C for 16 h, yielding- (Z) -1 , 3-dihydro-4- [3-hydroxy-3- (4-hydroxyphenyl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2- ona (Yield 62 mg, 47%).

Example 19: Synthesis of rae- (Z) -1,3-Dihydro-4 - [3- (4-dimethylaminophenyl) -3-hydroxy-1-propynyl] -3 - [(3-methoxy-1H-pyrrole-2 -yl) methylene-2H-indol-2-one (R) Using Method D described above, 3- (4-dimethylaminophenyl) -3-hydroxy-1-propyne (160 mg, 0.91 mmol) was coupled. (prepared by addition of ethynylmagnesium chloride (Aldrich) to 4-dimethylaminobenzaldehyde (Aldrich) according to Method A, described above) to (Z) -4-bromo-1,3-dihydro-3- [(3-methoxy-1H -pyrrol-2-yl) methylene] -2H-indol-2-one (108 mg, 0.34 mmol) (Starting Material 1) using (Ph3P) 2PdCl2 (30 mg) (Aldrich) and Cul (16 mg) (Aldrich) as catalyst, in DMF (3 mL) and Et3N (3 mL) as solvent, at 70 ° C for 19 h, yielding rae- (Z) -1, 3-dihydro -4- [3- (4-dimethylaminophenyl) -3-hydroxy-1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) ethylene] -2H-indol-2-one. (Yield 190 mg, 77%).

Example 20: Synthesis of rae- (Z) -1,3-Dihydro-4- [3-hydroxy-3- (4-phenoxyphenyl) -1-propynyl] -3- [(3-methoxy-lH-pyrrole-2 -yl) methylene] -2H-indol-2-one (S) Using Method C described above, 3-hydroxy-3- (4-phenoxyphenyl) -1-propyne (200 mg, 0.89 mmol) was coupled. (prepared by the addition of ethynylmagnesium chloride (Aldrich) to 4-phenoxybenzaldehyde (Aldrich) according to Method A described above) to (2) -1,3-dihydro-4-iodo-3- [(3-methoxy-1H- pyrrol-2-yl) methylene] -2H-indol-2-one (starting material 2) (146 mg, 0.40 mmol) using (Ph3P) 2PdCl (30 mg) (Aldrich) and Cul (16 mg) ( Aldrich) as catalyst, in DMF (3 mL) and Et3N (3 mL) as solvent, at 70 ° C for 16 h, yielding rae- (Z) -1,3-dihydro-4- [3-hydroxy-3- (4-phenoxyphenyl) -1-propynyl] -3- f (3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 100 mg, 54%).

Example 21: Synthesis of rae- (Z) -l, 3-Dihydro-4-13-hydroxy-3-phenyl-1-butynyl] -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-Indole-2-one (T) Using Method C described above, 2-phenyl-3-butyn-2-ol (70 mg, 0.48 mmol) (Aldrich) was coupled to (2) -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) using (Ph3P) 2PdCl2 (20 mg) (Aldrich) and Cul (10 mg). { Aldrich) as a catalyst; in DMF (2 mL) and Et3N (2 mL) as solvent, at 70 ° C for 15 h, yielding rae- (2) -1, 3-dihydro-4- [3-hydroxy-3-phenyl-1-butyl] -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 85 mg, 55%). Example 22: Synthesis of 3- [4- (3-Dimethylaminopropoxy) -phenyl] -3-hydroxy-1-propyne (U) To a solution of 4- (3-dimethylaminopropoxy) benzaldehyde (0.83 g, 4 mmol) (Aldrich) in dry tetrahydrofuran (30 mL) under argon at room temperature was added dropwise ethynylmagnesium chloride (5 mmol, 10 mL, 0.5M solution in tetrahydrofuran) (Aldrich). The resulting solution was stirred for 1.5 h at which time 100 mL of water was added, and the THF was removed in vacuo.The product was extracted with ethyl acetate (3 x 50 mL) and the combined organic phases were evaporated. dried over magnesium sulfate and concentrated in vacuo to give pure 3- [4- (3-dimethylaminopropoxy) -phenyl] -3-hydroxy-1-propyne which was used directly, without further purification. (Yield 831 mg, 89%) Example 23: Synthesis of rae- (Z) -1,3-Dihydro-4- [3- [4- (3-dimethylaminopropoxy) -phenyl] -3-hydroxy-1-propynyl] -3- [(3- methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (V) Using Method C described above, 3- [4- (3-dimethylaminopropoxy) -phenyl] -3-hydroxy-1-propyne (201 mg, 0.86 mmol) (from Example 22 described above) was coupled to (2) -1,3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (Starting Material 2) (146 mg, 0.4 mmol) using (Ph3P) 2PdCl2 (34 mg) (Aldrich) and Cul (15 mg) (Aldrich) as catalyst, in DMF (3 mL) and Et3N (3 L) as solvent, at 70 ° C for 16 h, to give rae- (2) -1,3-dihydro-4- [3- [4- (3-dimethylaminopropoxy) -phenyl] -3-hydroxy-1-propynyl] -3- [(3-methoxy-1H-pyrrole -2-yl) methylene] -2H-indol-2-one. (Yield 151 mg, 80%). Example 24: Synthesis of 3-Hydroxy-3- (3-pyridinyl) -1-propyne (W) 3-Hydroxy-3- (3-pyridinyl) -1-propyne was prepared according to Method A, described above using 3 pyridine-carboxaldehyde (0.428 g, 4 mmol) (Aldrich) in THF (20 mL) and ethynylmagnesium chloride (5 mmol, 10 mL, 0.5 M solution in tetrahydrofuran) (Aldrich). (Yield 440 mg, 83%). Example 25: Synthesis of rae- (Z) -l, 3-Dihydro-4- [3-hydroxy-3- (3-pyridinyl) -1-propynyl] -3- [(3-methoxy-1H-pyrrole-2-yl) il) methylene] 2H-indol-2-one (X) Using Method D described above, 3-hydroxy-3- (3-pyridinyl) -1-propyne (150 mg, 1.13 mmol) (from Example 24 described above) was coupled to (Z) -4-bromo-1. , 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (135 mg, 0.42 mmol) (Starting Material 1) using (Ph3P) 2PdCl (32 mg) (Aldrich) and Cul (17 mg) (Aldrich) as catalyst, in DMF (3 mL) and Et3N (3 mL) as solvent, at 70 ° C for 17 h, to give rae- (Z) -1, 3- dihydro-4- [3-hydroxy-3- (3-pyridinyl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 40 mg, 22%). Example 26: Synthesis of (Z) -1,3-Dihydro-3- [(3-methoxy-1H-pyrrol-2-yl) methylene] -4- (3-phenoxy-1-propynyl) -2H-indole 2-one (Y) Using Method C described above, phenylpropargyl ether (65 mg, 0.49 mmol) (Lancaster) was coupled to (2) -1,3-dihydro-4-iodo-3- [(3-methoxy-1H-pyrrol- 2-yl) methylene] -2H-indole-2-one (146 mg, 0.4 mmol) (Starting Material 2) using (Ph3P) PdCl (20 mg) (Aldrich) and Cul (10 mg) (Aldrich) as a catalyst, in DMF (2 mL) and Et3N (2 mL) as solvent, at 70 ° C for 18 h, yielding (2) -1, 3-dihydro-3- [(3-methoxy-1H pyrrole-2-yl) il) ethylene] -4- (3-phenoxy-1-propynyl) -2H-indol-2-one. (Yield 92 mg, 62%). Example 27: Synthesis of 3-Hydroxy-3- (lmethyl-pyrrol-2-yl) -1-propyne (Z) The 3-hydroxy-3- (l-methyl-pyrrol-2-yl) -1-propyne is prepared according to Method A described above using 1-methyl-2-pyrrolcarboxaldehyde (0.450 g, 4 mmol) (Aldrich) in THF (20 mL) and ethynylmagnesium chloride (5 mmol, 10 mL, 0.5 M solution in tetrahydrofuran) (Aldrich ). (Yield 422 mg, 76%).

Example 28: Synthesis of rae- (Z) -1,3-Dihydro-4- [3-hydroxy-3- (l-methyl-pyrrol-2-yl) -1-propynyl] -3- [(3-methoxy -lH-pyrrol-2-yl) methylene] -2H-indol-2-one (AA) Using Method D described above, 3-hydroxy-3- (1-methyl-pyrrol-2-yl) -1-propyne (132 mg, 0.98 mmol) (from Example 27 described above) was coupled to (Z) -4-bromo-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (112 mg, 0.35 mmol) (Starting Material 2) using (Ph3P) 2PdCl2 (31 mg) (Aldrich) and Cul (17 mg) (Aldrich) as catalyst, in DMF (3 mL) and Et3N (3 mL) as solvent, at 70 ° C for 28 h, yielding rae- (Z) -1, 3-dihydro-4- [3-hydroxy-3- (1-methyl-pyrrol-2-yl) -1-propynyl] -3- [(3-methoxy-lH-pyrrol- 2-yl) methylene] -2H-indol-2-one. (Yield 114 mg, 87%).

Example 29: Synthesis of rae- (Z) -1,3-Dihydro-4- [3-hydroxy-3- (thiophen-3-yl) -1-propynyl] -3- [(3-methoxy-lH-pyrrole -2-il) methylene] -2H-indol-2-one (BB) Using Method D described above, 3-hydroxy-3- (thiophen-3-yl) -1-propyne (131 mg, 0.95 mmol) was coupled. (prepared by the addition of ethynylmagnesium chloride (Aldrich) to 3-thiophenecarboxaldehyde (Aldrich) according to Method A described above) to (Z) -4-bromo-1,3-dihydro-3- [(3-methoxy-1H- pyrrol-2-yl) methylene] -2H-indole-2-one (107 mg, 0.34 mmol) (starting material 1) using (Ph3P) 2PdCl2 (32 mg) (Aldrich) and Cul (17 mg) ( Aldrich) as catalyst, in DMF (3 mL) and Et3N (3 mL) as solvent, at 70 ° C for 18 h, yielding rae- (Z) -1,3-dihydro-4- [3-hydroxy-3- (thiophen-3-yl) -1-propynyl] -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 93 mg, 72%).

Example 30: Synthesis of 3-Hydroxy-3- (1H-pyrrol-2-yl) -1-propyne (CC) 3-Hydroxy-3- (1H-pyrrol-2-yl) -1-propyne was prepared by Method B described above using 2-pyrrole-carboxaldehyde (0.389 g, 4 mmol) (Aldrich.) in THF (30 mL) and ethynylmagnesium chloride (20 mmol, 40 mL, 0.5 M solution in tetrahydrofuran) (Aldrich). (Yield 345 mg, 82%). Example 31; Synthesis of rae- (Z) -l, 3-Dihydro-4- [3-hydroxy-3- (lH-pyrrol-2-yl) -1-propynyl] -3- [(3-methoxy-lH-pyrrol- 2-yl) methylene] -2H-indol-2-one (DD) Using Method D described above, 3-hydroxy-3- (1H-pyrrol-2-yl) -1-propyne (212 mg, 1.75 mmol) (from Example 30 described above) was coupled to (Z) -4 -bromo-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (125 mg, 0.39 mmol) (starting material 1) using (Ph3P) 2PdCl2 (42 mg) (Aldrich) and Cul (20 mg) (Aldrich) as catalyst, in DMF (4 L) and Et3N (4 L) as solvent, at 70 ° C for 18 h, yielding rae- (Z) -1, 3-dihydro -4- [3-hydroxy-3- (1H-pyrrol-2-yl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2- ona (Yield 68 mg, 49%). Example 32: Synthesis of rae- (Z) -1,3-Dihydro-4- [3- (2,3-di ethoxyphenyl) -3-hydroxy-1-propynyl] -3- [(3-methoxy-1H- pyrrol-2-yl) methylene] -2H-indol-2-one (EE) Using Method D described above, 3- (2,3-dimethoxyphenyl) -3-hydroxy-1-propyne (132 mg, 0.69 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich.) Was coupled. to 2, 3-dimethoxybenzaldehyde (Aldrich.) according to Method A described above.} a (Z.) -4-bromo-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl.) Methylene] -2H-indole-2-one (Starting Material 1.) (98 mg, 0.31 mmol. Using (Ph3P) 2PdCl2 (38 mg.) (Aldrich.) and Cul (17 g.) (Aldrich.) as a catalyst, in DMF (3 mL.) and Et3N (3 L.). as solvent at 70 ° C for 17 h, yielding rae- (Z.) -1,3-dihydro-4- [3- (2,3-dimethoxyphenyl) -3-hydroxy-1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl.} Methylene] -2H-indol-2-one (Yield 98 mg, 71%.) Example 33: Synthesis of rae- (Z) - 1,3-Dihydro-4- [3- (3,4-dimethoxyphenyl) -3-hydroxy-1-propynyl] -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indole -2-ona (FF) Using Method C described above, 3- (3, 4-dimethoxyphenyl) -3-hydroxy-1-propyne (150 mg, 0.78 mmol) was coupled. (prepared by the addition of ethynylmagnesium chloride (Aldrich) to 3,4-dimethoxybenzaldehyde (Aldrich) according to Method A described above) to (Z) -1,3-dihydro-4-iodo-3- [(3-methoxy) lH-pyrrol-2-yl) ethylene] -2H-indole-2-one (Starting Material 2) (146 mg, 0.4 mmol) using (Ph3P) 2PdCl2 (40 mg) (Aldrich) and Cul (22 mg ) (Aldrich) as catalyst, in DMF (3 mL) and Et3N (3 mL) as solvent, at 70 ° C for 18 h, yielding rae- (Z) -1,3-dihydro-4- [3- (3 , 4-dimethoxyphenyl) -3-hydroxy-1-propynyl] -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 121 mg, 70%). Example 34: Synthesis of 3-Hydroxy-3- (3-hydroxy-4-methoxyphenyl) -1-propyne (GG) 3-Hydroxy-3- (3-hydroxy-4-methoxyphenyl) -1-propyne was prepared as Method B described above from 3-hydroxy-4-methoxybenzaldehyde (0.304 g, 2 mol) (Aldrich) in THF (20 L) and ethynylmagnesium chloride (5 mmol, 10 mL, 0.5M solution in tetrahydrofuran) ( Aldrich). (Yield 273 mg, 77%). Example 35: Synthesis of rae- (Z) -1,3-Dihydro-4- [3-hydroxy-3- (3-hydroxy-4-methoxyphenyl) -1-propynyl] -3- [(3-methoxy-lH -pyrrol-2-yl) methylene] -2H-indol-2-one (HH) Using Method D described above, 3-hydroxy-3- (3-hydroxy-4-methoxyphenyl) -1-propyne (105 mg, 0.59 mmol) (from Example 34 described above) was coupled to (Z) -4 -bromo-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (122 mg, 0.38 mmol) (Starting Material 1) using (Ph3P) 2PdCl2 (34 mg) (Aldrich) and Cul (15 mg) (Aldrich) as catalyst, in DMF (3 mL) and Et3N (3 mL) as solvent, at 70 ° C for 18 h, yielding rae- (Z) -1,3-dihydro-4- [3-hydroxy-3- (3-hydroxy-4-methoxyphenyl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. . { Yield 101 mg, 64%). Example 36: Synthesis of 3-Hydroxy-3- (2-pyridinyl) -1-propyne (II) 3-Hydroxy-3- (2-pyridinyl) -1-propyne was prepared according to Method A described above, starting from 2-pyridine carboxaldehyde (1.0 g, 9.3 mmol) (Aldrich) in THF (50 L) and ethynylmagnesium chloride (10 mmol, 20 L, 0.5 M solution in tetrahydrofuran) (Aldrich). (Yield 956 mg, 77%). Example 37: Synthesis of rae- (Z) -1,3-Dihydro-4- [3-hydroxy-3- (2-pyridinyl) -1-propynyl] -3- [(3-methoxy-lH-pyrrole-2 -yl) methylene] -2H-indol-2-one (JJ) Using Method C described above, 3-hydroxy-3- (2-pyridinyl) -1-propyne (133 mg, 1 mmol) (from Example 36 described above) was coupled to (Z) -1,3-dihydro-4. -iodo-3- [(3-methoxy-lH-pyrrol-2-yl) ethylene] -2H-indol-2-one (147 mg, 0.4 mmol) using (Starting Material 2) (Ph3P) 2PdCl2 ( 40 mg) (Aldrich) and Cul (20 mg) (Aldrich) as catalyst, in DMF (3 mL) and Et 3 N (3 L) as solvent, at 70 ° C for 19 h, yielding rae- (Z) -1, 3-dihydro-4-. { 3-hydroxy-3- (2-pyridinyl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 84 mg, 56%). Example 38: Synthesis of rae- (Z) -l, 3-Dihydro-4- [3-hydroxy-3- (2-thiophenyl) -1-propynyl] -3- [(3-methoxy-lH-pyrrole-2 -yl) methylene] -2H-indol-2-one (KK) Using Method D described above, 3-hydroxy-3- (2-thiophenyl) -1-propyne (102 mg, 0.74 mmol) was coupled. (prepared by addition of ethynylmagnesium chloride (Aldrich) to 2-thiophenecarboxaldehyde (Aldrich) according to Method A described above) to (Z) -4-bromo-1,3-dihydro-3- [(3-methoxy-1H- pyrrol-2-yl) methylene] -2H-indole-2-one (126 mg, 0.39 mmol) (Starting Material 1) using (Ph3P) 2PdCl2 (35 mg) (Aldrich) and Cul (17 mg) ( Aldrich) as catalyst, in DMF (3 mL) and EtN (3 L) as solvent at 70 ° C for 18 h, yielding rae- (Z) -1,3-dihydro-4- [3-hydroxy-3- ( 2-thiophenyl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 105 mg, 71%). Example 39: Synthesis of 3-Hydroxy-3- [3-methoxy-4- [2- (4-morpholinyl) -ethoxy] -phenyl] -1-propyne (LL) 3-hydroxy-3- [3- methoxy-4- [2- (4-morpholinyl) -ethoxy] -phenyl] -1-propyne according to Method A described above from 3-methoxy-4- (2-morpholin-4-yl-ethoxy) -benzaldehyde (0.60 g, 2.26 mmol) (see below) in THF (25 mL) and ethynylmagnesium chloride (5 mmol, 10 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 502 mg, 76%). 3-Methoxy-4- (2-morpholin-4-yl-ethoxy) -benzaldehyde was prepared from N- (2-hydroxyethyl) morpholine (Aldrich) and vanillin (Aldrich) by the H method described above. Example 40: Synthesis of rae- (Z) -1,3-Dihydro-4- [3-hydroxy-3- [3-methoxy-4- [2- (4-morpholinyl) -ethoxy] -phenyl] -1- propinyl] -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (MM) Using Method C described above, 3-hydroxy-3- [3-methoxy-4- [2- (4-morpholinyl) -ethoxy] -phenyl] -1-propyne (610 mg, 2.09 mmol) was coupled ( from Example 39 described above) to (Z) -1, 3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2H-indol-2-one (200 mg, 0.55 mmol) (starting material 2) using (Ph3P) 2PdCl2 (50 mg) (Aldrich) and Cul (25 mg).

(Aldrich) as catalyst, in DMF (3 mL) and Et3N (3 mL) as solvent, at 70 ° C for 22 h, yielding rae- (Z) -1,3-dihydro-4- [3-hydroxy-3 - [3-methoxy-4- [2- (4-morpholinyl) -ethoxy] -phenyl] -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole -2-ona. (Yield 154 mg, 53%). Example 41: Synthesis of rae- (Z) -1,3-dihydro-4- [3-hydroxy-3- [3-methoxy-4- [2- (4-morpholinyl) -ethoxy] -phenyl] -hydrochloride 1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (NN) Rae- (Z) -1,3-dihydro-4- [3-hydroxy-3- [3-methoxy-4- [2- (4-morpholinyl) -ethoxy] -phenyl] -1-propynyl] hydrochloride] -3- [(3-methoxy-lH-pyrrol-2-yl) ethylene] -2H-indol-2-one (compound MM of Example 40) was prepared by dissolving Compound MM in ethyl acetate and bubbling hydrogen chloride gas through the dissolution. Then, the resulting red precipitate was filtered and dried. Example 42: Synthesis of rae- (Z) -1,3-Dihydro-4- [3-hydroxy-3- (3-methoxy-2-thiophenyl) -1-propynyl] -3- [(3-methoxy-1H -pyrrol-2-yl) methylene] -2H-indol-2-one (00) Step A: 3-Hydroxy-3- (3-methoxy-2-thiophenyl) -1-propyne. 3-Methoxy-2-thiophenecarboxaldehyde was prepared by adding n-butyllithium (10.56 mmol, 2.5M solution in hexane) (Aldrich), without cooling, to a solution of 3-methoxythiophene (1 g, 8.8 mmol ) (Aldrich) in dry diethyl ether (5 mL) over a period of 5 min. The mixture was heated gently to reflux for 2 h, at which time the organolithic compound was transferred, via a cannula, to a solution of DMF (23 mmol) in diethyl ether (5 L) which was cooled in a water bath. ice. The reaction was stirred at room temperature for 14 h, and then 1N HCl (10 mL) was added and the phases were separated. The aqueous phase was extracted with diethyl ether (3x25 mL), and the combined organic extracts were dried over magnesium sulfate, and concentrated to give 3-methoxy-2-thiophenecarboxaldehyde as a pale yellow solid. The 3-methoxy-2-thiophenecarboxaldehyde was then added ethynylmagnesium chloride (Aldrich), according to Method A described above, to give 3-hydroxy-3- (3-methoxy-2-thiophenyl) -1-propyne. (Yield 151 mg, 0.9 mmol). Step B: Using Method C described above, 3-hydroxy-3- (3-methoxy-2-thiophenyl) -1-propyne (from Step A described above) was coupled to (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) using (Ph3P) 2PdCl2 ( 20 mg) (Aldrich) and Cul (10 mg) (Aldrich) as catalyst, in DMF (2 mL) and Et3N (2 mL) as solvent, at 70 ° C for 20 h, yielding rae- (Z) -1, 3-dihydro-4- [3-hydroxy-3- (3-methoxy-2-thiophenyl) -1-propynyl] -3 [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 98 mg, 59%: mp = 213-216 ° C). Example 43: Synthesis of 3-Hydroxy-3- (2,4,5-trimethoxyphenyl) -1-propy or 3-Hydroxy-3- (2,4,5-trimethoxyphenyl) -1-propyne was prepared according to Method A described above, from 2,4,5-trimethoxybenzaldehyde (0.784 g, 4 mmol) (Aldrich) in THF (20 mL) and ethynylmagnesium chloride (5 mmol, 10 mL, 0.5 M solution in tetrahydrofuran) (Aldrich) . (Yield 54 8 mg, 71%).

Example 44: Synthesis of rae- (Z) -1,3-Dihydro-4- [3-hydroxy-3- (2,4,5-trimethoxyphenyl) -1-propynyl] -3 - [(3-methoxy-1H -pyrrol-2-yl) methylene] -2H-indol-2-one (PP) Using Method C described above, 3-hydroxy-3- (2,4-, 5-trimethoxyphenyl) -1-propyne (150 mg, 0.67 mmol) (from Example 43 described above) was coupled to (Z) -1 , 3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (15O mg, 0.41 mmol) (Starting Material 2) using (Ph3P) 2PdCl (35 mg) (Aldrich) and Cul (16 mg) (Aldrich) as a catalyst, in DMF (3 L) and Et 3 N (3 mL) as solvent, at 70 ° C for 16 h, yielding rae- (Z) -1, 3-dihydro-4- [3-hydroxy-3- (2,4-, 5-trimethoxyphenyl) -1-propynyl] -3- [(3-methoxy-1H- pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 101 mg, 53%). Example 45: Synthesis of (4-formyl-2-methoxy-phenoxy) -acetic acid methyl ester Acid (4-formyl-2-methoxy-phenoxy) -acetic methyl ester was prepared by dissolving vanillin (4.1 mmol) (Aldrich) in dry THF (10 mL) and dry DMF (1 mL). Sodium hydride (109 mg, 4.5 mmol) was then slowly added to the solution and the resulting mixture was stirred at room temperature for 1 h at which time methyl bromoacetate (5 mmol) (Aldrich) was added dropwise. . The reaction was stirred at room temperature for 14 h and water (10 mL) was then added and the THF evaporated in vacuo. The aqueous phase was then extracted with ethyl acetate (3x15 mL), and the combined organic phases were dried over magnesium sulfate and concentrated. The resulting (4-formyl-2-methoxy-phenoxy) -acetic acid methyl ester was purified by flash column chromatography (Si02, 230-400 mesh) with ethyl acetate / hexane. Example 46: Synthesis of [4- (1-hydroxy-2-propy1) -2-ethoxy-phenoxy] -acetic acid methyl ester [4- (l-hydroxy-2-propynyl) -2-methoxy-phenoxy acid was prepared ] -acetic methyl ester according to Method A described above (except that the Grignard reagent was added at -78 ° C) from (4-formyl-2-methoxy-phenoxy) -acetic acid methyl ester (0.645 g, , 9 mmol) (from Example 45) in THF (30 L) and ethynylmagnesium chloride (3.45 mmol, 7 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 525 mg, 72%).

Example 47: Synthesis of Rae- (Z) - [4-13- [2,3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indole -4-yl] -1-hydroxy-2-propynyl] -2-methoxyphenoxy] acetic methyl ester (QQ) Using Method C described above, [4- (1-hydroxy-2-propynyl) -2-methoxy-phenoxy] -acetic acid methyl ester (158 mg, 0.63 mmol) (from Example 46) was coupled to ( Z) -1,3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (150 mg, 0.41 mmol) (Material from Part 2) using (Ph3P) PdCl2 (20 mg) (Aldrich) and Cul (10 mg) (Aldrich) as a catalyst, in DMF (2 mL) and Et3N (2 mL) as solvent, at 70 ° C for 16 h , yielding rae- (Z) - [4- [3- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indole-4 acid -yl] -l-hydroxy-2-propynyl] -2-methoxyphenoxy] acetic acid methyl ester. (Yield 91 mg, 46%).

Example 48: Synthesis of Rae- (Z) - [4- [3- [2,3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH- acid indol-4-yl] -1-hydroxy-2-propynyl] -2-methoxyphenoxy] acetic acid (RR) Rha- (Z) - [4- [3- [2, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indole-4 acid was hydrolyzed -yl] -1-hydroxy-2-propynyl] -2-methoxyphenoxy] acetic acid methyl ester (28 mg, 0.057 mmol) (from Example 47) with LiOH.H0 (55 mg, 1.15 mmol) in THF (0.5 mL) and H0 (0.5 mL) at room temperature for 20 h according to Method F described above to give rac- (Z) - [4- [3- [2, 3-dihydro-3 [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -l-hydroxy-2-propynyl] -2-methoxy-enoxy] -acetic acid.

(Yield 22 mg, 81%).

Example 49: Synthesis of 3-Hydroxy-3- (4-methoxy-1,3-benzodioxol-6-yl) -1-propyne 3-hydroxy-3- (4-methoxy-1,3-benzodioxole-6 was prepared -yl) -1-propyne according to Method A described above from 3-methoxy-4,5-methylenedioxybenzaldehyde (0.721 mmol) (Lancaster) in THF (20 mL) and ethynylmagnesium chloride (5 mmol, 10 mL, 0.5M solution in tetrahydrofuran) (Aldrich).

(Yield 629 mg, 76%). Example 50: Synthesis of rae- (Z) -4- [3-hydroxy-3- (4-methoxy-1,3-benzodioxol-6-yl) -1-propynyl] -1,3-dihydro-3- [ (3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indol-2-one (SS) Using Method C described above, 3-hydroxy-3- (4-methoxy-1,3-benzodioxol-6-yl) -1-propyne (153 mg, 0.74 mmol) was coupled (from Example 49 described above) a (2) -1,3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) ethylene] -2H-indol-2-one (147 mg, 0.4 mmol) (Starting material 2) using (Ph3P) 2PdCl2 (40 mg) (Aldrich) and Cul (20 mg) (Aldrich) as catalyst, in DMF (3 mL) and Et3N (3 mL) as solvent, at 70 ° C for 16 h, yielding rae- (2) -4- [3-hydroxy-3- (4-methoxy-1,3-benzodioxol-6-yl) -1-propynyl] -1,3-dihydro-3-. { (3-methoxy-lH-pyrrol-2-yl) ethylene] -2H-indol-2-one. (Yield 98 mg, 55%). Example 51: Synthesis of 3-Hydroxy-3- [4- [2-. { 4-morpholinyl) -ethoxy] -enyl] -1-propyne 3-Hydroxy-3- [4- [2- (4-morpholinyl) -ethoxy] -phenyl] -1-propyne was prepared according to Method A described above from 4- [2- (4-morpholinyl) -ethoxy] -benzaldehyde (0.630 g, 2.68 mmol) (see below.) in THF (20 L) and ethynylmagnesium chloride (3.0 mmol, 6). mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 492 mg, 70%) 4- [2- (4-morpholinyl) -ethoxy] -benzaldehyde was prepared from N- (2-hydroxyethyl) orpholine. (Aldrich) and vanillin (Aldrich) by the H method described above Example 52: Synthesis of rae- (Z) -1,3-Dihydro-4- [3-hydroxy-3- [4- [2- (4- morpholinyl) -ethoxyl-phenyl] -l-propinyl-3- [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indole-2-one (TT) Using Method C described above, 3-hydroxy-3- [4- [2- (4-morpholinyl) -ethoxy] -phenyl] -1-propyne (220 g, 0.84 mmol) was coupled (from Example 51} a (Z) -1,3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (147 mg, 0.4 mmol) (Starting Material 2) using (Ph3P) 2PdCl2 (38 mg) (Aldrich) and Cul (17 mg) (Aldrich) as catalyst, in DMF (3 mL) and Et3N (3 mL) as solvent, at 70 ° C. C for 20 h, yielding rae- (Z) -1, 3-dihydro-4- [3-hydroxy-3- [4- [2- (4-morpholinyl) -ethoxy] -phenyl] -1-propynyl] - 3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (Yield 164 mg, 82%) Example 53: Synthesis of 3- (4-Chloro-2-) methylsulfanylmethoxy-phenyl) -3-hydroxy-l-propyne Step A: A suspension of 4-chlorosalicylic acid (34.51 g, 0.2 mol) (Aldrich) in a methanol solution (100 mL) and sulfuric acid was prepared The mixture was heated to reflux for 17 h After allowing to cool to room temperature, the mixture was concentrated in a reduced ression. The resulting residue was dissolved in ether (400 mL) and washed successively with water (400 mL), saturated aqueous sodium bicarbonate (400 mL), and saturated aqueous sodium chloride (400 mL). The ethereal solution was then dried (MgSO 4), filtered, and concentrated. The resulting yellow oil was distilled to give methyl 4-chlorosalicylate.

(Yield 32.89 g, 88%, e.g. 86-90 ° C, 0.15 mm Hg). Step B: Sodium hydride (11.80 g, 50% in oil) was washed with petroleum ether twice to remove the oil. To this washed sodium hydride was added hexamethylphosphorimide (HMPA) (100 mL) (Aldrich) under argon atmosphere. The resulting mixture was magnetically stirred and cooled in an ice / water bath. Methyl 4-chlorosalicylate was added dropwise (37.32 9) (from Step A, described above) in HMPA (50 mL) and the mixture was stirred for 10 min., More. A solution of chloromethyl methyl sulfide (20 mL) (Aldrich) in HMPA (100 mL) was added and stirring was continued at room temperature for 24 h. The reaction mixture was then partitioned between toluene (3 X 1 L) and water (3 X 1 L). The toluene phases were combined, dried (MgSO), and concentrated under reduced pressure. The resulting oil was recrystallized from dichloromethane-hexane mixture to give the desired methyl thiomethyl ether.

(Yield 33.92 g, 68.75%, mp 64-65.5 ° C). Step C: A solution of the methyl thiomethyl ether (10.0 g, 40.5 mmol) from Step B above described in THF (50 mL) was added dropwise to a suspension of lithium aluminum hydride (LAH) (Aldrich ) in THF (50 L) under argon, with magnetic stirring, for 30 min. The suspension was then heated to reflux for 3 h. After allowing to cool, the mixture was poured onto 2N aqueous HCl (200 mL) and extracted with ether (2 X 200 mL). The ether phases were washed with saturated aqueous sodium chloride solution (200 mL), combined, dried (MgSO) and concentrated. The residue was filtered through silica gel (100 g) and the product was eluted with dichloromethane (Fisher Scientific). The product was then purified by vacuum distillation to give the benzyl alcohol product as a colorless oil. (Yield 7.24 g, 82%), e.g. 156-160 ° C, 0.07 mm Hg). Step D: The benzyl alcohol in the form of oil (5.66 g, 25.9 mmol) from Step C described above, was mixed in dichloromethane (70 mL), with pyridinium dichromate (20 g) (Aldrich) and stirred at 4 ° C for 20 h. The mixture was then diluted with dichloromethane (35 mL) and hexane (35 mL) and filtered through silica gel (50 9) and eluted with dichloromethane. The first 500 mL of the eluate was concentrated under reduced pressure and the residue was recrystallized from hexane to give 4-chloro-2-methylsulfanylmethoxybenzaldehyde as white needles. (Yield 4.99 g, 89%, mp 67-68 ° C). Step E: The desired 3- (4-chloro-2-methylsulfanylmethoxy-phenyl) -3-hydroxy-1-propyne was then prepared according to Method A described above, from 4-chloro-2-methylsulfanylmethoxybenzaldehyde (0.870 g) , 4 mmol) (from the D described above) in THF (20 mL) and ethynylmagnesium chloride (5 mmol, 10 mL, 0.5M solution in tetrahydrofuran) (Aldrich).

(Yield 802 mg, 83%). Example 54: Synthesis of rae- (Z) -4- [3- (4-Chloro-2-methyl-sulfanyl ethoxy-enyl) -3-hydroxy-1-propynyl] -1,3-dihydro-3- [( 3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (UU) Using Method D described above, 3- (4-chloro-2-methylsulfanylmethoxy-phenyl) -3-hydroxy-1-propyne (15 mg, 0.65 mmol) (from Example 53 described above) was coupled to (Z) -4-bromo-1,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene-2H-indol-2-one (152 mg, 0.48 mmol) (starting material 1 ) using (Ph3P) PdCl2 (40 mg) (Aldrich) and Cul (22 mg) (Aldrich) as catalyst, in DMF (3 mL) and EtN (3 mL) as solvent, at 70 ° C for 17 h, yielding rae - (Z) -4- [3- (4-chloro-2-methylsulfanylmethoxy-phenyl) -3-hydroxy-1-propynyl] -1,3-dihydro-3- [(3-methoxy-1H-pyrrole-2 -yl) methylene-2H-indol-2-one. (Yield 132 mg, 57%). Example 55: Synthesis of rae- (Z) -l, 3-Dihydro-4- [3- (2-furanyl) -3-hydroxy-l-propynyl-3 - [(3-methoxy-lH-pyrrole-2-yl) il) methylene] -2H-indol-2-one (W) Using Method C described above, 3- (2-furanyl) -3-hydroxy-1-propyne (148 mg, 1.24 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to 2-furfural (Aldrich) was coupled. ) according to Method A described above) to (Z) -1,3-dihydro-4-iodo-3- [(3-methoxy-1H-pyrrol-2-yl) methylene-2H-indol-2-one (152 mg, 0.42 mmol) (Starting Material 2) using (Ph3P) 2PdCl2 (34 mg) and Cul (16 mg) as a catalyst, in DMF (3 L) and Et3N (3 mL) co or solvent, at 70 ° C. C for 20 h, to give rae- (Z) -1, 3-dihydro-4- [3- (2-furanyl) -3-hydroxy-l-propynyl-3- [(3-methoxy-lH-pyrrol- 2-yl) methylene-2H-indol-2-one. (Yield 88 mg, 58%). Example 56: Synthesis of rae- (Z) -4- [3- (3-Chlorophenyl) -3-hydroxy-l-propynyl-l, 3-dihydro-3-l (3-methoxy-lH-pyrrole-2- il) methylene-2H-indol-2-one (WW) Using Method C described above, 3- (3-chlorophenyl) -3-hydroxy-1-propyne (150 mg, 0.9 mmol) (prepared by adding ethynylmagnesium chloride to 3-chlorobenzaldehyde according to Method A above) was coupled. described) to (Z) -1, 3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (148 mg, 0.4 mmol) (Starting Material 2), using (Ph3P) 2PdCl (35 mg) and Cul (16 mg) as catalyst, in DMF (3 mL) and Et ^ (3 mL) as solvent, at 70 ° C for 17 h, yielding rae- (Z) -4- [3- (3-chlorophenyl) -3-hydroxy-1-propynyl -1, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene-2H-indol-2-one. (Yield 132 mg, 81%). Example 57: Synthesis of [4- (1-hydroxy-2-propynyl) -phenoxy] -acetic acid 1,1-dimethyl ethyl ester Step A: Sodium hydride (109 mg, 4.5 mmol) was slowly added to a solution of 4-hydroxybenzaldehyde (4.1 mmol) (Aldrich) in dry THF (10 mL) and dry DMF (1 mL), and the resulting mixture was stirred at room temperature for 1 h, at which point it was added dropwise 1, 1-dimethylethyl bromoacetate (5 mmol) (Aldrich). The reaction was stirred at room temperature for 14 h. Then water (10 mL) was added and the THF was evaporated in vacuo. The aqueous phase was extracted with ethyl acetate (3x15 mL), and the combined organic phases were dried over magnesium sulfate and concentrated. The resulting product, (4-formyl-phenoxy) -acetic acid 1,1-dimethyl ethyl ester, was purified by flash column chromatography (Si02, 230-400 mesh) with ethyl acetate / hexane. Step B: [4- (1-Hydroxy-2-propynyl) -phenoxy] -acetic acid 1,1-dimethyl ethyl ester was then prepared according to Method A described above (except that the Grignard reagent was added to 0 ° C) from (4-formyl-phenoxy) -acetic acid 1,1-dimethyl ethyl ester (1.0 g, 4.2 mmol) (from Step A described above) in THF (20 L) and chloride of ethynylmagnesium (5.1 mmol, 10.2 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 817 mg, 74%). Example 58: Synthesis of rae- (Z) - [4- [3- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH- acid indol-4-yl] -1-hydroxy-2-propynyl] enoxy] acetic 1,1-dimethylethyl ester (XX) Using Method C described above, [4- (l-hydroxy-2-propynyl) -phenoxy] -acetic acid 1, 1-dimethyl ethyl ester (129 mg, 0.49 mmol) (from Example 57 described above) was coupled. a (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), using (Ph3P) 2PdCl2 (20 mg) (Aldrich) and Cul (10 mg) (Aldrich) as catalyst, in DMF (2 mL) and Et3N (2 L) as solvent, at 70 ° C for 20 h, yielding rae- (Z) - [4- [3- [2, 3-dihydro-3- [(3-rnetoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH- acid indol-4-yl] -l-hydroxy-2-propynyl] phenoxyl acetic acid 1, 1-dimethylethyl ester (Yield 106 mg, 52%: mp 173-175 ° C) Example 59: Synthesis of rae- (Z) acid ) - [4- [3- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -1-hydroxy -2-propynyl] phenoxy] acetic (YY) Using Method F described above, the acid rae- (Z) - [4- [3- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2 was hydrolysed -oxo-lH-indol-4-yl] -l-hydroxy-2-propynyl] phenoxy] acetic acid 1, 1-dimethylethyl ester (from Example 58 described above) (30 mg, 0.061 mmol) with LiOH.H20 (58 mg , 1.22 mmol) in THF (0.5 mL) and H20 (0.5 L) for 12 h, yielding rac- (Z) - [4- [3- [2, 3-dihydro-3- [ (3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -l-hydroxy-2-propynyl] phenoxy] acetic acid.

(Yield 24 mg, 89%). Example 60: Synthesis of rae- (Z) -1,3-Dihydro-4- [3-hydroxy-3- (3-nitrophenyl) -1-propynyl] -3- [(3-methoxy-1H-pyrrole-2 -yl) methylene] -2H-indol-2-one (ZZ) Using Method C described above, coupling 1- (3-nitro-phenyl) -2-propin-1-ol (126 mg, 0.71 mmol) (prepared by addition of ethynylmagnesium chloride (Aldrich) to 3-nitrobenzaldehyde (Aldrich) according to Method A described above) to (Z) -1,3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2- ona '(134 mg, 0.37 mmol). { Starting Material 2), using (Ph3P) 2PdCl2 (35 mg) (Aldrich) and Cul (20 mg) (Aldrich) as catalyst, in DMF (3 mL) and Et3N (3 mL) as solvent, at 70 ° C for 20 h, yielding rae- (Z) -1,3-dihydro-4- [3-hydroxy-3 - (3-nitrophenyl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one.

(Yield 84 mg, 52%). Example 61: Synthesis of rae- (Z) -4- [3- (3-Aminophenyl) -3-hydroxy-1-propynyl] -1,3-dihydro-3- [(3-methoxy-1H-pyrrole-2 -yl) methylene] -2H-indol-2-one (AAA) Rae- (Z) -1,3-dihydro-4- [3-hydroxy-3- (3-nitrophenyl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) was added methylene] -2H-indol-2-one (25 mg, 0.068 mmol) (from Example 60) at 10% H20 in methanol (2 mL) and to this mixture was added zinc powder (35 mg, 0.53 mmol) and Ammonium chloride (10 mg, 0.19 mmol). The reaction was refluxed for 3 h, at which time the reaction was cooled and the solid filtered. The solids were washed extensively with ethyl acetate, and the ethyl acetate and methanol were evaporated in vacuo. The resulting precipitate was filtered, dried and recrystallized from ethyl acetate / hexane to give rae- (Z) -4- [3- (3-amino-phenyl) -3-hydroxy-1-propynyl] -1,3. -dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 19 mg, 73%). Example 62: Synthesis of 3- (4-Acetamidophenyl) -3-hydroxy-1-propyne Step A: 1- (4-Nitro-phenyl) -2-propyn-1-ol (4.89 mmol) (prepared by addition of ethynylmagnesium chloride (Aldrich) to 4-nitrobenzaldehyde (Aldrich) according to method A, described above) to 10% H20 in methanol (150 mL) and to this mixture was added zinc powder (44.01 mmol) and chloride ammonium (10.67 mmol). The reaction was refluxed for 3 h, at which time the reaction was cooled and the solid filtered. The solids were washed extensively with ethyl acetate, and the ethyl acetate and methanol were evaporated in vacuo. The resulting precipitate was filtered, dried and recrystallized from ethyl acetate / hexane to give 1- (4-amino-phenyl) -2-propyn-1-ol. Step B: 1- (4-Amino-phenyl) -2-propyn-l-ol (3.0 mmol) (from Step A described above) was dissolved in dry THF (20 mL) and DMF (1 mL). Acetic anhydride (4.2 mmol) was added dropwise followed by triethylamine (3.0 mmol). The reaction was stirred at room temperature for 2 h, after which water (30 mL) was added, and the THF was evaporated in vacuo. The aqueous phase was extracted with ethyl acetate (3x50 mL), and the combined organic phases were dried over magnesium sulfate and concentrated. The resulting product, 3- (4-acetamidophenyl) -3-hydroxy-1-propyne, was purified by flash column chromatography (Si 2, 230-400 esh) with ethyl acetate / hexane. Example 63: Synthesis of rae- (Z) -4- [3- (4-acetamidophenyl) -3-hydroxy-1-propynyl] -1,3-dihydro-3- [(3-methoxy-1H-pyrrole-2 -yl) methylene] -2H-indole-2-one (BBB) Using Method C described above, 3- (4-acetamidophenyl) -3-hydroxy-1-propyne (111 mg, 0.59 mmol) was coupled. (from Example 62 described above) to (2) -1,3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (110 mg, 0.3 mmol) (starting material 2), using (Ph3P) 2PdCl2 (25 mg) (Aldrich) and Cul (10 mg) (Aldrich) as catalyst, in DMF (3 mL) and Et3N (3 mL) as solvent, at 70 ° C for 16 h, yielding rae- (2) -4- [3- (4-acetamidophenyl) -3-hydroxy-1-propynyl] -1 , 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indoi-2-one. (Yield 57 mg, 44%). Example 64: Synthesis of (Z) -1,3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- [(3-pyridinyl) ethynyl] -2H-indole-2 -one (CCC) Using Method D described above, 3-ethynyl pyridine (60.6 mg, 0.59 mmol) (see below) was coupled with (2) -4-bromo-1,3-dihydro-3- [(3-) methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (75 mg, 0.23 mmol) (Starting Material 1), using (Ph3P) 4Pd (13.3 mg) (Aldrich) and Cul (3 mg) (Aldrich) as catalyst, in DMF (4 mL) and Et3N (4 mL) as solvent, at 100 ° C for 18 h, to give (2) -1, 3-dihydro-3- [(3-methoxy-1H -pyrrol-2-yl) methylene] -4- [(3-pyridinyl) ethynyl] -2H -indol-2-one. (Yield 52 mg, 66%). 3-ethynyl pyridine was prepared by coupling 2-methyl-3-butin-2-ol with 3-bromopyridine using (Ph3P) 2PdCl_ (Aldrich) and Cul (Aldrich) as catalyst, in DMF and Et3N as solvent, according to method D described above. Example 65: Synthesis of (Z) -1,3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- [(2-pyridinyl) ethynyl] -2H-indole-2 -one (DDD) Using Method J described above, 2-bromopyridine (44.9 mg, 0.28 mmol) (Aldrich) was coupled with (2) -1,3-dihydro-4-ethynyl-3- [(3-methoxy-1H -pyrrol-2-yl) methylene] -2H-indole-2-one (Starting Material 5) (50 mg, 0.19 mmol), using DPPFPdCl2 (7.7 mg) (Aldrich) and Cul (2 mg) (Aldrich) as a catalyst, in DMF (3 mL) and Et3N (3 mL) as solvent, and heating under reflux for 2 days, yielding (2) -1, 3-dihydro-3- [(3-methoxy-1H- pyrrol-2-yl) methylene] -4- [(2-pyridinyl) ethynyl] -2H-indol-2-one. (Yield 30 mg, 47%).

Example 66: Synthesis of (Z) -1,3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- [(4-pyridinyl) ethynyl] -2H-indole-2 -one (EEE) Using Method J described above, 4-bromopyridine hydrochloride (110 mg, 0.57 mmol) (Aldrich) was coupled with (Z) -1,3-dihydro-4-ethynyl-3- [(3-methoxy-1H -pyrrol-2-yl) methylene] -2H-indole-2-one (Starting Material 5) (100 mg, 0.38 mmol). Using DPPFPdCl2 (15.4 mg) (Aldrich) and Cul (4 mg) (Aldrich) as catalyst, in DMF (5 L) and Et3N (5 L) as solvent, and heating at reflux for 1 day, yielding (Z) -1, 3-dihydro-3- [(3-methoxy-1H- pyrrol-2-yl) methylene] -4- [(4-pyridinyl) ethynyl] -2H-indol-2-one. (70 mg yield, 54%).

Example 67: Synthesis of rae- (Z) -1, 3-Dihydro-4- (3-hydroxy-3-phenyl-1-propynyl) -3- [(3-methoxy-1H-pyrrol-2-yl) methylene ] -2H-indol-2-one (FFF) Using Method D described above, 3-hydroxy-3-phenyl-1-propyne (0.1 g, 0.78 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to benzaldehyde) was coupled.

(Aldrich) by means of Method A described above) to (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), using DPPFPdCl2 (12.6 mg) (Aldrich) and Cul (3 mg) (Aldrich) as catalyst in DMF (5 L) and Et3N (5 mL) as solvent, at 85 ° C for 18 h, yielding rae- (Z) -1,3-dihydro-4- (3-hydroxy-3-) phenyl-1-propynyl) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one. (Yield 42 mg, 38%).

Example 68: Synthesis of (Z) -1,3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -5-nitro-4- [(3-pyridinyl) ethynyl] -2H -indol -2-one (GGG) Using Method D described above, 3-ethynyl pyridine (0.14 g, 1.38 mmol) was coupled (see Example 64) with (Z) -4-bromo-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -5-nitro-2H-indol-2-one (0.2 g, 0.55 mmol) (starting material 3), using (Ph3P) 4Pd (31.8 mg) (Aldrich) and (5.3 mg) (Aldrich) as catalyst, in DMF (6 mL) and Et3N (6 mL) as solvent, and at 85 ° C for 18 h, yielding (Z) -1, 3-dihydro-3- [( 3-methoxy-lH-pyrrol-2-yl) methylene] -5-nitro-4 [(3-pyridinyl) ethynyl] -2H-indol-2-one. (Yield 0.16 g, 71%). Example 69: Synthesis of (Z) -5-Amino-l, 3-dihydro-3-l (3-methoxy-lH-pyrrol-2-yl) methylene] -4-1 (3-pyridinyl) ethynyl] -2H -indol-2-one (HHH) Using Method L described above, it was reduced (Z) -1,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -5-nitro-4- [(3-pyridinyl) ethynyl] -2H-indole-2- Ona (0.1 g, 0.26 mmol) (from Example 68 described above) with Zn (0.15 g, 2.33 mmol) and NH4C1 (30.6 mg, 0.57 mmol) in 10% water in methanol (10 mL) with traces of DMF and heating at 90 ° C for 5 h, to give (Z) -5-amino-1,3-dihydro -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- [(3-pyridinyl) ethynyl] -2H-indol-2-one. (Yield 28 mg, 30%). Example 70: Synthesis of (Z) -N- [2, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-4- [(3-pyridinyl) ethynyl ] -lH-indol-5-yl] -2-thiopheneacetamide (III) Using Method M described above, (2) -5-amino-1,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- [(3-pyridinyl) was coupled. ethynyl] -2H-indol-2-one (18 mg, 0.051 mmol) (from Example 69) with 2-thiopheneacetyl chloride (16.2 mg, 0.10 mmol) (Aldrich) in THF (2 L) and bicarbonate saturated aqueous sodium (1 mL) at room temperature for 1 h, to give (2) -N- [2, 3-dihydro-3- [(3-methoxy-1H-pyrrol-2-yl) methylene] -2- oxo-4- [(3-pyridinyl) ethynyl] -lH-indol-5-yl] -2-thiopheneacetamide. (Yield 7.7 mg, 32%). Example 71: Synthesis of (2) -1,3-Dihydro-4-iodo-3- [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one (JJJ) A mixture of 4-iodooxindol (404.1 mg, 1.56 mmol) [see Fukuyama, supra) and pyrrole-2-carboxaldehyde (163.2 mg, 1.72 mmol) (Aldrich) in 2-propanol (6, 2 mL) was treated with 2 drops of piperidine. The reaction mixture was heated to reflux for 24 h and then allowed to cool to 23 ° C, at which time the reaction mixture was filtered. The solid was washed several times with cold distilled water and then allowed to air dry to provide (Z) -1,3-dihydro-4-iodo-3- [(1H-pyrrol-2-yl) methylene] -2H- Pure indole-2-one (341.8 mg, 65%) as a yellow solid which was used without further purification. Example 72: Synthesis of 4- [(E) -2- (2-Chlorophenyl) -ethenyl] -1,3-dihydro- (Z) -3- [(lH-pyrrol-2-yl) methylene-2H-indole -2-ona (KKK) A solution of (Z) -1,3-dihydro-4-iodo-3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (39 mg, 0.116 mmol) (from Example 71 described above), triethylamine (65 μL, 0.464 mmol), tri-o-tolylphosphine (7 mg, 0.023 mmol) (Aldrich), palladium (II) acetate (2 mg, 0.009 mmol) (Aldrich), and 2-chlorostyrene (24 mg, 0.173 mmol) (Aldrich) in 3 L of dry N, N-dimethylformamide was heated at 85 ° C under nitrogen atmosphere for 20 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck silica gel 60, 230-400 mesh, elution with 5% ethyl acetate-benzene) to give 4 - [(E) - 2- (2-chlorophenyl) -ethenyl] -1,3-dihydro- (Z) -3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one pure as a yellow solid.

(Yield 27 mg, 67%, mp = 257-258 ° C). Example 73: Synthesis of 1,3-Dihydro- (Z) -3- [(1H-pyrrol-2-yl) methylene] - [(E) -2-phenylethenyl] -2H-indol-2-one (LLL) To a stirred solution of (Z) -1,3-dihydro-4-iodo-3- [(1H-pyrrol-2-yl) ethylene] -2H-indol-2-one (from Example 71 described above) (500 mg, 1.49 mmol) in DMF (8 mL) and TEA (3 mL) was added styrene (0.34 mL, 2.98 mmol) (Aldrich), tri-o-tolylphosphine (361 mg, 1.19 mmol ) (Aldrich) and Pd (OAc) (67 mg, 0.30 mmol) (Aldrich). The reaction mixture was stirred at 85 ° C overnight in a pressurized tube. The solvent was removed in vacuo, and the residue was purified by chromatography on silica gel (Hex: EtOAc 5: 1) to 1,3-dihydro- (Z) -3- [(lH-pyrrol-2-yl) methylene. ] - [(E) -2-phenyl-ethenyl] -2H-indol-2-one. (Yield 371 mg, 80%). Example 74: Synthesis of 1,3-Dihydro- (Z) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] - [(E) -2-phenylethenyl] -2H-indol-2-one ( MMM) To a stirred solution of (Z) -1,3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) ethylene] -2H-indol-2-one (500 mg, , 49 mmol) (starting material 2) in DMF (8 mL) and TEA (3 mL) was added styrene (0.33 L, 2.92 mmol) (Aldrich), tri-o-tolylphosphine (361 mg, 1 , 19 mmol) (Aldrich) and Pd (OAc) 2 (67 mg, 0.30 mmol) (Aldrich). The reaction mixture was stirred at 85 ° C overnight in a pressurized 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- (Z) -3- [(3-methoxy-1H-pyrrole. -2-yl) methylene] - [(E) -2-phenylethenyl] -2H-indol-2-one as a yellow solid. (Yield 407 mg, 80%).

Example 75: Synthesis of 1,3-Dihydra-4- [(E) -2- (4-methoxy-phenyl) -ethenyl] - (Z) -3- [(lH-pyrrol-2-yl) methylene] - 2H-indol-2-one (NNN) A. p-Methoxy-styrene To a stirred solution of n-butyllithium (4 mL, 2.5M solution in Hexane, 10 mmol) (Aldrich) in ether (30 mL) was added methyltriphenylphosphonium bromide (3.57 g, 10 mmol) (Aldrich) for a period of 5 min. The reaction mixture was stirred for 4 h at room temperature. 4-methoxybenzaldehyde was added to the resulting orange solution (1.34 mL, 10 mmol) (Aldrich) dropwise. The solution became colorless, and a white precipitate separated. The mixture was then heated to reflux and immediately allowed to cool to room temperature. The precipitate was removed by filtration. The precipitate was washed with ether and the combined ether filtrates were washed with water until neutral and then dried over anhydrous MgSO 4, the solvent was removed, and the residue was used in the next reaction without further purification. B. 1, 3-Dihydro-4 - [(E) -2- (4-methoxyphenyl) -ethenyl] - (Z) -3- [(1 H -pyrrol-2-yl) methylene] -2H-indole- 2-one (NNN) To a stirred solution of (Z) -1,3-dihydro-4-iodo-3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (from Example 71 described above) (100 mg, 0.29 mmol) in DMF (3 mL) and TEA (2 L) was added p-methoxy-styrene (79 mg, 0.58 mmol) (from Step A, as described above), tri-o-tolylphosphine (107 mg, 0.35 mmol) (Aldrich) and Pd (OAc) 2 (20 mg, 0.089 mmol) (Aldrich). The reaction mixture was stirred at 85 ° C overnight in a pressurized tube. The solvent was removed in vacuo, and the residue was purified by chromatography on silica gel (Hex: EtOAc : 1) to give 1,3-dihydro-4- [(E) -2- (4-methoxyphenyl) -ethenyl] - (Z) -3- [(lH-pyrrol-2-yl) methylene] -2H -indole-2-one in the form of a yellow solid. (Yield 72mg, 7 3%). Example 76: Synthesis of 1,3-Dihydro- (Z) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- [(E) -2- (4-methoxy-phenyl) -etenil] -2H-indol-2-one (OOO) To a stirred solution of (Z) -1,3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (100 mg, 0.29 mmol) (starting material 2) in DMF (3 mL) and TEA (2 mL), p-methoxy styrene (79 mg, 0.58 mmol) was added (from Example 75A, described above), tri-o-tolylphosphine (107 mg, 0.35 mmol) (Aldrich) and Pd (0Ac) 2 (20 mg, 0.089 mmol) (Aldrich). The reaction mixture was stirred at 85 ° C overnight in a pressurized 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- (Z) -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- [(E) -2- (4-methoxy-phenyl) -ethenyl] -2H indole -2-one in the form of a yellow solid. (Yield 78 mg, 74%). Example 77: Acid Synthesis of 4-ethenyl-benzoic methyl ester To a stirred solution of n-butyllithium (4 mL, 2.5 M solution in hexane, 10 mmol) (Aldrich) in ether (30 mL) was added bromide of methyltriphenylphosphonium (3.57 g, 10 mmol) (Aldrich) over a period of 5 min. The reaction mixture was stirred for 4 h at room temperature. To the resulting orange solution was added dropwise methyl 4-formylbenzoate (1.54 mL, 10 mmol). The solution became colorless, and a white precipitate separated. The mixture was then heated to reflux and immediately allowed to cool to room temperature. The precipitate was removed by filtration. The resulting precipitate was washed with ether, and the combined ether filtrates were washed with water until neutral and then dried over anhydrous MgSO4, the solvent was removed and the residue, 4-ethenyl-benzoic acid methyl ester, was used in the next reaction without additional purification. Example 78: Synthesis of 4- [(E) -2- [2,3-dihydro- (Z) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH acid -indol-4-yl] ethenyl] benzoic methyl ester (PPP) To a stirred solution of (Z) -1,3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (100 mg, 0.29 mmol) (Starting Material 2) in DMF (3 mL) and TEA (2 L) was added 4-ethenyl-benzoic acid methyl ester (0.11 mL, 0.58 mmol) (from Example 77 described above ), tri-o-tolylphosphine (107 mg, 0.35 mmol) (Aldrich) and Pd (OAc): (20 mg, 0.089 mmol) (Aldrich). The reaction mixture was stirred at 85 ° C overnight in a pressurized tube. The solvent was removed in vacuo, and the residue was purified by chromatography on silica gel (Hex: EtQAc = 5: 1) to give 4 - [(E) -2- [2,3-dihydro- (Z)] acid. 3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] ethenyl] benzoic methyl ester in solid yellow form. (Yield 77 mg, 66%). Example 79: Synthesis of 1, 2-dimethoxy-4-ethenyl-benzene To a stirred solution of n-butyl-lithium (4 mL, 2.5 M solution in hexane, 10 mmol) (Aldrich) in ether (30 mL) was added methyltriphenylphosphonium bromide (3.57 g, 10 mmol) (Aldrich) for a period of 5 min. The reaction mixture was stirred for 4 h at room temperature. To the resulting orange solution was added dropwise 3,4-dimethoxybenzaldehyde (1.82 g, 11 mmol) (Aldrich). The solution became colorless, and a white precipitate separated. The mixture was then heated to reflux and immediately allowed to cool to room temperature. The precipitate was removed by filtration. The precipitate was washed with ether and the combined ether filtrates were washed with water until neutral and then dried over anhydrous MgSO, the solvent was removed and the residue, 1,2-dimethoxy-4-ethenyl-benzene, was used in the following reaction without further purification. Example 80: Synthesis of 1,3-Dihydro-4- [(E) -2- (3,4-dimethoxyphenyl) -ethenyl] - (Z) -3- [(3-methoxy-lH-pyrrol-2-yl ) methylene] -2H-indol-2-one (QQQ) To a stirred solution of (Z) -1,3-dihydro-4-iodo-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (100 mg, 0.29 mmol) (Starting Material 2) in DMF (3 L) and TEA (2 mL) was added 1,2-dimethoxy-4-vinyl-benzene (0.089 mg, 0.58 mmol) (from Example 79), tri-o-tolylphosphine (107 mg, 0.35 mmol) (Aldrich) and Pd (OAc) 2 (20 mg, 0.089 mmol) (Aldrich). The reaction mixture was stirred at 85 ° C overnight in a pressurized tube. The solvent was removed in vacuo, and the residue was purified by chromatography on silica gel (Hex: EtOAc = 5: 1) to provide 1,3-dihydro-4- [(E) -2- (3,4-dimethoxyphenyl) ) -etenyl] - (Z) -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one as a yellow solid. (Yield 78 mg, 67%). Example 81; Synthesis of (Z) -1, 3-Dihydro-3- [(lH-pyrrol-2-yl) methylene] -5- (trimethylsilyl) ethynyl-2H-indol-2-one (RRR) (Trimethylsilyl) acetylene (1.36 g, 13.8 mmol) (Aldrich) and (Z) -5-bromo-1,3-dihydro-3- [(lH-pyrrol-2-yl) methylene] -2H were dissolved. -indol-2-one (2.0 g, 6.9 mmol) (starting material 7) in 30 mL of DMF and 40 mL of triethylamine. The solution was degassed for 30 minutes by bubbling argon through the solution. Cul (130 mg, 0.68 mmol) (Aldrich) and (Ph3P) 2PdCl2 (400 mg, 0.57 mmol) (Aldrich) were then added, and the reaction was heated, under argon, at 70 ° C for 22 hours . Then water (20 mL) was added and the precipitate was filtered and dried. The product was purified by flash column chromatography (Si02, 230-400 esh) with 1% MeOH / CHCl3 to give (Z) -1,3-dihydro-3- [(1H-pyrrol-2-yl) ethylene] - 5- (Trimethylsilyl) ethynyl-2H-indol-2-one as a yellow powder. (Yield 1.07 g, 51%). Example 82: Synthesis of (Z) -l, 3-Dihydro-5-ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (SSS) To a solution of (Z) -1, 3-dihydro-3- [(1H-pyrrol-2-yl) methylene] -5- (trimethylsilyl) ethynyl-2H-indol-2-one (940 mg, 3.1 mmol) (from Example 81 described above) in 50 mL of ethanol and 15 mL of tetrahydrofuran (Fisher Scientific) was added dropwise a solution of silver nitrate (1.17 g, 6.89 mmol) in 5 mL of water and 15 L of ethanol, the formation of a precipitate takes place. The mixture was stirred at room temperature for 45 minutes, after which a solution of potassium cyanide (2.18 g, 33.47 mmol) in 8 mL of water was added and the precipitate dissolved. To the solution were then added 50 mL of a saturated aqueous solution of sodium bicarbonate followed by 500 mL of water. The product was then filtered and dried to give (Z) -1,3-dihydro-5-ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (yield 700 mg, 96%), which was recrystallized from EtOAc / Hex to give 540 mg of the product as yellow crystals. Example 83: Synthesis of (Z) -1,3-Dihydro-5- (4-hydroxyphenyl) ethynyl-3- [(lH-pyrrol-2-yl) methylene] -2H-ind01-2-one (TTT) A solution of (Z) -1,3-dihydro-5-ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (100 mg, 0.43 mmol) (from Example 82) and 4-iodophenol (104 mg, 0.47 mmol) (Aldrich) in N, N-dimethylformamide (2 mL) and triethylamine (2 mL) was degassed by bubbling argon through the solution for 15 minutes. Copper iodide was added (1) (8 mg, 0.042 mmol) (Aldrich) and (Ph3P) 2PdCl2 (25 mg, 0.021 mmol) (Aldrich), and the reaction was heated at 70 ° C for 16 hours. Then water (15 mL) was added and the precipitate was filtered and dried. The product was purified by flash column chromatography (Si02, 230-400 mesh) with ethyl acetate / hexane to give (Z) -1,3-dihydro-5- (4-hydroxyphenyl) ethynyl-3- [(1H-NMR). pyrrol-2-yl) methylene] -2H-indol-2-one in the form of a yellow powder. (Yield 121 mg, 86%). Example 84: Synthesis of (Z) -l, 3-Dihydro-5- (3-nitroenyl) ethynyl-3- [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one (UUU) This compound was prepared in a manner analogous to the preparation of (Z) -1,3-dihydro-5- (4-hydroxyphenyl) ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indole-2 -one (Compound TTT in Example 83 described above). In this example, (2) -1,3-dihydro-5-ethynyl-3- [(lH-pyrrol-2-yl) methylene] -2H-indole-2-one (150 mg, 0.64 mmol) was coupled. ) (from Example 82) with l-iodine-3-nitrobenzene (175 mg, 0.70 mmol) (Aldrich), using Cul (13 mg, 0.068 mmol) and (Ph3P) 2PdCl2 (22 mg, 0.031 mmol) (Aldrich ) as a catalyst, in 3 mL of DMF and 3 L of triethylamine, at 70 ° C for 13 hours to give (2) -1,3-dihydro-5- (3-nitrophenyl) ethynyl-3- [(1H -pyrrol-2-yl) methylene] -2H-indole-2-one as a red powder. (Yield 148 mg, 65%). Example 85: Synthesis of (Z) -1,3-Dihydro-5-phenylethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (WV) This compound was prepared analogously to the preparation of (2) -1,3-dihydro-5- (4-hydroxyphenyl) ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indole-2 -one in Example 83 described above. In this example, (2) -1,3-dihydro-5-ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (90 mg, 0.38 mmol) was coupled. ) (from Example 82) with iodobenzene (219 mg, 1.07 mmol) (Aldrich) using Cul (8 mg, 0.042 mmol) (Aldrich) and (Ph3P) 2PdCl2 (14 mg, 0.020 mmol) (Aldrich) as catalyst, in 1 mL of DMF and 2 mL of triethylamine, at 70 ° C for 15 hours, to give (2) -1,3-dihydro-5-phenylethynyl-3- [(1H-pyrrol-2-yl) methylene] - 2H-indol-2-one in yellow powder form. (Yield 92 mg, 78%). Example 86: Synthesis of (Z) -l, 3-Dihydro-5- (3-hydroxyphenyl) -etinyl-3- [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one (WWW) This compound was also prepared analogously to the preparation of (2) -1,3-dihydro-5- (4-hydroxyphenyl) ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indole-2- ona in Example 83 described above. In this example, (Z) -1,3-dihydro-5-ethynyl-3- [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one (100 mg, 0.43 mmol) was coupled. ) (from Example 82) with 3-iodophenol (110 mg, 0.50 mmol) (Aldrich), using Cul (8 mg, 0.042 mmol) (Aldrich) and (Ph3P) 2PdCl2 (15 mg, 0.021 mmol) (Aldrich) as catalyst, in 1 L of DMF and 3 mL of triethylamine at 70 ° C for 13 hours to give (i) -1,3-dihydro-5- (3-hydroxyphenyl) ethynyl-3- [(1H-pyrrole-2 -yl) methylene] -2H-indole-2-one in the form of a yellow powder. (Yield 100 mg, 71%).

Example 87 Synthesis of (Z) -l, 3-Dihydro-5- (2-nitrophenyl) ethynyl-3- [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one (XXX) This compound was also prepared analogously to the preparation of (Z) -1,3-dihydro-5- (4-hydroxyphenyl) ethynyl-3- [(1H-pyrrol-2-yl) ethylene] -2H-indole- 2-one in Example 83 described above. In this example, (Z) -1,3-dihydro-5-ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (150 mg, 0.64 mmol) was coupled. ) (from Example 82) with l-bromo-2-nitrobenzene (150 mg, 0.74 mmol) (Aldrich), using Cul (13 mg, 0.068 mmol) (Aldrich) and (Ph3P) 2PdCl (22 mg, 0.031 mmol) (Aldrich) as catalyst, in 2 mL of DMF and 4 mL of triethylamine at 70 ° C for 15 hours, to give (Z) -1,3-dihydro -5- (2-Nitrophenyl) ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one as a red powder. (Yield 115 mg, 51%).

Example 88: Synthesis of (Z) -5- [3- [2, 3-dihydro-2-oxo-3- (1H-pyrrol-2-ylmethylene) -lH-indol-5-yl] -2-propinyl] -6 (5H) -phenanthridinone (YYY) A solution of 5- (2-propynyl) -6 (5H) -phenanthridinone (42 mg, 0.18 mmol) (prepared according to Walser et al., J. Med. Chem., 34 (3), 1209-1221 ( 1991)) and (Z) -l, 3-dihydro-5-iodo-3- [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one (2.0 g, 0.12 mmol) (starting material 8) were dissolved in 3 mL of DMF and 0.04 mL of triethylamine. The solution was degassed for 30 minutes by bubbling argon through the solution. Then, Cul (1 mg) was added (Aldrich), triphenylphosphine (5 mg) (Aldrich), and palladium (II) acetate (2 mg) (Aldrich), and the reaction was stirred, under argon, at 27 ° C for 37 hours. Then water was added (20 mL) and the precipitate was filtered and dried. The product was purified by flash column chromatography (Si02, 230-400 mesh) with 5% MeOH in CHC13 to give (Z) -5- [3- [2, 3-dihydro-2-OXO-3- (lH- pyrrol-2-yl-methylene) -lH-indol-5-yl] -2-propynyl] 6 (5H) -phenanthridinone in the form of a yellow powder. (Yield 13 mg, 2 5%). Example 89: Synthesis of (Z) -1,3-Dihydro-5- (4-nitrophenyl) ethynyl-3- [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one (ZZZ) A solution of (Z) -1,3-dihydro-5-ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indole-2-one (150 mg, 0.64 mmol) (from Example 82) and l-iodo-4-nitrobenzene (175 mg, 0.70 mmol) (Aldrich) in N, N-dimethylformamide (3 L) (Fisher Scientific) and triethylamine (3 L) was degassed by bubbling argon through the solution for 15 minutes. Copper (I) iodide (13 mg, 0.068 mmol) (Aldrich) was added and (Ph3P) 2PdCl2 (22 mg, 0.031 mmol) (Aldrich), and the reaction mixture was heated at 70 ° C for 13 hours. Then water (15 mL) was added and the precipitate was filtered and dried.

The product was purified by flash column chromatography (Si02, 230-400 mesh) with ethyl acetate / hexane to give (Z) -1,3-dihydro-5- (4-nitrophenyl) ethynyl-3- [( lH-pyrrol-2-yl) ethylene] -2H-indol-2-one as a red powder. (Yield 111 mg, 49%). Example 90: Synthesis of (Z) -5- (4-Aminophenyl) ethynyl-l, 3-dihydro-3- [(lH-pyrrol-2-yl) rnetylene] -2H-indol-2-one (AAAA) To a solution of (Z) -1,3-dihydro-5- (4-nitrophenyl) ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (45 mg, 0.13 mmol) (from Example 89) in 1 mL of a solution of 10% water in methanol and 0.5 mL of THF was added zinc powder (145 mg, 2.210 mmol) followed by ammonium chloride ( 25 mg, 0.47 mmol). The reaction was heated to gentle reflux for 4 hours, at which time the reaction mixture was filtered through a pad of Celite® (Fisher Scientific) and washed extensively with ethyl acetate. The resulting solution was diluted with 5 L of water and the product was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated. The resulting powder was recrystallized from EtOAc / hex to give (Z) -5- (4-aminophenyl) ethynyl-1,3-dihydro-3- [(1H-pyrrol-2-yl) methylene] -2H-indole-2 -one in the form of red powder. (Yield 24 mg, 56%). Example 91: Synthesis of (Z) -5-Bromo-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (BBBB) A mixture of 5-bromo-l, 3-dihydro-2H-indol-2-one (0.94 g, 4.4 mmol) (Starting Material 6) and 3-methoxy-2-pyrrole-carboxyaldehyde (0.5 g, 4.0 mmol) (see Bellany et al., Supra) in 1% Piperidine in 2-propanol (10 mL) was heated at 65 ° C for 16 h. Hot water (10 L) was added. Upon cooling, the crystallized product was filtered, washed with aqueous 2-propanol and dried. (Yield 1.13 g, 89%).

Example 92: Synthesis of (Z) -1,3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -5- (trimethylsilyl) ethynyl-2H-indol-2-one (CCCC ) This compound was prepared analogously to the preparation of (Z) -1,3-dihydro-3- [(1H-pyrrol-2-yl) methylene] -5- (trimethylsilyl) -etinyl-2H-indole-2- ona in Example 81 described above. In this example, (Z) -5-bromo-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (740 mg, 2.32 mmol) (from Example 91) with (trimethylsilyl) acetylene (640 mg, 6.52 mmol) "(Aldrich) using Cul (40 mg, 0.21 mmol) (Aldrich) and (Ph3P) 2PdCl2 (90 mg, 0.13 mmol) (Aldrich) as a catalyst, in 10 L of DMF and 10 mL of triethylamine at 70 ° C for 22 hours, to give (Z) -1, 3 -dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -5- (trimethyl-silyl) ethynyl-2H-indol-2-one.

(Yield 410 mg, 52%).

Example 93: Synthesis of (Z) -1,3-Dihydro-5-ethynyl-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (DDDD) This compound was also prepared in a manner analogous to the preparation of (Z) -1,3-dihydro-5-ethynyl-3- [(1H-pyrrol-2-yl) ethylene] -2H-indol-2-one in the Example 82 described above. In this example, (Z) -1, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -5- (trimethylsilyl) ethynyl-2H-indol-2-one (100 mg , 0.3 mmol) (Example 92) in 5 mL of ethanol and 1.5 mL of tetrahydrofuran was treated with silver nitrate (0.112 g, 0.6 mmol) in 1.5 mL of ethanol and 0.5 mL of water, followed by potassium cyanide (218 mg, 3.35 mmol) in 1 L of water to give 70 mg (89%) of (Z) -1,3-dihydro-5-ethynyl-3- [(3-methoxy) -lH-pyrrol-2-yl) methylene] -2H-indol-2-one (61 mg after recrystallization).

Example 94: Synthesis of (Z) -1,3-Dihydro-5- (3-pyridinyl) ethynyl-3- [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one (EEEE) This compound was also prepared analogously to the preparation of (Z) -1,3-dihydro-5- (4-hydroxyphenyl) ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indole- 2-one in Example 83 described above. In this example, (Z) -1,3-dihydro-5-ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (47 mg, 0.21 mmol) (Example 82) with 3-bromopyridine (33 mg, 0.30 mmol) (Aldrich) using Cul (8 mg, 0.042 mmsl) (Aldrich) and (Ph3P) 2PdCl (15 mg, 0.021 mmol) (Aldrich) as a catalyst, in 1 mL of DMF and 1 mL of triethylamine at 70 ° C for 15 hours, to give (Z) -1,3-dihydro-5- ( 3-pyridinyl) ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indole-2-one as a red powder. (Yield 30 mg, 47%).

Example 95: Synthesis of (Z) -1,3-Dihydro-5- (2-pyridinyl) ethynyl-3- [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one (FFFF) This compound was also prepared analogously to the preparation of (Z) -1,3-dihydro-5- (4-hydroxyphenyl) ethynyl 3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one in Example 83 described above. In this example, (Z) -1,3-dihydro-5-ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (40 mg, 0.17 mmol) (Example 82) with 2-bromopyridine (25 mg, 0.17 mmol) (Aldrich), using Cul (8 mg, 0.042 mmol) (Aldrich) and (Ph3P) 2PdCl2 (14 mg, 0.020 mmol) (Aldrich) as catalyst, in 1 mL of DMF and 1 L of triethylamine at 70 ° C for 14 hours, to give (Z) -1,3-dihydro-5- (2-pyridinyl) ethynyl-3- [ (lH-pyrrol-2-yl) methylene] -2H-indole-2-one as a red powder. (Yield 42 mg, 80%).

Example 96: Synthesis of (Z) -l, 3-Dihydro-5- (4-hydroxyphenyl) ethynyl-3- [(3-methoxy-lH-pyrrol-2-yl) -methylene] -2H-indole-2- ona (GGGG) This compound was also prepared analogously to the preparation of (Z) -1,3-dihydro-5- (4-hydroxyphenyl) ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indole- 2-one in Example 83 described above. In this example, (Z) -1,3-dihydro-5-ethynyl-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (75 mg, 0.28 mmol) (from Example 93) with 4-iodophenol (75 mg, 0.34 mmol) (Aldrich), using Cul (8 mg, 0.042 mmol) (Aldrich) and (Ph3P) 2PdCl2 (14 mg, 0.020 mmol ) (Aldrich) as catalyst, in 1 mL of DMF and 1 mL of triethylamine at 70 ° C for 14 hours to give, (Z) -1, 3-dihydro-5- (4-hydroxy-phenyl) ethynyl-3- [ (3-methoxy-lH-pyrrol-2-yl) -methylene] -2H-indol-2-one as a yellow powder. (Yield 62 mg, 62%).

Example 97: Synthesis of (Z) -1,3-Dihydro-5- (4-methoxyphenyl) -etinyl-3- [(lH-pyrrol-2-yl) -methylene] -2H-indol-2-one (HHHH ) This compound was also prepared analogously to the preparation of (Z) -1,3-dihydro-5- (4-hydroxyphenyl) ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indole- 2-one in Example 83 described above. In this example, (Z) -1,3-dihydro-5-ethynyl-3- [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one (60 mg) was coupled., • 0.26 mmol) (Example 82) with 4-iodoanisole (30 mg, 0.34 mmol) (Aldrich), using Cul (6 mg, 0.031 mmol) (Aldrich) and (Ph3P) 2PdCl2 (14 mg, 0.020 mmol) (Aldrich) as catalyst, in 1 mL of DMF and 2 mL of triethylamine at 70 ° C for 16 hours to give (Z) -1,3-dihydro-5- (4-methoxyphenyl) ethynyl-3- [( 1H-pyrrol-2-yl) -methylene] -2H-indol-2-one as a yellow powder. (Yield 63 mg, 71%). Example 98: Synthesis of (Z) -1,3-Dihydro-3- [(lH-pyrrol-2-yl) -methylene] -5- (2-thiophenyl) ethynyl-2H-indol-2-one (IIII) This compound was also prepared analogously to the preparation of (Z) -1,3-dihydro-5- (4-hydroxyphenyl) ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indole- 2-one in Example 83 described above. In this example, (Z) -1,3-dihydro-5-ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indole-2-one (42 mg, 0.18 mmol) was coupled. ) (from Example 82) with 2-bromothiophene (30 mg, 0.18 mmol) (Aldrich), using Cul (8 mg, 0.042 mmol) (Aldrich) and (Ph3P) 2PdCl2 (14 mg, 0.020 mmol) (Aldrich) as catalyst, in 1 mL of DMF and 1 mL of triethylamine at 70 ° C for 14 hours, to give (Z) -1, 3-dihydro-3- [(lH-pyrrol-2-yl) -methylene] -5 - (2-thiophenyl) ethynyl-2H-indol-2-one in yellow powder form. (Yield 25 mg, 44%). Example 99: Synthesis of (Z) -5-Bromo-l, 3-dihydro-3- [(4-methyl-lH-imidazol-5-yl) methylene] -2H-indole-2-one (JJJJ) A mixture of 5-bromo-l, 3-dihydro-2H-indole-2-one (0.3 g, 1.41 mmol) (starting material 6), and 4-methyl-5-imidazolecarboxaldehyde in excess ( , 25 g, 2.27 mmol) (Aldrich) in 1% piperidine in 2-propanol (6 mL) was heated at 90 ° C for 4 h. Hot water (6 mL) was added. Upon cooling, the crystallized product was filtered, washed with aqueous 2-propanol and dried. (Yield 0.44 g, 100%). Example 100: Synthesis of (Z) -1,3-Dihydro-3-l (4-methyl-lH-imidazol-5-yl) methylene] -5- (trimethylsilyl) ethynyl-2H-indol-2-one (KKKK ) (Z) -5-Bromo-l, 3-dihydro-3- [(4-methyl-lH-imidazol-5-yl) ethylene] -2H-indol-2-one (0.17 g, 0, 56 mmol) (from Example 99) in 3 mL of DMF and 3 mL of triethylamine. The solution was degassed for 30 minutes by bubbling argon through the solution. They were added then (trimethylsilyl) acetylene (0.3 L, 2.1 mmol) (Aldrich), Cul (34 mg) (Aldrich) and (Ph3P) 2PdCl2 (34 mg) (Aldrich) and the reaction flask was sealed. The reaction was heated, under argon, at 90 ° C for 18 hours. After allowing to cool, the mixture was filtered through Celite® (Fisher Scientific) and the residue washed extensively with hot EtOAc and CH3CN. The combined filtrate and wash were concentrated under reduced pressure and the product was purified by flash column chromatography (Si02, 230-400 mesh) with 5% MeOH in CH2C12, (Yield 0.1 g, 56%). Example 101: Synthesis of (Z) -1,3-dihydro-5-ethynyl-3- [(4-methyl-lH-imidazol-5-yl) methylene] -2H-indol-2-one trifluoroacetate (LLLL) To a solution of (Z) -1,3-dihydro-3- [(4-methyl-lH-imidazol-5-yl) methylene] -5- (trimethylsilyl) ethynyl-2H-indol-2-one (0, 1 g, 0.31 mmol) (from Example 100) in 8 mL of ethanol was added dropwise a solution of silver nitrate (0.12 g, 0.68 mmol) in 1.5 mL of water and 0, 5 mL of ethanol forming a precipitate. The mixture was stirred at room temperature for 1 h, after which a solution of potassium cyanide (0.22 g, 3.37 mmol) in 1 mL of water was added and the precipitate dissolved. After stirring for 20 min. more 30 mL more water was added and the mixture was extracted with EtOAc (3X30 mL). The product was purified by reverse phase HPLC using water / acetonitrile / trifluoroacetic acid as solvent. (Yield 20 mg, 18%). Example 102: SAPK Inhibitory Activity The SAPK inhibitory activity of the compounds of the invention is demonstrated below. These effects indicate that the compounds of the present invention are useful for treating inflammatory diseases such as, for example, rheumatoid arthritis.

SAPK Test in Flash Plates The human JNK has a high homology with the Rat SAPK. To measure the inhibitory activity of the test compounds, the compounds were tested in the rat SAPK assay.

For the SAPK assay, purified GST-cJun (a chimeric protein containing cJun, a natural substrate of JNK) was used to coat 96-well Flash Plates (New England Nuclear, Boston, MA). Purified rat SAPK (ß isoform, Kyriakis et al., Supra) was preincubated with preparations containing MEKK-1 and MKK4 for 30 minutes at 37 ° C in assay buffer containing 25 mM HEPES, pH 7.5, 150 mM NaCl, 20 mM MgCl2, 2 mM DTT, 0.001% Tween 20, 1 μM newly added ATP In the preincubation step, MEKK-1 phosphorylates and activates MKK-4, which in turn phosphorylates and activates SAPK. The activated SAPK is then added to the cJun-coated Flash Plates, together with 3jP-ATP (0.32 μCi per reaction) and the test compounds. The plates were incubated for 30 minutes at 37 ° C, then washed with PBS, 0.01% Tween 20, and counted in a Topcount scintillation counter (Packard Instrument Co., Downers Grove, IL). In each test dilutions of the compounds were tested in duplicate. The percent inhibition of cJun phosphorylation (a measure of the inhibition of SAPK activity) was determined by the following formula: 100 X 1- compound tested - non-specific total - non-specific where "compound tested" refers to the average of counts per minute of the duplicates of the trial, "does not specify" refers to the average of accounts per minute when SAPK was not added, and "total" refers to the average of accounts per minute when no compound was added. The results of the SAPK test with several compounds tested are summarized below in Tables IA and IB. Table I A TABLE I B Assay based on MG-63 cells The MG63 cell line, a human osteosarcoma cell line, was obtained from the American Type Culture Collection (ATCC, Rockville, MD) and cultured in the medium recommended by the ATCC. When stimulated with human IL-1β, MG63 cells release matrix metalloproteinase 3 (MMP-3), an inflammation mediator dependent on AP-1 and IL-6, a mediator dependent on NF-? B. In this assay, the ability of a test compound to block the expression of MMP-3 without blocking the expression of IL-6 is an indication that the compound is a selective inhibitor of the AP-1 transcription pathway. On day 1 cells were plated at 2.5X10"cells / well in 96-well plates After 24 hours, dexamethasone (control assay) (Sigma, St. Louis, MO) and the compounds to be tested were diluted appropriate concentrations and were added to the MG63 cells.The cells were incubated with the compounds for 24 hours after which the supernatants were separated and analyzed by ELISA.In the ELISA, 96-well plates were coated with antibody against MMP-3 or the IL-6 supernatants were added to the coated plates and any antigen (MMP-3 or IL-6) in the supernatant was bound to the antibody that coated the plates.The plates were then washed with PBS containing 0.05. % Tween 20 (Sigma, St. Louis, MO) and the biotinylated secondary antibody was added.This secondary antibody binds to the antigen already bound creating a "sandwich effect." The plates were washed as described above and added to the r peroxidase conjugate plates bath (HRP) -streptavidin (Sigma, St. Louis, MO). The HRP-streptavidin was bound to the biotin-antibody conjugate. The plates were washed and the TMB substrate was added to the wells (Kirkegaard and Perry Labs, Gaithersburg, MD). This substrate changes color in the presence of HRP-streptavidin. The intensity of the color (measured at 450 nm) is proportional to the amount of MMP-3 or IL-6 produced by the MG63 cells when exposed to IL-lβ and the compounds tested. The optical density values were converted to concentration (pg / ml or Units / ml) based on a standard curve included in the assay. The IC50 values for each one. of the tested compounds were determined from the linear regression of a plot of the logarithm of the concentration of compound against the amount of secreted MMP-3 or IL-6. (Antibodies against MMP-3 were prepared using hybrid as standard technology and antibodies against IL-6 were obtained either from Genzyme, Cambridge, MA or Pharmingen, San Diego, CA.). The results of this test on several compounds tested are summarized below in Table II.

Table II Assay based on U937 cells U937 cells, a human monocyte / macrophage cell line, were obtained from the ATTC and cultured in the recommended medium. These cells, when stimulated with lipopolysaccharide (LPS), release TNF, another inflammatory mediator involved in the JNK pathway (Swantek et al., Supra) and IL-6. In this test the ability of the compound tested to block the expression of TNF is evaluated. The assay is very similar to that based on MG63 cells, except for the following modifications. U937 cells are cells in suspension but when stimulated with phorbol myristate acetate (PMA) (Sigma, St. Louis, MO) they become adherent. After stimulation with PMA the cells were washed with cell culture medium and plated at 1 × 10 5 cells / well in 96-well plates. The next day the tested co-positions and control of dexamethasone (Sigma, St. Louis, MO) were added to the cells for I hour of preincubation. The cells were then stimulated with LPS (Sigma, St. Louis, MO). After a further 24 hours of incubation, the supernatants were separated and assayed for TNF-a and IL-6 by ELISA. The ELISA for IL-6 was carried out as previously described for the MG63 assay. The ELISA for TNF was performed using a kit supplied by Genzyme (Cambridge, MA). The results of this test with several compounds tested are summarized below in Table III.

Table III Example 103: Tablet Formulation * E1 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. Granulate the powder mixture from Step 1 with 20% solution of Povidone K30 (item 4). 3. Dry the granulate from Step 2 at 50 ° C. 4. Pass the granulate from Step 3 through a suitable grinding equipment. 5. Add item 5 to the ground granulate from Step 4 and mix for 3 minutes. 6. Compress the granulate from Step 5 in a suitable press.

Example 104: Formulation of Capsules * E1 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.

Example 105: Dissolution for Injection / Emulsion Preparation CE1 Compound 1 represents a compound of the invention.

Manufacturing procedure 1. Dissolve item 1 in item 2, 2. Add Items 3, 4 and 5 to item 6 and mix until dispersed, then homogenize. 3. Add the solution from step 1 to the mixture from step 2 and homogenize until the dispersion is translucent. 4. Filter under sterile conditions through a filter 0.2 μm and pack in vials.

Example 106: Dissolution for Injection / Emulsion Preparation 'Compound 1 represents a compound of the invention.

Manufacturing procedure 1. Dissolve item 1 in item 2. 2. Add items 3, 4 and 5 to item 6 and mix until dispersed, then homogenize. 3. Add the solution from step 1 to the mixture from step 2 and homogenize until the dispersion is translucent. 4. Filter under sterile conditions through a 0.2 μm filter and pack in vials. Although the invention has been illustrated by reference to specific and preferred embodiments, it will be understood by those skilled in the art that variations and modifications can be made through the routine experimentation and practice of the invention. Therefore, it is not intended that the invention be limited by the above description, but that it is defined by the appended 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 that which is clear from the present description of the invention.

Claims

Claims Having described the invention as above, the content of the following claims is claimed as property: 1. A compound having the formula

And pharmaceutically acceptable salts thereof, characterized in that: R1 is lower alkyl which is substituted by aryl, aryloxy, heteroaryl, heteroaryloxy, substituted aryl, substituted aryloxy, substituted heteroaryl, and / or substituted heteroaryloxy, and optionally may also be substituted by R13, perfluoroalkyl, cycloalkyl (or cycloalkyl substituted by lower alkyl and / or R13), or heterocycle (or heterocycle substituted by lower alkyl and / or R13), and wherein the substituents on the substituted aryl, substituted aryloxy, substituted heteroaryl, and substituted heteroaryloxy are one or more of R13, lower alkyl (optionally substituted by R1), cycloalkyl (optionally substituted by R13), heterocycle (optionally substituted by R13); aryl (optionally substituted by R13, perfluoroalkyl, lower alkyl, lower alkyl substituted by R13, cycloalkyl, cycloalkyl substituted by R13 heterocycle (optionally substituted by R13), or heteroaryl (optionally substituted by R13, perfluoroalkyl, lower alkyl, lower alkyl substituted by R13) , cycloalkyl, cycloalkyl substituted by R13, or heterocycle or heterocycle substituted by R13): R is hydrogen, -OR4, -OCOR4, -COR4, -COOR4, -CONR6R7, -NRdR7, halogen, -N02, -CN, -S02R4, -S02NR6R7, perfluoroalkyl, lower alkyl or lower alkyl substituted by -OR8 or -NR6R7; R3 is hydrogen, -OR4, -COR4, -COOR4, -CONR6R7, halogen, -CN, -NR6 R7, perfluoroalkyl, lower alkyl or lower alkyl substituted by -OR8 or -NR6R7; R4 is hydrogen, lower alkyl (optionally substituted by (a), cycloalkyl and / or heterocycle), cycloalkyl (optionally substituted by (a), lower alkyl and / or heterocycle), heterocycle (optionally substituted by (a), lower alkyl and / or cycloalkyl), aryl (optionally substituted by (a), cycloalkyl, heterocycle and / or halogen) , heteroaryl (optionally substituted by (a), cycloalkyl, heterocycle, and / or halogen; wherein (a) is -OR5, -COOR8, -COR8, -CONR8R9, -NRdR7, -CN, -N0, -S02R8, and / or -S02NR8R9; R ° is hydrogen, -COR8, -CONR8R9 or lower alkyl (optionally substituted by OR9, -NR9R10, -N (COR9) R10, -COR9, -CONR9R10, -SR9 and / or -COOR9; R6 and R7 are each hydrogen, -COR8, -COOR8, -CONR8R ?, -S02Re8 , S02NR3R9, lower alkyl, lower alkyl substituted by (b), cycloalkyl (optionally substituted by (b), lower alkyl, and / or heterocycle), heterocycle, -heterocycle substituted by (b), lower alkyl and / or cycloalkyl), aryl, aryl substituted by (b), lower alkyl, cycloalkyl and / or heterocycle), heteroaryl, heteroaryl substituted by (b), lower alkyl, cycloalkyl and / or heterocycle); or Rd and R7 are each cycloalkyl (optionally substituted by (b), lower alkyl and / or heterocycle, heterocycle (optionally substituted by (b), lower alkyl and / or cycloalkyl, aryl (optionally substituted by (b), lower alkyl , cycloalkyl and / or heterocycle, or heteroaryl (optionally substituted by (b), lower alkyl, cycloalkyl and / or heterocycle, where (b) is OR 5, -NR- R- ',
-COOR *, -CORs -CONR8R9, -CN, -NO ~ -S0R alternatively, -NR6R7 can form a ring of 3 to 7 atoms, said ring optionally includes one or more additional heteroatoms and is optionally substituted by one or more alkyl lower, -OR5, -COR8, -COOR8, -CONR8R9, and -NR5R9; R8 is hydrogen, lower alkyl (optionally substituted by cycloalkyl, heterocycle, aryl, heteroaryl, -OR9, -NR9R10, and / or -N (COR9) R10), aryl (optionally substituted by (c), lower alkyl, cycloalkyl and / or heterocycle), heteroaryl (optionally substituted by (c), lower alkyl, cycloalkyl and / or heterocycle), cycloalkyl (optionally substituted by (c), lower alkyl and / or heterocycle), heterocycle (optionally substituted by (c), alkyl lower and / or cycloalkyl); where (c) is -OR9, -COOR9, -COR9, -CONR10R9, -NR10R9, -CN, -N02, -S02R9, -SO2NR10R ?; R9 and R10 are each independently hydrogen or lower alkyl; R13 is halogen, -OR4, -OCOR4, -COR4 -COOR4, -CONR6R7, -N02, -NR5R7, -CN, -S02R4, or -S02NR6R7;
X is = N- or -CH-; and the dotted line link represented by z is optional. 2. A compound according to claim 1, characterized in that R1 is lower alkyl which is substituted by aryl or substituted aryl, and optionally also substituted by halogen, -OR4, -COR4, -COOR4, -CONR6R7, cycloalkyl, heterocycle, - COOR4, CONR6R7, cycloalkyl which is substituted by OR5, -NR6R7, COOR4, CONR5R7, and / or heterocycle which is substituted by OR5, -NRdR7, COOR4, C0NRdR7; and wherein the substituents of the substituted aryl are selected from halogen, -OR4, -COR4, -COOR4, -CONR6R7, -N02, NR6R7, -S0R4, -S02NR6R7, -CN, perfluoroalkyl, lower alkyl, cycloalkyl, heterocycle, lower alkyl which is substituted by -OR5, and -NRdR7, COOR4, CONRdR7, cycloalkyl substituted by OR5, and -NR6R7, COOR4, CONRdR7, or heterocycle substituted by OR5, -NR6R7, COOR4, CONR6R7; lower alkyl which is substituted by heteroaryl or substituted heteroaryl, and optionally also substituted by halogen, -OR4, -COR4, -COOR4, -CONR6R7, cycloalkyl, heterocycle, cycloalkyl which is substituted by OR5, COOR4, CONR6R7, and / or - NRdR7, and / or heterocycle which is substituted by -OR5, COOR4, CONR6R7, and / or -NR6R7; and wherein the substituted heteroaryl substituents are selected from halogen, -OR4, -COR4, -COOR4, NR6R7, -S02R4, -S02NR6R7, -NO_, -CN, -CONR6R ', lower alkyl, cycloalkyl, heterocycle, lower alkyl, which is substituted by -OR5, -NRdR7, COOR4, C0NR6R7, cycloalkyl which is substituted by -OR5, -NRdR7, COOR4, CONR6R7, and / or heterocycle which is substituted by -OR5, -NR6R7, COOR4 and / or CONR6R7 ), aryl (optionally substituted by halogen, -OR4, -COR4, -COOR4, -CONR6R7, lower alkyl, cycloalkyl, heterocycle, lower alkyl which is substituted by -OR5, -NRdR7, COOR4, CONR6R7, cycloalkyl which is substituted by -OR5, COOR4, CONR6R7, and / or -NR6R7, and heterocycle which is substituted by -OR5, COOR4, CONRdR7, and / or -NRdR7, or heteroaryl (optionally substituted by halogen, -OR4, -COR4, -COOR4 , -C0NRdR7, lower alkenyl, cycloalkyl, heterocycle, lower alkyl which is substituted by -OR5, COOR4, CONR6R7, and / or -NRdR7, cycloal which is substituted by -OR5, COOR4, CONR ^, and / or -NR6R7, and / or heterocycle which is substituted by -OR5, COOR4, CONR6R7, and / or -NRdR7). 3. A compound according to any one of claims 1 or 2, characterized in that X is CH and R3 is lower alkoxy.
4. A compound according to any one of claims 1-3, characterized in that R1 is lower alkyl substituted by phenyl which is substituted by one to three substituents of the hydroxyl group, lower alkoxy, di- (lower alkyl) -amino, di- (lower alkyl) to ino-lower alkoxy, morpholino-lower alkyl, carboxy-lower alkoxy and lower alkanoylamino; or R1 is lower alkyl substituted as above and additionally by hydroxyl.
5. A compound according to any one of claims 1-4, characterized in that R1 is lower alkyl substituted by pyridyl, pyrrolyl, N-lower alkyl-pyrrolyl, thienyl, thienyl substituted by lower alkoxy, furyl, 1,3-benzodioxolyl , 1,3-benzodioxolyl substituted by lower alkoxy; or R1 is lower alkyl substituted as above and additionally by hydroxyl.
6. A compound according to any one of claims 1-3, characterized in that R1 is pyridyl.
7. A compound according to any one of claims 1 or 2, characterized in that the optional bond z is present.
8. A compound according to claim 4, characterized in that it is rae- (Z) -1, 3-Dihydro-4- [3-hydroxy-3- (4-methoxyphenyl) -1-propynyl] -3- [(3- methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (H), rae- (Z) -1, 3-Dihydro-4- [3-hydroxy-3- (3-hydroxyphenyl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (I), rae- (Z) -1, 3-Dihydro-4- [3-hydroxy-3- (3-methoxyphenyl) -1-propynyl] -3- [(3-methoxy-lH-pyrrol-2-yl) methylene ] -2H-Indole-2-one (J), Rae- (Z) -4- [3- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene]] -2-oxo-lH-indol-4-yl] -l-hydroxy-2-propynyl] benzoic methyl ester (K), Rae- (Z) -4- [3- [2, 3-Dihydro-3-acid [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -l-hydroxy-2-propynyl] benzoic acid (L), rae- (Z) -1 , 3-Dihydro-4- [3-hydroxy-3- (2-methoxyphenyl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2- ona (M), rae- (Z) -4- [3- (1, 3-benzodioxol-5-yl) -3-hydroxy-l-propynyl] -1, 3-dihydro-3- [(3-methoxy -lH-pyrrol-2-yl) methylene] -2H-indol-2-one (N), rac-. { Z) -1,3-Dihydro-4- [3-hydroxy-3- (4-hydroxy-3-methoxyphenyl) -1-propynyl] -3- [(3-methoxy-1H-pyrrol-2-yl) methylene ] -2H-indol-2-one (O), rae- (Z) -1, 3-Dihydro-4- [3-hydroxy-3- (4-hydroxy-enyl) -1-propynyl] -3- [( 3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (Q), rae- (Z) -1, 3-Dihydro-4- [3- (4-dimethylaminophenyl) -3 -hydroxy-1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) ethylene] -2H-indol-2-one (R), rae- (Z) -1, 3-Dihydro- 4- [3-hydroxy-3- (4-phenoxyphenyl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (S) , rae- (Z) -1, 3-Dihydro-4- [3-hydroxy-3-phenyl-1-butynyl] -3- [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H- indol-2-one (T), rae- (Z) -1, 3-Dihydro-4- [3- [4- (3-dimethylaminopropoxy) -phenyl] -3-hydroxy-l-propynyl] -3- [ (3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (V), rae- (Z) -1, 3-Dihydro-4- [3- (2,3-dimethoxyphenyl) ) -3-hydroxy-1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (EE), rae- (Z) -1, 3 -Dihydro-4- [3- (3, 4-dimethoxifeni) l) -3-hydroxy-1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (FF), rae- (Z) -1, 3-Dihydro-4- [3-hydroxy-3- (3-hydroxy-4-methoxyphenyl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole -2-one (HH), rae- (Z) -1, 3-Dihydro-4- [3-hydroxy-3- [3-methoxy-4- [2- (4-morpholinyl) -ethoxy] -phenyl] -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (MM), Rae- (Z) -1, 3-dihydrohydrochloride 4- [3-hydroxy-3- [3-methoxy-4- [2- (4-morpholinyl) -ethoxy] -phenyl] -1-propynyl] -3- [(3-methoxy-lH-pyrrole-2-yl) il) ethylene] -2H-indol-2-one (NN), rae- (Z) -1, 3-Dihydro-4- [3-hydroxy-3- (2,4,5-tri-ethoxyphenyl) -1- propynyl] -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (PP), Rae- (Z) - [4- [3- [2, 3 -dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -l-hydroxy-2-propynyl] -2-methoxyphenoxy] acetic acid methyl ester (QQ), Rae- (Z) - [4- [3- [2, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo- lH-indol-4-yl] -l-hi droxy-2-propynyl] -2-methoxyphenoxy] acetic (RR), rae- (Z) -4- [3-Hydroxy-3- (4-methoxy-1,3-benzodioxol-6-yl) -1-propynyl ] -1,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (SS), rae- (Z) -1,3-Dihydro- 4- [3-hydroxy-3- [4- [2- (4-morpholinyl) -ethoxy] -phenyl] -1-propynyl] -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (TT), rae- (Z) -4- [3- (4-Chloro-2-methylsulfanylmethoxy-phenyl) -3-hydroxy-1-propynyl] -1,3-dihydro- 3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (UU), rae- (Z) -4- [3- (3-Chlorophenyl) -3-hydroxy -l-propinyl] -1,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (W), Rae- (Z) - [ 4- [3- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] -l-hydroxy-2- propinyl phenoxy] acetic 1,1-dimethylethyl ester (XX), Rae- (Z) - [4- [3- [2, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) acid) ethylene] -2-oxo-lH-indol-4-yl] -l-hydroxy-2-propynyl] phenoxy] acetic acid (YY), rae- (Z) -1, 3-Dihydro- 4- [3-hydroxy-3- (3-nitrophenyl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (ZZ), rae- (Z) -4- [3- (3-Aminophenyl) -3-hydroxy-l-propynyl] -1,3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (AAA), rae- (Z) -4- [3- (4-Acetamidophenyl) -3-hydroxy-l-propynyl] -1,3-dihydro-3- [(3- methoxy-lH-pyrrol-2-yl) ethylene] -2H-indol-2-one (BBB), or rae- (Z) -1, 3-Dihydro-4- (3-hydroxy-3-phenyl-propynyl) -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole -2-ona (FFF).
9. A compound in accordance with the claim 5, characterized in that it is rae- (Z) -1, 3-Dihydro-4- [3-hydroxy-3- (3-pyridinyl) -1-propynyl] -3- [(3-methoxy-1H-pyrrole-2 -yl) methylene] -2H-indol-2-one (X), Synthesis of rae- (Z) -1, 3-Dihydro-4- [3-hydroxy-3- (1-methyl-pyrrol-2-yl ) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (AA), rae- (Z) -1, 3-Dihydro-4 - [3-hydroxy-3- (thiophen-3-yl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one ( BB), rae- (Z) -1, 3-Dihydro-4- [3-hydroxy-3- (lH-pyrrol-2-yl) -1-propynyl] -3- [(3-methoxy-lH-pyrrole -2-yl) methylene] -2H-indol-2-one (DD), rae- (Z) -1, 3-Dihydro-4- [3-hydroxy-3- (2-pyridinyl) -1-propynyl] -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indole-2-one (JJ), rae- (Z) -1, 3-Dihydro-4- [3-hydroxy] 3- (2-thiophenyl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (KK), rae- (Z) -1 , 3-Dihydro-4- [3-hydroxy-3- (3-methoxy-2-thiophenyl) -1-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H- indole-2-one (00), or rae- (Z) -1, 3- Dihydro-4- [3- (2-furanyl) -3-hydroxy-l-propynyl] -3 - [(3-methoxy-lH-pyrrol-2-yl) ethylene] -2H-indole-2-one (W ).
10. A compound according to claim 6, characterized in that it is (Z) -1, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- [(3-pyridinyl) ) ethynyl] -2H-indole-2-one (CCC), (Z) -1, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- [(2- pyridinyl) ethynyl] -2H-indole-2-one (DDD), (Z) -1, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- [(4 -pyridinyl) ethynyl] -2H-indole-2-one (EEE), (Z) -1, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -5-nitro- 4- [(3-pyridinyl) ethynyl] -2H-indol-2-one (GGG), (Z) -5-Amino-l, 3-dihydro-3- [(3-methoxy-lH-pyrrole-2- il) methylene] -4- [(3-pyridinyl) ethynyl] -2H-indol-2-one (HHH), or (Z) -N- [2, 3-Dihydro-3- [(3-methoxy-1H -pyrrol-2-yl) methylene] -2 -? XO-? - [(3-pyridinyl) ethynyl] -lH-indol-5-yl] -2-thiopheneacetamide (III).
11. A compound according to claim 1, characterized in that it is 4- [(E) -2- (2-Chlorophenyl) -ethenyl] -1,3-dihydro- (Z) -3- [(lH-pyrrol- 2-yl) ethylene] -2H-indol-2-one (KKK), 1,3-Dihydro- (Z) -3- [(lH-pyrrol-2-yl) methylene] - [(E) -2- phenylethenyl] -2H-indol-2-one (LLL), 1,3-Dihydro- (Z) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] - [(E) -2- phenylethenyl] -2H-indol-2-one (MMM), 1,3-Dihydro-4- [(E) -2- (4-methoxyphenyl) -ethenyl] - (Z) -3- [(lH-pyrrol- 2-yl) methylene] -2H-indol-2-one (NNN), 1,3-Dihydro- (Z) -3 - [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- [ (E) -2- (4-methoxy-phenyl) -ethenyl] -2H-indol-2-one (OOO), 4- [(E) -2- [2, 3-Dihydro- (Z) -3 acid - [(3-methoxy-lH-pyrrol-2-yl) methylene] -2-oxo-lH-indol-4-yl] ethenyl] benzoic methyl ester (PPP), or 1,3-Dihydro-4- [( E) -2- (3,4-dimethoxyphenyl) -ethenyl] (Z) -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H-indol-2-one (QQQ).
12. A compound according to claim 1, characterized in that it is (Z) -1, 3-Dihydro-4- (phenylethynyl) -3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H -indol-2-one (D), (Z) -1, 3-Dihydro-4- [(4-methoxyphenyl) ethynyl] -3- [(3-methoxy-lH-pyrrol-2-yl) ethylene] - 2H-indol-2-one (G) or (Z) -1,3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -4- (3-phenoxy-1-propynyl) ) -2H-indol-2-one (Y).
13. A compound that has the formula: and pharmaceutically acceptable salts thereof, characterized in that: R11 is hydrogen, -COR4, -COOR4, lower alkenyl (optionally substituted by -OR5, -NR6R7, Hologen, -N02, -S02R4, -S02NR6R7, -CN, -COR4, -COOR4, -CONR6R7, cycloalkyl, heterocycle, aryl, and / or heteroaryl), cycloalkyl (optionally substituted by -OR5, -NRdR7, halogen, -N02, -S02R4, -S02N R6R7, -CN, -COR4, -COOR4, -CONR6R7, lower alkyl, heterocycle, aryl, and / or heteroaryl) heterocycle (optionally substituted by -0R ~, -NR6R7, halogen, -OR5, -NRdR7, hologenic, -N0_, -S0R4, -S02NR6R7, -CN, - COR4, -COOR4, -C0NRdR7, lower alkyl, cycloalkyl, aryl, and / or heteroaryl), aryl (optionally substituted by -0RD, hologen, -NO £, -S02R4, -S02NR6 ?, -CN, -COR4, -COOR4 , -CONR6R7, lower alkyl, and / or perfluoroalkyl) or heteroaryl (optionally substituted by -OR5, -NRdR7, hologenic, -N02, -S02R4, -SO £ NRdR7, -CN, -COR4, -COOR4, -CONR6R7, alkyl lower, and / or perfluoroalkyl); R12 is hydrogen, -OR4, -OCOR4, -COR4, -COOR4, -CONRdR7, -NR6R7 halogen, -N02, -CN, -S02R4, -S02NR6R7, perfluoroalkyl, lower alkyl (optionally substituted by OR4, -NR6R7, cycloalkyl, heterocycle, -COR4, -COOR4, CONR6R7, -CN, -N02, -S02R4, -S0NR5R7, and / or halogen), cycloalkyl (optionally substituted by OR4, -NR6R7, lower alkyl, heterocycle, -COR4, -COOR4, CONRdR7 , -CN, -N02, -S02R4, -S02NRdR7, and / or halogen), or heterocycle (optionally substituted -OR4, -NRdR7, lower alkenyl, cycloalkyl, -COR4, -COOR4, CONR6R7, -CN, -N02, - S02R4, -S02NRdR7, and / or halogen), and R3 to R7, X and z are as defined for formula I in claim 1.
14. A compound according to claim 1 or 13, characterized in that R4 is hydrogen, lower alkyl (optionally substituted by (a), cycloalkyl and / or heterocycle), cycloalkyl (optionally substituted by (a), lower alkyl and / or heterocycle) , heterocycle (optionally substituted by (a), lower alkyl and / or cycloalkyl), aryl (optionally substituted by (a), cycloalkyl, heterocycle and / or halogen), heteroaryl (optionally substituted by (a), cycloalkyl, heterocycle, and / or halogen, where (a) is -OR5, -COOR8, -CORR, -CONR8R9, -NR6R7, -CN, -N02, -SO: R8, and / or -S02NR8R9, and R5 is hydrogen, -COR8, - CONR8R9 or lower alkyl (optionally substituted by OR9, -NR9R10, -N (C0R9) R10, -COR9, -C0NR9R10, and / or -COOR9; and R1, R2, R3, R8, Rq, R10, X and z are as in claim 1.
15. A compound according to claim 13, characterized in that RJ is hydrogen, -OR, -NR R, and / or lower alkyl (optionally substituted by -OR, -NR6R7); R4 is hydrogen, lower alkyl (optionally substituted by one or more -OR5, -COOR8, -COR8, -CONR8R9), cycloalkyl (optionally substituted by one or more -OR5, -COOR8, -COR8, and -CONR8R9), or heterocycle (optionally substituted by one or more -OR5, -COOR8, -COR8, and -CONR8R9); R5 is hydrogen, -COR8, -CONR8R9, or lower alkenyl; Rd and R7 are each independently hydrogen, -COR8, -COOR8, -CONR8R9, or lower alkyl (optionally substituted by one or more of -OR9, -NR8R9, COOR8, and CONR8R9) or alternatively, -NRdR7 optionally forms a ring having from 3 to 7 atoms, said ring optionally including one or more additional heteroatoms and being optionally substituted by one or more lower alkyl, -OR5, -COOR8, -CONR8R9, and -NR5R9; R8 is hydrogen or lower alkyl (optionally substituted by one or more of aryl, heteroaryl, -OR9, COOR8, CONR9R10, and -NR9R10); R11 is aryl (optionally substituted by -OR5, and / or -NRdR7); R12 is hydrogen, -COR4, -COOR4, and -CONRdR7, lower alkyl (optionally substituted by one or more of -OR4, -NR5R7, cycloalkyl, heterocycle, -COR4, -COOR4, and -CONR6R7, -CN, -N02, -S02R4, -S02, NR6R7, and halogen), cycloalkyl (optionally substituted by one or more of -OR4, -NR6R7, lower alkenyl, heterocycle, -COR4, -COOR4, and -C0NR6R7, -CN, -N02, -S02R4 , -S02, NR6R7, and halogen), or heterocycle (optionally substituted by one or more of -OR4, -NRdR7, lower alkyl, cycloalkyl, -COR4, -COOR4, and -CONR6R7, -CN, -N0, -S02R4, -S0, NR5R ~, and halogen); and the optional link z is present.
16. A compound according to claim 13, characterized in that it is: (Z) -1, 3-Dihydro-5-ethynyl-3- [(lH-pyrrol-2-yl) methylene] -2H-indole-2- ona (SSS), (Z) -1, 3-Dihydro-5- (4-hydroxyphenyl) ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (TTT), (Z) -1,3-Dihydro-5- (3-nitrophenyl) ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (UUU), (Z) -1 , 3-Dihydro-5-phenylethynyl-3- [(lH-pyrrol-2-yl) methylene] -2H-indol-2-one (VW), (Z) -1, 3-Dihydro-5- (3- hydroxyphenyl) ethynyl-3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (WWW), (Z) -1, 3-Dihydro-5- (2-nitrophenyl) ethynyl-3 - [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (XXX), (Z) -1, 3-Dihydro-5- (4-nitrophenyl) ethynyl-3- [(1H- pyrrol-2-yl) methylene] -2H-indol-2-one (ZZZ), (Z) -5- (4-Aminophenyl) ethynyl-1,3-dihydro-3- [(1H-pyrrol-2-yl) methylene] -2H-indol-2-one (AAAA), (Z) -1, 3-Dihydro-5-ethynyl-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -2H- indole-2-one (DDDD), (Z) -1, 3-Dihydro-5- (3-pyridinyl) ethynyl-3- [(lH-py rol-2-yl) -methylene] -2H-indol-2-one (EEEE), (Z) -1, 3-Dihydro-5- (2-pyridinyl) ethynyl-3- [(lH-pyrrsl-2- il) methylene] -2H-indol-2-one (FFFF), (Z) -1, 3-Dihydro-5- (4-hydroxyphenyl) ethynyl-3- [(3-methoxy-lH-pyrrol-2-yl ) -methylene] -2H-indol-2-one (GGGG), (Z) -1, 3-Dihydro-5- (4-methoxyphenyl) ethynyl-3- [(1H-pyrrol-2-yl) -methylene] -2H-Indole-2-one (HHHH), (Z) -l, 3-Dihydro-3- [(lH-pyrrol-2-yl) -methylene] -5- (2-thiophenyl) ethynyl-2H-indole -2-ona (IIII), or (Z) -1,3-Trifluoroacetate, 3-Dihydro-5-ethynyl-3- [(4-methyl-1H-imidazol-5-yl) methylene] -2H-indole-2-one, (LLLL).
17. The compounds, characterized in that they comprise: 1, 3-Dihydro-5-fluoro-4-iodo-2H-indol-2-one, (Z) -1, 3-Dihydro-3- [(1H-pyrrole-2) -yl) methylene] -5- (trimethylsilyl) ethynyl-2H-indol-2-one, (Z) -5-Bromo-l, 3-dihydro-3- [(3-methoxy-lH-pyrrol-2-yl methylene] -2H-indol-2-one, (Z) -1, 3-Dihydro-3- [(3-methoxy-lH-pyrrol-2-yl) methylene] -5- (trimethylsilyl) ethynyl-2H- indol-2-one, (Z) -5-Bromo-l, 3-dihydro-3- [(4-methyl-lH-imidazol-5-yl) methylene] -2H-indol-2-one, (Z) -1, 3-Dihydro-3- [(4-methyl-lH-imidazol-5-yl) methylene] -5- (trimethylsilyl) ethynyl-2H-indol-2-one.
18. A pharmaceutical composition comprises as an active ingredient a compound according to claim 1 or 13, characterized in that it comprises a pharmaceutically acceptable carrier or excipient.
19. The compounds according to claims 1 and 13, characterized in that they are used as medicaments. The use of a compound according to claim 1 or 13 or of pharmaceutically active prodrugs and etabolites of this compound, characterized in that it is used in the preparation of a medicament for the treatment or control of inflammatory diseases, in particular of rheumatoid arthritis .