Title of Invention	NOVEL CYSTEINE PROTEASE INHIBITORS AND PROCESS FOR PREPARATION THEREOF
Abstract	The present invention concerns new compounds of formula (I), their process of preparation and their therapeutic use.

Full Text

NOVEL CYSTEINE PROTEASE INHIBITORS AND THEIR THERAPEUTIC APPLICATIONS The present invention concerns new inhibitors of cysteine proteases, their process of preparation and their therapeutic use. Protease can be categorized based on their substrate specificities or mechanisms of catalysis. Upon the basis of the mechanism of peptide hydrolysis, five major protease classes are known: serine, cysteine, aspartic, threonine and metalJo-proteases. Cysteine proteases comprise, inter allia, de-ubiquitination enzymes, caspases, cathepsins, calpains as well as viral, bacterial or parasitic cysteine proteases. De-ubiquitination enzymes include Ubiquitin Specific Proteases (USPs) and Ubiquitin Carboxy Hydrolases (UCHs). Broadly speaking, the ubiquitin pathway regulates protein degradation and is more particularly involved in cancer, in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, in inflammation, in viral infectivity and latency (in particular for Herpes simplex virus-1, Epstein-Barr virus, SARS coronavirus), or in cardiovascular diseases {Chem, Rev, 1997, 97, p. 133-171; Chem. Rev, 2002, 102. p. 4459-4488; J. Biochem. 2003, 134. p. 9-18 ; J. Virology, 2005, 79(7), p. 4550-4551; Cardiovasc. Res. 2004, 61, p. 11-21). Caspases have been shown to be involved in apoptosis and hence are targets in hepatitis, liver failure, inflammation, cardiac ischemia and failure, renal failure, neurodegeneration, deafness, diabetes, or stroke (J. Pharmacol Exp. Ther., 2004, 308(3), p. 1191-1196, J. Cell. Physiol, 2004, 200(2), p. 177-200; Kidney Int, 2004, 66(2), p. 500-506; Am. J. Pathol., 2004, 165(2), p. 353-355; Mini Rev. Chem., 2004, 4(2), p. 153-165; Otol Neurotol, 2004, 25(4), p. 627-632; Ref. 7, 21, 22, 23, 24, 25. Cathepsins generally have been shown to be involved in cancer and metastasis, inflammation, immunology/immunoregulation {Eur Respin J., 2004, 23(4), p. 620-628) and atherosclerosis (Ageing Res. Rev.. 2003, 2(4). p. 407-418). More particularly, cathepsins include cathepsin B and B-like which are implicated in cancer and metastasis, and arthritis {Cancer Metastasis Rev., 2003, 22(2-3), p. 271-286; BioL Cham., 2003, 384(6), p. 845-854 and Biochem. Soc. Symp., 2003, 70, p. 263-276), cathepsin D, involved in particular in cancer and metastasis {din. Exp. metastasis, 2004, 21(2), p. 91-106), cathepsin K acting in osteoporosis and arthritis {Int J. Pharm,, 2004, 277(1-2), p. 73-79), cathepsin S which has been shown to play a role in antigen presentation in immunology {Drug News Perspective, 2004, 17(6), p. 357-363). Calpains play a role in aging in general {Ageing Res. Rev. 2003, 2(4), p. 407-418), as well as diabetes (/Wo/. Cell. Biociiem., 2004, 261(1), p.161-167) and cataract {Trends MoL Med, 2004, 10(2), p. 78-84) more particularly. Viral cysteine proteases have been identified in rhinoviruses, poliomyelitis virus, hepatitis A virus, hepatitis C virus, adenovirus, or SARS coronavirus (CA?em. Rev. 1997, 97, p. 133-171; Chem. Rev. 2002, 102, p. 4459-4488 ; J. Virology, 2005, 79(7), p. 4550-4551 and Acta MicrobioL Immunol. Hung., 2003, 50(1), p. 95-101). Bacterial cysteine proteases include streptopain, staphylococcal cysteine protease, clostripain or gingipains; yeasts such as Aspergillus flavus have also been shown to express cysteine proteases which may constitute a virulence factor (C/7e/77. Rev^. 1997, 97, p. 133-171). Parasitic cysteine proteases have been reviewed in Molecular & Biochemical Parasitology (2002, 120, p. 1-21) and Chem. Rev. (2002, 102, p. 4459-4488) for example. It is worth noting that the parasitic agents responsible for most major parasitic diseases are making use of their own cysteine proteases at some point or another of their infective, nutritive or reproductive cycles; such diseases include malaria, Chagas' disease, African trypanosomiasis, leishmaniasis, giardiasis, trichomoniasis, amoebiasis, crypto- sporidiasis, toxoplamiasis, schistosomiasis, fasciolasis, onchocercosis, and other infections by some other flat or round worms. Therefore, identifying a novel class of inhibitors of cysteine proteases is of significant importance in a wide range of diseases and pathological conditions. Cyano-pyrazine derivatives have been disclosed, mainly as charge-transporting agents for electrophotographic photoreceptors (WO03/055853, JP200128885, JP200122316, JP07281460, JP07179440, JP07098508, JP06345742, JP07175235, JP07199487, JP07199486, JP07281460 and Helvetica Chemica Acta, 1986, 69(4), 793-802, Tetrahedron Letters 1974, 45, 3967-70, J. Heteterocyclic Chemistry, "[Qll, 9(6), 1399-401, Tetraliedron Letters, 1990, 31(49), 7215-18). However, it has never been disclosed nor suggested that cyano-pyrazine derivatives can inhibit cysteine proteases. According to a first object, the present invention concerns a compound of formula (I): wherein : m is 0 ; 1 or 2 , wherein when m=0, — (X(R2)m')m — is none so as to form an open ring or a single bond; n is 0, 1 or 2, , wherein when n=0, — (Y(R7)n')n — is none so as to fomi an open ring or a single bond; m' and n' are independently 0, 1 or 2; X is a carbon atom or S or N; Y is a carbon atom, or S or N; Provided m and n are not simultaneously 0; is eitlier a single or double bond, as appropriate ; is either none or a single bond, as appropriate; R1 is chosen from the group consisting in H, CN, Hal, OAlk, OH, NRCN, C(CN)=C(OH)(OAIk), SR. NRR', (Alk)p-C(0)NRR\ Heterocycle, Aryle, Heteroaryle, where Alk, Aryle, Heteroaryle, heterocycle are optionally substituted by Hal, NRR\ CN. OH, CF3, Aryle, Heteroaryle , OAlk, Where p is 0 or 1; R3, R4, R5, R6 are each identical or different and are independently chosen from the group consisting in H, OAlk, Alk, Hal, NRR*, CN, OH, CF3, Aryle, Heteroaryle; R2 is chosen from the group consisting in H, O, OH, N-OH, N-Aryle, N-OAlk, N-0-Aryle, N-0-Alk-Aryle, N-NR-CONRR', N-0-CO-Alk, or 2 R2 bound at the same X form together with that X an heterocycle; wherein said Alk, Aryle or heterocycle are optionally substituted by OAlk, Alk, Hal, NRR\ CN, OH, CF3, OAryl, -CO-(NR-AIk-CO)p-OAIk, -C0(NR-Alk-C0)p-OH, Where p' is 0 or 1; R7 is chosen from the group consisting in H, O, OH, N-OH, N-Aryle, N-OAlk, N-0-Aryle, N-O-Alk-Aryle. N-NR-CONRR\ N-0-CO-Alk, or 2 R7 bound at the same Y form together with that Y an heterocycle; wherein said Alk, Aryle or heterocycle are optionally substituted by OAlk, Alk, Hal, NRR\ CN, OH, CF3, OAryl, -CO-(NR-Alk-C0)p-"0Alk, "CO(NR-Alk-CO)p'-OH, Where p' is 0 or 1; R and R' are each identical or different and are independently chosen from the group consisting in H, AlK wherein Alk is optionally substituted by Hal, NRR\ CN, OH, CF3, Aryle, Heteroaryle; or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic crystalline structures of these compounds or their optical isomers, .racemates, diastereomers or enantiomers, R3, R4, R6=H, R5=0Me, R1=CN, ™(X(R2)m')m— represents a single bond, and ™(Y{R7)n')n"- represents "C(=0)-, or R3, R4, R5, R6=H, R1=NH2, ~(X{R2)m')m-" represents a single bond, and ™(Y(R7)n')n— represents -CH2-; or R3, R4, R5, R6=H, R1=NH2, ~(X(R2)m')m~ represents -CH2- and ™(Y(R7)n')n— represents a single bond. Preferably, R1 is chosen from the group consisting in H, CN. Hal, OAlk, OH, NRCN. C(CN)=C(OH)(OAIk), SR, NRR\ C(0)NRR\ Heterocycle, where Alk ' is optionally substituted by OAIk and where Heterocycle is optionally substituted by Hal. Preferably, R3, R4, R5, R6 are each identical or different and are independently chosen from the group consisting in H, OAIk, OH, Alk, Hal. Preferably, ~(Y(R7)n')n— is a single bond or Y represents a carbon atom or a S atom. Preferably, ~(X(R2)mOm"-- represents a single bond. Preferably, R2 is chosen from the group consisting in H, O. Preferably, R7 is chosen from the group consisting in H, O, OH, N-OH, N-OAlk, N-Aryle, N-O-Aryle or N-0-Alk-Aryle, N-0-Alk-Oaryle, N"0-Alk-C0-(NR-AIk"CO)p-OAIk, N-0-A!k-CO(NR-Alk-CO)p-OH, N-NR-CO-NRR', N-0-CO-Alk or 2 R7 bound at the same Y form together with that Y an heterocycle, where p' is Oor 1. Preferably, R and R' are each identical or different and are independently chosen from the group consisting in H, Alk. More preferably, in formula (I), ---(X(R2)mOm~ represents a single bond, n is 1, n' is 1, Y is a carbon atom; R1 is chosen from the group consisting in H, CN, Hal, OAIk, OH, NRCN, C{CN)=C(OH)(OAIk), SR, NRR', C(0)NRR\ Heterocycle, where AIk is optionally substituted by OAlk and where Heterocycle is optionally substituted by Hal; R3, R4, R5, R6 are each identical or different and are independently chosen from the group consisting in H, 0AIk, OH, Alk, Hal; R7 is chosen from the group consisting in O, N-OH, N-OAlk, N-Aryle, N-0-Aryle or N-0-Alk-Aryle; R and R' are each identical or different and are independently chosen from the group consisting in H, Alk; or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers. Preferred compounds of the Invention are chosen from the group consisting in: 7-Chloro-9-(2-phenoxy"ethoxyimino)-9H-indeno[1,2--b]pyrazine-2,3-dicarbonitrile 9-Allyloxyimino-6-chloro-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 7-Fluoro-8-methyl-9-oxo-9H-indeno[1,2"b]pyrazine"2,3-dicarbonitrile 6,7-dichloro-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6-ethyl-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 2-cyano-9-[hydroxyimino]-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide 9-Allyloxyimino-2-cyaho-9H-indeno[1,2-b]pyrazine-3-carboxyIic acid amide2-Cyano-9-ethoxyimino-9H-indeno[1,2-b]pyrazine--3--carboxylic acid amide 2-Cyano-9-(2-methoxy-ethoxyimino)-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide 2-Cyano-9-methoxyimino-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide 2-cyano-9-acetoxyimino-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide 2-cyano-9-oxo-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide (3-carbamoyl-2-cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)-acetic acid ethyl ester (3-carbamoyl-2-cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)-acetic acid [2-(3-carbamoyl-2-cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)" acetyiamino]-acetic acid ethyl ester [2-(3-carbamoyl"2-cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)-acetylamino]-acetic acid 7"ChlorO"3-hydroxy-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 9-[(aminocarbonyl)hydrazono]-7-.chloro-9H"indeno[1,2-b]pyrazine-2,3-dicarbonitrile or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers. According to another aspect, preferred compounds of the invention chosen from the group consisting in: 9-hydroxy-3-methoxy-9H"indeno[1,2-b]pyrazine-2-carbonitrile 3-methoxy-9-oxo-9H-indeno[1,2"b]pyrazine-2"Carbonitrile 3-dlmethylamino-9-oxo-9H-lndeno[1,2-b]pyrazine-2-carbonitrile 3-(2-methoxy-ethoxy)-9-oxo-9H-indeno[1,2"b]pyrazlne-2-carbonitrile 3-hydroxy-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 3-amino-9-oxo-9H-indeno[1,2"b]pyrazine-2-carbonitrile 3-(4,4-difluoro-piperidJn-1-yl)-9-oxo-9H-indeno[1,2"b]pyrazine"2-carbonit 3-chloro-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 9-(1',3'-dioxolan-2'-yI)-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 2-cyano-9-[hydroxyimino]-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide 9-(methoxyimino)-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 9-(Allyloxyimino)-9H-indeno[1,2-b]pyrazine"2,3-dicarbonitrile 9-Benzyloxyimino-9H-indeno[1,2-b]pyrazine-2,3-dicarbonltrile 9-Ethoxyimino-9H-indeno[1,2-b]pyrazine"2,3-dicarbonitrile 9-PhenoxyJmino-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6-Methoxy-9H-indeno[1,2-b]pyrazine-2,3-dicarbonJtrile 67-Dimethoxy-gH-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 8-Methyl-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 7,8"DJmethoxy-9H"-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6-Methyl-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitriIe 5,8-Dimethoxy-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6-Methoxy"9-oxo-9H"indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6,7-Dimethoxy-9-oxo-9H-indeno[1,2-b]pyrazine-2,3"dicarbonitrile 8-Methyl-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 7,8-Dimethoxy-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6-Methyi-9"OXo-9H-indeno[1,2"b]pyrazine-2,3-dicarbonitrile 5,8-Dimethoxy-9-oxo-9H"indeno[1,2-b]pyrazine-2,3-dicarbonitriie 7-Chloro-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 7-Fluoro-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 7-Hydroxy-9-oxO"9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile benzo[4,5]thieno[2,3-b]pyrazine-2,3-dicarbonitrile 5,10-dioxo-5,10-dihydro-benzo[g]quinoxaline-2,3-dicarbonitrile 2-cyano-9-oxo-9H-indeno[1,2-b]pyrazin-3-yl-cyanamide 3-(1-cyano-2-ethoxy-2"hydroxy-viny[)-9-oxo-9H-indeno[1,2-b]pyrazine-2- carbonitrile 3-ethylsulfanyI-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 7-Chloro-9-methoxyimino-9HHndeno[1,2-b]pyrazine-2,3-dicarbonitrile 9-Allyloxyimino-7-chloro-9H"indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6-Chloro-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 2-(2-cyano-9-oxo-9H-indeno[1,2-b]pyrazin-3-yl)-acetamide 9-(2-Phenoxy-ethoxyimino)-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 7-Chloro-9-(2-phenoxy-ethoxyimino)-9H-indeno[1,2-b]pyrazine-2,3- dicarbonitrile 9-Allyloxyimino-6-chloro-9H-indeno[1.2-b]pyrazine-2,3-dicarbonitrile 7-Fluoro-8-methyl-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6,7-dichloro-9-oxo-9H-indenoI1,2"b]pyrazine-2,3-dicarbonitrile 6-ethyI-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 2-cyano-9-[hydroxyimino]-9H-indeno[1,2-b]pyrazine-3-carboxylicacid amide 9-Allyloxyimino-2-cyano-9H-indeno[1,2-b]pyrazine-3-carboxylicacid amide2-Cyano-9-ethoxyimino-9H"indeno[1,2-b]pyrazine-3-carboxylicacid amide 2-Cyano-9-(2-methoxy"ethoxyimino)-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide 2-Cyano-9-methoxyimino-9H"indeno[1,2-b]pyrazine-3-carboxylic acid amide 2-cyano-9-acetoxyimino-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide 2-cyano-9-oxo--9H-indeno[1,2-b]pyrazine"3-carboxylic acid amide (3-carbamoyl-2-cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)-aceticacid ethyl ester (3-carbamoyl-2-cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)-aceticacid t2-(3-carbamoyl-'2-cyano-indeno[1,2-b]pyra2in-9-yIicleneaminooxy)- acetylamino]-acetic acid ethyl ester [2-(3-carbamoyl-2-cyano-indeno[1,2-b]pyra2in-'9-ylideneaminooxy)- acetylamino]-acetic acid 7-chloro-3-hydroxy-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 9-[(aminocarbonyl)hydra2ono]-7-chioro-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers. More preferred compounds of the invention are chosen from the group consisting in: 2-cyano-9-[hydroxyimino]-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide 9-(methoxyimino)-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 9-Benzyloxyimino-9H"Jndeno[1,2-b]pyrazine-2,3-dicarbonitrlle (13c). 9-Ethoxyimino-9H-indeno[1,2-b]pyrazine-2,3-dlcarbonitrile(13d), 9-Phenoxyimino-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile(13e). 8-Methyl-9"Oxo-9H-indeno[1,2-b]pyra2ine-2,3-dicarbonitriIe 6-Methyl-9-oxo-9H"indeno[1,2-b]pyrazine-2,3-dicarbonitrile 5,8-Dimethoxy-9-oxo-9H-indeno[1,2-b]pyrazine-2,3- or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers. According to a further object, the present invention concerns also the pharmaceutical compositions comprising a compound of formula (I) wherein: m is 0 ; 1 or 2 , wherein when m=0, — (X(R2)mOm — is none so as to form an open ring or a single bond; n is 0, 1 or 2, , wherein when n=0, — (Y(R7)n')n — is none so as to form an open ring or a single bond; m' and n' are independently 0, 1 or 2; X is a carbon atom or S or N; Y is a carbon atom, or S or N; Provided m and n are not simultaneously 0; is either a single or double bond, as appropriate ; -- is either none or a single bond, as appropriate; R1 is chosen from the group consisting in H, CN, Hal, OAlk, OH, NRCN, C(CN)=C(OH)(OAIk), SR, NRR', (Alk)p-C(0)NRR', Heterocycle. Aryle, Heteroaryle, where Alk, Aryle, Heteroaryle, Heterocycle are optionally substituted by Hal, NRR', CN, OH, CF3, Aryle, Heteroaryle , OAlk Where p is 0 or 1; R3, R4, R5, R6 are each identical or different and are independently chosen from the group consisting in H. OAlk, Alk, Hal, NRR\ CN, OH, CF3, Aryle, Heteroaryle; R2 is chosen from the group consisting In H, 0, OH, N-OH, N-Aryle, N-OAlk, N-0-Aryle, N-O-Alk-Aryle. N-NR-CONRR'. N-O-CO-Alk, or 2 R2 bound at the same X form together with that X an heterocycle; wherein said Alk, Aryle or heterocycle are optionally substituted by OAlk, Alk, Hal, NRR\ CN, OH, CF3, OAryl, -CO-(NR-Alk-CO)p-OAIk, -CO(NR-Alk-CO)p-OH, I Where p' is 0 or 1; R7 is chosen from the group consisting in H, O, OH, N-OH, N-Aryle, N-OAlk, N-0-Aryle, N-0-Alk-Aryle, N-NR-CONRR', N-0-CO-Alk, or 2 R7 bound at the same Y form together with that Y an heterocycle; wherein said Alk, Aryle or heterocycle are optionally substituted by OAlk, Alk, Hal, NRR\ CN, OH, CF3, OAryl, -CO-(NR-Alk-CO)p-OAIk, -CO(NR-Alk-CO)p-OH, Where p' is 0 or 1; R and R' are each identical or different and are independently chosen from the group consisting in H, Alk, wherein Alk is optionally substituted by Hal, NRR\ CN, OH, CF3, Aryle, Heteroaryle; or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers. According to a still further object, the present invention concerns the use of a compound of formula (I) as defined in respect of the pharmaceutical compositions of the invention, for the preparation of a medicament for inhibiting cysteine protease. Preferred embodiments of formula (I) for the pharmaceutical compositions and use of the invention are defined as above. Preferred compounds for the pharmaceutical compositions and use of the invention are chosen from the group consisting in: 9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 9-hydroxy-3-methoxy-9H-indeno[1,2-b]pyrazine-2-carbonitrile 3-methoxy-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitriie 3-dimethylamino-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 3-(2-methoxy"ethoxy)-9-oxo-9H-indeno[1,2"b]pyrazine-2-carbonitrile 3-hydroxy-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 3-amino-9-oxo-9H-indeno[1,2-b]pyrazine-2"Carbonitrile 3-(4,4-difluoro-piperidin-1-yl)-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 3-chloro-9"OXO-9H-indeno[1,2"b]pyrazine-2-carbonitrile 9-(1',3'-dioxolan-2'-yl)-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 2-cyano-9-[hydroxyimino]-9H-indeno[1,2-b]pyrazlne-3-carboxylic acid amide 9-[hydroxyimino]-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 9-(methoxyimino)-9H"indeno[1,2-b]pyra2ine-2,3-dicarbonitrile 9-(Allyloxyimino)-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 9-Benzyloxyimino-9H-indeno[1,2-b]pyra2ine-2,3-dicarbonitrile 9-Ethoxyimino-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 9-Phenoxyimino-9H-indeno[1,2-b]pyrazine-"2;3-dicarbonitrile 9-[phenylimino]-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6-Methoxy-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6,7-Dimethoxy-9H"indeno[1,2-b]pyrazine-2,3-dicarbonrtrile 8-Methyl-9H-indeno[1,2"b]pyrazine-2,3-dicarbonitrile 7,8-Dimethoxy-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6-Methyl-9H-indeno[1,2"b]pyrazine-2,3-dicarbonitrile 5,8-Dimethoxy-9HHndeno[1,2-b]pyrazine-2,3-dicarbonitrile 6-Methoxy-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6,7-Dimethoxy-9-oxo-9H-lndeno[1,2-b]pyrazine-2,3-dicarbonitrile 2-Cyano-9-methoxyimino-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide 2-cyano-9-acetoxyimino-9H-indeno[1,2-b]pyrazine-3"Carboxylic acid amide 2-cyano-9-oxo-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide (3-carbamoyl-2-cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)-acetic acid etiiyl ester (3-carbamoyl-2-cyano-indeno[1.2-b]pyrazin"9-ylideneaminooxy)-acetic acid [2-(3-carbamoyl-2-cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)- acetyjaminoj-acetic acid etiiyl ester [2-(3-carbamoyl-2-cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)- acetyiamino]-acetic acid 7-chloro-3-hydroxy-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrlle 9-[(aminocarbonyl)hydrazono]-7-chloro-9H-indeno[1,2-b]pyrazine-2,3- dicarbonitrile or tlieir pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorpinic crystalline structures of tiiese compounds or their optical isomers, racemates, diastereomers or enantiomers. More preferred compounds for the pharmaceutical compositions and use of the invention are chosen from the group consisting in: 9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrlle 2-cyano-9-[hydroxyimino]-9H-indeno[1,2-b]pyrazine-3-carboxyIic acid amide 9-(methoxyimino)-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 9-Benzyloxyimino-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (13c). 9-Ethoxyimino-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (13d). 9"Phenoxyimino-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (13e). 9-[phenylimino]-9H-indeno[1,2-b]pyrazine-2,3-dicarbon!triIe 8-Methyl-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6-Methyl-9"OXO-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 5,8-Dimethoxy-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 7-ChIoro-9-oxo-9HHndeno[1,2-b]pyrazine-2,3-dicarbonitrile 7-Fluoro-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 2-cyano-9-oxo-9H-incleno[1,2-b]pyrazine-3-carboxylic acid amide or their pliarmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers. As used hereabove or hereafter: Alk represents alkyl, alken or alkyn. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched having 1 to 20 carbon atoms in the chain. Preferred alkyl groups have 1 to 12 carbon atoms in the chain. "Branched" means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, /-propyl, n-butyl, butyl, n-pentyl, 3-pentyl, octyl, nonyl, decyl. "Alken" means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having 2 to 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to 12 carbon atoms in the chain; and more preferably about 2 to 4 carbon atoms in the chain. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, /-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, nonenyl, decenyl. "Alkyn" means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having 2 to 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to12 carbon atoms in the chain; and more preferably 2 to 4 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl and decynyl. "Halogen atom" refers to fluorine, chlorine, bromine or iodine atom; preferably fluorine and chlorine atom. "Aryl" means an aromatic monocyclic or multicyclic hydrocarbon ring system of 6 to 14 carbon atoms, preferably of 6 to 10 carbon atoms. Exemplary aryl groups include phenyl or naphthyl. As used herein, the terms "heterocycle" or "heterocyclic" refer to a saturated, partially unsaturated or unsaturated, non aromatic stable 3 to 14, preferably 5 to 10 membered mono, bi or multicyclic rings wherein at least one member of the ring is a hetero atom. Typically, heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur, selenium, and phosphorus atoms. Preferable heteroatoms are oxygen, nitrogen and sulfur. Suitable heterocycles are also disclosed in The Handbook of Chemistry and Physics, 76*^ Edition, CRC Press, Inc., 1995-1996, p. 2-25 to 2-26, the disclosure of which is hereby incorporated by reference. Preferred non aromatic heterocyclic include, but are not limited to pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxiranyl, tetrahydrofuranyl, dioxolanyl, tetrahydro-pyranyl, dioxanyl, dioxolanyl, piperidyl, piperazinyl, morpholinyi, pyranyl, imidazolinyl, pyrrolinyl, pyrazolinyl, thiazolidinyl, tetrahydrothiopyranyl, dithianyl, thiomorpholinyl, dihydro-pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydro-pyridyl, dihydropyridyl, tetrahydropyrinidinyl, dihydrothiopyranyl, azepanyl, as well as the fused systems resulting from the condensation with a phenyl group. As used herein, the term "heteroaryl" or aromatic heterocycles refers to a 5 to. 14, preferably 5 to 10 membered aromatic hetero, mono-, bi- or multicyclic ring. Examples include pyrrolyl, pyridyl, pyrazolyl, thienyl, pyrimidinyl, pyrazinyl, tetrazolyl, indolyl, quinolinyl, purinyl, imidazolyl, thienyl, thiazolyl, benzothiazolyl, furanyl, benzofuranyl, 1,2,4-thiadiazolyl, isothiazolyl, triazoyi, tetrazolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, carbazolyl, benzimidazolyl, isoxazolyl, pyridyl-N-oxide , as well as the fused systems resulting from the condensation with a phenyl group. "Alkyl", "cycloalkyl", "alkenyl", "alkynyl", "aryl", "heteroaryl", "heterocycle" and the likes refers also to the corresponding "alkylene", "cycloalkylene", "alkenylene", "alkynylene", "arylene", "heteroarylene", "heterocyclene" and the likes which are formed by the removal of two hydrogen atoms. As used herein, the temn "patient" refers to either an animal, such as a valuable animal for breeding, company or preservation purposes, or preferably a human or a human child, which is afflicted with, or has the potential to be afflicted with one or more diseases and conditions described herein. As used herein, a "therapeutically effective amount" refers to an amount of a compound of the present invention v/hich is effective in preventing, reducing, eliminating, treating or controlling the symptoms of the herein-described diseases and conditions. The term "controlling" is intended to refer to all processes wherein there may be a slowing, interrupting, arresting, or stopping of the progression of the diseases and conditions described herein, but does not necessarily indicate a total elimination of all disease and condition symptoms, and is intended to include prophylactic treatment. As used herein, the temri "pharmaceutically acceptable" refers to those compounds, materials, excipients, compositions or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem complications commensurate with a reasonable benefit/risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, tartaric, citric, methanesulfonic, benzenesulfonic, glucoronic, glutamic, benzoic, salicylic, toluenesulfonic, oxalic, fumaric, maleic, lactic and the like. Further addition salts include ammonium salts such as tromethamine, meglumine, epolamine, etc., metal salts such as sodium, potassium, calcium, zinc or magnesium. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting I the free acid or base fomns of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference. The compounds of the general formula (1) having geometrical and stereoisomers are also a part of the invention. According to a further object, the present invention is also concerned with the process of preparation of the compounds of formula (I). The compounds and process of the present invention may be prepared in a number of ways well known to those skilled in the art. The compounds can be synthesized, for example, by application or adaptation of the methods described below, or variations thereon as appreciated by the skilled artisan. The appropriate modifications and substitutions will be readily apparent and well known or readily obtainable from the scientific literature to those skilled in the art. In particular, such methods can be found in R.C. Larock, Compreliensive Organic Transformations, Wiley-VCH Publishers, 1999. It will be appreciated that the compounds of the present invention may contain one or more asymmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms. Thus, all chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare and isolate such optically active forms. For example, mixtures of stereoisomers may be separated by standard techniques including, but not limited to, resolution of racemic forms, normal, reverse-phase, and chiral chromatography, preferential salt formation, recrystallization, and the like, or by chiral synthesis either from chiral starting materials or by deliberate synthesis of target chiral centers. Compounds of the present invention may be prepared by a variety of synthetic routes. The reagents and starting materials are commercially available, or readily synthesized by well-known techniques by one of ordinary skill in the arts. All substituents, unless otherwise indicated, are as previously defined. In the reactions described hereinafter, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T.W. Greene and P. G. M. Wuts in Protective Groups in Organic Cliemistry, 3^^ ed., John Wiley and Sons, 1999; J. F. W. McOmie in Protective Groups in Organic Ciiemistry, Plenum Press, 1973. Some reactions may be carried out in the presence of a base. There is no particular restriction on the nature of the base to be used in this reaction, and any base conventionally used in reactions of this type may equally be used here, provided that it has no adverse effect on other parts of the molecule. Examples of suitable bases include: sodium hydroxide, potassium carbonate, triethylamine, alkali metal hydrides, such as sodium hydride and potassium hydride; aikyllithium compounds, such as methyllithium and butyllithium; and alkali metal alkoxides, such as sodium methoxide and sodium ethoxide. Usually, reactions are carried out in a suitable solvent. A variety of solvents may be used, provided that it has no adverse effect on the reaction or on the reagents involved. Examples of suitable solvents include: hydrocarbons, which may be aromatic, aliphatic or cycloaliphatic hydrocarbons, such as hexane, cyclohexane, benzene, toluene and xylene; amides, such as dimethylformamide; alcohols such as ethanol and methanol and ethers, such as diethyl ether and tetrahydrofuran. The reactions can take place over a wide range of temperatures. In general, we find it convenient to carry out the reaction at a temperature of from 0°C to 150X (more preferably from about room temperature to 100X). The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 3 hours to 20 hours will usually suffice. The compound thus prepared may be recovered from the reaction mixture by conventional means. For example, the compounds may be recovered by distilling off the solvent from the reaction mixture or, if necessary after distilling off the solvent from the reaction mixture, pouring the residue into water followed by extraction with a water-immiscible organic solvent and distilling off the solvent from the extract. Additionally, the product can, if desired, be further purified by various well known techniques, such as recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography or preparative thin layer chromatography. The process of preparation of a compound of formula (I) of the invention is a further object of the present invention. According to a first aspect, compounds of the invention of formula (I) can be obtained from corresponding compounds of formula (II) wherein R3, R4, R5, R6, X, Y, m, m\ n, n' are defined as in formula (I) and R7' is R7 as defined in formula (I) or a precursor thereof and R1' is R1 as defined in formula (I) or a precursor thereof. According to the present invention, the expression "precursor group" of a functional group refers to any group which can, by one or more reactions, lead to the desired function, by means of one or more suitable reagents. Those reactions include de-protection, as well as usual addition, substitution or functionalization reactions. Preferably, in formula (II), RV represents a CN group. Generally, the compound of formula (I) is obtained from compound of formula (II) by one or more step allowing a precursor function to be transformed into the desired -R1 group. Simultaneously, the R7' group can be transformed to the desired R7, if appropriate. The compounds of formula (II) can be obtained from corresponding compounds of formula (III): wherein R3, R4, R5, R6, X, Y, m, m', n, n' are defined as in formula (I) and R7' is defined as in formula (II). Generally, when R1'=CN, this reaction is usually carried out in the presence of diaminomaleodinitrile. According to an alternative embodiment, the compounds of formula (II) can be obtained from corresponding compounds of formula (111'); wherein R3, R4, R5, R6, X, Y, m, m\ n, n' are defined as in formula (I) and R7' is defined as in formula (IIT). Generally, when R1'=CN, this reaction is usually carried out in the presence of diaminomaleodinitrile. According to an alternative embodiment, the compound of formula (II) can be obtained from corresponding compounds of fomnula (IV); wherein R3, R4, R5, R6, X, Y, m, m', n, n* are defined as in formula (!) and R7" represents R7' or a precursor thereof, if appropriate. The compound of formula (III) can be obtained from a corresponding compound of formula (V): wherein R3, R4, R5, R6, X, Y, m, m\ n, n' are defined as in formula (I) and R7' is defined as in formula (II). The compound of formula (IV) can be obtained from a corresponding compound of fonnula (III). Generally, this reaction is carried in the presence of diaminomaleodinitrile. The above reactions can be carried out by the sl Further, the process of the invention may also comprise the additional step of isolating the compound of formula (I). This can be done by the skilled person by any of the known conventional means, such as the recovery methods described above. The starting products are commercially available or may be obtained by applying or adapting any known methods or those described in the examples. The synthesis may also be carried out in one pot as a multicomponent reaction. According to a further object, the present invention is also concerned with pharmaceutical compositions comprising a compound of formula (!) together with pharmaceutically acceptable excipients. The compounds of the invention are useful for inhibiting cysteine proteases, in particular de-ubiquitination enzymes (such as USPs and UCHs), caspases, cathepsins (in particular cathepsin B, D, K, S and the likes), calpains as well as viral, bacterial or parasitic cysteine proteases in patients in the need thereof. The compounds of the invention are particularly useful for treating and/or preventing cancer and metastasis, neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, deafness, disorders associated with ageing, inflammatory disorders, arthritis, osteoporosis, hepatitis, liver failure, cardiac ischemia and failure, stroke, atherosclerosis, renal failure, diabetes, cataract; viral acute or latent infections by Herpes simplex virus-1, Epstein-Barr virus, SARS coronavirus, rhinoviruses, poliomyelitis virus, hepatitis A virus, hepatitis C virus, adenoviruses, and the like; bacterial or fungal infections by pathogenic agents belonging to the Streptococcus sp., Staphylococcus sp., Clostidium sp., Aspergillus sp., genera and the like; protozoal infections by species members of the Trypanosoma sp., Plasmodium sp,, Leishmania sp., Trichomonas sp., Entamoeba sp., Giardia sp., Toxoplasma sp., Cryptosporidium sp., genera and the like; flat or round worm infections by species members of the Fasciola sp., Schistosoma sp., Onchocerca sp., Ascaris sp., Taenia sp., Caenorhabitis sp., Toxocara sp., Haemonchus sp., Ancylostoma sp., Thchuris sp., Trichinella sp., Strongyloides sp., Brugia sp., genera and the like; as well as immunological, immunoregulatory or antigen presentation disorders. The present invention also concerns the corresponding methods of treatment comprising the administration of a compound of the invention together with a pharmaceutlcally acceptable carrier or excipient to a patient in the need thereof. The identification of those subjects who are in need of treatment of herein-described diseases and conditions is well within the ability and knowledge of one skilled In the art. A veterinarian or a physician skilled in the art can readily identify, by the use of clinical tests, physical examination, medical/family history or biological and diagnostic tests, those subjects who are in need of such treatment. A therapeutically effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the therapeutically effective amount, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of subject; its size, age, and general health; the specific disease involved; the degree of involvement or the severity of the disease; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristic of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. The amount of a compound of formula (1), which is required to achieve the desired biological effect, will vary depending upon a number of factors, including the chemical characteristics (e.g. hydrophobicity) of the compounds employed, the potency of the compounds, the type of disease, the species to which the patient belongs, the diseased state of the patient, the route of administration, the bioavailability of the compound by the chosen route, all factors which dictate the required dose amounts, delivery and regimen to be administered. "Pharmaceutically" or "pharmaceutically acceptable" refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. As used herein, "pharmaceutically acceptable excipient" includes any carriers, diluents, adjuvants, or vehicles, such as preserving or antioxidant agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions as suitable therapeutic combinations. In the context of the invention, the term "treating" or "treatment", as used herein, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. "Therapeutically effective amount" means an amount of a compound/ medicament according to the present invention effective in preventing or treating a pathological condition requiring the inhibition of an active cysteine protease involved in its pathogenesis. According to the invention, the term "patient", or "patient in need thereof, is intended for an animal or a human being affected or likely to be affected with a pathological condition involving an active cysteine protease in its pathogenesis. Preferably, the patient is human. In general terms, the compounds of this invention may be provided in an aqueous physiological buffer solution containing 0.1 to 10% w/v compound for parenteral administration. Typical dose ranges are from 1 |ag/kg to 0.1 g/kg of body weight per day; a preferred dose range is from 0.01 mg/kg to 10 mg/kg of body weight per day or an equivalent dose in a human child. The preferred dosage of drug to be administered is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, the fonnulation of the compound, the route of administration (intravenous, Intramuscular, or other), the pharmacokinetic properties of the compound by the chosen delivery route, and the speed (bolus or continuous infusion) and schedule of administrations (number of repetitions in a given period of time). The compounds of the present invention are also capable of being administered in unit dose fonns, wherein the term "unit dose" means a single dose which is capable of being administered to a patient, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising either the active compound itself, or as a pharmaceutically acceptable composition, as described hereinafter. As such, typical total dally dose ranges are from 0.01 to 100 mg/kg of body weight. By way of general guidance, unit doses for humans range from 1 mg to 3000 mg per day. Preferably the unit dose range is from 1 to 500 mg administered one to six times a day, and even more preferably from 10 mg to 500 mg, once a day. Compounds provided herein can be fomiulated into pharmaceutical compositions by admixture with one or more pharmaceutically acceptable excipients. Such unit dose compositions may be prepared for use by oral administration, particularly in the form of tablets, simple capsules or soft gel capsules; or intranasally, particularly in the form of powders, nasal drops, or aerosols; or dermally, for example, topically in ointments, creams, lotions, gels or sprays, or via trans-dermal patches. The compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington: The Science and Practice of Pfiamiacy, 20*^ ed.; Gennaro, A. R., Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000. Preferred formulations include pharmaceutical compositions in which a compound of the present invention is formulated for oral or parenteral administration. For oral administration, tablets, pills, powders, capsules, troches and the like ' can contain one or more of any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, or gum tragacanth; a diluent such as starch or lactose; a disintegrant such as starch and cellulose derivatives; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, or methyl salicylate. Capsules can be in the form of a hard capsule or soft capsule, which are generally made from gelatin blends optionally blended with plasticizers, as well as a starch capsule. In addition, dosage unit forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or enteric agents. Other oral I dosage forms syrup or elixir may contain sweetening agents, preservatives, dyes, colorings, and flavorings, in addition, the active compounds may be incorporated into fast dissolve, modified-release or sustained-release preparations and formulations, and wherein such sustained-release formulations are preferably bi-modal. Preferred tablets contain lactose, cornstarch, magnesium silicate, croscarmellose sodium, povidone, magnesium stearate, or talc in any combination. Liquid preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. The liquid compositions may also include binders, buffers, preservatives, chelating agents, sweetening, flavoring and coloring agents, and the like. Non-aqueous solvents include alcohols, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and organic esters such as ethyl oleate. Aqueous carriers include mixtures of alcohols and water, buffered media, and saline. In particular, biocompatible, biodegradable lactide polymer, iactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds. Intravenous vehicles can include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Other potentially useful parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Alternative modes of administration include formulations for inhalation, which include such means as dry powder, aerosol, or drops. They may be aqueous solutions containing, for example, polyoxyethylene-9-iauryl ether, glycochoiate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Formulations for buccal administration include, for example, lozenges or pastilles and may also include a flavored base, such as sucrose or acacia, and other excipients such as glycochoiate. Formulations suitable for rectal administration are preferably presented as unit-dose suppositories, with a solid based carrier, such as cocoa butter, and may include a salicylate. Formulations for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which can be used include petroleum jelly, lanolin, polyethylene glycols, alcohols, or their combinations. Formulations suitable for transdermal administration can be presented as discrete patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. The invention is further illustrated but not restricted by the description in the following examples. Representative compounds of the invention are summarized in the table below: Experimental Representative compounds of the invention can be synthesized according to the following procedures: Synthesis of9'Oxo-9t1'mdeno[1,2-b]pyrazine'2,3-dicarbonitrUe (1): To a solution of ninhydrin (18.58 g, 104.3 mmo!) in HzO/EtOH/AcOH (130:195:9.1; 167 ml) a solution of diaminomaleodinitrile (11.27 g, 104.3 mmol) in HaO/EtOH/AcOH (130:195:9.1; 167 ml) was added and the mixture was stirred at 60°C. After 3 hours, the precipitate was collected by filtration, washed with EtOH (100 ml) and dried under vacuum, affording 1 (23.64 g, 98%) as yellow-brown solid. ^H NMR (300 MHz, CDCI3): 5 8.07 (d, 1H), 7.98 (d, 1H), 7.87 (dd, 1H), 7.76 (dd, 1H). ESrMS: calcd for C13H4N4O: 232.20; found: 233.0 (MH""). Synthesis of 9-hydroxy'3'methoxy'-9H-'indeno[% Z-blpyrazine-Z-carbonitrile (2): To a suspension of 1 (150 mg, 0.646 mmol) in MeOH (6.5 ml), cx)oled at OX, NaBH4 (24 mg, 0.646 mmol) was added. After 30 min, water (5 ml) was added, MeOH was evaporated and the residue was extracted with CH2CI2 (3x5 ml). The organic layers were dried over Na2S04, filtered and evaporated. EtOH was added and the precipitate was collected by filtration affording 2 (82 mg, 53%) as white solid. 1H NMR (300 MHz, DMSO d6): 5 7.93 (d, IN), 7.76 (d, IN), 7.65 (dd. 1H), 7.58 (dd, 1H), 6.27 (d, 1H), 5.50 (d. 1H), 4.17 (s, 3H). ESIMS: calcd for C13H9N3O2: 239.24; found: 240.1 (MH"). Synthesis of 3'methoxy-9-oxO'9H'indeno[1,2'b]pyrazine-2-carbonitrile (3): To a suspension of 1 (1.10 g, 4.7 mmol) in MeOH (47 ml) sodium (110 mg) was added and the mixture was stirred at room temperature for 16 hours. The precipitate was filtered, washed with EtOH and dried under vacuum, yielding 3 (1.03 g, 93%) as yellow-green solid. 1H NMR (300 MHz, DMSO de): 5 7.92 (d, 1H), 7.83 (m, 2H), 7.71 (dd,1H), 4.25 (s, 3H). ESIMS: calcd for C13H7N3O2: 237.22; found: 238.0 (MH+). Synthesis of 3'dimethylaminO'9-oxO'9H-indeno[1,2-b]pyrazine'2-carbonitrile (4): To a solution of 1 (53 mg, 0.228 mmol) in THF (2 ml) dimethylamine (2M in THF, 1.1 ml, 2.28 mmol) was added. The mixture was stirred at room temperature for 16 hours, then the solvent was evaporated affording 4 (56 mg, 98%) as yellow solid. 1H NMR (300 MHz, DMSO de): 6 7.85 (d, 1H), 7,80-7.73 (m, 2H), 7.67 (dd. 1H), 3.47 (s,6H). ESrMS:Galcd for C14H10N4O: 250.26; found: 251.1 (MH+). Synthesis of 3'(2-methoxy'ethoxy)'9-oxO'9H-indeno[1,2'b]pyrazine'2'-carbonitrile (5): A suspension of 1 (59 mg, 0.254 mmol) in methoxyethanol (2.5 ml) was heated by MW (150°C, 30 min) in a sealed tube. The resulting suspension was filtered and the solid collected, washed with EtOH and dried under vacuum, yielding 5 (50 mg, 70%) as green solid. 1H NMR (300 MHz, DMSO de): 5 7.90 (d, IN), 7.83 (dd, 1H), 7,82 (d, 1H), 7.71 (dd, 1H), 4.79 (m, 2H), 3.80 (m, 2H). 3.36 (s, 3H). ESIMS: calcd for CisHnNsOs: 281.27; found: 282.0 (MH+). Synthesis of3-hydroxy-9'OXO'9H-indeno[1,2-b]pyrazine'2-carbonitrile (6): A suspension of 1 (5.66 g, 24.3 mmol) in aqueous NaOH (2% w/v, 81 ml) was stirred at room temperature for 16 hours. The mixture was acidified with 3N HCI to pH 1, the precipitate was collected by filtration, washed with water and dried under vacuum, affording 6 (4.88 g, 90%) as light brown solid. 1H NMR (300 MHz, DMSO de): 5 7.89 (d, 1H), 7.79-7.62 (m, 3H). ESIMS: calcd for C12H5N3O2: 223.19; found: 224.0 (MH""). Synthesis of 3'amino-9'OxO'9H'indeno[1,2'b]pyrazine-2-carbonitriie (7): A mixture of 1 (201 mg, 0.86 mmol), ammonium acetate (331 mg, 4,3 mmol) and Na2S04 (200 mg) in THF (2.9 ml) was stirred at 70.C in sealed tube for 18 hours. The solvent was evaporated, water (5 ml) was added and the precipitate filtered, washed with water and dried under vacuum, affording 7 (171 mg, 90%) as green solid. 1H NMR (300 MHz, DMSO de): 6 8.45 (bs, 2H), 7.78-7.63 (m, 4H). ESI^MS: calcd for C12H6N4O: 222.21; found: 223.1 (MH^). Synthesis of 3-(4,4-difluoro-piperidin-1'yl)'9-oxo-9H-indeno[1,2-b]-pyrazine'2'Carbonitrile (8): 4,4-Difluoropiperidine hydrochloride (249 mg, 1.58 mmol) was dissolved in 1N NaOH (5 ml) and extracted with CH2Cl2 (2x5 ml). Organic phase was dried over Na2S04. filtered and evaporated. The residue was dissolved in THF (2 ml) and this solution was added to a solution of 1 (185 mg, 0.79 mmol) in THF (2 ml); the mixture was stirred at room temperature for 48 hours. The solvent was evaporated, the crude solid washed with EtOH and dried under vacuum, affording 8 (245 mg, 95%) as yellow-brown solid. 1H NMR (300 MHz, DMSO de): 6 7.89 (d, 1H), 7.79 (dd, 1H), 7.78 (d, 1H), 7.69 (dd, 1H). 4.13 (m, 4H), 2.22 (m. 4H). ESIMS: calcd for C17H12F2N4O: 326.31; found: 327.1 (MH^), Synthesis of 3'Chloro-9'OXO'9H'indeno[1,2-b]pyrazine'2-carbonitrile (9): A suspension of 6 (671 mg, 3.0 mmol) in POCI3 (8.4 ml) was heated under stirring to 100°C for 17h. Excess of POCI3 was evaporated under reduced pressure and the crude was purified by flash chromatography on silica (CH2CI2), affording 9 (320 mg, 44%) as yellow solid. 1H NMR (300 MHz, DMSO de): 6 8.02 (d, 1H), 7.90 (m, 2H), 7.78(dd, 1H). ESIMS: calcd for C12H4CIN3O: 241.64; found: 241.9 (MH+). Synthesis of 9-(1',3'-dioxolan-2'-yl)-9H-indeno[1,2'b]pyrazme-2,3-dicarbonitrile (10): To a suspension of 1 (5.09 g, 21.9 nnmol) in toluene (146 ml) ethylene glycol (2.4 ml, 43.8 mmol) and PTSA (6.25 g, 32.8 mmol) were added. The mixture was refluxed in a Dean-Stark apparatus for 28 hours, then, the solvent was evaporated. The crude was purified by flash chromatography on silica (CH2CI2), affording 10 (3.87 g, 64%) as light yellow solid. ^H NMR (300 MHz, DMSO de): 5 8.03 (m, 1H), 7.83-7.70 (m, 3H), 4.47 (s, 4H). ESrMS: calcd for C15H8N4O2: 276.26; found: 277.3 (MH*). Synthesis of 2'Cyano-9-[hydroxyimino]-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide (11): To a solution of 1 (500 mg, 2.1 mmol) in CH3CN (20 ml) hydroxylamine (50% wt. in water, 0.25 ml, 4.2 mmol) was added at O'C. The mixture was stirred at this temperature for 2.5 hours, then the formed precipitate was collected by filtration and dried under vacuum, affording 11 (355 mg, 62%) as red-brown solid. ^H NMR (300 MHz, DMSO ds): 6 10.96 (s, 1H), 8.11 (d, 1H), 7.89 (dd, 1H), 7.88 (d, 1H), 7.74 (dd, 1H), 6.32 (bs, 2H). ESfMS: calcd for C13H7N5O2: 265.23; found: 265.9 (MH*). Synthesis of 9'[hydroxyimino]-9H'indeno[1,2-b]pyrazine'2,3'dicarbonitrn^ (12): To a suspension of 1 (150 mg, 0.646 mmol) in pyridine (10 ml) hydroxylamine hydrocliloride (134 mg, 1.94 mmol) was added at 0°C. Molecular sieves were added and the mixture was stirred at room temperature for 16 hours. The insoluble residue was filtered, the solvent evaporated and the crude purified by flash chromatography on silica (petroleum spirit/EtOAc 9:1), affording 12 (55 mg, 35%) as yellow solid in diastereoisomeric ratio 9:1. ^H NMR for the main product (300 MHz, DMSO ds): main product: 5 14.28 (bs, 1H), 8.54 (d, 1H), 8.22 (d, 1H), 7.84 (dd, 1H), 7.78 (dd, 1H). ESrMS: calcd for C13H5N5O: 247.22; found: 247.9 (MH""). General procedure A: synthesis of alkyloxyimines To a suspension of 1 (620 mg, 2.67 mmol) in pyridine (15 ml) a solution of O-alkyl-hydroxylamine hydrochloride (8.31 mmol) in pyridine (15 ml) was added dropwise at 0°C. Molecular sieves were added and the mixture was stirred at room temperature for 16 hours. The insoluble residue was filtered, the solvent evaporated and the crude purified by flash chromatography on silica (petroleum spirit/EtOAc9:1). Synthesis of 9-(methoxyfmino)-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (13a): Prepared according to the general procedure A in 35% yield as yellow solid In diastereoisomeric ratio 3:1. 1H NMR (300 MHz, CDCI3) (mixture of syn-anti diastereolsomers): main product: S 8.09 (dd, 1H), 7.94 (dd, 1H), 7.79-7.68 (m, 2H); 4.34 (s, 3H). Minority product: 8 8.38 (m, 1H), 8.18 (m, 1H), 7.86-7.78 (m, 2H); 4.39 (s, 3H). ESfMS: calcd for C14H7N5O: 261.24; found: 262.1 (MH*). 9-(Allyloxyimino)-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (13b). Prepared according to the general procedure A in 15% yield as yellow solid in diastereoisomeric ratio 1:1. 1H NMR (300 MHz, DMSO de) (mixture of syn-anti diastereolsomers): 5 8.43 (m, 1H), 8.22 (m, 1H), 7.90-7.80 (m, 2H), 6.20 (m, 1H), 5.47 (m, 1H), 5.35 (m, 1H), 5.13 (ddd, 2H), and 8.12 (m, 1H), 7.96 (m, 1H), 7.80-7.69 (m, 2H), 6.14 (m, 1H), 5.53 (m, 1H), 5.38 (m, 1H), 5.08 (ddd, 2H). ESIMS: calcd for C16H9N5O; 287.28; found: 288.2 (MH*). 9-Benzyioxyimino-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (13c). Prepared according to the general procedure A in 32% yield as yellow solid in diastereoisomeric ratio 2:1. ^H NMR (300 MHz, DMSO dg) (mixture of syn-anti diastereolsomers): 8 8.42 (m, 1H), 8.21 (m, 1H), 7.88-7.78 (m, 2H), 7.56-7.49 (m, 2H), 7.47-7.33 (m, 3H), 5.67 (s, 2H) and 8.11 (m, 1H), 7.97 (m, 1H), 7.79-7.69 (m, 2H), 7.56-7.49 (m, 2H), 7.47-7.33 (m, 3H), 5.63 (s, 2H). ESfMS: calcd for C20H11N5O: 337.34; found: 338.2 (MH*). 9-Ethoxyimino-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile(13d). Prepared according to the general procedure A in 28% yield as yellow solid in diastereoisomeric ratio 7:3. 'H NMR (300 MHz, DMSO de) (mixture of syn-anti diastereolsomers): 5 8.44 (m, 1H), 8.22 (m, 1H), 7.84 (m, 2H), 4.65 (q, 2H), 1.48(t, 3H) and 8.12 (m, 1H), 7.98 (m, 1H), 7.75 (m, 2H), 4.61 (q, 2H), 1.44 (t, 3H). ESrMS: calcd for C15H9N5O: 275.27; found: 276.2 (MH""). Synthesis of9'[phenylimino]'9H-indeno[1,2-b]pymzine'2,3-dicarbonitrile (14): To a suspension of 1 (118 mg, 0.51 mmol) and molecular sieves in toluene (3 ml) aniline (0.037 ml, 0.41 mmol) was added. The mixture was lieated by M\N (150°C, 10 min), then the solvent was evaporated and the crude purified by flash chromatography on silica (petroleum spirlt/EtOAc 9:1), affording 14 (93 mg, 60%) as red solid in diastereoisomeric ratio 7:3. 1H NMR (300 MHz, CDCI3): 5 8.14 (d, 1H), 7.65 (dd, 1H), 7.50 (dd. 2H), 7.44-7.29 (m, 3H), 7.05 (d, 2H). ESrMS: calcd for C19H9N5: 307.32; found: 308.0 (MH^). General procedure B: synthesis of 1,2-indandiones To a suspension of substituted 1-indanone (5 mmol) in MeOH (12 ml) warmed to 40°C isopentyl nitrite (0.73 ml, 5.5 mmol) and HCI 37% (0.5 ml) were added. After 1 hour at 40°C the formed precipitate was collected by filtration, washed with MeOH and dried under vacuum. The solid obtained was suspended in CH2O (36% aqueous, 1.6 ml) and HCI 37% (3.2 ml) and the mixture was stirred at room temperature for 16 hours. Water (20 ml) was added and the suspension was extracted with CH2CI2 (3x15 ml). Collected organic phases were dried over Na2S04, filtered and evaporated. The crude product was used without further purification. 6-Methoxy-indan-1,2-dione (15a). Prepared according to the general procedure B in 60% yield as yellow solid. ESrMS: calcd for C10H8O3: 176.17; found: 177.0 (MH""). 5,6-Dimethoxy-indan-1 ,2-dione (15b). Prepared according to the general procedure B in 95% yield as light brown solid. ESrMS: calcd for CiiHio04: 206.20; found: 207.0 (MH+). 4-Methyl-indan-1,2-dione (15c). Prepared according to the general procedure B in 60% yield as yellow solid. ESrMS: calcd for CioHaOa: 160.17; found: 161.0 (MH""). 4,5-Dimethoxy-indan-1,2-dione (15d). Prepared according to the general procedure B in 94% yield as yellow solid. ESI^MS: calcd for C11H10O4: 206.20; found: 207.0 (MH""). 6-Methyl-indan-1,2-dione (15e). Prepared according to the general procedure B in 61% yield as yellow solid. ESrMS: calcd for C10H8O2:160.17; found: 161.0 (MH""). 4,7-Dimethoxy-indan-1,2-dione(15f). Prepared according to the general procedure B in 52% yield as light brown solid. ESrMS: calcd for C11H10O4: 206.20; found: 207.0 (MH^). 5-Chloro-indan-1,2-dione (15g). Prepared according to the general procedure B in 57% yield as yellow solid. ESrMS: calcd for C9H5CIO2:180.59; found: 181.0 (MH""). 5-Fluoro-indan-1,2-dione (15h). Prepared according to the general procedure B in 63% yield as yellow solid. ESrMS: calcd for C9H5FO2: 164,14; found: 165.0 (MH^). 5-Methoxy-indan-1,2-dione (15i). Prepared according to the general procedure B in 70% yield as yellow solid. ESrMS: calcd for CIOHBOS: 176.17; found: 177.1 (MH^). 5-Hydroxy-indan-1,2-dione {15j)- Prepared according to the general procedure B in 64% yield as yellow solid. ESrMS: calcd for CgHeOs: 162.15; found: 163.0 (MH'). General procedure C: pyrazine ring formation To a suspension of 15 (3 mmol) in iPrOH (15 ml) a suspension of diamino-maleodinitrile (324 mg, 3 mmol) in iPrOH (15 ml) was added. The mixture was stirred at room temperature for 24 hours, then, the precipitate was collected by filtration, washed with EtOH and dried under vacuum. 6-Methoxy-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (16a). Prepared according to the general procedure C in 65% yield as brown solid. ESrMS: calcd for C14H6N4O: 248.25; found: 249.0 (MH""). 6,7-Dimethoxy-9H-lndeno[1,2-b]pyrazine-2,3-dicarbonitrile(16b). Prepared according to the general procedure C in 91% yield as light brown solid. ESrMS: calcd for C15H10N4O2: 278.27; found: 279.0 (MH^). 8-Methyl-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (16c). Prepared according to the general procedure C in 60% yield as light brown solid. ""H NMR (300 MHz, CDCI3): 6 8.03 (d, 1H), 7.57-7.46 (m, 2H), 4.03 (s, 2H), 2.50 (s, 3H). ESrMS: calcd for C14H8N4: 232.25; found: 233.0 (MH^). 7,8-Dimethoxy-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (16d). Prepared according to the general procedure C in 72% yield as yellow solid. 'H NMR (300 MHz, CDCI3): 5 7.90 (d, 1H), 7.17 (d, 1H), 4.10 (s, 2H); 4.02 (s, 3H), 4.01 (s, 3H). ESrMS: calcd for C15H10N4O2: 278.27; found: 279.2 (MH*). 6-Methyl-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (16e). Prepared according to the general procedure C in 48% yield as light brown solid. ESrMS: calcd for C14H8N4: 232.25; found: 233.0 (MH*). 5,8-Dimethoxy-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (16f). Prepared according to the general procedure C in 45% yield as light brown solid. ESrMS: calcd for C15H10N4O2: 278.27; found: 278.9 (MH""). General procedure D: oxidation of mettiylenic group To a suspension of 16 (0.8 mmol) in AcOH (1.6 ml) a suspension of K2Cr207 (434 mg, 1.44 mmol) in AcOH (0.8 ml) and water (0.2 ml) was added. The mixture was slowly heated to 100°C and it was vigorously stirred at this temperature for 1 hour. The hot suspension was poured in water (10 ml) and the precipitate collected by filtration, washed with water and dried under vacuum. 6-Methoxy-9-oxo-9H-mdeno[1,2-b]pyrazine-2,3-dicarbonrtrile(17a). Prepared according to the general procedure D in 70% yield as light brown solid. ^H NMR (300 MHz, CDCI3) 6 7.92 (d, 1H), 7.48 (d, 1H), 7.18 (dd, 1H), 4.04 (s, 3H). ESrMS: calcd for C14H6N4O2: 262.23; found: 263.0 (MH""). 6,7-Dimethoxy-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile(17b). Prepared according to the general procedure D in 37% yield as red solid. ^H NMR (300 MHz, CDCI3): 5 7.39 (s, 1H), 7.37 (s, 1H), 4.10 (s, 3H), 4.03 (s, 3H). ESrMS: calcd for C15H8N4O3: 292.26; found: 293.0 (MH*). 8-Methyl-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (17c). Prepared according to the general procedure D in 91% yield as yellow solid. ^H I NMR (300 MHz, DMSO dg 368K): 6 7.90 (d, 1H), 7.79 (dd, 1H), 7.61 (d. 1H); 2.69 (s, 3H). ESrMS: calcd for C14H6N40:246.23; found: 247.0 (MH^). 7,8-Dimethoxy-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile(17d). Prepared according to the general procedure D in 71% yield as red solid. ^H NMR (300 MHz, DMSO dg 368K): 5 7.74 (d, 1H), 7.49 (bd, 1H), 4.07 (s. 3H), 3.99 (s, 3H). ESrMS: calcd for C15H8N4O3: 292.26; found: 293.0 (MH""). 6-Methyl-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (17e). Prepared according to the general procedure D in 73% yield as yellow solid. 'H NMR (300 MHz, DMSO de): 5 7.95 (d, 1H), 7.86 (d, 1H), 7.63 (dd, 1H), 2.52 (s, 3H). ESrMS: calcd for C14H6N4O: 246.23; found: 247.0 (MH*). 5,8-Dimethoxy-9-oxo-9H-indeno[1,2-b]pyrazlne-2,3-dicarbonitrile (17f). Prepared according to the general procedure D in 68% yield as brown solid. 'H NMR (300 MHz, CDCI3): 8 7.35 (d, 1H), 7.24 (d, 1H), 4.06 (s, 3H), 4.05 (s, 3H). ESi^MS: calcd for C15H8N4O3: 292:26; found: 293.0 (MH*). General procedure E: one-pot pyrazine ring formation and oxidation To a suspension of 15 (3 mmol) in iPrOH (15 ml) a suspension of diamino-maleodinitrile (324 mg, 3 mmol) in iPrOH (15 ml) was added. The mixture was stirred at room temperature for 24 hours then for 48 hours at SCC. The precipitate was collected by filtration, washed with EtOH and dried under vacuum. 7-Chloro-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile(17g). Prepared according to the general procedure E in 40% as yellow solid. 'H NMR (300 MHz, DMSO dg): 5 8.13 (d, 1H), 8.04 (bs, 1H), 7.97 (bd, 1H). ESrMS: calcd for C13H3CIN4O: 266.65; found: 266.9 (MH*). 7-Fluoro-9-oxo-9H-lnd6no[1,2-b]pyrazine-2,3-dicarbonitrile (17h). Prepared according to the general procedure E in 55% as pink solid. 'H NMR (300 MHZ, CDCI3): 6 8.03 (dd, 1H), 7.74 (dd, 1H), 7.42 (ddd, 1H). ESI^MS: calcd for C13H3FN4O: 250.19; found: 251.0 (MH^). 7-Methoxy-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile(17i). Prepared according to the general procedure E in 23% as liglit brown solid. ""H NMR (300 MHz, CDCI3): 5 7.92 (d, 1H), 7.48 (d, 1H), 7.18 (dd, 1H). 4.03 (s, 3H). ESrMS: calcd for C14H6N4O2: 262.23; found: 263.0 (MH^). 7-Hydlroxy-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile(17j)- Prepared according to the general procedure E in 35% as orange solid. The product was not purified by precipitation but, after evaporation of the solvent, by flash chromatography (CHaC^/MeOH 9:1). "^H NMR (300 MHz, DMSO ds): 5 11.66 (bs, 1H), 7.84 (d, 1H), 7.30 (d, 1H), 7.09 (dd, 1H). ESrMS: calcd for C13H4N4O2: 248.20; found: 249.0 (MH""). Synthesis of benzo[b]thiophene-2,3'dione (18): To a solution of benzenthiol (1 ml, 9.7 mmol) in EtaO (30 ml) at 0°C oxalyl chloride (0.94 ml, 10.7 mmol) was added dropwise. The mixture was stirred at room temperature for 1.5 hour, then, the solvent was evaporated under reduced pressure. The crude was dissolved in CH2CI2 (40 ml) and a solution of AICI3 (4.75 g, 35 mmol) in CH2CI2 (32 ml) was added dropwise at 0°C. The mixture was stirred for 16 hours at room temperature, then, ice and 1M HCI were added until a clear mixture was obtained. After 1 hour, the phases were separated and the aqueous layer was extracted with CH2CI2 (3x30 ml). The collected organic phases were dried over Na2S04, filtered and evaporated, affording 18 (1.2 g, 78%) as orange solid that was used without further purification. ESrMS: calcd for C8H4O2S: 164,18; found: 165.1 (MH"*"). Synthesis ofbehzo[4,5]thieno[2,3'b]pyrazine-2,3'dicarbonitrile (19): 18 (300 mg, 1.83 mmol) and diaminomaleodinitrile (198 mg, 1.83 mmol) were added to boiling water (10 ml). The mixture was refluxed for 1h then the crude precipitate was filtered, suspended in MeOH and refluxed for 10 min. After cooling at room temperature, the solid was filtered and dried under vacuum, yielding 19 (216 mg, 50%) as brown powder. ^H NMR (300 MHz, DMSO de): 5 8.58 (d, 1H). 8.38 (d, 1H), 7.94 (dd, 1H), 7.80 (dd, 1H), ESi'^MS: calcd for C12H4N4S: 236.26; found: 237.1 (MH""), Synthesis of 5j10'dioxO'5,10'dihydro-benzo[g]quinoxaline-2,3' dicarbonitrile (20): A suspension of 1,2,3,4-tetraoxo-1,2,3,4-tetrahydro-naphtaline dihydrate (214 mg, 0.95 mmol) and diamminomaleodinitrile (102 mg, 0.95 mmol) in EtOH (9.5 ml) and a catalytic amount of AcOH was stirred at room temperature for 24 hours. The precipitate was collected by filtration, washed with EtOH and dried under vacuum, obtaining 20 (65 mg, 35%) as light brown solid. ^H NMR (300 MHz, DMSO de): 5 9.16 (m, 2H), 8.24 (m, 2H). Synthesis of2-cyano-9-oxo-9H'indeno[1,2-b]pyrazin-3-yl'Cyanamide (21):. 1 1 Under inert atmosphere, cyanamid (44 mg, 1.037 mmol) was dissolved in dry DMF (1 ml) and NaH (21 mg, 0.519 mmol) was added in one portion. After 20 min, a solution of 1 (96 mg, 0.415 mmol) in dry DMF (2 ml) was added dropwise. After 111 the solvent was evaporated and the crude purified by flash chromatography (CHaCJa/MeOH 8:2) affording 21 (84 mg, 82%) as orange solid. ^H NMR (300 MHz, DMSO de): 5 7.85 (ddd, 1H), 7.77 (ddd, 1H), 7.76 (m, 1H), 7.67 (ddd, 1H). ESrMS: calcd for C13H5N5O: 247.22; found: 248.1 (MH*). I Synthesis of 3-(1'Cyano-2-^ethoxy-2-hydroxy'Vinyl)'9'OXO'9H'indeno[1,2' b]pyrazine'2'Carbonitrile (22): Ethylcyanoacetate (110 mg, 0.970 mmol) was dissolved, under inert atmosphere, in dry DMF (1 ml) and NaH (39 mg, 0.970 mmol) was added in one portion. After 30 min, a solution of 1 (150 mg, 0.646 mmol) in dry DMF (2 ml) was added dropwise. After 15 min MeOH was added and the solution stirred for 10 min. The solvents were evaporated and the crude purified by flash chromatography (EtOAc:MeOH 9:1) affording 22 as a darl ^H NMR (300 MHz, DMSO de): 8 7.78-7.55 (m. 4H), 4.11 (q, 2H), 1.22 (t, 3H). ESrMS: calcd for C17H10N4O3: 318.29; found: 319.2 (MH""). Synthesis of 3'ethylsulfanyl-9'Oxo-9H-incleno[1,2'b]pyrazine-2'carbonitrile (23): To a mixture of ethanethiol (62 jal, 0.84 mmol) and 1N NaOH (0.5 ml, 0.5 mmol) in THF (2.1 ml) 9 (101 mg, 0.42 mmol) was added. Tlie mixture was stirred at room temperature for 30 min then the solvent was evaporated under reduced pressure. The residue was dissolved in H2O (4 ml) and extracted with CH2CI2 (2x4 ml). The collected organic phases were dried over Na2S04, filtered and evaporated. The crude was purified by flash chromatography (CH2CI2) affording ' 23 (98 mg, 87%) as orange solid. ^H NMR (300 MHz, CDCI3): 6 7.92 (d, 1H), 7.86 (d, 1H), 7.73 (ddd, 1H), 7.63 (ddd, 1H), 3.44 (q, 2H), 1.51 (t, 3H). ESrMS: calcd for C14H9N3OS: 267.31; found: 268.1 (MH"). General procedure F: synthesis of all(yloxyimines To a suspension of 17g (151 mg, 0.56 mmol) in pyridine (5.6 ml) 0-alkyl-hydroxylamine hydrochloride (1.68 mmol) and molecular sieves were added and the mixture was stirred at 60°C for 1.5h. The insoluble residue was filtered, ) the solvent evaporated and the crude purified by flash chromatography on silica (petroleum spirit/CH2Cl21:1). 7'Chloro-9-methoxyimino-9H-indeno[1,2-b]pyrazine-2,2-dicarbonitrile(24a) Prepared according to the general procedure F in 65% yield as light brown solid in diastereoisomeric ratio 1:1. 'H NMR (300 MHz, CDCI3) (nnixture of syn-anti diastereoisomers): 5 8.36 (d, 1H), 8.04 (d, 1H), 7.64 (dd, 1H), 4.43 (s, 3H) and 7.94 (d, 1H), 7.89 (d, 1H), 7.54 (dd, 1H), 4.36(s, 3H). ESrMS: calcd for C14H6CIN5O: 295.69; found: 296.0 (MH^). 9-AUyloxyimino-7'ChlorO'9H'indeno[1,2-b]pyrazine'2,3'dicarbonitrne(24b) Prepared according to the general procedure F in 56% yield as light brown solid in diastereoisomeric ratio 1:1. 'H NMR (300 MHz, CDCI3) (mixture of syn-anti diastereoisomers): 5 8.41 (d, 1H), 8.07 (d, 1H), 7.67 (dd, 1H), 6.22-6.03 (m, 1H), 5.47 (m, 1H), 5.36 (m, 1H), 5.15 (m, 2H) and 7.97 (d, 1H), 7.94 (d, 1H), 7.57 (dd, 1H), 6.22-6.03 (m, 1H), 5.47 (m, 1H), 5.40 (m, 1H), 5.05 (m, 2H). ESrMS: calcd for CieHsCINsO: 321.73; found: 322.1 (MH*). 6-Chloro-9-oxo-9H-indeno[1,2'bJpyrazine-2,3-dicarbonitrne(25): A mixture of 5-chloro-1-indanone (1.05 g, 6.28 mmol) and N-bromosuccinimide (2.23 g, 12.56 mmol) in DMSO (25 ml) was stirred overnight at 40X and 5h at 80°C under vacuum. Water (125 ml) was added and the mixture was extracted with CH2CI2 (25 ml). The aqueous phase was saturated with brine and solid NaCI and extracted with CH2CI2 (4x80 ml). The collected organic phases were dried over Na2S04 and the solvent evaporated. The crude was dissolved in EtOH (63 ml), diaminomaleonitrile (678 mg, 6.28 mmol) and a catalytic amount of AcOH were added and the mixture stirred at 80°C for 45min. The precipitate was collected by filtration and washed with EtOH (464 mg). The filtered solution was evaporated and the crude purified by flash. Synthesis of 2'(2'CyanO'9'OXO'9H'indeno[1,2'b]pyrazin'3-yl)-acetamide (26): The procedure for the preparation of the starting material 1 was described in a previous experimental section. tert-Butyl cyanoacetate (292 mg, 2.07 mmol) was dissolved, under inert atmosphere, in dry DMF (4 ml) and NaH (60% dispersion in mineral oil, 90 mg, 2.24 mmol) was added portionwise. After 15 min, a solution of 1 (400 mg, 1.72 mmol) in dry DMF (3 ml) was added dropwise. After 16h MeOH was added, the solvents were evaporated and the crude purified by flash chromatography (EtOAc:MeOH 9:1) affording cyano-(2-cyano-9-oxo-9H-indeno[1,2-b]pyrazin-3-yl)-acetic acid fe/f-butyl ester as dark red solid. A solution of intermediate in dioxane/HaO/TFA (5:1:1, 7 ml) was stirred at 50^*0 for 4h. The precipitate was collected by filtration and crystallized from CH3CN, affording 26 (172 mg, 38% over 2 steps) as pink solid. ^H NMR (300 MHz, DMSO de): 5 8.22 (bs, 1H), 7.94 (dd, 1H), 7.93 (bs, 1H), 7.85 (dd, 1H), 7.84 (ddd, 1H), 7.69 (ddd, 1H), 4.75 (s, 2H). ESrMS: calcd for C14H8N4O2: 264.25; found: 265.1 (MH^). To a suspension of 1, 17g, 25 (0.72 mmol) in pyridine (7 ml) 0-all 9-(2-Phenoxy-ethoxyimino)-9H-indeno[1,2'-b]pyrazine-2,3'dicarbonitrile (27a). Prepared according to the general procedure D in 46% yield as yellow solid in diastereoisomeric ratio 1:1. 'H NMR (300 MHz, DMSO de) (mixture of syn-anti diastereoisomers): 5 8.11 (d, 1H), 7.98 (d, 1H), 7.75 (m, 2H), 7.28 (m, 2H), 7.01 (m, 2H), 6.93 (m, 1H), 4.89 (m, 2H), 4.46 (m, 2H) and 8.40 (d, 1H), 8.21 (d, 1H), 7.82 (m, 2H), 7.28 (m, 2H), 7.01 (m, 2H), 6.93 (m, 1H), 4.94 (m, 2H), 4.46 (m, 2H). ESrMS: calcd for C21H13CIN5O2: 367.37; found: 368.1 (MH*). 7-Chloro-9-(2-phenoxy-ethoxyimmo)-9H-incleno[1,2-b]pyrazine-2,3-dicarbonitrile (27b). Prepared according to the general procedure D in 75% yield as yellow solid in diastereoisomeric ratio 6:4. 'H NMR (300 MHz, CDCI3) (mixture of syn-anti diastereoisomers): 6 8.00 (d, IN), 7.96 (d, 1H), 7.61 (dd, 1H), 7.27 (m, 2H), 6.95 (m, 3H), 4.94 (m, 2H), 4.45 (m, 2H) and 8.46 (d, 1H), 8.09 (d, 1H), 7.70 (dd, 1H), 7.27 (m, 2H), 6.95 (m, 3H), 5.02 (m, 2H), 4.46 (m, 2H). ESfMS: calcd for C21H12CIN5O2: 401.82; found: 402.0 (MH*). 9-Allyloxyimino-6-chloro-9H-indeno[1,2-b]pyrazme-2,3-dicarbonitnle(27c). Prepared according to the general procedure D in 87% yield as light yellow solid in diastereoisomeric ratio 6:4. ^H NMR (300 MHz, CDCI3) (mixture of syn-anti diastereoisomers): 5 8.34 (d, IN), 8.10 (d, 1H), 7.65 (dd, 1H), 6.10 (m, 1H), 5.48 (m, 1H), 5.34 (m, 1H), 5.11 (m, 2H) and 8.01 (d, 1H), 7.88 (d, 1H), 7.58 (dd, 1H), 6.10 (m, 1H), 5,42 (m, 1H), 5.33 (m, 1H), 5.03 (m, 2H). ESrMS: calcd for CISHBCINSO: 321.73; found: 322.1 (MH*). General procedure H: synthesis of substituted 1-indanones 5'FiuorO'4-mettiyl'indan'1'One (28a) A solution of 3-fluoro-2-methyI benzaldehyde (1.9 g, 14.0 mmol), malonic acid (2.2 g, 21.0 mmol) and piperidine (138 pi. 1.4 mmoi) in pyridine (14 ml) was refluxed for 16h. After cooling, 6N HCI was added up to pH = 1, then the precipitate was collected by filtration and washed with H2O. The dried solid was hydrogenated at 30 psi for 2h using a Parr apparatus with 10% Pd/C (0.2 g) as catalyst and MeOH (140 ml) as solvent. The suspension was filtered through a Celite pad and the solvent was evaporated under reduced pressure. To a solution of aryl propionic acid (2.24 g, 12.3 mmol) in CH2CI2 (61 ml), oxalyl chloride (3.2 ml, 36.9 mmol) and few drops of DMF were added and the mixture was stirred for 1h at room temperature. The solvent was evaporated and the residue was added, dissolved in CH2CI2 (61 ml), to a suspension of AICI3 (4.92 g, 36.9 mmol) in CH2CI2 (61 ml) cooled at 0°C. The mixture for refluxed for 16h and then it was poured in ice. The phases were separated and the aqueous one was extracted with CH2CI2 (2x50 ml). Collected organic phases were dried over Na2S04, filtered and evaporated. The crude was purified by flash chromatography (petroleum ether/EtOAc 7:3) affording 28a (1.85 g, 76% over 3 steps) as white solid. ""H NMR (300 MHz, CDCI3): 5 7.60 (dd, 1H), 7.05 (dd, 1H), 3.03 (dd, 2H), 3.72 (dd, 2H), 2,27 (d, 3H). ESrMS: calcd for C10H9FO: 164.18; found: 165.2 (MH""). 5,6-Dichloro-indan'1'One (28b) A mixture of 3,4-dichlorophenyl propionic acid (1.95 g, 8.9 mmol) and polyphosphoric acid (19 g) was stirred at 120°C for 8h. Ice was added and the mixture was extracted with CH2CI2 (2x20 ml). Collected organic phases were dried over Na2S04, filtered and evaporated. The crude was purified by flash chromatography (petroleum ether/EtOAc 8:2) affording the expected 5,6-disubstituted indanone 28b (143 mg, 8%) as white solid. '"H NMR (300 MHz, CDCI3): 5 7.82 (s 1H), 7.60 (bs, 1H), 3.11 (dd, 2H), 3.73 (dd, 2H). ESrMS: calcd for CgHeClaO: 201.05; found: 202.1 (MH*). 6-Ethyl-indan-1-one (28c). To a slurry of polyphosphoric acid (20 g) heated to eCC 4-ethyl-phenyl propionic acid (1.26 g, 7.1 mmol) was added portionwise. The mixture was heated to 80'C for 2h and then it was poured into ice. The suspension was extracted with CH2CI2 (2x10 ml), the organic phase were dried over NaaSOA, filtered and evaporated. The product (1.13 g, 99%) was used without further purification. ESrMS: calcd for C11H12O: 160.22; found: 161.1 (MH*). To a suspension of substituted 1-indanone (5 mmol) in MeOH (12 ml) warmed to 40°C isopentyl nitrite (0.73 ml, 5.5 mmol) and HCI 37% (0.5 mi) were added. After 1h at 40°C the formed precipitate was collected by filtration, washed with MeOH and dried under vacuum. The solid obtained was suspended in CH2O (36% aqueous, 1..6 ml) and HCI 37% (3.2 ml) and the mixture was stirred at room temperature for 16h. Water (20 ml) was added and the suspension was extracted with CH2CI2 (3x15 ml). Collected organic phases were dried over Na2S04, filtered and evaporated. The crude product was used without further purification. 5-Fluoro'4'methyNndan'1,2'dione(29a) Prepared according to the general procedure F in 95% yield as yellow solid. ESrMS: calcd for C10H7FO2: 178.16; found: 179.2 (MH^). 6-£f/7y/-i7K/an-f,2-d/one (29c) Prepared according to the general procedure F in 98% yield as yellow solid. ES^MS: calcd for C11H10O2: 174.20; found: 175.1 (MH*). Synthesis of 7'Fluoro-8'methyh9'OXO'9H'indeno[1,2-b]pyrazine'2,3' dicarbonitrile (30): To a suspension of 29a (578 mg, 3.24 mmol) in MeOH (32 ml) diaminomaleodinitriie (420 mg, 3.89 mmol) and AcOH (1.6 ml) were added. The mixture was stirred at room temperature for 16h and then the solvent was evaporated under reduced pressure. The crude was purified by flash chromatography (CH2CI2) affording 7"fluoro-8-methyl-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile as light brown solid, To a suspension of intermediate (2.94 mmol) in 95:5 ACOH/H2O (10 ml) K2Cr207 (865 mg, 2.94 mmol) was added portionwise. The mixture was stirred at 60°C for 4h. The hot suspension was poured in water (50 ml) and the precipitate collected by filtration, washed with water and dried under vacuum. The crude was purified by flash chromatography (CH2Cl2/petroieum ether 7:3) affording 30 (707 mg, 83% over 2 steps) as orange solid. 'H NMR (300 MHz, CDCI3): 5 7.86 (dd, 1H), 7.40 (dd, 1H), 2.62 (s, 3H). ESrMS: calcd for C14H5FN4O: 264.22; found: 265.1 (MH""). Synthesis of 6,7-dichloro-9-oxo-9H-indeno[1,2'b]pyrazme-2,3-dicarbonitrile (31): A mixture of 29b (161 mg, 0.80 mmol) and N-bromosuccinimide (285 mg, 1.6 mmol) in D!\/ISO (3.2 ml) was stirred overnight;at 40X and 5h at 80°C under vacuum. Brine (7 ml) was added and the mixture was extracted with CH2CI2 (3x5 ml). The collected organic phases were dried over Na2S04 and the solvent evaporated. The crude was dissolved in EtOH (8 ml), diaminomaleonitrile (112 mg, 1.04 mmol) and a catalytic amount of AcOH were added and the mixture stirred at 80°C for 2h. The solvent was evaporated and the crude purified by flash chromatography (CH2Cl2/petroleum ether 1:1) affording 31 (30 mg, 13% over 2 steps) as yellow solid. ^H NMR (300 MHz, CDCI3): 6 8.07 (s, 1H), 7.96 (s, 1H). ESrMS: calcd for C13H2CI2N4O: 301.09; found: 301.2 (MH""). Synthesis of 6-ethyl'9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (32): A suspension of 29c (298 mg, 1.71 mmol) and diaminomaleonitrile (185 mg, 1.71 mmol) in iPrOH (17 ml) was stirred at SOX for 20h. The solvent was evaporated under reduced pressure and the crude was purified by flash chromatography (CH2CI2). The obtained product was purified by preparative HPLC, obtaining 32 as yellow solid as 7:3 regioisomeric mixture with the 7-ethyl analogue. ^H NMR (300 MHz, CDCI3): main product: 5 7.95 (d, 1H), 7.80 (m, 1H), 7.67 (bd, 1H), 2.83 (q, 2H), 1.33 (t, 3H); minority product: 5 7.89 (d, 1H), 7.89 (m, 1H), 7.56 (bd, 1H), 2.86 (q, 2H), 1.36 (t, 3H). ESl^US: calcd for C15H8N4O: 260.26; found: 261.1 (MH""). Synthesis of 2'Cyano-9-[hydroxyimino]-9H'indeno[1,2-b]pyrazine-3-carboxylic acid amide (33): To a solution of 1 (4.89 g, 21.0 mmol) in CH3CN (140 mi) liydroxylamine (50% wt. in water, 2.6 ml, 42 mmol) was added at 0°C. Tlie mixture was stirred at tliis temperature for 2.5h, then tfie formed precipitate was collected by filtration and dried under vacuum, affording 33 (5.41 g, 97%) as light brown solid. ""H NMR (300 MHz, DMSO de): 6 10.96 (s, 1H), 8.11 (d, 1H), 7.89 (dd, 1H), 7.88 (d, 1H), 7.74 (dd, 1H), 6.32 (bs, 2H). ESrMS: calcd for C13H7N5O2: 265.23; found: 265.9 (MH*). General procedure J: synthesis of 9'ail(yloxyimino-9H-indeno[1,2' b]pyrazine-3-carboxylic acid amide A suspension of 33 (610 mg, 2.3 mmol), CS2CO3 (1.5g, 4.6 mmol), Kl (1.14 g, 6.9 mmol) and alkyl bromide (6.9 mmol) in DMF (12 ml) was stirred at 50°C overnight. The solvent was evaporated under reduced pressure and the crude was purified by flash chromatography (CHaCla/MeOH 95:5). 9-Allyloxyimino-2-cyano-9H-indeno[1,2'b]pyrazine-3-carboxylic acid amide (34a). Prepared according to the general procedure G in 35% yield as orange solid in diastereoisomeric ratio 55:45. ""H NMR (300 MHz, DMSO de): 5 8.68 (bs, 2H), 8.00 (d, 1H), 7.90-7.78 (m, 2H), 7.65 (dd, 1H), 6.16-6.01 (m, 1H), 5.42 (m, 1H), 5.28 (m, 1H), 4.78 (ddd, 2H) and 8.56 (bs, 2H), 7.90-7.78 (m, 3H). 7.66 (dd, 1H), 6.16-6.01 (m, 1H), 5.36 (m, 1H), 5.24 {m, 1H), 4.75 (ddd, 2H). ESrMS: calcd for CieHnNgOz: 305.30; found: 306.1 (MH^). 2-Cyano-9'ettioxyimino-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide (34b). Prepared according to the general procedure G in 28% yield as yellow solid in diastereoisomeric ratio 6:4. ^H NMR (300 MHz, CDCI3): 6 8.05 (d, 1H), 7.77 (d, IN), 7.67 (m, 1H), 7.52 (m, 1H), 4.48 (q. 2H), 1.42 (t, 3H) and 7.87 (d, 1H), 7.77 (d, 1H), 7.67 (m, 1H), 7.52 (m, 1H), 4.42 (q, 2H), 1.39 (t, 3H). ESfMS: calcd for C15H11N5O2: 293.29; found: 294.1 (MH""). 2-Cyano-9-(2-metfioxy-ettioxyimino)-9H-indeno[1,2-b]pyrazine-3' carboxylic acid amide (34c) Prepared according to the general procedure G in 48% yield as light brown solid in diastereoisomeric ratio 6:4. 'H NMR (300 MHz, DMSO de): 5 8.63 (bs, 2H), 7.89-7.77 (m, 3H), 7.65 (dd, 1H), 4.36 (m, 2H), 3,67 (m, 2H), 3.31 (s, 3H) and 7.99 (bs, 2H), 7.89-7.77 (m, 3H), 7.65 (dd, 1H), 4.33 (m, 2H), 3,67 (m, 2H), 3.30 (s, 3H). ESrMS: calcd for C16H13N5O3: 323.31; found: 324.1 (MH""). 2-Cyano-9-metlioxyimino-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide (34d) Prepared according to the general procedure G (the reaction mixture was stirred 48h at room temperature) in 25% yield as orange solid in diastereoisomeric ratio 6:4. 'H NMR (300 MHz, DMSO de): 5 8.10 (m, 1H), 7.89 (m, 2H), 7.74 (m, 1H), 6.61 (bs, 2H), 3.93 (s, 3H) and 8.01 (d, 1H), 7.89 (m, 2H), 7.74 (m, 1H), 6.37 (bs, 2H), 3.89 (s, 3H). ESrMS: calcd for C14H9N5O2: 279.26; found: 280.1 (MH^). Synthesis of 2-cyanO'9-acetoxyimino-9H-indeno[1,2-b]pyrazine-3' carboxylic acid arnide (35): To a solution of 33 (1.0 g, 3.77 mmol) in dry pyridine (30 ml) cooled at O'C, acetyl chloride (0.8 ml, 11.3 mmol) was added dropwise and the mixture was stirred 16h at room temperature. Water (40 ml) was added and the precipitate was collected by filtration. The crude was purified by flash chromatography (CHaCb/acetone/MeOH 8:2:0.5) and triturated with EtaO/ CHaCla/IVIeOH, affording 35 (251 mg, 21%) as yellow solid as single isomer. ""H NMR (300 IVIHz, DMSO ds): 5 8.12 (d, 1H), 7.91 (m, 2H), 7.77 (ddd, 1H), 7.43 (bs, 2H), 2.27 (s, 3H), ESrMS: calcd for C15H9N5O3: 307.27; found: 308.1 (MH""). Syntfiesis of2-cyanO'9-oxo-9H-indeno[1,2'b]pyrazine-3-carboxylic acid amide (36): A suspension of 33 (522 mg, 1.97 mmol) and [bis(trifluoroacetoxy)iodo3benzene (1.69 g, 3.9 mmol) in CH3CN/H2O (9:1, 20 ml) was stirred 24h at room ) temperature. The solid was collected by filtration and washed with CH3CN. The residue was dissolved In DMSO (2 ml) and precipitated by addition of H2O. The obtained solid was filtered and dried under vacuum, affording 36 (286 mg, 58%) as light brown solid. ^H NMR (300 MHz, DMSO de): 5 8.65 (bs, 1H), 8.31 (bs, 1H), 8.09 (dd, 1H), 7.93 (m, 2H), 7.77 (ddd, 1H). ESrMS: calcxi for C13H5N4O2: 250.22; found: 251.1 (MH^^. Synthesis of (3'Carbamoyh2'CyanO'indeno[1,2-b]pyrazin'9' ylideneaniinooxy)'acetic acid etfuyl ester (37): To a suspension of 33 (300 mg, 1.1 mmol) and CS2CO3 (405 mg, 1.2 mmol) in DMF (15 ml), ethyl bromoacetate (0.14 ml, 1,26 mmol) was added dropwise and the mixture was stirred at 70°C for 24h. The suspension was cooled at room temperature, H2O (30 ml) was added and the mixture was extracted with CH2CI2 (70 ml). The organic phase was dried over Na2S04 and the volatile solvent was evaporated under reduced pressure. A 1:1 mixture of n-hexane/iPr20 was added and after 2h the obtained solid was collected by filtration. The crude was purified by flash chromatography (CH2Cl2/MeOH 85:15) affording 37 (85 mg, 22%) as green-brown solid. ^H NMR (300 MHz, DMSO de): 5 8.78 (bs, 1H), 8.73 (bs, 1H). 8.00 (dd, 1H). 7.82 (m, 2H). 7.67 (ddd, 1H), 4.87 (s, 2H), 4.19 (q, 2H), 1.25 (t, 3H). ESrMS: calcd for C17H13N5O4: 351,32; found: 352.1 (MH'). Synthesis of (3'Carbamoyl'2'Cyano-indeno[1,2'b]pyrazin'9' yUdeneaminooxy)-acetic acid (38): To a solution of 37 (70mg, 0.2 mmol) in THF/H2O (1:1, 15 ml) LiOH-HsO (41 mg, 1.0 mmol) was added and the mixture was stirred at room temperature. After 2h 2N HCI was added up to pH = 5. The solvent was removed under reduced pressure and the crude was purified by flash chromatography (CHzCIa/MeOH/AcOH 90:10:1) affording 38 (41 mg, 63%) as yellow solid. ESi^MS: calcd for C15H9N5O4: 323.27; found: 324.3 (MH"*). Synttiesis of (2'bromO'*acetylamino)'acetic acid ethyl ester (39): To a mixture of glycine ethyl ester hydrochloride (2.0 g, 14.3 mmol) and K2CO3 (2.1 g, 15.2 mmol) in CH2CI2 (35 ml) cooled at 0-5°C bromoacetyl bromide (1.36 ml, 15.6 mmol) was added dropwise. The suspension was stirred at room temperature and after 3h H2O (20 ml) was added. The phases were separated and the organic one was washed with a saturated solution of NaHCOa (20 ml) and H2O (20 ml) and dried over Na2S04. The solvent was evaporated obtaining 39 as white solid (1.2 g, 40%). ESi^MS: calcd for CeHioBrNOs: 224.06; found: \ 224.0 and 226.0 (MH""). Synthesis of [2'(3'Carbamoyl'2'CyanO'indeno[1,2'b]pyrazin'9' ylideneaminooxyj-acetylaminoj-acetic acid ethyl ester (40): To a suspension of 33 (212 mg, 0.80), CS2CO3 (260 mg, 0.80) in DMF (15 mi), 39 (200 mg, 0.89 mmol) was added portionwise and the mixture was stirred at room temperature for 2 days. H2O (30 ml) was added and tine suspension was extracted with CH2CI2 (70 ml). The organic phase was dried over Na2S04 and the solvent was evaporated under reduced pressure. The crude was purified by flash chromatography (CH2Ci2/MeOH 9:1) affording 40 (56 mg, 17%) as yellow-brown solid. ^H NMR (300 MHz, DMSO de): 5 8.78 (m, 2H), 8.12 (bs, 1H), 8.05-7.78 (m, 3H), 7.67 (m, 1H), 4.72 and 4.69 (s, 2H), 4.10 (q, 2H), 3.92 and 3.90 (s, 2H), 1.19 (t, 3H). ESrMS: calcd for CisHisNeOs: 408.38; found: 409.1 (MH"). Synthesis of [2-(3'Carbamoyl-2'CyanO'indeno[1,2'b]pyrazin'9' ylideneam!nooxy)-acetylamino]-acetic acid (41): To a solution of 40 (60 mg, 0.15 mmol) in THF/H2O (1:1, 15 ml) LiOH-H20 (30 mg, 0.71 mmol) was added. The mixture was stirred at room temperature and after 2h 2N HCI was added up to pH = 5. The solvent was removed under reduced pressure and a 1:1 mixture of CH2Cl2/MeOH (10 ml) was added. The solution was cooled at 0**C and the precipitate was collected by filtration, affording 41 (40 mg, 70%) as green solid. ^H NMR (300 MHz, DMSO de + TFA): 5 8.35 (t, 1H), 8.13 (dd, 1H), 7.91 (m, 2H), 7.78 (ddd, 1H), 4.92 (s, 2H), 3.87 (d, 2H). ESrMS: calcd for C17H12N6O5: 380.32; found: 381.4 (MH^), Synthesis of 7'CMorO'3'hydroxy'9^oxO'9H'indeno[1,2'b]pyrazine'2' carbonitrile (42) To a suspension of 50mg (0,19mmol) 17g and 2,2mg (5Mol-%) Na2Mo04 in 2 ml DMSO was added dropwise 82|jl (0,95mmol) of an aqueous solution of H2O2 (35%). The colour turned to red, and the mixture was stirred for 48h at room temperature. After addition of 20 mL Dichloromethane, the resulting solution was washed with water and sat. brine (3x5mi). After drying, filtration and evaporation, the crude product was purified by chromatography (DCM/MeOH 8/2) to yield 35mg (70%) compound 42 as yellow-orange powder. 'H-NMR (de-DMSO, 300MHz): 5(ppm) = 7.55 (s, 1H); 7.64 (m, 2H). ESI'MS: calcd for C12H4CIN3O2: 257.64; found: 255.9 (M-H""). Synthesis of 9^[(aminocarbonyl)hydrazono]'7-chloro'9H-indeno[1,2' b]pyrazine-2,3-dicarbonitrile (43) A mixture of 600mg (2,25mmol) 17g and 329mg (2,92mmol) semicarbazide hydrochloride in 20 ml acetonitrile was heated 14h under reflux. After that time, TLC indicated complete conversion of the starting product. After evaporation of the solvent, the crude product was recrystallised from aqueous ethanol, and compound 43 was obtained in slightly greenish crystals (90%). 'H-NMR (dg-DMSO, 400MHz): 5(ppm) = 7.40 (si. 1H); 7.70 (si, 1H); 7.71 (d, J = 8 Hz, 1H); 8.17 (d, J = 8 Hz, 1H); 8.89 (s, 1H); 10.95 (s, 1H). ESrMS: calcd for CuHeCINrO: 323.70; found: 324 (MM*). Representative cysteine proteases USPS activity assay USPS was diluted in USP buffer (50 mM Tris HCI; 0.5 mM EDTA; 5 mM DTT; 0.01% Triton X-100; Bovine Serum Albumin 0.05 mg.ml"' pH7.6). Compounds stocks (100 mM) were stored at -20°C in DMSO. Compounds were tested at the following final concentrations: 100 gM; 33.3 pM; 11.1 pM; 3.7 pM; 1.23 pM; 412 nM; 137 nM; 45.7 nM; 15.2 nM; 5 nM. Reactions were performed as duplicates in Black LJL 96 well plates (HE microplates; Molecular Devices; 20 pi final reaction volume).The substrate concentration for USP5 was 400 nM Ub-AMC (Boston Biochem). The concentrations of the enzyme (USPS) in specificity assays was 300 pM. The concentrations were determined in order to perform specificity assays under initial velocities at fixed substrate concentration. Compounds were pre- incubated with enzymes for 30 minutes at 25'C. Reactions were initiated by addition of substrate to the plates containing the enzymes (+/- compounds) diluted in assay buffer. Reactions were incubated for 60 minutes at 37°C. Reactions were stopped by adding acetic acid (100 mM final). Readings were performed on a Pherastar Fluorescent Reader (BMG). X Emission 380 nm; X Excitation = 460 nm. Data (mean values +/- standard deviation) were analyzed as % of control (no compound) and plotted as percentage versus the Log of the compound concentration using GraphPad (Prism). Data were fitted to a sigmoidal model (variable slope). Cloning & purification of USP7 The cDNA encoding USP7 was obtained by PCR amplification from placenta mRNA. USP7 cDNA was subcloned by PCR into a baculovirus expression vector (pFastBac-HT; Invitrogen). A cDNA encoding a mutated USP7 was generated by mutagenic PCR. The corresponding protein encodes a cysteine to alanine substitution at residue 223. The sequences were ascertained by sequencing of the entire open reading frame. Bacmids encoding USP7 were generated following DHIObac transposition. The corresponding bacmids were transfected into insect cells (Sf9). Viruses were recovered from culture supernatant and amplified twice. Insect cells (Sf9 or High Five; Invitrogen) were infected for 72 hours. Total cell lysates were harvested and lyzed in lysis buffer (Tris HCI 50 mM pH7,6; 0.75 % NP40; 500 mM NaCI; 10 % glycerol; 1 mM DTT; 10 mM imidazole; Protease Inhibitor Cocktail; AEBSF 20 pg.ml"'; Aprotinin 10 pg.ml"'). Proteins were affinity purified on metal affinity resins (Talon Metal affinity resin; BD Biosciences). Bound materials were extensively washed in wash buffer (50mM Sodium Phosphate pH7.0; 300 mM NaCI; 10 mM imidazole; 0.5% Triton X-100; 10% glycerol) and eluted from the resin in 250 mM imidazole-containing wash buffer. Proteins were dialyzed in dialysis buffer (Tris HCI pH 7.6 20 mM; NaCI 200 mM; DTT 1 mM; EDTA 1 mM; 10% Glycerol). Proteins purifications were analyzed on 4-12% NuPAGE (Invitrogen). USP7 activity assay USP7 was diluted in USP buffer (50 mM Tris HCI; 0.5 mM EDTA; 5 mM DTT; 0.01% Triton X-100; Bovine Serum Albumin 0.05 mg.ml'' pH7.6). Compounds stocks (100 mM) were stored at -20'*C in DMSO. Compounds were tested at the following final concentrations: 100 pM; 33.3 pM; 11.1 pM; 3.7 pM; 1.23 pM; 412 nM; 137 nM; 45.7 nM; 15.2 nM; 5 nM. Reactions were perfonned as duplicates in Black LJL 96 well plates (HE microplates; Molecular Devices;. 20 pi final reaction volume)The substrate concentration for USP7 was 400 nM Ub-AMC {Chem. BioL, 2003, 10, p. 837-846) (Boston Biochem). The concentrations of the enzyme (USP7) in specificity assays was 152 pM. The concentrations were determined in order to perform specificity assays under initial velocities at fixed substrate concentration. Compounds were pre-incubated with enzymes for 30 minutes at 25°C. Reactions were initiated by addition of substrate to the plates containing the enzymes (+/- compounds) diluted in assay buffer. Reactions were incubated for 60 minutes at 37°C. Reactions were stopped by adding acetic acid (100 mM final). Readings were performed on a Pherastar Fluorescent Reader (BMG). X Emission 380 nm; X Excitation = 460 nm. Data (mean values +/- standard deviation) were analyzed as % of control (no compound) and plotted as percentage versus the Log of the compound concentration using GraphPad (Prism). Data were fitted to a sigmoidal model (variable slope). Cloning & purification of USPS The cDNA encoding USPS was obtained by PCR amplification from placenta mRNA. USPS cDNA was subcloned by PCR into a baculovirus expression vector (pFastBac-HT; Invitrogen). A cDNA encoding a mutated USPS was generated by mutagenic PCR. The corresponding protein encodes a cysteine to alanine substitution at residue 786. The sequences were ascertained by sequencing of the entire open reading frame. Bacmids encoding USP7 were generated following DHIObac transposition. The corresponding bacmids were transfected into insect cells (Sf9). Viruses were recovered from culture supernatant and amplified twice. Insect cells (Sf9 or High Five; Invitrogen) were Infected for 72 hours. Total cell lysates were harvested and lyzed in lysis buffer (Tris HCI 50 mM pH7.6; 0.75 % NP40; 500 mM NaCI; 10 % glycerol; 1 mM DTT; 10 mM imidazole; Protease Inhibitor Cocktail; AEBSF 20 pg.ml"'; Aprotinin 10 tjg.ml"'). Proteins were affinity purified on metal affinity resins.(Talon Metal affinity resin; BD Biosciences). Bound materials were extensively washed in wash buffer (50 mM Sodium Phosphate pH 7.0; 300 mM NaCI; 10 mM imidazole; 0.5% Triton X-100; 10% glycerol) and eluted from the resin in 250 mM imidazole-contalning wash buffer. Proteins were dialyzed in dialysis buffer (Tris HCI pH 7.6 20 mM; NaCI 200 mM; DTT 1 mM; EDTA 1 mM; 10% Glycerol). Proteins purifications were analyzed on 4-12% NuPAGE (Invitrogen). USPS activity assay USPS was diluted in USP buffer (50 mM Tris HCI; 0.5 mM EDTA; 5 mM DTT; 0.01% Triton X-100; Bovine Serum Albumin 0.05 mg.ml"^ pH8.8). Compounds stocks (100 mM) were stored at -20°C in DMSO. Compounds were tested at the following final concentrations: 100 JJM; 33.3 |JM; 11.1 nM; 3.7 [JM; 1.23 MM; 412 nM; 137 nM; 45.7 nM; 15.2 nM; 5 nM. Reactions were performed as duplicates in Black UL 96 well plates (HE microplates; Molecular Devices; 20 \}\ final reaction volume).The substrate concentration for USPS was 400 nM Ub-AMC (Boston Biochem). The concentrations of the enzyme (USP8) in specificity assays was 630 pM. The concentrations were determined in order to perform specificity assays under initial velocities at fixed substrate concentration. Compounds were pre-incubated with enzymes for 30 minutes at 25°C. Reactions were initiated by addition of substrate to the plates containing the enzymes (+/- compounds) diluted in assay buffer. Reactions were incubated for 60 minutes at 37°C. Reactions were stopped by adding acetic acid (100 mM final). Readings were performed on a Pherastar Fluorescent Reader (BMG). X Emission 380 nm; X Excitation = 460 nm. Data (mean values +/- standard deviation) were analyzed as % of control (no compound) and plotted as percentage versus the Log of the compound concentration using GraphPad (Prism). Data were fitted to a sigmoidal model (variable slope). UCH-L3 activity assay Uch-L3 was diluted in USP buffer (50 mM Tris HCI; 0.5 mM EDTA; 5 mM DTT; 0.01% Triton X-100; Bovine Serum Albumin 0.05 mg.mi"^ pH7.6). Compounds stocks (100 mM) were stored at -20*^0 in DMSO. Compounds were tested at the following final concentrations: 100 pM; 33.3 pM; 11.1 pM; 3.7 pM; 1.23 pM; 412 nM; 137 nIVI; 45.7 nM; 15.2 nM; 5 nM. Reactions were performed as duplicates in Black LJL 96 well plates (HE microplates; Molecular Devices; 20 pi final reaction volume)The substrate concentration for Uch-L3 was 400 nM Ub-AMC (Boston Biochem). The concentration of the enzyme (Uch-L3) in specificity assays was 13 pM. The concentrations were determined in order to perform specificity assays under initial velocities at fixed substrate concentration. Compounds were pre-incubated with enzymes for 30 minutes at 25^*0. Reactions were initiated by addition of substrate to the plates containing the enzymes (+/- compounds) diluted in assay buffer. Reactions were incubated for 60 minutes at 37°C. Reactions were stopped by adding acetic acid (100 mM final). Readings were performed on a Pherastar Fluorescent Reader (BMG). 5 Emission 380 nm; 5 Excitation = 460 nm. Data (mean values +/- standard deviation) were analyzed as % of control (no compound) and plotted as percentage versus the Log of the compound concentration using GraphPad (Prism). Data were fitted to a sigmoidal model (variable slope). Caspase 3 activity assay Caspase 3 was diluted in Caspase 3 buffer (100 mM Hepes pH 7.5; 10% sucrose; 0.1% CHAPS). Compounds stocks (100 mM) were stored at -20°C in DMSO. Compounds were tested at the following final concentrations: 100 pM; 33.3 MM; 11.1 |JM; 3.7 [JM; 1.23 ^M; 412 nM; 137 nM; 45.7 nM; 15.2 nM; 5 nM. Reactions were performed as duplicates in Black LJL 96 well plates (HE microplates; Molecular Devices; 20 pi final reaction volunne). The substrate concentration for caspase 3 specificity assay was 500 nM (Ac-DEVD-AMC; Promega). Ttie concentration of tlie enzyme (Caspase 3) in specificity assays was 3.2 nM, The concentrations were determined in order to perform specificity assays under initial velocities at fixed substrate concentration. Compounds were pre-incubated with enzymes for 30 minutes at 25°C. Reactions were initiated by addition of substrate to the plates containing the enzymes (+/-compounds) diluted in assay buffer. Reactions were incubated for 60 minutes at 37°C. Reactions were stopped by adding acetic acid (100 mM final). Readings were performed on a Pherastar Fluorescent Reader (BMG). 5 Emission 380 nm; 6 Excitation = 460 nm. Data (mean values +/- standard deviation) were analyzed as % of control (no compound) and plotted as percentage versus the Log of the compound concentration using GraphPad (Prism). Data were fitted to a sigmoidal model (variable slope). Cathepsin B activity assay Cathepsin B was diluted in Cathepsin B buffer (20 mM Tris HCI pH 6.8; 1 mM EDTA; 1 mM DTT). Compounds stocks (100 mM) were stored at -20X in DMSO. Compounds were tested at the following final concentrations: 100 pM; 33.3 MM; 11.1 pM; 3.7 pM; 1.23 pM; 412 nM; 137 nM; 45.7 nM; 15.2 nM; 5 nM. Reactions were performed as duplicates in Black LJL 96 well plates (HE microplates; Molecular Devices; 20 pi final reaction volume). The substrate concentration for cathepsin B specificity assay was 36 pM (z-RR-AMC; Calbiochem).The concentration of the enzyme (Cathepsin B) in specificity assays was 3.6 nM. The concentrations were determined in order to perform specificity assays under initial velocities at fixed substrate concentration. Compounds were pre-incubated with enzymes for 30 minutes at 25°C. Reactions were initiated by addition of substrate to the plates containing the enzymes (+/- compounds) diluted in assay buffer. Reactions were incubated for 60 minutes at 37°C. Reactions were stopped by adding acetic acid (100 mM final). Readings were performed on a Pherastar Fluorescent Reader (BMG). 5 Emission 380 nm; 5 Excitation = 460 nm. Data (mean values +/- standard deviation) were analyzed as % of control (no compound) and plotted as percentage versus tlie Log of the compound concentration using GraphPad (Prism). Data were fitted to a sigmoidal model (variable slope). Cell viability and proliferation methods HCT116 cell viability and proliferation assay HCT116 colon cancer cells were obtained from ATCC (American Type Culture Collection), and maintained in Mc Coy's 5A medium containing 10% FBS, 3 mM glutamine and 1% penicillin/streptomycin. Cells were incubated at ST'^C in a humidified atmosphere containing 5% CO2. Cell viability was assayed using the MTS technique in 96-well culture plates (CellTiter 96® Aqueous Non-Radioactive Cell Proliferation Assay, Promega) according to the manufacturer's instructions. MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) is a MTT-derived tetrazolium that is reduced in metabolically active cells into a soluble, cell-permeant formazan. The amount of formazan, detected by its absorbance at 492 nm is proportional to the number of living, metabolically active cells. 10^ HCT116 cells were seeded per well. 24 hours later, the medium was changed and the cells treated in triplicate with the following concentrations of each compound: lOpM - 3.33|JM - 1.11 pM - 370nM - 123nM - 41nM - 14 nM and 5 nM. The compounds were diluted in 100% DMSO, whose final concentration on cells was kept at 0.5%. Cells were incubated with the compounds for 72 hours, and their viability then assayed by the addition of MTS for 2 hours. Absorbance at 492 nm was measured directly from the 96-well culture plates. G150 (Growth Inhibition 50) concentrations for each compound were calculated using a sigmoidal variable slope fit (Prism 4.0, Graphpad Softwares). Values represent mean of 3 independent experiments. PC3 cell viability and proliferation assay PC-3 prostate cancer cells were obtained from ATCC, and maintained in F-12K medium containing 7% FBS and 1% penicillin/streptomycin. Cells were incubated at 37°C in a humidified atmosphere containing 5% CO2. Cell viability was assayed using the MTS technique in 96-well culture plates (CellTiter 96® Aqueous Non-Radioactive Ceil Proliferation Assay, Promega) according to the manufacturer's instructions. MTS (3-(4,5-dimethyl-thiazol-2-yl)-5-(3-carboxymethoxyphenyl) -2-(4-sulfophenyl)-2H-tetrazolium) is a MTT"derived tetrazolium that is reduced in metabolically active cells into a soluble, cell-pemrieant formazan. The amount of formazan, detected by its absorbance at 492 nm is proportional to the number of living, metabolically active cells. 2x10^ PC3 cells were seeded per well. 24 hours later, the medium was changed and the cells treated in triplicate with the following concentrations of each compound: 10pM-3.33[JM-1,11|JM-370nM - 123nM-41nM - 14 nM and 5 nM. The compounds were diluted in 100% DMSO, whose final concentration on cells was kept at 0.5%. Ceils were incubated with the compounds for 72 hours, and their viability then assayed by the addition of MTS for 2 hours. Absorbance at 492 nm was measured directly from the 96-well culture plates. GI50 (Growth Inhibition 50) concentrations for each compound were calculated using a sigmoidal variable slope fit (Prism 4.0, Graphpad Softwares). Values represent mean of 3 independent experiments. CLAIMS 1. A compound of formula (I): wherein : m is 0,1 or 2 , wherein when m=0, — (X(R2)m')m — is none so as to form an open ring or a single bond; n is 0, 1 or 2, wherein when n=0, — (Y{R7)n')n — is none so as to form an open ring or a single bond; m' and n' are independently 0,1 or 2; X is a carbon atom or S or N; Y is a carbon atom, or S or N; Provided m and n are not simultaneously 0; is either a single or double bond, as appropriate ; is either none or a single bond, as appropriate; ; R1 is chosen from the group consisting in H, CN, Hal, OAlk, OH, NRCN, C(CN)=C(OH)(OAIk), SR, NRR', (Alk)p-C(0)NRR' Heterocycle, Aryle, Heteroaryle, where Alk, Aryle, Heteroaryle, heterocycle are optionally substituted by Hal, NRR\ CN, OH, CF3, Aryle, Heteroaryle , OAlk, Where p is 0 or 1; R3, R4, R5, R6 are each identical or different and are independently chosen from the group consisting in H, OAlk, Alk, Hal, NRR', CN, OH, CF3, Aryle, Heteroaryle; R2 is chosen from the group consisting in H, O, OH, N-OH, N-Aryle, N-OAlk, N-O-Aryle, N-O-Alk-Aryle, N-NR-CONRR', N-0-CO-Alk, or 2 R2 bound at the same X form together with that X an heterocycle; wherein said Alk, Aryle or heterocycle are optionally substituted by OAlk, Alk, Hal, NRR', CN, OH, CF3, OAryl, -CO-(NR-Alk-CO)p-OAIk, -CO(NR-Alk-CO)p-OH, Where p' is 0 or 1; R7 is chosen from the group consisting in H, O, OH, N-OH, N-Aryle, N-OAlk, N-0-Aryle, N-O-Alk-Aryle, N-NR-CONRR', N-0-CO-Alk, or 2 R7 bound at the same Y form together with that Y an heterocycle; wherein said Alk, Aryle or heterocycle are optionally substituted by OAlk, Alk, Hal, NRR", CN, OH, CF3, OAryl, -CO-(NR-Alk-CO)p-OAIk, -CO(NR-Alk-CO)p-OH, Where p' is 0 or 1; R and R' are each identical or different and are independently chosen from the group consisting in H, Alk, wherein Alk is optionally substituted by Hal, NRR', CN, OH, CF3, Aryle, Heteroaryle; or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers, with the exception of compounds where: R3, R4, R5, R6=H, R1=CN, —(X(R2)rT,-)m- represents a single bond, and -(Y(R7)n')n-- represents -C(=N-(2-,4-,6-trimethylphenyl))-, -C(=N-(2-,6-dimethylphenyl))-, -C(=N-(2-,6-diethylphenyl))-, -C(=N-(2-methylphenyl))-, -C(=N-(2-ethylphenyl))-, -C(=N-(2-trifluoromethylphenyl))-, -C(=N-(2-isopropyl- phenyl))-, -C(=N-phenyl)-, -C(=N-(naphtyl)- or-C(=0)-, -CH2-, or R3, R5, R6=H, R4=0Me, R1=CN, --(X(R2)m')m— represents a single bond, and --(Y(R7)n')n— represents -C(=0)-, or R3, R4, R5, R6=H, R1=NH2, —(X(R2)m')m~- represents a single bond, and —(Y(R7)n')n— represents -CH2- or-CH2-CH2-; or R3, R4, R5, R6=H, R1=NH2, "-(X(R2)mOm— represents -CH2" or -CH2-CH2- and —(Y(R7)nOn— represents a single bond. 2. Compound according to claim 1 with the further exception of the following compound: R3, R4, R5, R6=H. R1=CN, —(X(R2)m')m— represents a single bond, and -(Y(R7)n')n™ represents -C{=N-OH)-. 3. Compound according to claim 1 or 2, wherein: R1 is chosen from the group consisting in H, CN, Hal, OAlk, OH, NRCN, C(CN)=C(OH)(OAIk), NRR', (Alk)p-C(0)NRR\ Heterocycle, where Alk is optionally substituted by OAlk and where Heterocycle is optionally substituted by Hal Where p is 0 or 1; R3, R4, R5, R6 are each identical or different and are independently chosen from the group consisting in H, OAlk, Alk, Hal; -(Y(R7)n')n- is a single bond or Y represents a carbon atom or a S atom; R2 is chosen from the group consisting in H, O; R7 is chosen from the group consisting in H, O, OH, N-OH, N-OAlk, N-Aryle, N- 0-Aryle, N-0-Alk-Aryle. N-0-AlkOAryle, N-0-Alk-CO(NR-Alk-CO)p*~OAIk, N-0- Alk-CO(NR-Alk-CO)p'-OH, -N-NR-C0NRR' N-CO-AIk, or 2 R7 bound at the same Y form together with that Y an heterocycle Where p' is 0 or 1; R and R' are each identical or different and are independently chosen from the group consisting in H, Alk; 4. Compound according to anyone of the preceding claims, wherein -(X(R2)m')m™ represents a single bond, n is 1, n' is 1, Y is a carbon atom. 5. Compound according to anyone of the preceding claims, wherein R1 is chosen from the group consisting in H, CN, Hal, OAlk, OH, NRCN, C(CN)=C(OH)(OAIk), SR, NRR\ C(0)NRR', Heterocycle. where Alk is optionally substituted by OAlk and where Heterocycle is optionally substituted by Hal; 6. Compound according to anyone of the preceding claims, wherein R3, R4, R5, R6 are each identical or different and are independently chosen from the group consisting in H, OAlk, Alk, Hal. 7. Compound according to anyone of the preceding claims, wherein R7 is chosen from the group consisting in O, N-OH, N-OAlk, N-Aryle, N-0-Aryle, N-0-Alk-Aryle. 8. Compound according to anyone of the preceding claims, wherein R and R' are each identical or different and are independently chosen from the group consisting in H, Alk. 9. Compound according to anyone of the preceding claims chosen from the group consisting in: 9-hydroxy-3-methoxy-9HHndeno[1,2-b]pyrazine-2"Carbonitrile 3-methoxy-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 3-dimethylamino-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 3-(2-methoxy-ethoxy)"9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 3-hydroxy-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 3-amino-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 3-(4,4-difluoro-piperidin-1-yl)-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 3-chloro-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 9-(r,3'-dioxolan-Z-yl)-9H-indeno[1,2"b]pyrazine-2,3-dicarbonitrile 2-(2-cyano-9-oxo-9H-incleno[1,2-b]pyrazin-3-yl)-acetamide 9-(2-Phenoxy-ethoxyimino)-9H-indeno[1,2-b3pyra2ine-2,3-dicarbonitrile 7-Chloro-9-(2-phenoxy-ethoxyimino)-9H"indeno[1,2-b]pyrazine-2,3-dicarbonitrile 9-Allyloxyimino-6-chloro-9H-indeno[1,2-b]pyra2ine-2,3"dicarbonitriIe 7-Fluoro-8-methyl-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6,7-dichloro-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6-ethyl-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 2-cyano-9-[hydroxyimino]-9H-indeno[1,2-b]pyra2ine-3-carboxylicacid amide 9-Allyloxyimino-2-cyano-9H-indenoI1,2-b]pyrazine-3-carboxylicacid amide2"Cyano-9-ethoxyimino-9H-indeno[1,2-b]pyrazine-3-carboxylicacid amide 2-Cyano-9-(2-methoxy-ethoxyimino)-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide 2-Cyano-9"methoxyimino-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide 2-cyano-9-acetoxyimino-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide 2-cyano-9-oxo-9H-indeno[1,2-b]pyrazine-3"Carboxylic acid amide (3-carbamoyl-2-cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)-acetlcacid ethyl ester (3-carbamoyl-2-cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)-aceticacid [2-(3-carbamoyl-2-cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)-acetyiamino]-acetic acid ethyl ester [2-(3-carbamoyl-2-cyano-indeno[1,2-b]pyrazin-9-yiideneaminooxy)-acetylamino]-acetic acid 7-chloro-3-hydroxy-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 9-[(aminocarbonyl)hydrazono]-7-chloro-9H-lndeno[1,2-b]pyrazine-2,3-dicarbonitrile or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers. (3"Carbamoyl-2"Cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)-aceticacicl [2-(3-carbamoyl-2-cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)-acetylamino]-acetic acid ethyl ester [2-{3-carbamoyl-2-cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)- acetylamino]-acetic acid 7-chloro-3-hydroxy-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 9"[(aminocarbonyl)hydrazono]-7-chloro-9H-indeno[1,2"b]pyrazine-2,3-dicarbonitrile or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers. 11. Compound according to anyone of the preceding claims chosen from the group consisting in: 2-cyano-9-[hydroxyimino]-9H-indeno[1,2-b]pyrazine-3-carboxylicacid amide 9-(methoxyimino)-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 9-Benzyioxyimino-9H-indeno[1,2-b]pyrazine-2.3-dicarbonitrile (13c). 9-Ethoxyimlno-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (13d). 9-Phenoxyimino-9H-indenot1,2-b]pyrazine-2,3-dicarbonitrile (13e), 8-Methyl-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6-Methyl-9"Oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 5,8-Dimethoxy-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrlle 7-Chioro-9-oxo-9H"indeno[1,2-b]pyrazine-2,3"dicarbonitri!e 7-Fluoro-9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 2-cyano-9-oxo-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers. 12. Process of preparation of a compound according to anyone of the preceding claims comprising the step of reacting a corresponding compound of formula (II) wherein R3, R4, R5, R6, X, Y, m. m\ n, n' are defined as in fomiula (I) and R7' is R7 as defined in formula (I) or a precursor thereof and R1' is R1 as defined in formula (I) or a precursor thereof. 13. Process according to claim 12, wherein R1' is CN. 14. Process according to claim 12 or 13, wherein —{Y(R7)n')n~ is -C(=0)-. 15. Process according to claim 12 to 14, wherein said compound of formula (II) is obtained from a corresponding compound of formula (III) or (III') wherein R3, R4, R5, R6, X, Y, m, m\ n, n' are defined as in formula (I) and R7' is defined as in formula (II). 16. Process according to claim 15, wherein when R1'=CN, this step is carried out in the presence of diaminomaleodinitrile. 17. Process according to claim 12 to 14, wherein said compound of formula (II) is obtained from a corresponding compound of formula (IV) wherein R3, R4, R5, R6, X, Y, m, m', n, n' are defined as in formula (I) and R7" represents R7' or a precursor thereof, if appropriate. 18. A pharmaceutical composition comprising a compound of formula wherein : m is 0 ; 1 or 2 , wherein when m=0, — (X(R2)m')m — is none so as to form an open ring or a single bond; n is 0, 1 or 2, , wherein when n=0, — (Y(R7)n)n — is none so as to fonri an open ring or a single bond; m' and n' are independently 0, 1 or 2; X is a carbon atom or S or N; Y is a carbon atom, or S or N; Provided m and n are not simultaneously 0; is either a single or double bond, as appropriate ; is either none or a single bond, as appropriate; R1 is chosen from the group consisting in H, CN, Hal, OAlk, OH, NRCN, C(CN)=C(OH)(OAIk), NRR' -(Alk)p-C(0)NRR', Heterocycle, Aryle, Heteroaryle, where Alk, Aryle, Heteroaryle, Heterocycle are optionally substituted by Hal, NRR', CN, OH, CFs, Aryle, Heteroaryle , OAlk And p is 0 or 1; R3, R4, R5, R6 are each identical or different and are independently chosen from the group consisting in H, OAlk, Alk, Hal, NRR', CN, OH, CF3. Aryle, Heteroaryle; R2 is chosen from the group consisting in H, O, OH, N-OH, N-Aryle, N-OAlk, N-0-Aryle, N-O-Alk-Aryle, N-NR-CONRR', N-0-CO-Alk, or 2 R2 bound at the same X form together with that X an heterocycle; wherein said Alk, Aryle or heterocycle are optionally substituted by OAlk. Alk, Hal, NRR\ CN, OH, CF3, OAryl, -CO-(NR-Alk-CO)p.-OAIk, -CO(NR-Alk-CO)p-OH, Where p' 0 or 1; R7 is chosen from the group consisting in H, O, OH, N-OH, N-Aryle, N-OAlk, N-O-Aryle, N-0-Alk-Aryle, N-NR-CONRR', N-O-CO-Alk, or 2 R7 bound at the same Y form together with that Y an heterocycle; wherein said Alk, Aryle or heterocycle are optionally substituted by OAlk, Alk, Hal, NRR', CN, OH, CF3. OAryl, -CO-(NR-Alk-CO)p-OAIk, -CO(NR-Alk-CO)p'-OH, Where p' is 0 or 1; R and R' are each identical or different and are independently chosen from the group consisting in H, Alk, wherein Alk is optionally substituted by Hal, NRR', CN, OH, CF3, Aryle, Heteroaryle; or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or he polymorphic crystalline structures of these compounds or their optical somers, racemates, diastereomers or enantiomers. 19. Pharmaceutical composition according to claim 18, wherein the compound of formula (1) is defined as in anyone of claims 1 to 9. 20. Pharmaceutical composition according to claim 18 or 19, wherein said compound of formula (I) is chosen from the group consisting in: 9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 9-hydroxy-3-methoxy-9H-indeno[1,2-"b]pyrazine"2-carbonitrile 3-methoxy-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 3-dimethylamino-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 3-(2-methoxy-ethoxy)-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 3-hydroxy-9"Oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 3-amino-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 3-(4,4-difluorO"piperidin-1-yl)-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 3-chloro-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 9-(r,3'-dioxolan-2'-yl)-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 2-cyano-9-[hydroxyimino]-9H-indeno[1,2-b]pyrazine-3-carboxylicacid amide 9-[hydroxyimino]-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 9"(methoxyimino)-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 9-(AllylGxyimino)-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrlle 9-Benzyloxyimino-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 9-Ethoxyimino-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 9-Phenoxyimino-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 9-[phenylimino]-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6-Methoxy-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 6,7"Dimethoxy-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 8-Methyl-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 7,8"Dimethoxy-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile 9-Allyloxyimino-2-cyano-9H-indeno[1,2-b]pyra2ine-3"Carboxylic acid amide2-Cyano-9-ethoxyimino-9H-indeno[1,2-b]pyra2ine-3-carboxylic acid amide 2-Cyano-9-(2-methoxy-ethoxyimino)-9HHndeno[1,2-b]pyrazine"3- carboxylic acid amide 2-Cyano-9-methoxyimino-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide 2-cyano-9-acetoxyimino-9H-indeno[1,2-b]pyrazine-3-carboxylic acid amide 2-cyano-9-oxo-9H-indeno[1,2-blpyrazine-3-carboxylic acid amide (3-carbamoyl-2-cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)-acetic acid ethyl ester (3-carbamoyl-2-cyano-indeno[1,2-b]pyrazin-9-ylideneamlnooxy)-acetic acid [2-(3-carbamoyl"2-cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)-acetylamino]-acetic acid ethyl ester [2-(3-carbamoyl-2-cyano-indeno[1,2-b]pyrazin-9-ylideneaminooxy)-acetylamino]-acetic acid 7-chloro-3"hydroxy-9-oxo-9H-indeno[1,2-b]pyrazine-2-carbonitrile 9-[(aminocarbonyl)hydrazono]-7-chloro-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile or their pharmaceutically acceptable salts, hydrates, or hydrated salts, or the polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers. 21. Use of a compound of formula (I) as defined in anyone of claims 18 to 20 for the preparation of a medicament for inhibiting one or more cysteine proteases. 22. Use according to claim 21, wherein said cysteine proteases belong to one or more groups of de-ubiquitination enzymes, caspases, cathepsins, calpains as well as viral, bacterial, fungal or parasitic cysteine proteases. 23. Use of a compound of formula (I) as defined in anyone of claims 18 to 20 for the preparation of a medicament for treating and/or preventing cancer and metastasis, neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, inflammatory disorders, cardiovascular diseases and/or viral infectivity and/or latency in particular for Herpes simplex virus-1, Epstein-Barr virus or SARS coronavirus. 24. Use according to claim 23, wherein said compound inhibits one or more de-ubiqultination enzymes. 25. Use of a compound of formula (I) as defined in anyone of claims 18 to 20 for the preparation of a medicament for treating and/or preventing inflammatory disorders, neurodegenerative disorders, preferably nervous cell damage caused by stroke, liver damage and liver failure resulting from acute or chronic infectious, ischemic or chemical liver injury, renal damage and renal failure resulting from acute or chronic infectious, ischemic or chemical kidney injury, heart damage and heart failure resulting from acute or chronic infectious, ischemic or chemical cardiac injury, diabetes resulting from acute or chronic autoimmune, chemical, oxidative or metabolic injury to the insulin beta-cells of the pancreatic islets. 26. Use according to claim 25, wherein said compound inhibits one or more caspases. 27. Use of a compound of formula (I) as defined in anyone of claims 18 to 20 for the preparation of a medicament for treating and/or preventing cancer and metastasis, cardiovascular diseases, immunological disorders, bone and joint diseases, osteoporosis and arthritis. 28. Use according to claim 27, wherein said compound inhibits one or more cathepsins. 29. Use of a compound of formula (I) as defined in anyone of claims 18 to 20 for the preparation of a medicament for treating and/or preventing ageing disorders, late onset diabetes and cataract. 30. Use according to claim 29, wherein said compound inhibits one or more calpalns. 31. Use of a compound of formula (I) as defined in anyone of claims 18 to 20 for the preparation of a medicament for treating and/or preventing viral infections and diseases. 32. Use according to claim 31, wherein said viral infections and diseases are chosen from hepatitis A, hepatitis C, SARS coronavirus infection and disease, rhinoviral infections and diseases, adenoviral infections and diseases, poliomyelitis. 33. Use according to claim 31 or 32, wherein said compound inhibits one or more viral cysteine proteases. 34. Use of a compound of formula (I) as defined in anyone of claims 18 to 20 for the preparation of a medicament for treating and/or preventing bacterial infections and diseases. 35. Use according to claim 34, wherein said bacterial infections or diseases are chosen from streptococcal infections and diseases, infections and diseases caused by bacteria of the Clostridium sp. Genus, staphylococcal infections and diseases, gingivitis and periodontal diseases. 36. Use according to claim 34 or 35, wherein said compound inhibits one or more bacterial cysteine proteases. 37. Use according to anyone of claims 34 to 36, wherein said compound inliibits one or more bacterial cysteine proteases chosen from streptopain, clostripain, staphylococcal cysteine protease, gingipain. 38. Use of a compound of formula (I) as defined in anyone of claims 18 to 20 for the preparation of a medicament for treating and/or preventing fungal infections and diseases. 39. Use according to claim 38, wherein said compound inhibits one or more fungal cysteine protease. 40. Use of a compound of formula (I) as defined in anyone of claims 18 to 20 for the preparation of a medicament for treating and/or preventing protozoal parasitic infections and diseases. 41. Use according to claim 40, wherein said compound inhibits one or more cysteine proteases from protozoal parasites. 42. Use of a compound of formula (I) as defined in anyone of claims 18 to 20 for the preparation of a medicament for treating and/or preventing flat worm parasitic infections and diseases. 43. Use according to claim 42, wherein said compound inhibits one or more cysteine proteases from flat worm parasites. 44. Use of a compound of formula (1) as defined in anyone of claims 18 to 20 for the preparation of a medicament for treating and/or preventing round wonn parasitic infections and diseases. 45. Use according to claim 44, wherein said compound inhibits one or more cysteine proteases from round worm parasites. 46. Use according to anyone of claims 23 to 45, wherein said medicament is used in combination with one or more therapies chosen from anti-cancer therapies, neurological therapies, thrombolytic therapies, antioxidant therapies, anti-infective, anti-hypertensive therapies, diuretic therapies, thrombolytic therapies, immunosuppressive therapies, cardiovascular therapies, immunomodulatory therapies, anti-inflammatory therapies, antiviral therapies, anti-bacterial therapies, anti-fungal therapies, anti-protozoal therapies, antiparasitic therapies.

Documents:

593-CHENP-2008 AMENDED CLAIMS 15-05-2012.pdf

593-CHENP-2008 AMENDED PAGES OF SPECIFICATION 15-05-2012.pdf

593-chenp-2008 correspondence others 09-06-2011.pdf

593-CHENP-2008 EXAMINATION REPORT REPLY RECEIVED 15-05-2012.pdf

593-CHENP-2008 FORM-1 15-05-2012.pdf

593-CHENP-2008 FORM-3 15-05-2012.pdf

593-CHENP-2008 OTHER PATENT DOCUMENT 1 15-05-2012.pdf

593-CHENP-2008 OTHER PATENT DOCUMENT 15-05-2012.pdf

593-CHENP-2008 POWER OF ATTORNEY 15-05-2012.pdf

593-chenp-2008-abstract.pdf

593-chenp-2008-claims.pdf

593-chenp-2008-correspondnece-others.pdf

593-chenp-2008-description(complete).pdf

593-chenp-2008-form 1.pdf

593-chenp-2008-form 18.pdf

593-chenp-2008-form 3.pdf

593-chenp-2008-form 5.pdf

593-chenp-2008-pct.pdf