MXPA04008130A

MXPA04008130A - Tricyclic pyrazole derivatives for the treatment of inflammation.

Info

Publication number: MXPA04008130A
Application number: MXPA04008130A
Authority: MX
Inventors: Richard M Weier
Original assignee: Pharmacia Corp
Priority date: 2002-02-19
Filing date: 2003-02-19
Publication date: 2004-11-26
Also published as: CA2476665A1; EP1476431A1; JP2005526730A; BR0307796A; AU2003225580A1; WO2003070706A1

Abstract

The present invention relates to substituted tricyclic pyrazole derivatives, compositions comprising such, intermediates, methods of making tricyclic pyrazole derivatives, and methods for treating cancer, inflammation, and inflammation-associated disorders, such as arthritis.

Description

TRICICLIC DERIVATIVES OF PIRAZOL FOR THE TREATMENT OF INFLAMMATION FIELD OF THE INVENTION The present invention generally belongs to the field of anti-inflammatory pharmaceutical agents and in particular it refers to tricyclic substituted pyrazole derivatives, to compositions comprising them, and to their use as therapeutic agents in the treatment of diseases related to protein kinases, in particular in the treatment of cancer, inflammation and inflammatory diseases, such as arthritis.

BACKGROUND OF THE INVENTION The following description of the background of the invention is provided to aid the understanding of the invention, but it is not recognized that it constitutes or describes the prior art in relation to the invention. The NF- ?? is a ubiquitous transcription factor that plays a prominent role in immune system activation and stress responses, regulating the transcription of many inducible early genes including proinflammatory cytokines, adhesion molecules, growth factors and receptors (Ghosh, S., May, MJ and Koop, E. (1998) Annu Rev. Immunol.16, 1 5-260; Zandi, E. and Karin, M. (1999) Mol. Ceil Biol. 19, 4547-4551; Karin, M. (1999) J. Biol. Chem. 274, 27339-27342). The specificity of gene expression is determined at the cellular level by a diverse set of external stimuli such as bacterial products, which include LPS, as well as cytokines, mostly the tumor necrosis factor (TNFa) and interleukin-β (IL1ß). Through synergistic interaction with other transcription factors, even more specificity can be achieved while maintaining a huge potential to coordinate a large number of functionally related genes in a coordinated manner. The NF-? is composed of homodimers and heterodimers of the Re1 family of proteins and is sequestered in an active form in the cytoplasm by family members ??? of inhibitory proteins (Ghosh, S., May, MJ and Kopp, E. (1998) Annu Rev. Immunol., 16, 15-260; Zandi, E. and Karin, M. (1999) Mol. Cell. Biol. 19, 4547-4551; Karin, M. (1999) J. Biol. Chem. 274, 27339-27342). The ??? they mask the nuclear localization signal in the NF-γ, preventing nuclear translocation and therefore the binding of DNA to the promoter regions of the response genes. Stimulation of cells with an agonist that activates NF- ?? leads to a series of biochemical signals, which ultimately result in the phosphorylation, ubiquitinylation and degradation of the?, thereby releasing the NF-? responsible for nuclear translocation (Ghosh, S., May, MJ and Koop, E. (1998) Annu Rev. Immunol.16, 1 15-260; Zandi, E. and Karin, M. (1999) Mol. Biol., 19, 4547-4551; Karin, M. (1999) J. Biol. Chem. 274, 27339-27342). Recently, two kB-kinases (IKK1 or IKK and IKK2 or ??? ß), which phosphorylate the ??? and that in this way initiate their degradation, they have been cloned and characterized in several laboratories (Ghosh, S., May, MJ and Koop, E. (1998) Annu Rev. Immunol. 16, 1 15-260; Zandi, E and Karin, M. (1999) Mol Cell Biol. 19, 4547-4551; Karin, M. (1999) J. Biol. Chem. 274, 27339-27342). The catalytic subunits, IKK1 and IKK2, are similar structurally and also enzymatically and exist in the form of a heterodimer in a large protein complex called the IKK signalomerase (Regnier, C, Song, H., Gao, X., Goeddle, D ., Cao, Z. and Rothe, M., (1997) Cell 90, 373-383; DiDonato, JA, Hayakawa, M., Rothwarf, DM, Zandi, E. and Karin, M. (1997) Nature 388, 548-554; Mercury; F., Zhu, H., Murray, BW, Schevchenko, A., Bennett, BL, Li, JW, Young, DB, Barbosa, M. Mann, M., anning, A. and Roa , A. (1997) Science 278, 860-866, Zandi E., Rothwarf, DM, Delhase, M., Hayadawa, M. and Karin, M. (1997) Cell 91, 243-252; Woronicz, JD, Gao, X., Cao, Z., Rothe, M. and Goeddel, DV (1997) Science 278, 866-869). A third protein, NEMO (????, IKKAP1), is an adapter regulatory protein necessary for the activation of IKK and for kinase activity (Yamaoka, S., Courtois, G., Bessia, C, Whiteside, ST, Weil, R., Agou, F., Kirk, HE, Kay, RJ and Ireal, A. (1998) Cell 93, 1231-1240; Rothwarf, D.M., Zandi, E., Natoli, G., Karin, M. (1998) Nature 395, 297; Mercury, F., Murray, B.W., Schevchenko, A., Bennett, B.L., Young, D.B., Li, J.W., Pascual, G., Motiwala, A., Zhu, H., Mann, M. and Manning, A.M. (1999) Mol. Cell Biol. 2, 1526-1538). IKK1 and IKK2 are coexpressed in many adult human tissues as well as in different stages of mouse embryos (Regnier, C, Song, H., Gao, X., Goeddle, D., Cao, Z. and Rothe, M. (1997 ) Cell 90, 373-383; DiDonato, JA, Hayakawa, M., Rothwarf, DM, Zandi, E. and Karin, M. (1997) Nature 388, 548-554; Mercury, F., Zhu, H., Murray, BW, Schevchenko, A., Bennett, BL, Li, JW, Young, DB, Barbosa, M., Mann, M., Manning, A. and Roa, A. (1997) Science 278, 860-866; Zandi, E., Rothwarf, DM, Delhase, M., Hayadawa, M. and Karin, M. (1997) Cell 91, 243-252; Woronicz, JD, Gao, X., Cao, Z., Rothe, M and Goeddel, DV (1997) Science 278, 866-869; Hu, MCT and Wang, Y. (1988) Gene 222, 31-40). This complex of kinases happens to represent a so-called critical and common in the activation of NF- ?? in various signal transduction pathways, stimulated by various agonists including cytokines, such as TNF e? _ 1 ß, microbial products such as LPS, and viral proteins such as TAX, as well as phorbol esters, oxidizing agents and serine / tyrosine -phosphatases (Ghosh, S., May, MJ and Koop, E. (1998) Annu., Rev. Immunol., 16, 15-260; Zandi, E. and Karin, M. (1999) Mol. Cell Biol. 19, 4547-4551; Karin, M. (1999) J. Biol. Chem. 274, 27339-27342). IKK1 (also called IKKa, Regnier, C, Song, H., Gao, X., Goeddle, D., Cao, Z. and Rothe, M. (1997) Cell 90, 373-383; DiDonato, JA, Hayakawa , M., Rothwarf, DM, Zandi, E. and Karin, M. (1997) Nature 388, 548-554, Mercury, F., Zhu, H., Murray, BW, Schevchenko, A., Bennett, BL, Li, JW, Young, DB, Barbosa, M., Mann, M., Manning, A. and Roa, A. (1997) Science 278, 860-866) was cloned simultaneously by a standard biochemical purification of the activity of ??? kinase, from HeLa S3 cells stimulated by TNFa, and by its interaction with MAP3K, kinase that induces NF-? (NIK) (from the English, "NF- ?? ducing Kinase"), in a system of scrutiny of two hydrides in yeast. IKK1 was identified as the previously cloned serine-threonine kinase, CHUK (Connelly,., And Marcu, K. (1995) Cell.Mol. Biol. Res. 41, 537- 549. The IKK1 (also called IKKa) is a a protein of 745 amino acids, 85 kDa, containing a serine / threonine kinase N-terminal catalytic domain, an amphipathic helix similar to the leucine zipper, and a C-terminal helix-loop-helix domain. called ??? ß) was also cloned by a standard biochemical purification, copurified with IKK1 from HeLa S3 cells stimulated by TNF, as well as identifying it in the public database, of an EST clone with sequence homology with response to IKK1 (Mercury; F., Zhu, H., Murray, BW, Schevchenko, A., Bennett, BL, Li, JW, Young, DB, Barbosa, M. Mann, M., Manning, A. and Roa, A. (1997) Science 278, 860-866, Zandi E., Rothwarf, DM, Delhase, M., Hayadawa, M. and Karin, M. (1997) Cell 91, 243-252; Woronicz, JD, Gao, X ., Cao, Z., Rothe, M. and Goeddel, D.V. (1997) Science 278, 866-869). IKK2 is a protein of 756 amino acids, 87 kDa, with the same global topology as IKK1, except for the addition of a 1 1 amino acid extension at the C-terminal end. IKK1 and IKK2 have a global identity of 52% with a 65% identity in the kinase domain and with a 44% identity in the interaction domains of the proteins at the C-terminal end. The data obtained using a transient expression analysis in mammals, by in vitro translation experiments and by co-expression in a baculovirus system, reveal that IKK1 and IKK2 are preferably associated in the form of a heterodimer through their leucine zipper motifs . Although homodimers have also been described in these systems, it is thought that the heterodimer is the physiological form of the kinase in mammalian cells (Zandi, E. Rothwarf, DM, Delhase, M., Hayadawa, M. and Karin, M. ( 1997) Ce // 91, 243-252; Li, J., Peet, GW, Pullen, SS, Schembri-King, J., Warren, TC, Marcu, KB, Kehry, MR, Barton, R. and Jakes, S. (1998) J. Biol. Chem. 273, 30736-30741). Finally, NEMO (also called ????) contains three helix regions that include a leucine zipper, interacts preferentially with IKK2 and is required for the activation of the heterodimer complex of kinases, perhaps by binding to other proteins in the interior of the signalosome complex (Yamaoka, S., Courtois, G., Bessia C, Whitside, ST, Weil, R., Agou, F., Kirk, HE, Kay, RJ and Ireal, A. (1998) Cell 93, 1231 -1240; Rothwarf, DM, Zandi, E., Natoli, G., Karin, M. (1998) Nature 395, 297; Mercury, F., Murray, BW, Schevchenko, A., Bennett, BL, Young, DB, Li, JW, Pascual, G., Motiwala, A., Zhu, H., Mann, M. and Manning, AM (1999) Mol Cell Biol. 2, 1526-1538). The kinase activities of IKK1 and IKK2 are regulated by phosphorylation and require a leucine zipper (LZ) (intact for dimerization, as well as an intact helix-loop-helix domain) (HLH) which exert a positive regulatory effect on kinase activity even when it is expressed in trans along with the rest of the IKK protein (Regnier, C, Song, H., Gao, X., Goeddle, D., Cao, Z . and Rothe, M., (1997) Ce // 90, 373-383; DiDonato, J.A., Hayakawa, M., Rothwarf, D.M., Zandi, E. and Karin, M. (1997) Nature 388, 548-554; Mercury; F., Zhu, H., Murray, BW, Schevchenko, A., Bennett, BL, L, JW, Young, DB, Barbosa, M. Mann, M., Manning, A. and Roa, A. (1997 ) Science 278, 860-866; Zandi E., Rothwarf, D.M., Delhase, M., Hayadawa, M. and Karin, M. (1997) Cell 91, 243-252; Woronicz, J.D., Gao, X., Cao, Z., Rothe, M. and Goeddel, D.V. (1997) Science 278, 866-869; Dehase, M., Hayakawa, M., Chen, Y. and Karin, M. (1999) Science 284, 309-313). The two subunits of IKK contain a canonical motif in the MAPKK activation loop, located near the N-terminus, which is the target for phosphorylation and activation of kinase activity by the action of MAP3K such as NIK and MEKK1, although the physiological regulation exerted by these two upstream kinases awaits further characterization (Zandi, E., and Karin, M. (1999) Mol Cell Bio, 19, 4547-4551; Karin, M. (1999) J. Biol Chem. 274, 27339-27342; Karin, M. and Delhase, M. (1998) Proc. Nati, Acad. Sci. USA, 95 9067-9069). Finally the phosphorylation of serines at the C-terminal end of IKK2 produces a decrease in the activity of IKK and it is postulated that it is responsible for the transient kinase activity observed after stimulation of the cells with an agonist (Dehase, M. , Hayakawa, M., Chen, Y., and Karin, M. (1999) Science 284, 309-313). IKK2 shows a more potent kinase activity compared to IKK1 when it is used ??? a or ??? ß as a substrate (Mercurio, F., Zhu, H., Murray, BW, Schevchenko, A., Bennett, BL, Li, JW, Young, DB, Barbosa, M. Mann, M., Manning, A. and Roa, A. (1997) Science 278, 860-866, Zandi E., Rothwarf, DM, Delhase, M., Hayadawa, M. and Karin, M. (1997) Ce // 91, 243-252; Woronicz, JD, Gao, X., Cao, Z., Rothe, M. and Goeddel, DV (1997) Science 278, 866 -869; Dehase, M., Hayakawa, M., Chen, Y. and Karin, M. (1999) Science 284, 309-313). Mutations of serine acceptor residues of phospho groups, included in the activation loop of MAPKK, alter the kinase activity of IKK2; Substitutions of serine by alanine produce a decrease in kinase activity while substitutions of serine by glutamic acid produce a constitutively active kinase. Similar mutations in the alanines present in IKK1 do not produce a decreased stimulation of the total activity of the IKK in response to TNFcc or α1β (Dehase, M., Hayakawa, M., Chen, Y. and Karin, M. (1999) Science 284, 309-313). That IKK2 is the dominant kinase activity in the IKK complex is also supported by the analysis of fibroblasts from mice deficient in IKK1 or IKK2. Fibroblasts that lack IKK1, retain the normal activity of IKK in response to cytokines and could activate NF-γ. In contrast, fibroblasts lacking IKK2 do not exhibit IKK activity when stimulated with cytokines or activate NF-α. In addition, each of the "knock ouf" phenotypes of IKK (deficient phenotypes lacking IKK protein) is unique, producing deficiency in IKK1 skin and skeletal defects, with IKK2 deficiency being lethal to the embryo due to apoptosis. hepatocytes (Li, Q. Antwerp, DV, Mercury, F., Lee, K. and Verma,? .... (1999) Science 284, 321-325; Takeda, K., Tekeuchi, O., Tsujimura, T ., Itami, S., Adachi, O., Kawai, T., Sanjo, H., Yoshikawa, K., Terada, N. and Akira, S. (1999) Science 284, 313-316; Hu, Y. , Baud, V., Delhase, M., Zhang, P., Deerinck, T., Ellisman, M., Johnson, R. and Karin, M. (1999) Science 284, 315-320; Li, Q., Lu, Q., Hwang, JY, Buscher, D., Lee, K., Izpisua-Belmonte, JC and Verma, IM (1999) Gene and Development 13, 1322-1328; Tanaka, M., Fuentes, ME Yamaguchi , K., Dumin, MH, Dalrymple, SA, Hardy, KL and Goeddel, DV (999) Immunity 10, 421-429) It is well known that NF- ?? plays a key role in the regulated expression of a large n number of proinflammatory mediators including cytokines such as IL-6 and IL-8, cell adhesion molecules such as ICA and VCAM, and inducible nitric oxide synthetase (NOS). It is known that these mediators play a role in the recruitment of leukocytes at sites of inflammation and, in the case of NOS, can lead to the destruction of organs in some inflammatory and autoimmune diseases. The importance of NF- ?? in inflammatory diseases it is further reinforced by studies of airway inflammation, which includes asthma, in which it has been observed that NF-? It is activated. This activation may be the cause of the increased production of cytokines and the leukocyte infiltration characteristic of these diseases. In addition, inhaled steroids are known to reduce airway hyperreactivity and suppress the inflammatory response in asthmatic airways. In light of recent discoveries related to the inhibition of NF- ?? produced by glucocorticoids, it could be speculated that these effects are mediated through an inhibition of NF-γ. Other evidence of the existence of a role of NF-? in inflammatory diseases comes from studies of rheumatoid synovial fluid. Although the NF- ?? normally present in the form of an inactive cytoplasmic complex, recent immunohistochemical studies have indicated that NF-KB is present in the nuclei, and therefore is active, in the cells that are part of the rheumatoid synovial fluid. In addition, it has been observed that the NF- ?? is activated in human synovial cells in response to stimulation with TNF-a. This distribution may be the mechanism underlying the increased production of cytokines and eicosanoids, characteristic of this tissue. See, Roshak, A.K., J. Biol. Chem. 271, 31496-31501 (1996). The role of the NF- ?? in inflammatory diseases is also reinforced by studies of airway inflammation, which includes asthma, in which it has been observed that NF- ?? It is activated. This activation may be the cause of the increased production of cytokines and the leukocyte infiltration characteristic of these diseases. In addition, inhaled steroids are known to reduce airway hyperreactivity and suppress the inflammatory response in asthmatic airways. In light of recent discoveries related to the inhibition of NF- ?? produced by glucocorticoids, it could be speculated that these effects are mediated through an inhibition of NF-γ. Other evidence of a role of NF-? in inflammatory diseases comes from studies of rheumatoid cenobial fluid. Although the NF-? is normally present in the form of an inactive cytoplasmic complex, recent immunohistochemical studies have indicated that NF- ?? it is present in the nuclei, and therefore is active, in the cells that are part of the rheumatoid synovial fluid. In addition, it has been observed that the NF- ?? is activated in human synovial cells in response to stimulation with TNF-oc. This distribution may be the underlying mechanism of the increased production of cytokines and eicosanoids, characteristic of this tissue. See, Roshak, A.K., J. Biol. Chem. 271, 31496-31501 (1996). It is also likely that the proteins NF-KB / Rel e ??? play a key role in the neoplastic transformation. Members of these families are associated with cell transformation in vitro and in vivo due to overexpression, gene amplification, gene rearrangements, or translocations (Gilmore, T.D., Trends Genet, 7: 318-322, 1991).; Gillmore, T.D. Oncogene 18: 6925-6937, 1999; Rayet B. et al., Oncogene 18: 6938-6947, 1991). In addition, the rearrangement and / or amplification of the genes that modify these proteins are observed in 20% -25% of some human lymphoid tumors. In addition, it has been reported on a role of NF- ?? in the regulation of apoptosis, cell cycle progression, invasion and metastasis (Bours, V. et al., Biochemical Pharmacology 60: 1085-1090, 2000), reinforcing the role of this transcription factor in the control of cell proliferation . It has been observed that the inhibition of NF- ?? potentiates TNF- and cancer therapy through increased apoptosis (Wang CY et al., Science 274: 784-787; 1996; Wang CY et al., Nat Med. 5: 412-4 7, 1999) . It has also been observed that in the cells Infected by the type 1 virus of human T cell leukemia (HTLV1) (The etiological agent of an aggressive malignancy of activated CD4 + T lymphocytes), IKKα and βββ are expressed in a manner constitutive, expression that is normally carried out transiently (Chu ZL et al., J. of Biological! Chemistry 273: 15891-5894, 1988). The transforming and transactivating protein (Tax) of HTLV1 has been observed to bind to MEKK1 and increase the activity of ??? to increase the phosphorylation of serine residues present in? ? a, which leads to its degradation. The use of pyrazoles in the treatment of inflammation has been described. U.S. Patent No. 5,134,142, issued to Matsuo et al., Discloses 1,5-diaryl-pyrazoles, and specifically, describes 1- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl ] -3-trifluoromethyl-pyrazole possesses anti-inflammatory activity. U.A. Patent No. 3,940,418, issued to R. Hamilton, describes tricyclic 4,5-dihydrobenz [g] indazoles as anti-inflammatory agents. In addition, R. Hamilton [J. Heterocycllc Chem., 13, 545 (1976) describes tricyclic 4,5-dihydrobenz [g] indazoles as anti-inflammatory agents. The patent of E. U. A. No. 5,134,155 discloses tricyclic pyrazoles that carry a saturated ring linking the pyrazole and the phenyl radical, which are inhibitors of HMG-CoA reductase. EP 477,049, published on March 25, 1992; describes [4,5-dihydro-1-phenyl-H-benz [g] indazol-3-yl] amides having antipsychotic activity. EP 347,773, published on December 27, 1989, discloses [4,5-dihydro-1-phenyl-1 H-benz [g] indazol-3-yl] propanamides which are immunostimulants. M. Hashem et al., [J. Med. Chem., 19; 229 (1976)] describes fused tricyclic pyrazoles, which carry a saturated ring joining the pyrazole and a phenyl radical, which are antibiotics. Some substituted pyrazolyl-benzenesulfonamides have been described in the literature as synthetic intermediates. In particular, 4- [5- (4-chlorophenyl) -3-phenyl-1 H -pyrazol-1-yl] benzenesulfonamide has been prepared from a pyrazoline compound, as an intermediate of compounds having hypoglycemic activity [ R. Solimán et al., J. Pharm. Sci ,. 76, 626 (1987)]. 4- [5- [2- (4-Bromophenyl) -2H-1, 2,3-tnazol-4-yl] -3-methyl-1 H-pyrazol-1-yl-benzenesulfonamide has been prepared from a compound of pyrazoline and has been reported to potentially possess hypoglycemic activity [H. Mokhtar, Pak. J. Sci. Ind. Res., 31, 762 (1988)]. Similarly, 4- [4-bromo-5- [2- (4-chlorophenyl) -2H-1, 2,3-triazol-4-yl] -3-methyl] -1H-pyrazole has been prepared. -1-yl] benzenesulfonamide [H. Mokhtar et al., Pak. J. Sci. Ind. Res., 34, 9 (1991)]. The phytotoxicity of pyrazole derivatives [M. Coceo et al., II., Drug-Ed. Sci., 40, 272 (1985)], in particular that of 1- [4- (am'inosulfonyl) phenyl] -5-phenyl-1H-pyrazole-3,4-dicarboxylic acid. The use of styryl esters of pyrazole in antidiabetic drugs has been described [H. Mokhtar Pharmazie, 33, 649-651 (1978)]. The use of styryl pyrazole carboxylic acids in antidiabetic drugs has been described [R. Soliman et al., Pharmazie, 33, 184-185 (1978). The use of 4- [3,4,5-trisubstituted pyrazol-1-yl] -benzenesulfonamides as intermediates of antidiabetic agents based on sulfonylurea has been described., and in particular, 1- [4- (aminosulfonyl) phenyl] -3-methyl-5-phenyl-1 H-pyrazole-4-carboxylic acid. [R. Solimán et al., J. Pharm. Sci., 72, 1004 (1983)]. A series of 4- [3-substituted methyl-5-phenyl-1 H-pyrazol-1-yl-benzenesulfonamides has been prepared as intermediates of antidiabetic agents, and more specifically, 4- [3-methyl-5-phenyl-1] H-pyrazol-1-yl] benzenesulfonamide [H. Feid-Alian, Pharmazie, 36, 754 (1981)]. In addition, 1- [4- (aminosulfonyl) phenyl] -5-phenylpyrazole-3-carboxylic acid was prepared from the compound 4- [3-methyl-5-phenyl-1 H-pyrazol-1-yl] benzenesulfonamide above. described [R. Solimán et al., J. Pharm. Sci., 70, 602 (1981)]. WO 00/27822 describes tricyclic pyrazole derivatives, WO 00/59901 describes dihydroindene-pyrazoles, WO 95/15315 discloses diphenylpyrazole compounds, WO 95/15317 discloses triphenyl-pyrazole compounds, WO 95/15318 discloses trisubstituted pyrazole compounds, and WO 96/09293 discloses benz [g] indazolyl derivatives. WO 95/15316 discloses substituted pyrazolyl-benzenesulfonamide derivatives.

DETAILED DESCRIPTION OF THE INVENTION A class of compounds, which are useful in the treatment of cancer, inflammation and inflammatory diseases, is defined by means of Formula I: wherein A is selected from the group consisting of: (CH2) m and (CH2) n-CH = CH- (CH2) n; wherein each CH2 can be independently substituted with one or more substitutions selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl and alkynyl; m is from 0 to 8; n is independently selected from 0, 1 or 2; Q is a heteroaryl of 5 or 6 members, or an aryl, optionally saturated, or optionally substituted with R, R2 or R 2; B is an aromatic heterocyclic radical; X is selected from the group consisting of: N and C; Y and Z are independently selected from the group consisting of: N, C, CH, CR3, S and O; R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO2, OR5, OCOOR5, C02R7, CON (R6) R7, COR6, SR6, SOR6, SO2R6, NR6R7 , NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7 and SO2N (R6) R7 in which R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from the group constituted by: S, SO, SO2, O and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl and OR5 are optionally substituted with hydrido; halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, NO2, OR5, OCOOR5, CO2R7 with (R6) R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7 and SO2N (R6) ) R7 in which R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from the group consisting of: S, SO, SO2, O and NR6; R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, NO2, SR6, NHR6, CON (R6) R7, NHCONHR6, CO2H and haloalkyl; R1 and R2 can go together to form a saturated or unsaturated carbocyclic ring, of 5 to 7 members, optionally containing from 0 to 3 heteroatoms selected from the group consisting of: N, O, or S, and wherein said ring is optionally substituted with R; R3 is selected from the group consisting of: amidine, alkylamino, aminoalkyl, CONHR16, NH2, NHCOR6 and CH2NHCOR6, substituted or unsubstituted; R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic radical, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, SO2N (R8) R8 ', NHR9, NHCOR9, NR9COR9, NHCO (OR9), NR9CO (OR9), NR8S02R10, NHSO2N (R10) R10', NR6CON (R10) R10 ', COR9, CO2R8, CON (R8) R8', wherein R8 and R8 'can go together to form a 3- to 7-membered carbocyclic ring, bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, SO2, O, N and NR6, and wherein R10 and R10 they can go together to form a 3- to 7-membered carbocyclic ring, bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, SO2O and NR6 wherein said aryl, heterocyclic, heteroaryl or alkenyl compound are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of group consisting of: OR14, N (R14) R14 'and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclic alkyl and heterocyclic radical; R7 is independently selected from the group consisting of; hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclic alkyl and heterocyclic radical; R8 is independently selected from the group consisting of; hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R8 'is independently selected from the group consisting of; hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R9 is independently selected from the group consisting of; hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclic radical, cycloalkyl, heterocyclic alkyl, haloalkyl, arylalkylamino, amino, aminoalkyl, aminoacyl, nitro, azido and heteroarylalkyl, wherein alkyl, aryl, heteroaryl, aminoalkyl or arylalkyl are optionally substituted with one or more radicals selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanate, isothiocyanate, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy and heterocyclic radical optionally substituted by alkyl, alkylamino , aminoalkyl, hydroxyalk ilo and alkylaminoalkyl; R10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, and heterocyclic radical; R10 'is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, and heterocyclic radical; R11 is independently selected from the group consisting of: hydrido, halogen, haloalkyl, CN, C02R5, lower alkyl, lower alkenyl, lower alkynyl, alkoxy and CONH2; R 12 is selected from the group consisting of: hydrido, halogen, alkyl and alkoxy; R13 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of group constituted by; OR14, N (R14) R14 'and glycols; R14 is independently selected from the group consisting of: hydrido and lower alkyl; R14 'is independently selected from the group consisting of: hydrido and lower alkyl; R15 is independently selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic radical, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamine, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyan , alkylthio, alkylisulfinyl and alkylsulfoniio; wherein aryl or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic radical; and R16 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy and alkoxyalkyl; or their isomers, tautomers, vehicles, esters and prodrugs, and their pharmaceutically acceptable salts. Another class of compounds is defined by means of Formula II pilen that A is selected from the group consisting of: (CH2) m and (CH2) n-CH = CH- (CH2) n; wherein each CH2 can be independently substituted with one or more substitutions selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl and alkynyl; m is from 0 to 8; n is independently selected from 0, 1 or 2; Q is a 5- or 6-membered heteroaryl, or an aryl, optionally saturated, or optionally substituted with R, R2 or R12; B is an aromatic heterocyclic radical; R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, N02, OR5, OCOOR5, C02R7, CON (R6) R7, COR6, SR6, SOR6, SO2R6, NR6R7 , NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7 and SO2N (R6) R7 in which R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from the group constituted by: S, SO, SO2, O and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optionally substituted with hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, NO2, OR5, OCOOR5, CO2R7, CON (R6) R7 , COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7 NR6SO2R7, NR6SO2NHR7 and SO2N (R6) R7 in which R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing from 1 to 3 substituted heteroatoms or unsubstituted, selected from the group consisting of: S, SO, SO2, O and NR6; R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, NO2, SR6, NHR6, CON (R6) R7, NHCONHR6, CO2H and haloalkyl; R1 and R2 can together form a saturated or unsaturated carbocyclic ring, from 5 to 7 members, optionally containing from 0 to 3 heteroatoms selected from the group consisting of: N, O, or S, and wherein said ring it is optionally substituted with R1; R3 is selected from the group consisting of: amidine, alkylamino, aminoalkyl, CONHR16, NH2, NHCOR6 and CH2NHCOR6, substituted or unsubstituted; R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic radical, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, S02N (R8) R8 ', NHR9, NHCOR9, NR9COR9, NHCO (OR9), NR9CO (OR9), NR8S02R1 °, NHSO2N (R0) R10', NR6CON (R0) R10 ', COR9, CO2R8, CON (R8) R8', in that R8 and R8 'can go together to form a 3- to 7-membered carbocyclic ring, carrying from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, SO2, O, N and NR6, and wherein R10 and R10 can go together to form a 3- to 7-membered carbocyclic ring, bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, SO2, O, N and NR6, wherein said aryl, radical S, SO, SO2, O, N and NR6, wherein said aryl, heterocyclic radical, heteroaryl or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkio, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkio, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of group consisting of: OR14, N (R14) R14 and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclic alkyl, and heterocyclic radical; R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclic alkyl and heterocyclic radical; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R9 is independently selected from the group consisting of: hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclic radical, cycloalkyl, heterocyclic alkyl, haloalkyl, arylalkylamino, amino, aminoalkyl, aminoacyl, nitro, azido and heteroarylalkyl, wherein alkyl, aryl, heteroaryl, aminoalkyl or arylalkyl are optionally substituted with one or more radicals selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanate, isothiocyanate, alkyloxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy and heterocyclic radical optional substituted with alkyl, alkylamino, aminoalkyl, hydroxyalkyl and alkylaminoalkyl; R10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more selected radicals between alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy and heterocyclic radical; R 0 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy and heterocyclic radical; R11 is selected from the group consisting of: hydrido, halogen, haloalkyl, CN, CO2R5, lower alkyl, lower alkenyl, lower alkynyl, alkoxy and CONH2; R is selected from the group consisting of: hydrido, halogen, alkyl and alkoxy; R 13 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkio, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkio, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of group consisting of: OR 4, N (R 14) R 14 'and glycols; R14 is independently selected from the group consisting of: hydrido and lower alkyl; R14 is independently selected from the group consisting of: hydrido and lower alkyl; R15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic radical, alkylalkene, alkylaquin, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl and alkylsulfonyl; wherein aryl or arylalkio are optionally substituted with one or more radicals selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic radical; and R16 is independently selected from the group consisting of: hydrido, aryl, arylalkio, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, and alkoxyalkyl; or their isomers, tautomers, vehicles, esters and prodrugs, and their pharmaceutically acceptable salts. A preferred class of compounds is defined by means of Formula III wherein A is selected from the group consisting of: (CH2) m, wherein each CH2 may be independently substituted with one or more substitutions selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl , alkylamino, alkenyl and alkynyl; m is from 0 to 8; Q is a 5- or 6-membered heteroaryl, or an aryl, optionally saturated, or optionally substituted with R1, R2 or R12; B is an aromatic heterocyclic radical; R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO2, OR5, OCOOR5, CO2R7, CON (R6) R7, COR6, SR6, SOR6, S02R6, NR6R7 , NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7 and SO2N (R6) R7 in which R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from the group constituted by: S, SO, S02, O and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optionally substituted with hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, NO2, OR5, OCOOR5, CO2R7, CON (R6) R7 , COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7 and SO2N (R6) R7 in which R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing 1 to 3 heteroatoms substituted or unsubstituted, selected from the group consisting of: S, SO, SO2, O and NR6; R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, NO2, SR6, NHR6, CON (R6) R7, NHCONHR6, CO2H and haloalkyl; R1 and R2 can go together to form a saturated or unsaturated carbocyclic ring, of 5 to 7 members, optionally containing from 0 to 3 heteroatoms selected from the group consisting of: N, O, or S, and wherein said ring is optionally substituted with R; R3 is CONHR 6; R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, akoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic radical, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, SO2N (R8) R8 ', NHR9, NHCOR9, NR9COR9, NHCO (OR9), NR9CO (OR9), NR8SO2R10, NHSO2N (R10) R10', NR6CON (R0) R10 ', COR9, CO2R8, CON (R8) R8', wherein R8 and R8 'can go together to form a 3- to 7-membered carbocyclic ring, bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, SO2, O, N and NR6, and in that R10 and R10 can go together to form a 3- to 7-membered carbocyclic ring, carrying from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, SO2, O, N and NR6, wherein said aryl , heterocyclic radical, heteroaryl or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of group consisting of: OR14, N (R4) R14 'and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclic alkyl, and heterocyclic radical; R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclic alkyl and heterocyclic radical; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclic alkyl; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R9 is independently selected from the group consisting of: hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclic radical, cycloalkyl, heterocyclic alkyl, haloalkyl, arylalkylamino, amino, aminoalkyl, aminoacyl, nitro, azido and heteroarylalkyl, wherein alkyl, aryl, heteroaryl, aminoalkyl or arylalkyl are optionally substituted with one or more radicals selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, Haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkylloxy, phenoxy, nitro, azido, benzyloxy, dyalkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanate, isothiocyanate, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamine, alkenyl, alkynyldkylaminoalkyloxy and heterocyclic radical option ally substituted with alkyl, alkylamino, aminoalkyl, hydroxyalkyl and alkylaminoalkyl; R 0 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy and heterocyclic radical; R10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more selected radicals between alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy and heterocyclic radical; R11 is selected from the group consisting of: hydrido, halogen, haloalkyl, CN, C02R5, lower alkyl, lower alkenyl, lower alkynyl, alkoxy and CONH2; R 12 is selected from the group consisting of: hydrido, halogen, alkyl and alkoxy; R13 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of group consisting of: OR 4, N (R 4) R 14 and glycols; R14 is independently selected from the group consisting of: hydrido and lower alkyl; R14 is independently selected from the group consisting of: hydrido and lower alkyl; R15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic radical, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic radical; Y R16 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy and alkoxyalkyl; or their isomers, tautomers, vehicles, esters and prodrugs, and their pharmaceutically acceptable salts.

Definitions The present invention includes the use of all hydrates, solvates, complexes and prodrugs of the compounds of this invention. Prodrugs are compounds bound by covalent bonds, which release in vivo the active parenteral drug according to Formula I. If a chiral center or other form of an isomeric center is present in a compound of the present invention, all forms of that isomer or isomers, including enantiomers and diastereomers, are understood to be encompassed in this invention. The compounds containing a chiral center can be used in the form of a racemic mixture, a mixture enriched with enantiomers, or the racemic mixture can be separated using well-known techniques and a single enantiomer can be used alone. In cases where the compounds contain unsaturated carbon-carbon double bonds, both cis (Z) and trans (E) isomers are linked in the bond of this invention. In cases where the compounds can exist in tautomeric forms, such as the keto-enol tautomers, it is contemplated that each tautomeric form is included in this invention either existing in equilibrium or in one of the predominantly forms. The meaning of any substituent in any one of the formula I presentations or any of its sub-formulas is independent of its meaning, or the meaning of the other substituents, in any other presentation, unless otherwise specified. The present invention includes the use of all hydrates, solvates, complexes and prodrugs of the compounds of this invention. Prodrugs are compounds linked by covalent bonds, which release in vivo the active parenteral drug according to Formula I or Formula II. If its chiral center or other form of an isomeric center is present in a compound of the present invention, all forms of that isomer or isomers, including enantiomers and diastereomers, are understood to be encompassed by this invention. The compounds containing a chiral center can be used in the form of a racemic mixture, a mixture enriched with enantiomers, or the racemic mixture can be separated using well-known techniques and a single enantiomer can be used alone. In cases where the compounds contain unsaturated carbon-carbon double bonds, both cis (Z) and trans (E) isomers are included in the link of this invention. In cases where the compounds can exist in tautomeric forms, such as the keto-enol tautomers, it is contemplated that each tautomeric form is included in this invention either existing in equilibrium or in one of the predominantly forms. The meaning of any substituent in any one of the formula I or Formula II formulations or any of its sub-formulas is independent of its meaning, or the meaning of the other substituents, in any other presentation, unless otherwise specified. otherwise. The term "alkyl" is used either alone or included in other terms such as "haloalkyl" and "alkylsulfonyl"; covers linear or branched radicals containing from one to about twenty carbon atoms or, preferably, from one to about twelve carbon atoms. The most preferred alkyl radicals are the radicals of a "lower alkyl" containing from one to about ten carbon atoms. More preferred are lower alkyl radicals containing from one to about five carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl and the like. The term "hydride" indicates a single hydrogen atom (H). This hydrido radical can be linked, for example, to an oxygen atom to form a hydroxyl radical, or two hydrocarbon radicals can be attached to a carbon atom to form a methylene radical (-CH 2 -). The term "halo" means halogens such as fluorine, chlorine and bromine or iodine atoms. The term "haloalkyl" embraces radicals in which one or more of the carbon atoms of the alkyl is substituted with a halo as defined above. In particular, monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals are encompassed. A monohaloalkyl radical, for example, may contain a bromine, chlorine or fluorine atom within the radical. The dihalo radicals may contain two or more of these same halo atoms or a different halo radical combination, and the polyhaloalkyl radicals may contain more than two of these same halo atoms or a combination of different halo radicals. The term "hydroxyalkyl" embraces linear or branched alkyl radicals containing from one to about ten carbon atoms, some of which may be substituted with one or more hydroxyl radicals. The terms "alkoxy" and "alkoxyalkyl" embrace oxy-linear or branched radicals, each containing alkyl portions from one to about ten carbon atoms, such as the methoxy radical. The term "alkoxyalkyl" also embraces alkyl radicals that carry two or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. The "alkoxy" and "alkoxyalkyl" radicals may also be substituted with one or more halo atoms, such as fluorine, chlorine or bromine, to provide "haloalkoxy" or "haloalkoxyalkyl" radicals. Examples of "alkoxy" radicals include methoxy, butoxy and trifluoromethoxy. The term "aryl", either alone or in combination, means an aromatic carbocyclic system containing one, two or three rings, in which those rings may be linked together so that they may or may be fused together. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. The term "heterocyclic radical" embraces radicals having a ring conformation, saturated, partially saturated and unsaturated, containing heteroatoms, the heteroatoms being selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include pyrrolidyl and morpholinyl. The term "heteroaryl" embraces unsaturated heterocyclic radicals. Examples of unsaturated heterocyclic radicals, also referred to as "heteroaryls", include thienyl, pyrrolyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl and tetrazolyl. The term also encompasses radicals in which the heterocyclic radicals are fused to aryl radicals. Examples of such bicyclic fused radicals include benzofuran, benzothiophene and similar bicyclic radicals. The term "heterocyclic alkyl" embraces an alkyl attached to the heterocyclic radical. The term "sulfonyl", whether used alone or attached to other terms such as alkylsulfonyl, indicates divalent radicals -S02- respectively.

"Alkyl sulfonyl" embraces alkyl radicals attached to a sulfonyl radical, wherein alkyl is defined in the above-mentioned manner. The term "arylsulfonyl" embraces sulfonyl radicals substituted with an aryl radical. The terms "sulfamyl" or "sulfonamidyl", either alone or used with terms such as "N-alkylsulfamyl", "N-arylsulfamyl", "?,? - dialkylsulfamyl" and "N-alkyl-N-arylsulfamyl", indicate a sulfonyl radical substituted with an amino radical, forming a sulfonamide (-SO2-NH2). The terms "N-alkylsulfamyl" and "α, β-dialkylsulfamyl" indicate substituted sulfamyl radicals, respectively, with a single alkyl radical, with a cycloalkyl ring, or with two alkyl radicals. The terms "N-arylsulfamyl" and "N-alkyl-N-arylsulfamyl" indicate substituted sulfamyl radicals, respectively, with a single aryl radical, and with an alkyl radical and an aryl radical. The terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", denote -CO2H. The term "carboxyalicyl" embraces radicals containing a carboxy radical as defined above, attached to an alkyl radical. The term "carbonyl", whether used alone or with other terms, such as "alkylcarbonyl", indicates - (C = O) -. The term "alkylcarbonyl" embraces radicals containing a carbonyl radical substituted with an alkyl radical. An example of an "alkylcarbonyl" radical is CH3- (C = 0) -. The term "alkylcarbonylalkyl" denotes an alkyl radical substituted with an "alkylcarbonyl" radical. The term "alkoxycarbonyl" denotes a radical containing an alkoxy radical, as defined above, linked through an oxygen atom to a carbonyl radical (C = O). Examples of such "alkoxycarbonyl" radicals include (CH3) 3CO-C (= 0) - and - (0 =) C-OCH3. The term "alkoxycarbonylalkyl" embraces radicals containing an "alkoxycarbonyl" as defined above, as a substituent on an alkyl radical. Examples of such "alkoxycarbonylalkyl" include radicals (CH3) 3COC (= 0) (CH2) 2- and - (CH2) 2 (0 =) COCH3. The term "amido" when used alone or with other terms, such as "amidoalkyl", "N-monoalkylamido", "N-monaryl-amido", "?,? - dialkylamido", "N-alkyl-N-arylamido "," N-alkyl-N-hydroxyamido "and" N-alkyl-N-hydroxyamidoalkyl "embraces a carbonyl radical substituted with an amino radical. The terms "N-alkylamido" and "α, β-dialkylamido" indicate amido groups that have been substituted with an alkyl radical and with two alkyl radicals, respectively. The terms "N-monoarylamido" and "N-alkyl-N-arylamido" denote amido radicals substituted, respectively, with an aryl radical, and with an alkyl radical and an aryl radical. The term "N-alkyl-N-hydroxyamido" embraces amido radicals substituted with a hydroxy radical and with an alkyl radical. The term "N-alkyl-N-hydroxyamidoalkyl" embraces alkyl radicals substituted with an N-alkyl-N-hydroxyamido radical. The term "amidoalkyl" embraces alkyl radicals substituted with amino radicals. The term "alkylaminoalkyl" embraces aminoalkyl radicals which carry the nitrogen atom substituted with an alkyl radical. The term "amidino" denotes a radical -C (= NH) -NH2. The term "cyanoamidino" denotes a radical -C (= N-CN) NH2. The term "heterocycloalkyl" embraces alkyl radicals substituted with a heterocyclic radical, such as pyridylmethyl and thienylmethyl. The term "aralkyl" embraces alkyl radicals substituted with an aryl, such as benzyl, diphenylmethyl, triphenylmethyl, phenethyl and diphenethyl. The terms benzyl and phenylmethyl are interchangeable. The term "cycloalkyl" embraces radicals having from three to ten carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "cycloalkenyl" embraces unsaturated radicals having from three to ten carbon atoms, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexeniio and cycloheptenyl. The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, from one to ten carbon atoms, attached to a divalent sulfur atom. An example of "alkylthio" is methylthio, (CH3-S-). The term "alkylsulfinyl" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent atom -S (= 0) -. The terms "N-alkylamino" and "N, N-dialkylamino", indicate amino groups that have been substituted with an alkyl radical and with two alkyl radicals, respectively. The term "acyl", whether used alone, or within a term such as "acylamino", indicates a radical provided by the residue after removing the hydroxyl from an organic acid. The term "acylamino" embraces an amino radical substituted with an acyl group. An example of the radical "acylamino" is acetylamino (CH3C (= 0) -ÑH-). Another aspect of the present invention is constituted by chemical intermediates of the synthesis of the claimed compounds. Another aspect of the present invention are methods of synthesis of the claimed compounds.

The compounds of Formula I or Formula II would be useful for, but not limited to, the treatment of inflammation in a patient, and for the treatment of other inflammatory diseases, as in the case of an analgesic in the treatment of pain. and of headaches, or of an antipyretic in the treatment of fever. For example, compounds of Formula I or Formula II would be useful in the treatment of arthritis, including, but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis. These compounds of Formula I or Formula II would be useful in the treatment of asthma, bronchitis, dysmenorrhea, tendinitis, bursitis and dermatological diseases such as psoriasis, eczema, burns and dermatitis. The compounds of Formula I or Formula II would also be useful for treating gastrointestinal diseases such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis, and for the prevention of colorectal cancer. The compounds of Formula I or Formula II would be useful in the treatment of inflammation in diseases of the vascular disease type such as vascularitis, migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type diabetes I, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet syndrome, polymyositis, gingivitis, hypersensitivity, conjunctivitis, swelling after trauma, myocardial ischemia and similar diseases. The compounds of the present invention can also be used for pain. These compounds are useful as anti-inflammatory agents, as for example, in the treatment of arthritis, with the additional benefit of having significantly less harmful side effects. The compounds of Formula I or II are useful as agents for the treatment of cancer or as anticancer agents. The compounds of Formulas I or II can be proapoptosis, antiapoptosis, antiprogression of the cell cycle, antiinvasive, antiproliferative, anti-angiogenic and anti-metastatic. The cancer can be colon, ovarian, breast, prostate, gastric, B-cell lymphoma and multiple myeloma. More specifically, the compounds of this invention are useful in the treatment of various types of cancer including, but not limited to: carcinoma such as carcinoma of bladder, breast, colon, kidney, liver, lung, including small cell cancer of lung, esophagus, gallbladder, ovaries, pancreas, cervix, thyroid, prostate and skin, including squamous cell carcinoma; hematopoietic tumors of the lymphoid lineage including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of the myeloid lineage including acute and chronic myelogenous leukaemias, myelodiplasic syndrome and promyelocytic leukemia; tumors of mesenchymal origin including fibrosarcoma and rhabdomyosarcoma; tumors of the central nervous system and the peripheral nervous system, including astrocytoma, neuroblatoma, glioma, and schwannomas; other tumors, including melanoma, seminoma, taratocarcinoma, osteosarcoma, xeroderma pigmentosusm, keratoxanthoma, follicular thyroid cancer, and Kaposi's sarcoma. Due to the key role of protein kinases in the regulation of cell proliferation, these compounds are also useful in the treatment of various proliferative cell diseases such as, for example, benign prostatic hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis, proliferation of smooth vascular cells associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis, and postoperative stenosis and restenosis. The compounds of Formula I or II can be used as antiviral agents. The compounds of this invention are useful as inhibitors of protein kinases. The compounds of this invention are useful as inhibitors of IKK1 and / or IKK2, of the heterodimer ??? a / ??? ß, TBK or Ikk /. The compounds of this invention may also be useful as inhibitors of other protein kinases such as, for example, protein kinase C in their different isoforms, cyclin-depen kinase (cdk) ("c ciin depen kinase"), Met, PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Aurora 1, Aurora 2, Bub-1, PLK, Chk1, Chk2, HER2, Rafl, EK1, MAPK, EGF-R, PDGF-R, FGF-R, IGF-R, VEGF-R, P13K, weel kinase, Src, Abl, Akt, ILK, MK-2 Cdc7, Nek, and therefore are effective in the treatment of diseases associated with other protein kinases. The present invention preferably includes compounds, which selectively inhibit IKK2 relative to other kinases. Preferably those compounds have a selectivity value of inhibition of IKK2 relative to the inhibition of other kinases of at least 50, and more preferably of; at least 100. The present invention preferably includes compounds that selectively inhibit IKK2 relative to IKK1. Preferably, the compounds have an IC50 for IKK2 of less than 1 μ ?, and have a selectivity value of inhibition of IKK2 relative to the inhibition of IKK1 of at least 50, and more preferably of at least 100. Even more preferably, the compounds have an IC50 for IKK1 greater than 10 μ? and more preferably greater than 100 μ ?. The compounds of the Formula can also be used to treat cardiovascular, ophthalmological and osteoporotic diseases associated with angiogenesis. The compounds of the present invention can also be used in the treatment of knee injuries such as sports injuries. Although it is possible for an active ingredient to be administered alone in the form of an unprocessed chemical compound, it is preferable to present it in the form of a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in association with at least one carrier, pharmaceutically acceptable adjuvant or diluent. The present invention also comprises a method for treating inflammation or inflammatory diseases in a patient, which method comprises administering to the patient presenting this inflammation or those inflammatory diseases, a therapeutically effective amount of a compound of the present invention. Also included in the family of compounds of the present invention are their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" encompasses salts normally used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds of the present invention can be prepared from an inorganic acid or an organic acid. Examples of these inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acids. Suitable organic acids may be selected from the classes of aliphatic organic acids, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric , citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzene sulfonic acid, pantothenic, toluenesulfonic, 2- hydroxylethanesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, beta-hydroxybutyric, salicyclic, galactharic and galacturonic. The suitable addition salts and pharmaceutically acceptable compounds of the present invention include metallic salts made based aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N, N'-dibencilet¡lendiamina , chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. All these salts can be prepared by conventional means from the corresponding compound of the present invention, by reacting, for example, the appropriate acid or base with the compound of the present invention. Also encompassed within this invention are pharmaceutical compositions comprising one or more compounds of the present invention, in association with one or more carriers and / or diluents and / or adjuvants and / or non-toxic pharmaceutically acceptable (here called excipients such are collective "vehicle" materials) and, if desired, other active ingredients. Therefore, the compounds of the present invention can be used in the manufacture of a medicament. The pharmaceutical compositions of the compounds of the present invention, prepared in the manner described above, may be formulated in the form of a solution or lyophilized powders for parenteral administration. The powders can be reconstituted by adding a suitable diluent or another pharmaceutically acceptable carrier before use. The liquid formulation can be an aqueous solution, buffered and isotonic. The compounds of the present invention can be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to that route, and in an effective dose for the desired treatment. The compounds and composition can be administered, for example, intravascularly, intraperitoneally, intravenously, subcutaneously, intramuscularly, intramedullary, orally or topically. For oral administration, the pharmaceutical composition may be in the form of, for example, tablet, capsule, suspension or liquid. The active ingredient can also be administered by injection in the form of a composition in which, for example, normal saline solution, 5% dextrose standard solution in water or a buffered sodium acetate solution can be used as the suitable vehicle. Ammonium This formulation is especially suitable for parenteral administration, but it can also be used for oral administration or it can be introduced into a metered dose inhaler or into a nebulizer for insufflation. It may be convenient to add excipients such as poly (vinylpyrrolidone), gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. The pharmaceutical composition is preferably prepared in the form of a dosage unit containing a particular amount of the active ingredient. Examples of those dosage units are tablets or capsules. The amount of therapeutically active compound that is administered and the dosage schedule indicated for treating a disease with the compound and / or compositions of this invention, depend on several factors, including the age, weight, sex and health status of the patient, of the severity of the disease, of the route and frequency of administration, and of the particular compound used, and therefore, can vary widely. The pharmaceutical composition may contain the active ingredient in the range of from about 0.1 mg to 2,000 mg, preferably in the range of from about 0.5 mg to 500 mg, and more preferably between about 1 mg and 100 mg. A daily dose of about 0.01 to 100 mg / kg of body weight, preferably between about 0.1 mg / kg and about 50 mg / kg of body weight, and more preferably between about 1 to 20 mg / kg of weight may be appropriate. bodily. The daily dose can be administered in one to four doses per day. For therapeutic purposes, the compounds of this invention are usually combined with one or more appropriate adjuvants by the indicated route of administration. If administered orally, the compounds can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, alkyl cellulose esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of the phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, poly (vinylpyrrolidone) and / or poly (vinyl alcohol), and can then be compressed or encapsulated for the appropriate administration. These capsules or tablets may contain a controlled release formulation such as that which can be provided in a dispersion of the active compound in a prolonged release material, such as glyceryl monostearate, glyceryl distearate, hydroxypropylmethylcellulose alone or with a wax. Formulations for parenteral administration may be in the form of sterile and sterile solutions or suspensions for injection, aqueous or non-aqueous. These solutions and suspensions can be prepared from sterile powders or granules containing one or more of the mentioned carriers or diluents for use in the formulations for oral administration. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and / or various buffers. Pharmaceutical preparations are made following conventional pharmacy techniques that include, grind, mix, granulate and compress, as needed, for tablet forms; or grind, mix and fill, to form hard gelatin capsules. When a liquid carrier is used, the preparation will be in the form of syrup, elixir, emulsion, or an aqueous or non-aqueous suspension. This liquid formulation can be administered orally or can be filled into a soft gelatin capsule. For rectal administration, the compounds of the present invention can also be mixed with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository. The methods of the present invention include topical administration of the compounds of the present invention. Topical administration means non-systemic administration, including the application of a compound of the invention externally in the epidermis, in the buccal cavity or the instillation of that compound within the ear, eye and nose, so that the compound does not enter significant way in the bloodstream. By systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration. The amount of a compound of the present invention (hereinafter referred to as the active ingredient), required to obtain a therapeutic or prophylactic effect after its topical administration, will of course vary according to the compound chosen, the nature and the severity of the disease that is present. being treated and the animal that undergoes the treatment, and will ultimately depend on the medical criterion. The topical formulations of the present invention, both for veterinary use and for medical use in humans, comprise an active ingredient together with one or more acceptable carriers therefor, and optionally other therapeutic components. The vehicle can be "acceptable" in the sense of being compatible with the other components of the formulation, and of being non-deleterious to the recipient thereof. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the place where the treatment is required, such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration in the eye, ear and nose. The active principle may constitute, in the case of topical administration, 0.01% to 5.0% by weight of the formulation. The drops according to the present invention can comprise sterile aqueous solutions or suspensions or oily solutions and can be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and / or fungicidal agent and / or of any other suitable preservative, and preferably including a surfactant. The resulting solution can then be clarified by filtration, transferred to a suitable container, which is then sealed and sterilized in an autoclave or maintained at a temperature of 90 ° C-100 ° C for half an hour. Alternatively, the solution can be sterilized by filtration and transferred to the vessel by aseptic technique. Examples of suitable bactericidal and fungicidal agents for inclusion in the drops are nitrate or phenylmercuric acetate (0.00217 c), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an aqueous solution include glycerol, dilute alcohol and propylene glycol. Lotions according to the present invention include lotions suitable for application to the skin or eyes. An ocular lotion may comprise a sterile aqueous solution, optionally containing a bactericide, and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent for accelerating the drying and cooling of the skin, such as an alcohol or acetone, and / or a moisturizing agent such as glycerol or an oil such as castor oil or peanut oil. . The creams, ointments or pastes according to the present invention are semisolid formulations of the active ingredient for external application. They can be made by mixing the active ingredient in a finely divided form or in powder form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the help of the appropriate machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap, a mucilage; an oil of natural origin such as almond, corn, peanut, castor or olive oil; wool fat or its derivatives, or a fatty acid such as stearic acid or oleic acid together with an alcohol such as propylene glycol or macrogols. The formulation may incorporate some suitable surfactant such as an anionic, cationic or nonionic surfactant, such as sorbitan esters or their polyoxyethylene derivatives. Suspension promoting agents such as natural drops, cellulose derivatives, or inorganic materials such silicas, siliceous, and other components such as lanolin may also be included. Other adjuvants and modes of administration are well known and widely used in the pharmaceutical art. Although this invention has been described with respect to specific embodiments, the details of these embodiments should not be construed as limitations.

General Synthesis Procedures The starting materials used herein are commercially available or are prepared by routine methods well known to those of ordinary skill in the art and can be found in standard reference books, such as COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I -IV (published by Wiley-lnterscience). The compounds of the invention can be synthesized according to the following procedures of Schemes I-XVI, wherein the substituents R1-R7 and the linker group A are as defined for Formula I and Formula II, wherein above, except where indicated below.

Synthesis Scheme I illustrates the procedure used to prepare the anti-inflammatory pyrazoles of the present invention. 1,3-dicarbonyl compounds, such as compound 1, or the enol form shown which is in equilibrium with 1,3-diketone, are allowed to react with a substituted hydrazine hydrochloride 2 in hot methanol or ethanol or acetic acid to obtain pyrazoles 3 through a condensation reaction.

SCHEME II 1 4 Synthesis Scheme II illustrates the process for the preparation of substituted diketones 1. An appropriately substituted acetone, including, but not limited to: indanones, 3-coumaranones, 3-thiocumaranones, 3-azocumaranones, 1-tetralones, chromanones, Thiochromanones, azacromanones, isochromanones, isothiochromones, isoazachromanones, 4 are first treated with a base, such as sodium methoxide, lithium bistrimethylsilylamide or lithium diisopropylamide (LDA), followed by condensation with a suitable acylating agent, such as oxalate. dimethyl or diethyl, in an appropriate solvent, such as methanol, diethyl ether or tetrahydrofuran, to obtain 1,3-dicarbonyl compounds, 1, which are suitable for conversion to anti-inflammatory pyrazoles, as illustrated in Scheme I. Alternatively, the dicarbonyl compounds 1 can be prepared directly from commercially available cyclic ketones 4.

SCHEME III Synthesis Scheme III illustrates the three-step procedure for the preparation of substituted isothiochromones. In step one, an appropriately substituted benzyl alcohol is converted into the corresponding benzyl chloride by stirring with concentrated hydrochloric acid and immediately afterwards converted to a thiouronium salt 6 after treatment with refluxing thiourea. In step two, the thiouronium salt is converted to the free mercaptide, according to the procedure of Lumma and Berchtold (J. Org. Chem., 34, 1566 (1969)), and then captured with chloroacetic acid or a salt related to obtain the acetic acid derivatives 7. In step three, the acids 7 are reacted with trifluoroacetic anhydride (TFAA) in trifluoroacetic acid (TFA) to obtain the products of isothiochromones 8. The salts of thiouronium 6 can also be prepared from appropriate benzyl halides, commercially available.

Synthesis scheme IV illustrates the three-step procedure for the preparation of substituted thiochromanones. In step one, an appropriate substituted thiophenol 9 is converted into the corresponding propionic acid derivatives after treatment with acrylic acid at a temperature in the range from room temperature to about 50 ° C. In step two, the propionic acids 10 are subjected to treatment with a mixture of trifluoroacetic anhydride and trifluoroacetic acid to effect an intramolecular Friedel-Crafts acylation, thus obtaining thiochromanones 1. Alternatively, the Friedel-Crafts acylation can be carried out with H2S04. The dicarbonyl compounds 1 can also be prepared directly from thiochromanones available commercially.

SCHEME V Synthesis Scheme V illustrates the three-step procedure for the preparation of substituted azacromanones. In stage one, a suitable substituted aniline 12 is converted into the corresponding propionic acid derivatives 13 after treatment with acrylic acid at a temperature in the range from room temperature to about 50 ° C. In step two, the propionic acids 13 are subjected to treatment with a mixture of? 2 = 04 to effect an intramolecular Friedel-Crafts acylation, thereby obtaining azacromanones 14. The dicarbonyl compounds 1 can also be prepared directly from azacromanones. commercially available. The adequate protection of nitrogen aza is carried out when necessary using protective groups such as benzyl, benzoyl, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc) or sulfonamido groups (mesyl, Ms or tosyl, Ts).

SCHEME VI Synthesis Scheme VI details the three-step procedure used to prepare substituted chromanone derivatives 17. In step one, substituted phenols are condensed with acrylic acid to obtain 3-phenoxypropionic acid 16. In step two, acids 16 treated with a mixture of trifluoroacetic anhydride and trifluoroacetic acid to effect an intramolecular Friedel-Crafts acylation that results in selected chromanones 17. Alternatively, the Friedel-Crafts acylation can be carried out with H2SO4. The dicarbonyl compounds 1 can be formed directly from commercially available chromanones 17.

SCHEME VII Synthesis Scheme VII illustrates a process used to prepare isochromanone derivatives 19. In step one, selected benzyl alcohol derivatives 5 are treated with sodium hydride or other suitable base and then treated with ethyl bromoacetate to obtain the desired ethers. . In step two, the ester group of the compounds 18 is hydrolyzed with aqueous sodium hydroxide and then treated with a mixture of trifluoroacetic acid and trifluoroacetic anhydride to promote an intramolecular Friedel-Crafts acylation that gives rise to isocromanone derivatives 19.

SCHEME VIII Synthesis Scheme VIII illustrates a process used to prepare isoazochromanone derivatives 22. In step one, selected benzylamine derivatives are treated with ethyl bromoacetate and with an appropriate acid scavenger, such as triethylamine, to obtain the desired amines. . In step two, the ester group of compounds 21 is hydrolyzed with aqueous sodium hydroxide and then treated with a mixture of trifluoroacetic acid and trifluoroacetic anhydride to promote an intramolecular Friedel-Crafts acylation resulting in isocromanone derivatives 22. Adequate protection of nitrogen aza is carried out when necessary using protecting groups such as benzyl, benzoyl, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc) or sulfonamido groups (mesyl, Ms or tosyl, Ts).

Synthesis Scheme IX illustrates a procedure used to prepare substituted 3-coumaronones 24. Phenols 15 are first treated with a base, such as NaOH, lithium diisopropylamide (LDA) or sodium methoxide, followed by condensation with ethyl bromoacetate in a solvent suitable as diethyl ether, ethanol or tetrahydrofuran to obtain phenoxyacetate 23. In step two, the ester group of compound 23 is hydrolysed with aqueous sodium hydroxide and then treated with a mixture of trifluoroacetic acid and trifluoroacetic anhydride to promote an acylation of Friedel-Crafts intramolecular that gives rise to derivatives of 3-coumaranones SCHEME X Synthesis Scheme X illustrates a procedure used to prepare substituted 3-azacumaranones 26. Anilines 12 are treated with an acid scavenger, such as triethylamine, followed by alkylation with ethyl bromoacetate in an appropriate solvent such as diethyl ether, ethanol or tetrahydrofuran to obtain the phenoxyacetate 25. In step two, the ester group of compound 25 is hydrolysed with aqueous sodium hydroxide and then treated with a mixture of trifluoroacetic acid and trifluoroacetic anhydride to promote an intramolecular Friedel-Crafts acne which results in 3-azacumaranone derivatives 25. Adequate protection of aza nitrogen is carried out when necessary using protective groups such as benzyl, benzoyl, benzyloxycarbonium (Cbz), t-butoxycarbonyl (Boc) or sulfonamido groups (mesyl, Ms or tosyl, Ts) .

SCHEME XI Synthesis Scheme XI illustrates a procedure used to prepare substituted 3-thiocumaranones 28. Thiophenols 9 are first treated with a base, such as NaOH, lithium diisopropylamide (LDA) or sodium methoxide, followed by condensation with ethyl bromoacetate in a solvent Such as diethyl ether, ethanol or tetrahydrofuran to obtain phenoxyacetate 27. In step two, the ester group of compound 27 is hydrolyzed with aqueous sodium hydroxide and then treated with a mixture of trifluoroacetic acid and trifluoroacetic anhydride to promote an acylation of Friedel-Crafts intramolecular that gives rise to derivatives of 3-coumaranones 28.

SCHEME XII O 29 30 5 Synthesis Scheme XII illustrates a two-stage process for the preparation of substituted benzylic alcohols 5. In step one, a mixture of potassium tert-butoxide and anhydrous tetrahydrofuran, cooled to a temperature of -78 ° C and treated with a 1.6 M solution of n-butyl lithium in hexanes, is added to an appropriate substituted benzene 29, the anion thus generated is reacted with carbon dioxide to obtain the benzoic acid 30. In step two, the Benzoic acid 30 is dissolved in a solvent, such as tetrahydrofuran, and treated with a reducing agent, such as a complex of borane dimethyl sulfide, to form the desired benzyl alcohol.

SCHEME XIII Scheme XIII describes the synthesis of pyrazoles with fused heterocycles such as substituted pyrimidine and pyrazole. In step one,, 2-cyclohexanedione (31) was brought to reflux with alcohols such as methanol or ethanol in benzene to provide the desired enone (32). In step two, enone 32 was treated with a base such as lithium bistrimethylsilylamide, followed by condensation with diethyl oxylate to give 1,3-diketone (33). In step three, 1,3-diketone was allowed to react with an appropriately substituted phenylhydrazine to form pyrazole 34. Suitable substituents could be, but are not limited to: methyl sulfone or sulfonamide, which may be protected. A suitable protecting group for the sulfonamide is 2,5-dimethylpyrrole. In step 4, the pyrazole was treated with di-tert-butylacetal of dimethylformamide to obtain enaminone 35. In step five, the enaminone is condensed with cyclization agents such as hydrazine, guanidine or thiourea to give pyrazoles and fused pyrimidines 36. In the last step, the ester was converted to amide 37 by treatment with ammonium hydroxide in methanol. In the case of the compounds in which the sulfonamide is protected with 2,5-dimethylpyrrole, the deprotection is carried out by treatment with refluxing trifluoroacetic acid with water.

SCHEME XIV Synthesis Scheme XIV illustrates a procedure used for the preparation of the 3-merged, anti-infammatory tricyclic pyrazoles containing the oxidized thio group. The appropriate pyrazole 3 of scheme I, wherein A is S or - (CH 2) mS (CH) 2) n-, is treated with an oxidizing agent such as m-chloroperbenzoic acid (MCPBA) hydrogen peroxide, peracids or peroxymonosulfate of potassium Compounds with different amounts of oxidation (sulfinyls and sulfones) can be prepared by controlling the stoichiometry of the oxidant relative to the sulfide or can be separated by chromatography.

SCHEME XV Scheme XV illustrates a method for the preparation of substituted ariihydrazines 2. Anilines 12 can be treated with hydroxylamine-O-sulfonic acid to generate aridihydrazines 2 (JOC, 14, 813, 1949). The anilines 12 can also be subjected to diazotization using sodium nitrite, or an alkyl nitrite, followed by a catalytic reduction to generate aridihydrazines 2. In selected cases, suitably activated aryl rings, such as 4-fluoronitrobenzene or 4-fluorophenylmethylsulfone (EWG = group Electron withdrawals (such as nitro or methylsulfone) can be converted into aryhydrazines through the displacement of fluorine with hydrazine or a carbazate, followed by hydrolysis of the protecting group.

SCHEME XVI Synthesis Scheme XVI shows methods for preparing anti-inflammatory agents 3 of Formula I, wherein R 3 = OCH 3 is converted to OH or NHR 7 Esters 1, R 3 = OCH 3, which can be prepared as shown in Scheme I, are Dissolve in aqueous methanol and add a base such as 10% NaOH. The reaction is stirred at room temperature or heated to reflux to obtain the acids 3, R3 = OH. The acids 3, R3 = OH, can be converted into the appropriate amides 3, the acids 3, R3 = NHR7, dissolving them in methanol and treating them with an appropriate amine in the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC) or carbonyldiimidazole (CDI). The amides 3, R3 = NHR7, can also be prepared by direct aminolysis of 3, R3 = OCH3. The following examples contain detailed descriptions of the methods of preparation of the compounds of Formula I. These detailed descriptions are included in the scope of the invention and serve as examples of the general synthesis procedures described above forming part of the invention. These detailed descriptions are presented for illustrative purposes only and are not to be construed as restricting the scope of the invention. All parts are expressed by weight and temperatures are expressed in degrees centigrade unless otherwise indicated. The compounds of the present invention can be synthesized according to the methods of the U.S.A. No. 5,547,975 The complete contents of all the publications, patents and patent applications cited in this description are incorporated herein by reference as if each publication, patent or patent application individually was specifically and individually indicated to be incorporated as a reference. . Although the invention discussed above has been described in some detail by way of illustration and examples for the purpose of achieving clarity of understanding, it will be apparent to the person skilled in the art in light of the teachings of this invention, that Changes and modifications can be made without departing from the spirit and scope of the present invention. The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention, which has been described broadly in the foregoing.

EXAMPLES EXAMPLE 1 1-. { 4-r (aminothio) peroxyphenyl} -8-Nitro-4,5-dihydro-1 H-benzofq] ndazole-3-ethyl carboxylate To 7-n-tetra-1-tetralone (4.6 g, 0.024 mole) and ethyl oxalate (3.5 ml, 0.026 mole) in ether (100 ml), bis (trimethylsilyl) amide was added dropwise. lithium (1 M in THF, 26 ml). The suspension was stirred overnight and filtered to obtain the product as an olive green solid, 6.2 g (87% yield). H-NMR (DMSO-d6 / 300 MHz) 8.45 (d, 1 H); 8.05 (d of d, 1 H); 7.42 (d, 1 H); 4.08 (q, 2H); 2.82-2.72 (m, 2H); 2.51-2.43 (m, 2H); 1.21 (t, 3H).

Stage 2 The material of stage 1 (6.2 g, 0.021 moles) and the hydrochloride of 4-Sulfonamidophenylhydrazine (5.1 g, 0.023 mol) was stirred in methanol (100 ml) overnight. To the slurry was added concentrated HCl (2 mL) and the contents were heated in a steam bath for 1 hour. The contents were allowed to cool and filtered to obtain an off white solid 6.9 g. NMR and LC / MS analysis show that the solid contains two components, the desired one and the hydrated pyrazole. To the solid were added TFA (60 ml) and TFAA (20 ml) and heated in a steam bath for 1 hour. The contents were concentrated in vacuo giving the product as a 6.4 g solid (69% yield). FABHRMS m / z 443.1020 (M + H, CzoH ^ OeS requires 443. 1025). 1 H-NMR (D SO-d 6/300 MHz) 8.10 (d of d, 1 H); 8.03 (d, 2H); 7.82 (d, 2H); 7.70 (d, 1 H); 7.62 (s, 1 H); 7.50 (d, 1H); 4.33 (q, 2H); 3.20-2.95 (m, 4H); 1.33 (t, 3H). Analysis, calculated for C2oHi8N406S: C, 54.29; H, 4.10; N, 12.66. Found: C, 54.49; H, 4.00; N, 12.52.

EXAMPLE 2 1-. { 4-r (aminothio) peroxyphenyl} -8-nitro-4,5-dihydro-1H-benzo [q1indazol-3-carboxamide] The final product of Example 1 (718 mg, 0.0016 mole), concentrated ammonium hydroxide (30 ml) and methanol (15 ml) were stirred in a stoppered flask for 72 hours. The contents were filtered to obtain a light amber solid (606 mg). The solid was recrystallized from acetonitrile to obtain the product as a light amber solid, 450 mg (68% yield). FABHRMS m / z 414.0902 (M + H, Ci8Hie 505S requires 414. 0872).

H-NMR (DMSO-d6 / 300 MHz) 8.15-7.95 (m, 3H); 7.83 (d, 2H); 7.80-7.40 (m, 6H); 3.20-2.95 (m, 4H). Analysis, calculated for C ^ H ^ NsC-sS: C, 52.30; H, 3.66; N, 16. 94. Found: C, 52.04; H, 3.64; N, 16.61.

EXAMPLE 3 8-amino-1-r 4 - (aminosulfonyl) phenyl} -4,5-dihydro-1 H-benzofqlinda2ol-3-ethyl carboxylate The final product of Example 1 (2.0 g) and Pd / C (350 mg) in DMF (20 ml) were stirred at a hydrogen pressure of 3.74 atm (55 psi) for 3 hours. The contents were filtered and the filtrate was concentrated in vacuo to give an amber colored wax. The wax was triturated with methanol and filtered to obtain the product as a light amber solid, 1.6 mg (86% yield). FABHRMS m / z 413.1293 (M + H, C20H2iN4O4S requires 413. 1284). 1 H-NMR (DMSO-de / 300 MHz) 8.00 (d, 2H); 7.73 (d, 2H); 7.50 (s, 2H); 7.01 (d, 1 H); 6.43 (d of d, 1 H); 6.00 (d, 1 H); 4.83 (broad s, 2H); 4.30 (q, 2H); 2.85-2.70 (m, 4H); 1.31 (t, 3H). Analysis, calculated for C2oH2oN404S (0.25 H20): C, 57.61; H, 4.96; N, 13.44. Found: C, 57.62; H, 5.11; N, 13.15.

EXAMPLE 4 8-amino-1-. { 4-r (aminothio) peroxy-phenyl} -4,5-dihydro-1H-benzofg1indazol-3-carboxamide Example 4 was prepared in a manner similar to Example 2 in 70% yield. FABHRMS m / z 384.1 136 (M + H, C18H18N503S requires 384. 1130). 1 H-NMR (DMSO-d 6/300 MHz) 7.95 (d, 2H); 7.75 (d, 2H); 7.53 (s, width, 1 H); 7.43 (broad s, 1 H); 7.32 (broad s, 1 H); 7.01 (d, H); 6.44 (d of d, 1 H); 6.03 (s, 1 H); 4.81 (s, 2H); 2.93-2.65 (m, 4H).

Analysis, calculated for C-18H17N5O3S 18.27. Found: C, 56.31; H, 4.42; N, 18.31.

EXAMPLE 5 A 6-hydroxy-1-tetralone (10.4 g, 0.064 moles) and ethyl oxalate (17.4 mL, 0.128 mol) in THF (100 mL), lithium bis (trimethylsilyl) amide (1 in THF) was added dropwise., 130 mi). The suspension was stirred overnight and filtered to obtain a solid. The solid was dissolved in water and acidified to pH 2.5 with 3 N HCl, precipitating a waxy solid. The waxy solid was extracted into EtOAc, dried (MgSO4) and concentrated in vacuo to give a dark solid (15.7 g). The solid was purified by chromatography on silica gel eluting with 15% EtOAc / hexane to obtain a yellow solid (5.9 g). The solid was recrystallized from EtOAc / hexanes to obtain the product as a yellow solid, 3.7 g (22% yield). FABHRMS m / z 263.0925 (M + H, C14H15O5 requires 263.0919). 1 H-NMR (CDCl 3 / 3OO MHz) 7.93 (d, 1 H); 6.80 (d of d, 1 H); 6.68 (s, 1 H); 5.72 (s, 1 H); 4.39 (q, 2H); 3.00-2.75 (m, 4H); 1 .40 (t, 3H). Analysis, calculated for C 14 H 1405: C, 64.12; H, 5.38.

Found: C, 63.79; H, 5.35.

EXAMPLE 6 1-f4- (Aminosulfonyl) phen-7-hydroxy-4,5-dihydro-1H-benzo q] indazole-3-ethyl carboxylate The material prepared in Example 5 (2.0 g, 0.0076 mol) and 4-sulfonamidophenylhydrazine hydrochloride (1.9 g, 0.0085) were stirred in glacial acetic acid (25 ml) for 96 hours. The contents were heated at 55 ° C for 5 hours, allowed to cool, diluted with water (75 ml) and filtered to obtain the product as a white solid, 3.1 g (90% yield). FABHRMS m / z 414.1146 (M + H, C20H20N3O5S requires 414. 1124). 1 H-NMR (D SO-d 6/300 MHz) 9.72 (s, 1 H); 8.00 (d, 2H); 7.73 (d, 2H); 7.53 (s, 1 H); 6.80 (s, H); 6.60-6.40 (m, 2H); 4.30 (q, 2H); 2.90 (s, 2H); 1.30 (t, 3H). Analysis, calculated for C2oHi gN305 (0.2 H20): C, 57.60; H, 4.69; N, 10.08. Found: C, 57.72; H, 4.91; N, 9.68 EXAMPLE 7 1- [4- (Aminosulfonyl) phenyl-6-benzyl-1,4,516-tetrahydropyrrolor-2,3-q] indazole-3-carboxylate ethyl Stage 1 To 1, 5,6,7-tetrahydro-4H-indol-4-one (5.0 g, 0.037 mole) in DMF (20 mL) were added benzyl chloride (4.4 mL, 0.038 mole) and potassium carbonate (5.3 g, 0.038 moles). The contents were heated to a temperature of 70 ° C overnight. The contents were allowed to cool and partitioned between EtOAc and water. The EtOAc layer was dried (MgSO4) and concentrated in vacuo to give an amber oil, 7.9 g. The oil was purified by chromatography on silica gel, eluting with 25% EtOAc / hexanes to obtain the desired product as a white solid, 7.1 g (85% yield). FABHRMS m / z 226.1213 (M + H, Ci5H16NO, requires 226. 232). 1 H-NMR (CDCl 3/300 MHz) 7.40-7.28 (m, 3H); 7.10-7.00 (m, 2H); 6.63-6.53 (m, 2H); 5.02 (s, 2H); 2.70-2.60 (m, 2H); 2.50-2.40 (m, 2H); 2.10-2.06 (m, 2H). Analysis, calculated for C15H15NO: C, 79.97; H, 6.71; N, 6.22. Found: C, 79.90; H, 6.65; N 6.09.

Stage 2 The product of step 2 was prepared in a similar manner to example 5, starting from the material of step 1 and with a yield of 67%. FABHRMS m / z 326.1393 (M + H, C19H2oN04l requires 326.1392). 1 H-N R (CDCl 3 / 30O MHz) 7.40-7.26 (m, 3H); 7.10-7.00 (m, 2H); 6.70-6.60 (m, 2H); 5.06 (s, 2H); 4.33 (q, 2H); 3.20-3.08 (m, 2H); 2.75-2.60 (m, 2H); 1.40 (t, 3H). Analysis, calculated for C19H19N04: C, 70.14; H, 5.89; N, 4.31. Found: C, 70.09; H, .5.75; N 4.08.

Step 3 The final product of Example 7 was prepared in a manner similar to Example 6, starting from the material of step 2 with a yield of 37%. FABHRMS m / z 477.1609 (M + H, C15H25N404 requires 477.1596). H-NMR (DMSO-d6 / 300 MHz) 8.00 (d, 2H); 7.80 (d, 2H); 7.50 (s, 1 H); 7.40-7.20 (m, 3H); 7.20-7.05 (m, 2H); 6.80 (s, 1 H); 5.62 (s, 1 H); 5.13 (s, 2H); 4.25 (q, 2H); 3.10-2.92 (m, 2H); 2.89-2.70 (m, 2H); 1.30 (t, 3H). Analysis, calculated for C25H24N404S: C, 63.01; H, 5. 08; N 1 1.76. Found: C, 62.95; H, 5.02; N 11.76.

EXAMPLE 8 1-r4- (aminosulfonyl) phenyl-1-6-benzyl-1, 4,5,6-tetrahydro-pyrrolof2,3-q indazole-3-carboxamide Example 8 was prepared in a manner similar to Example 2 starting from the compound of Example 7 in 75% yield FABHRMS m / z 448.1477 (M + H, C23H22N5O3S: required 448. 1443). 1 H-NMR (DMSO-d 6/300 MHz) 8.00 (d, 2H); 7.80 (d, 2H); 7.60-7.15 (m, 3H); 7.10 (d, 2H); 6.79 (d, 1 H); 5.65 (d, 1 H); 5.12 (s, 2H); 3.10-2.93 (m, 2H); 2.82-2.68 (m, 2H). Analysis, calculated for C 23 H 21 N 5 O 3 S: C, 61.73; H, 4.73; N, 15. 65. Found: C, 61.33; H, 4.52; N, 15.43.

EXAMPLE 9 1-r4- (Aminosulfonyl) phenan-6-benzyl-1, 4,5,6-tetrahydro-pyrazolof3,4-e] indazole-3-carboxylate ethyl The product from step 1 was prepared in a manner similar to Example 5 starting from 1,5,6,7-tetrahydro-1- (phenylmethyl) indazol-4-one [Hetero-cycles, 32 (1), 41 -72 ( 1991)] with a yield of 89%. FABHRMS m / z 327.1347 (M + H, C18H19N204 requires 327.1345). 1 H-NMR (CDCl 3/300 MHz) 8.00 (s, 1 H); 7.40-7.30 (m, 3H); 7.13 (d, 2H); 5.30 (s, 2H); 4.31 (q, 2H); 3.19-3.03 (m, 2H); 2.80-2.68 (m, 2H); 1.38 (t, 3H). Analysis, calculated for Ci8H 8N204: C, 66.25; H, 5.56; N, 8.58. Found: C, 66.35; H, 5.47; N, 8.78.

Step 2 The product of Example 9 was prepared in a manner similar to! Example 6 starting from the compound of step 1 with a yield of 64%. FABHRMS m / z 478.1549 (M + H, C24H24N504S requires 478.1551). 1 H-NMR (DMSO-d 6/300 MHz) 8.02 (d, 2H); 7.82 (d, 2H); 7.51 (s, 1 H); 7.40-7.22 (m, 3H); 7.21-7.13 (m, 2H); 7.10 (s, 1 H); 5.40 (s, 2H); 4.30 (q, 2H); 3.20-2.90 (m, 4H); 1.30 (t, 3H). Analysis, calculated for C24H23N50 S: C, 60.36; H, 4.85; N, 14.67. Found: C, 60.60; H, 4.86; N, 14.71.

EXAMPLE 10 1- [4- (Aminosulfonyl) phenyl-1-6-benzyl-1, 4,5,6-tetrahydro-pyrazolor-3,4-enedazol-3-carboxamide Example 10 was prepared in a manner similar to Example 2 by starting the product of Example 9 in 79% yield. FABHRMS m / z 449.1399 (+ H, C22H2iN603S requires 449. 1396). 1 H-NMR (DMSO-d 6/300 MHz) 8.00 (d, 2H); 7.84 (d, 2H); 7.60-7.40 (m, 2H); 7.40-7.22 (m, 3H); 7.25-7.10 (m, 2H); 5.37 (s, 2H); 3.20-2.90 (m, 4H). Analysis, calculated for C 24 H 20 N 6 O 3 S (0.8 H 20): C, 57.08; H, 4.70; N, 18.15. Found: C, 57.54; H, 4.56; N, 17.77.

EXAMPLE 11 1- [4- (Aminosulfonyl) phenyl] -1,4,5,6-tetrahydro-pyrazolof3,4-enedazole-3-carboxylate ethyl The material of Example 9 (4.2 g, 0.009 mole), DMF (40 ml), glacial acetic acid (20 ml) and Pearlman's catalyst (1.5 g) were stirred at a hydrogen pressure of 3.74 atm (55 psi) for 96 hours. hours. The contents were filtered through celite and the filtrate was concentrated in vacuo to give the product as a gray solid, 2.5 g (70% yield). FABHRMS m / z 388.1 124 (M + H, C17H18N504S requires 388. 1080). H-NMR (DMSO-d6 / 300 MHz) 8.02 (d, 2H); 7.80 (d, 2H); 7.60 (broad s, 1 H); 7.30 (s, 1 H); 4.35 (q, 2H); 3.15-3.00 (m, 2H); 3.00-2.80 (m, 2H); 1.32 (t, 3H). Analysis calculated for Ci7H17N504S: C, 52.70; H, 4.42; N, 18. 08. Found: C, 52.47; H, 4.18; N, 17.89.

EXAMPLE 12 1-4- (AminosulfonylphenylH-1,4,5,6-tetrahydro-pyra-3-eor-3,4-e] indazole-3-carboxamide Example 12 was prepared in a manner similar to Example 2 starting from material 11 with a yield of 86%. FABHR S m / z 359.0939 (M + H, C15Hi5N603S requires 359. 0926). H-NR (DMSO-d6 / 300 MHz) 8.02 (d, 2H); 7.87 (d, 2H); 7.56 (s, 1 H); 7.50 (broad s, 2H); 7.35 (s, 2H); 3.20-3.00 (m, 2H); 2.95-2.80 (m, 2H). Analysis, calculated for C 50.27; H, 3.94; N, 3.45. Found: C, 50.07; H 3.73; N, 23.08.

EXAMPLE 13 l-f ^ aminosulfoniQ phenyl -. S - dihydro - I H - thieno ^^ - cylindazole - S-carboxylate ethyl Stage 1 4- (2-thienyl) butyric acid (9.7 g, 0.057 mol), acetic anhydride (12 ml) and phosphoric acid (85%, 0.25 ml) were refluxed for 3 hours. The contents were allowed to cool and partitioned between EtOAc and water. The EtOAc layer was dried (MgSO4) and concentrated in vacuo to give a dark oil 9.0 g. The oil was distilled in a Kugelrohr apparatus at a temperature of 50 ° C (0.1 mm) to obtain a white solid 5.0 g (58% yield). 1 H-NMR (CDCl 3/300 MHz) 7.37 (d, 1 H), 7.02 (d, 1 H); 3.08-2.95 (m, 2H); 2.60-2.50 (m, 2H); 2.30-2.10 (m, 2H).

Stage 2 The product from step 2 was prepared in a manner similar to step 1 of Example 1, using the material from step 1 in a 77% yield. 1 H-NMR (DMSO-d 6/300 MHz) 7.32-7.05 (m, 2H), 4.05 (q, 2H), 2.85-2.50 (m, 4H); 1.20 (t, 3H).

Step 3 The final product of Example 13 was prepared in a manner similar to Example 6, starting from the material of step 2 in 86% yield. FABHRMS m / z 404.0702 (M + H, C18H18N304S2 requires 404. 0739). 1 H-NMR (DMSO-d 6/300 MHz) 8.05 (d, 2H); 7.70 (d, 2H); 7.59 (s, 1 H); 7.39 (d, 1 H); 6.40 (d, 1 H); 4.35 (q, 2H); 3.10 (s, 4H); 1.35 (t, 3H). Analysis, calculated for C18H17N3O4S2: C, 53.58; H, 4.25; N, 10. 41. Found: C, 53.51; H, 4.02; N, 10.45.

EXAMPLE 14 1-f4- (aminosulfonyl) phenin-4,5-dihydro-1H-thieno [2,3-q1indazol-3-carboxamide Example 14 was prepared in a manner similar to Example 2 starting from! compound of Example 13 with a yield of 85% FABHRMS m / z 375.0601 (+ H, C16H15N O3S2 requires 375. 0586). 1 H-NMR (DMSO-d 6/300 MHz) 8.05 (d, 2H); 7.70 (d, 2H); 7.59 (s, 1 H); 7.55 (s, 2H); 6.47 (d, 1 H); 3.10 (s, 4H). Analysis, calculated for C 16 H 14 N 4 O 3 S 2: C, 56.06; H, 4.70; N, 13. 08. Found: C, 56 49; H, 4.74; N, 13.21.

EXAMPLE 15 1- [4- (Aminosulfonyl) phenylethyl-4,5-dihydro-1 H-pyrazolf3,4-f1izoquinolin-3-carboxamide To 7,8-dihydroisoquinolin-5 (6H) -one (1.17 g, 8 mmol) in diethyl ether (50 mL) was added 1 M LiHMDS (8 mL, 8 mmol) dropwise over several minutes (cotégese Lardenois) , P. et al., Synthetic Communications 26 (12), 2305-2308, 1996). A precipitate formed slowly and the reaction turned light yellow. After approximately 15 minutes, dimethyl oxalate (944 mg, 8 mmol) was added as a solid and the reaction was stirred at room temperature for 72 hours. The resulting precipitate was collected by suction filtration and washed extensively with diethyl ether. A strong yellow solid was obtained. Yield: 1.7 g (89%). H-NMR (d6-DMSO) 2.41 (t, 2H); 2.63 (t, 2H); 3.56 (s, 3H); 7.51 (d, 1 H); 8.37 (s, 1 H); 8.40 (d, 1 H).

The enolate from step 1 (717 mg, 3 mmol) was mixed with 4-sulfonamidophenii hydrazine hydrochloride (669 mg, 2 mmol) in methanol (10 ml) and stirred at room temperature for 72 hours, then the The resulting precipitate was collected by suction filtration and washed with methanol. The resulting hydrated pyrazole (502 mg) was resuspended in methanol and concentrated HCl (0.5 ml) was added. The reaction was stirred at room temperature for two hours and then concentrated to a yellow solid under vacuum. The solid was triturated with methanol and collected by suction filtration. 7 Yield: 250 mg (22%). 1 H-NMR (d 6 -DMSO) 3.09 (s, 4H); 3.87 (s, 3H); 6.91 (d, 1 H); 7.60 (s, 2H); 7.84 (d, 2H); 8.03 (d, 2H); 8.50 (d, 1 H); 8.80 (s, 1 H). FABHRMS m / z 385.0987 (M + H, C 8H17N404S requires 385.0971).

Step 3 The methyl ester from step 2 (240 mg, 0.625 mmol) was suspended in methane (10 mL) and concentrated ammonium hydroxide (2 mL) was added. The reaction was heated to a temperature of 95 ° C in a sealed tube for 16 hours. The reaction was cooled and concentrated to a reddish solid which was triturated with methane. The 1H-NMR suggested that some carboxylic acid could be present, whereby the solid was dissolved in methane (15 ml) and 1 N HCl (3 ml). The homogeneous solution was then made basic with a saturated solution of NaHCC > 3 to pH = 8. After concentrating the solution under a stream of nitrogen, a brown solid (100 mg) was collected. This solid was filtered through a plug of silica gel (0 g) using 10% methanoi in dichloromethane to obtain an off white solid. Yield: 90 mg (39%). FABHRMS m / z 370.0966 (M + H, C 7H16N503S requires 370. 0974). 1 H-NMR (d 4 -MeOH + TFA) 3.25 (s, 4H); 7.25 (d, H); 7.83 (d, 2H); 8.14 (d, 2H); 8.49 (d, 1 H); 8.79 (s, 1 H).

EXAMPLE 16 l - ^ - Caminosulfoniljfenill-I. .S ^ -tetrahydropyrazolo ^ S-qlindazol-S carboxamide Step 1 A mixture of 1,2-cyclohexanedione (26.0 g) and ethanol (100 ml) in 500 ml of benzene was refluxed overnight with a Dean-Stark trap. After the solvent was removed, the residue was purified by chromatography on silica gel (ethyl acetate / hexane, 2: 8) to obtain 15.3 g of the desired 2-ethoxy-2-cyclohexene-1-one in the form of a light yellow oil (47% yield). To 120 mL of a 1.0 M solution of LiHMDS in THF was added a solution of the above compound (15.3 g, 0.11 mmol) in 100 mL of ether at a temperature of -78 ° C. After the addition, the dark brown mixture was stirred at this temperature for ½ hour, and a solution of diethyl oxylate (17.5 g, 0.12 mol) in 30 ml of ether was added all at once. The reaction was allowed to acclimate until reaching room temperature over 18 h. Water was added and acidified to pH ~ 4 with 1N HCl. The aqueous phase was extracted with ethyl acetate and the organic phase was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated to obtain 21.5 g of the product as a dark brown liquid which was used without further purification.

Step 2 A mixture of the crude from Step 1 (20.0 g, 0.083 mole) and 1- (4-hydrazinophenylsulfonyl) 2,5-dimethylpyrrole (22.0 g, 0.083 mole) in 400 ml of acetic acid was stirred at room temperature. the night. The solvent was removed and the residue partitioned between ethyl acetate and concentrated ammonium hydroxide. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel (ethyl acetate / hexane, 3: 7) to obtain 16.2 g of the pure product as a pure product in the form of a yellow solid.

Step 3 A mixture of the product from step 2 (3.1 g, 0.0062 mol) and the di-tert-butyl acetal of N, N-dimethylformamide (10.2 g, 0.062 mol) was heated to reflux overnight. After cooling, the excess reagent was removed in vacuo and the residue was triturated with cold ethanol to obtain 2.3 g of the pure product as the pure product as a yellow solid (77% yield); p.f .: 230-231 ° C; Analysis, Calculated for C25H28N4O5S: C, 60.47; H, 5.68; N, 1.28; S, 6.46. Found: C, 59.98; H, 5.42; N, 10.92; S, 6.11.

Step 4 To a suspension of the product from step 3 (0.045 g 0.0009 mole) in 10 ml of ethanol was added hydrazine (0.03 ml, 0.0009 mole) and the mixture was stirred at reflux overnight. The solvent was removed and the residue was purified by chromatography on silica gel (ethyl acetate / hexane, 2: 8) to obtain 0.38 g of product as a light yellow solid (93% yield); m.p .: 134-136 ° C; Analysis, Calculated for C23H23N5O4S: C, 59.34; H, 4.98; N, 15.04; S, 6.89. Found: C, 59.28; H, 4.95; N, 14.76; S, 6.93.

Step 5 The product from step 4 (0.35 g, 0.00075 moles) was treated with a mixture of TFA (15 ml) and water (5 ml) and the dark brown solution was refluxed under nitrogen atmosphere for 2 hours. It was cooled and basified with concentrated ammonium hydroxide to precipitate 0.18 g of the crude product as a pale yellow solid. A suspension of this solid in a mixture of the concentrated ammonium hydroxide (15 ml) and methanol (5 ml) was stirred at RT ("Room Temperature") for 3 days. Half the volume of the solvent was removed and the solid was filtered to obtain 0.1 g of the product as a white powder (50% yield corresponding to two steps). p.f .: 347 ° C (decomp.); Analysis, Calculated for C 5H14N603S: C, 50.27; H, 3.94; N, 23. Four. Five; S, 8.95. Found: C, 49.65; H, 3.81; N, 22.78; S, 8.77.

EXAMPLE 17 8-amino-1-f4- (aminosulfonyl) phenin-4,5-dihydro-1 H-pyrazolof4,3-h1-quinazoline-3-carboxamide Step 1 To a suspension of the product from step 3 of Example 16 (8.7 g, 0.0018 mole) and guanidione hydrochloride (1.7 g, 0.018 mole) in 250 ml of ethanol, sodium ethoxide (1.22 g, 0.018 mole) was added. and the mixture was refluxed under a nitrogen atmosphere overnight. After removing the solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate / hexane: 3: 7) to obtain 5.2 g of product as a brown solid (60% yield); p.f .: 1 1 ° C-112 ° C; Analysis, Calculated for C24H24N604S: C, 58.52; H, 4.91; N, 17.06; S, 6.51. Found: C, 58.24; H, 4.84; N, 16.80; S, 6.68.

Step 2: This compound was synthesized following the same procedure as step 5 of Example 1 with a yield of 52%; m.p .: 332 ° C (decomp.); Analysis, Calculated for C 16 H 15 N 7 O 3 S: C, 49.86; H, 3.92; N, 25.44; S, 8.32. Found: C, 49.49; H, 3.86; N, 25.52; S, 7.93. Examples 18 and 19 were prepared according to scheme XVIII. Related compounds such as A, B and C, shown in Scheme XVIII, can be prepared in a similar manner using the appropriate R4 group.

ESQUENA XVIII Stage 1 (2-ro-8-oxo-5,6,7,8-tetrahydroquinolyl-7-yl) (oxo) ethyl acetate To a suspension of 10.8 g of 2-ro-6,7-dihydroquinolin-8 (5H) -one 38 in 30 ml of anhydrous ethanol, cooled to a temperature of about 10 ° C, 24.4 ml of a solution was added dropwise. 21% by weight sodium ethoxide solution (65.46 mmoles) in anhydrous ethanol (24.4 ml), with stirring under nitrogen atmosphere for 10 minutes. After 5 minutes, 8.82 g of diethyl oxalate (59.54 mmoles) were added over 2 minutes. The reaction mixture was stirred at a temperature of 10 ° C for 30 minutes, and then 1 hour at room temperature. To this reaction mixture, cooled to a temperature of about 0 ° C, 66 ml of a solution of 1 M HCl in ethanol was added dropwise, over 0 minutes. And a white precipitate was separated by filtration and washed with 30 ml of roform. The organic portions were mixed and the solvents were removed to obtain 16.5 g (99% yield) of the desired crude product 39, which was used in the next synthesis without further purification. 1 H-NMR (300 MHz, d, DCCl 3): 1.45 (t, 3H, J = 7.15 Hz); 2.88-3.02 (m, 4H); 4.44 (q, 2H, J = 7.15 Hz); 7.43 (d, 1 H, J = 8.05 Hz); 7.62 (d, 1 H, J = 8.05 Hz); 13.6-14.2 (1 H, wide).

Mass spectrum by ESI of (Ci3Hi2CIN04 + 1) +: 282.1.

Stage 2 S-ro-l-1-fluorophenyl-H-dihydro-I H-pyrazolo-3-S-hlquinoline-S-carboxylate The mixture of (2-ro-8-oxo-5,6,7,8-tetrahydro-quinolin-7-yl) (oxo) ethyl acetate 39 from stage 1 (13 g, 46.15 mmol) and hydroride of 4-fluorophenylhydrazine (7.51 g, 46.15 mmol) in 500 ml of a 1 M HCl solution in ethanol was placed in a 1 liter flask fitted with a condenser, under a nitrogen atmosphere, and heated to reflux for 1 hour. It was then cooled to room temperature and placed in a refrigerator overnight at a temperature of -5 ° C. The white crystalline precipitate was filtered and washed with ether to obtain 12.3 g of 8-ro-1- (4-fluorophenyl-4,5-dihydro-1 H -pyrazolo [4,3-h] quinoline-3-carboxylate ethyl 40 (71% yield) This compound was used in the following synthesis without further purification H NMR (300 MHz, d, DCC! 3): 1.48 (t, 3H, J = 7.15 Hz); 3.01 - 3.25 (m, 4H), 4.49 (q, 2H, J = 7.15 Hz), 7.10-7.24 (m, 3H), 7.50-7.62 (m, 3H).

Mass spectrum by ESI of (C19Hi5CIFN3C> 2 + 1) +: 372.1.

Step 3 8-ro-1- (4-fluorophenyl) -4,5-dhydro-1 H -pyrazolo [4,3-h] quinoline-3-carboxamide A mixture of 1 g of ethyl 8-ro-1- (4-fluorophenyl) -4,5-dihydro-1 H-pyrazolo [4,3-h] quinolin-3-carboxylate from step 2.25 my methane! and 25 ml of liquid ammonia were placed in an autoclave and stirred overnight at a temperature of 130 ° C. After cooling to room temperature and removing the ammonia, a suspension of a gray crystalline precipitate in methanol was obtained. This solid was isolated by filtration to obtain 0.8 g (87% yield) of 8-ro-1- (4-fluorophenyl) -4,5-dihydro-1 H -pyrazolo [4,3-h] quinoline-3. carboxamide. H-NMR (400 Hz, d, DCCI3): 3.01-3.25 (m, 4H); 5.38 (s, 1 H); 6.81 (s, 1 H); 7.09 (d, 1 H, J = 7.9 Hz); 7.11-7.19 (m, 2H); 7.45-7.56 (m, 3H). Mass spectrum by ESI of (C17Hi2CIFN40 + 1) +: 343.1.

EXAMPLE 19 1- (4-fluorophenyl) -N- (4-methoxybenzyl) -8-f (4-methoxybenzyl) amino-1,4-dihydro-1 H -pyrazolo [4,3-h1-quinoline-3-carboxamide Ethyl 8-cyclo-1 - (4-fluorophenol) -4,5-dhydro-1 H-pyrazolo [4,3-h] quinoline-3-carboxylate 40 (3.8 g, 10.22 mmol) ) in 35 ml of 4-methoxybenzylamine was heated at a temperature of 185 ° C for 26 hours. The reaction mixture contained the title compound as a major product. This compound was isolated by thin layer chromatography on silica (ethyl acetate-exan, 60:40). • 1H-NR (400 Hz, d, DCCI3): 2.86-2.92 (m, 2H); 3.14-3.21 (m, 2H); 3.76-3.78 (m, 6H); 3.95 (d, 2H, J = 5.9 Hz); 4.28 (t, H, J = 5.8 Hz); 4.54 (d, 2H, J = 5.9 Hz); 6.20 (d, 1 H, J = 8.2 Hz); 6.78-6.86 (m, 4H); 6.93-7.02 (m, 2H); 7.01-7.06 (m, 2H); 7.20 (t, 1 H, J = 5.64 Hz); 7.26-7.30 (m, 3H); 7.42-7.48 (m, 2H). Mass spectrum by ESI of (C33H3oFN503 + 1) +: 564.2.

Table 1 shows the biological activity of the compounds of the examples, measured in the enzyme assay of the IKK heterodimer bound to a resin, and expressed as the LC50.

TABLE 1 COMPOSITE STRUCTURE EXAMPLE HetD 1- [4- (aminosulfonyl) phenyl] - Example 7 > 200 μ? 6-Benzyl-1, 4,5,6-tetrahydro-pyrrolo [2,3-g] indazole-3-carboxylate, ethyl ester 1- [4- (aminosulfonyl) phenyl] - Example 8 > 200 μ? 6-benzyl-1, 4,5,6-kAN_ N tetrahydro-pyrrolo [2,3-g] indazole-3-carboxamide 1 - [4- (aminosulfonyl) phenyl] - Example 9 > 200 μ? 6-benzyl-1, 4,5,6-tetrahydro-pyrazolo [3,4-e] ndazole-3-carboxylic acid ethyl ester [R] 1- [4- (aminosulfonyl) phenyl] - Example 10 > 200 μ? 6-benzyl-1, 4,5,6-k __ N tetrahydro-pyrazolo [3,4-e] indazole-3-carboxamide 1- [4- (aminosulfonyl) fenii] - Example 11 > 200 μ? 6-benzyl-1, 4,5,6-tetrahydro-pyrazolo [3,4-e] indazole-3-carboxylic acid ethyl ester 1- [4- (aminosulfonyl) phenyl] - Example 12 0.67 μ? 1, 4,5,6-tetrahydropyrazolo [3,4-e] indazole-3-carboxamide 1- [4- (aminosulfonyl) phenyl] - Example 13 > 200 μ? Ethyl 4,5-dihydro-1 H-thieno [2,3-g] indazole-3-carboxylate 1- [4- (aminosulfonyl) phenyl] - Example 14 3.2 μ? 4,5-dihydro-1 H-thieno [2,3-g] indazole-3-carboxamide kJ ° 1 - [4- (aminosulfonyl) phenyl] - Vo Example 15 8.21 μ? 4,5-dihydro-1 H-pyrrazolo [3,4-fjisoquinoline-3-carboxamide COMPOSITE STRUCTURE EXAMPLE HetD 1- [4- (aminosulfonyl) phen] - Example 16 0.96 μ? 1, 4,5,8-tetrahydropyrazole [4,3-J 2 g] indazole-3-carboxamide 8-amino-1 - [4- (amino- Example 17 2.3 μ? Sulfonyl) phenyl] -4,5-dihydro - 1 H-pyrazolo [4,3-h] quinazoline-3-carboxamide Similarly, the following compounds from Table 2 can also be prepared.

TABLE 2 TABLE 2 continued 1-. { 4 - [(Butylamino) sulfonyl] phenyl} -1, 4,5,6-tetrahydropyrazolo [3,4-e] indazole-3-carboxamide 1 - . 1 - . 1 - . 1 -. { 4 - [(dimethylamino) sulfonyl] phenyl} -1, 4,5,6- A tetrahydropyrazolo [3,4-e] indazole-3-carboxamide 1 / H 1 - [4 - [(aminocarbonyl) phenyl] -, 4,5,6-tetrahydropyrazolo [3,4-e] ndazole-3-carboxamide 1- (4-methoxyphenyl) -1,4,5,6-tetrahydro-tetrarazolo [3,4-e] indazole-3-carboxamide 1 - [4- (aminosulfonyl) pheny] -1,6-dihydropyrazolo [3,4-e] indazole-3-carboxamide 1 - . 1 -. { 4 - [(Butylamino) sulfonyl] phenyl} -1,6-dihydropyrazolo [3,4-e] indazole-3-carboxamide H 1-. { 4 - [(methylamino) sulfonyl] pheni)} -1,6-dihydropyrazolo [3,4-e] indazole-3-carboxamide 1-. { 4 - [(dimethylamino) sulfonyl] phenyl} - 1, 6-dihydropyrazolo [3,4-e] indazole-3-carboxamide Ethyl 1-phenyl-1, 6-dihydropyrazolo [3,4-e] indazole-3-carboxylate Ethyl 4- (4-sulfamoyl-phenyl) -4,7-dihydro-1 H-cyclopental [1, 2-c; 3,4-c '] dipirazole-6-carboxylic acid ethyl ester H BIOLOGICAL EVALUATION Materials The Biotin SAM2 ™ capture plates came from Promega. The anti-FLAG affinity resin, the FLAG peptide, NP-40 (Nonidet P-40), BSA, ATP, ADP, AMP, LPS (serotype 01 11: B4 of E. coli) and dithiothreitol were obtained from Sigma Chemicals . Antibodies specific for NEMO (????) (FL-4 9), IKK1 (H-744), IKK2 (H-470) and kBa (C-21) were purchased from Santa Cruz Biotechnology. The Ni-NTA resin was purchased from Quiagen. The peptides are purchased from the American Peptide Company. The tablets of a cocktail of protease inhibitors were from Boehringer Mannheim. The Sephacryl S-300 column was from Pharmacia LKB Biotechnology. Concentrators Centriprep-10 with an exclusion value of molecular weights of 10 kDa and membranes with an exclusion value of molecular weights of 30 kDa were obtained from Amicon. [? "33?] ??? (2,500 Ci / mmol) and [?" 32?] ??? (6000 Ci / mmol) were purchased from Amersham. The rest of the reagents used was the highest commercially available grade.

Cloning and expression The human 1KK1 and IKK2 cDNAs were amplified by a reverse transcriptase reaction-polymerase chain reaction from human placental RNA (Clonetech). HIKK1 was subcloned into pFastBac HTa (Life Technologies) and expressed as a fusion protein linked to a His6 marker sequence at the N-terminus. The hlKK2 cDNA was amplified using an inverse oligonucleotide primer incorporating the peptide sequence corresponding to a marker sequence constituted by the FLAG epitope at the C-terminal end of the coding region of IKK2 (DYKDDDDKD). The HIKK2: FLAG cDNA was subcloned into the baculovirus pFastBac vector. The rhlKK2 mutant (S177S, E177E) was constructed in the same vector used for the wild type rhlKK2 using a QuickChange ™ mutagenesis kit (Stratagene). Virus reserve preparations from each of the constructs were used to infect insect cells cultured in a 40 liter suspension culture. The cells were lysed at the time when the expression and activity of rhIKK was shown to be maximal. The cell lysates were stored at a temperature of -80 ° C until the purification of the recombinant proteins was carried out as described below.

Isolation of enzymes All purification procedures were carried out at a temperature of 4 ° C, unless otherwise indicated. The buffers used are: buffer A: 20 mM Tris-HCl, pH, 7.6, containing 50 mM NaCl, 20 mM NaF, 20 mM β-glycerophosphate, 500 μM sodium ortho-vanadate ?, 2.5 mM metabisuifite, 5 mM benzamidine, 1 mM EDTA, 0.5 mM EGTA, 10% glycerol, 1 mM DTT, 1X Complete protease inhibitors; buffer B: same as buffer A except for 150 mM NaCl; and buffer C: same as buffer A except for 500 mM NaCl.

Isolation of the rhIKKI homodimer Cells from a fermentation of 8 liters of IKK1 expressed in baculovirus and containing the marker sequence of the His peptide, were centrifuged and the cell pellet (MOI 0.1, 1 = 72 h) was resuspended in 100 ml of the buffer C. The cells were microfluidized and centrifuged at 100,000 Xg for 45 min. The supernatants were pooled, imidazole was added to a final concentration of 10 mM and incubated with 25 ml of Ni-NTA resin for 2 hours. The suspension was poured into a 25 ml column and washed with 250 ml of buffer C and then with 125 ml of 50 mM imidazole in buffer C. The rhIKKI homodimer was eluted using 300 mM imidazole in buffer C. BSA and NP were added. -40 to the enzymatic fractions until reaching the final concentration of 0.1%. The enzyme was dialyzed against buffer B, aliquoted and stored at -80 ° C.

Isolation of the rhlKK2 homodimer A 10 liter culture of IKK2 expressed in baculovirus and containing the marker sequence of the FLAG peptide, was centrifuged and the cell pellet (MOI 0.1 el = 72 h) was resuspended in buffer A. The cells were microfluidized and centrifuged at 100,000 Xg for 45 min. The supernatants were passed through a G-25 column equilibrated with buffer A. The peak corresponding to proteins was collected and incubated with an anti-FLAG affinity resin in a rotary apparatus, overnight, in buffer B. The resin was washed in batches with buffer volumes C equal to 10-15 times the volume of the bed. The washed resin was poured into a column and the rhlKK2 homodimer was eluted using a volume of 5 times the volume of the buffer B bed containing 5 mM FLAG.DTT peptide, 0.1% NP-40 and BSA (concentrated to 0.1. % of the final amount) were added to the eluted enzyme before concentrating it using an Amicon membrane with a molecular weight exclusion value of 30 kDa. The enzyme was aliquoted and stored at a temperature of -80 ° C.

Isolation of the heterodimer rhlKK1 / IKK2 The heterodimeric enzyme was produced by co-infection in a baculovirus system (FLAG IKK2 / IKK1 His; MOI = 0.1 e \ = 72 h). The infected cells were centrifuged and the cell pellet (10.0 g) was suspended in 50 ml of buffer A. The protein suspension was microfluidized and centrifuged at 100,000 Xg for 45 min. Imidazole was added to the supernatant until a final concentration of 10 mM was reached. The protein was allowed to bind to 25 ml of Ni-NTA resin by mixing for 2 hours. The protein-resin suspension was poured into a 25 ml column and washed with 250 ml of buffer A containing 10 mM imidazole, followed by 125 ml of buffer A containing 50 mM imidazole. Buffer A containing 300 mM imidazole was then used to elute the protein. A pooled volume of 75 ml was collected and NP-40 was added until a final concentration of 0.1% was reached. The protein solution was then dialyzed against buffer B. The dialyzed heterodimeric enzyme was then allowed to bind to 25 ml of an anti-FLAG M2 agarose affinity gel, overnight, with constant mixing. The protein-resin suspension was then centrifuged for 5 min at 2,000 rpm. The supernatant was collected and the resin was resuspended in 100 ml of buffer C containing 0.1% NP-40. The protein-resin was poured into a 25 ml column and the enzyme was eluted using buffer B containing FLAG peptide. Enzymatic fractions (100 ml) were collected and concentrated to a volume of 20 ml using an Amicon membrane with a molecular weight exclusion value of 30 kDa. Bovine serum albumin was added to the concentrated enzyme until a final concentration of 0.1% was reached. The enzyme was then separated into aliquots and stored at a temperature of -80 ° C.

Cell culture The wild-type pre-B cell line (wt), 70Z / 3, and its mutant, 1.3E2, were generously supplied by Dr. Carol Sibley. The 70Z / 3 wt and 1, 3E2 cells were cultured in RP I 1640 (Gibco) supplemented with 7% bovine serum (Hyclone) and 50 μm 2-mercaptoethanol. THP-1 cells of human monocytic leukemia, obtained from the ATCC, were cultured in RPMI 1640 supplemented with bovine serum defined at 10%, 10 mM HEPES, 1.0 mM sodium pyruvate and 50 μM 2-mercaptoethanol. For the experiments the cells were seeded in 6-well plates, at a density of 1x106 cells / ml in freshly prepared medium. The pre-B cells were stimulated by the addition of LPS at a concentration of 1 for variable time periods ranging from 0 hours to 4 hours. THP-1 cells were stimulated by the addition of LPS at a concentration of 1 μg / ml for 45 minutes. The cells were pelleted, washed with cold 50 mM sodium phosphate buffer, pH 7.4, containing 0.15 M NaCl and lysed at a temperature of 4 ° C in 20 mM Hepes buffer, pH 7.6, containing 50 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM sodium ortho-vanadate, 10 mM ß-glycerophosphate, 1 mM NaF, 1 mM PMSF, 1 mM DTT and 0.5% NP-40 (lysis buffer). The cytosolic fractions obtained after centrifugation at 10,000 Xg were stored at a temperature of -80 ° C until the moment of use.

Immunoprecipitation and Western Blot The SF9 cell paste containing the rhIKK was centrifuged (100,000 Xg, 10 min) to remove cell debris. The rhIKK were immunoprecipitated (100 cell paste) from the supernatant of the cells using 3 μg of anti-NEMO antibody (FL-419), followed by coupling to protein A-Sepharose beads. The rhIKK were also immunoprecipitated from purified protein preparations by affinity chromatography (1 g) using anti-FLAG, anti-His or anti-NEMO (1-4 μg), followed by coupling to protein A-Sepharose. The complex of the natural human IKK was immunoprecipitated from homogenates of THP-1 cells (100 g in each case) using the anti-NEMO antibody. The immunocomplexes were pelleted and washed 3 times with 1 ml of cold lysis buffer. Immunoprecipitated rhIKKs were chromatographed by SDS-PAGE (8% Tris-glycine), and transferred to nitrocellulose membranes (Novex) and detected by chemiluminescence (Super-Signal) using specific anti-IKK antibodies (1KK2 H-470, IKK1 H-744). The natural proteins IKK2, αα and NEMO from cytosolic lysates (20-80 μg) were separated by SDS-PAGE and visualized by chemiluminescence using specific antibodies.

Phosphatase treatment Immunoprecipitated rhIKK were washed twice with 50 mM Tris-HCl, pH 8.2, containing 0.1 mM EDTA, 1 m DTT, 1 mM PMSF and 2 mM MnCl2, and resuspended in 50 μM. The phosphatase (Ppasa, 1,000 U) was prediluted in the same buffer and added to the IKK samples. After an incubation at room temperature for 30 minutes with intermittent mixing, cold lysis buffer was added to the tubes to stop the reaction. After several washes, 10% of the pellets were separated for a Western analysis, and the rest of the material was pelleted and resuspended in 100 μ? of the buffer used for the in vitro kinase assay.

Enzymatic assay of IKKaSAM The kinase activity of IKKa was measured using a peptide ??? to biotinylated (Gly-Leu-Lys-Lys-Glu-Arg-Leu-Leu-Asp-Asp-Arg-His-Asp-Ser32-Gly-Leu-Asp-Ser-36-Met-Lys-Asp-Glu- Glu), a Biotina 96 SAM2 ™ capture plate, and a vacuum system. The standard reaction mixture contained 5 μ? Biotinylated peptide? [? '33?] ??? 1 μ? (approximately 1 x 105 cpm), 1 mM DTT, 50 mM KCI, 2 mM MgCl 2, 2 mM MnCl 2, 10 mM NaF, 25 mM Hepes buffer, pH 7.6, and enzyme solution (1-10 μ) in a final volume of 50 μ ?. After an incubation at a temperature of 25 ° C for 30 min, 25 μ? of the reaction mixture and SAM2 ™ 96 Biotin were added to a 96-well capture plate. Each well was then washed successively with 800 μ? of NaCl 2 M, 1.2 ml of NaCl containing 1% H3PO4, 400 μ? of H20 and 200 μ? of 95% ethanol. The plate was allowed to dry in a hood at a temperature of 25 ° C for 1 hour and then 25 μ? Were added to each well. of scintillation fluid (Microscint 20). The incorporation of [? "33?] ??? was measured using a Top-Count NXT (Packard) counter.In these test conditions, the phosphorylation degree of the substrate peptide ??? was linear with time and with the concentration in the case of all purified enzymes The results of the assay performed with the biotinylated peptide were confirmed by SDS-PAGE analysis of the kinase reaction, using y [α "33?]. The resulting radioactively labeled substrate was quantified by Phosphoimager (Molecular Dynamics). An analysis with an ion exchange resin was also used, using a fusion protein of [? "33?] ??? and as substrates.Each test system produced consistent results in relation to Km and the specific activities of each. of purified kinase isoforms A unit of enzymatic activity is defined as the amount required to catalyze the transfer of 1 nmole of phosphate from ATP to peptide ??? a per min.The specific activity was expressed as units per mg of In the experiments related to the determination of Km of the purified enzymes, different concentrations of ATP or peptide? a were used in the assays, at a fixed concentration of ATP or at a fixed concentration of ??? a. Km with respect to ??? a, the tests were carried out with 0.1 μg of enzyme, ATP 5 μ? And peptide?? A in concentration of 0.5 μ to 20 μ. To determine the Km with respect to ATP, the trials took performed with 0.1 μl of enzyme, peptide ??? to 10μ? and ATP in 0.1 μ? at 10 μ ?. To determine the Km of the rhIKKI homodimer, due to its low activity and the highest Km with respect to the peptide ??? a, the homodimer rhIKKI (0.3 μg) was tested with peptide? ? a 125 μ? and with a specific activity 5 times higher than ATP (from 0.1 μ? to 10 μ?) for the experiments of determination of the Km with respect to ATP, and with a specific activity 5 times higher of ATP 5 μ and with peptide ?? ? a (from 5 μ? to 200 μ?) for the experiments of determination of the Km with respect to ??? a.

Enzyme Assay of β-β Linked to a Resin The activity of kinase of ββ was measured using a biotinylated peptide (Gly-Leu-Lys-Lys-Glu-Arg-Leu-Leu-Asp-Asp). -Arg-His-Asp-Ser32-Gly-Leu-Asp-Ser-36-Met-Lys-Asp-Glu-Glu) (American Peptide Co.,). Twenty microliters of the standard reaction mixture contained 5 μ? Biotinylated kBa peptide, a concentration of 0.1 μ ???? ß ???? of reaction of [? "33P] ATP (Amersham) (approximately 1 x 105 cpm), ATP (Sigma) 1μ ?, DTT (Sigma) 1mM, MgCl2 (Sigma) 2mM, MnCl2 (Sigma 2mM), NaF (Sigma) 10 mM, Hepes buffer (Sigma) 25 mM, pH 7.6, and 20 μl of enzyme solution and 10 μl of inhibitor in a final volume of 50 μm. After an incubation at a temperature of 25 ° C for 30 min, 150 μm of resin (Dowex AG1X8 anion exchange resin, 200-400 mesh) in 900 mM formate, pH 3.0, were added to each well to stop the reaction. sediment for one hour and 50 μl of the supernatant were removed and taken to a flat bottom Micolite-2 plate (Dynex), 150 μl of scintillation fluid (Microscint 49) (Packard) was added to each well. [? "33?] ??? was measured using a Top-Count NXT (Packard) counter.

Enzymatic assay of the IKK heterodimer bound to a resin The kinase activity of the IKK heterodimer was measured using a peptide ??? biotinylated (Gly-Leu-Lys-Lys-Glu-Arg-Leu-Leu-Asp-Asp-Arg-His-Asp-Ser32-Gly-Leu-Asp-Ser-36-et-Lys-Asp-Glu-Glu) (American Peptide Co.,). Twenty microliters of the standard reaction mixture contained 5 μ biotinylated peptide, a 0.1 concentration reaction [? "33?] (Amersham) (approximately 1 x 105 cpm), ATP (Sigma) 1 μ ?, DTT (Sigma) 1 mM, MgCl2 (Sigma) 2 mM, MnCl2 (Sigma) 2 mM, NaF (Sigma) 10 mM, Hepes buffer (Sigma) 25 mM, pH 7.6, and 20 μ? of the enzyme and 10 μl of inhibitor in a final volume of 50 μm. After an incubation at a temperature of 25 ° C for 30 min, 50 μm of resin (Dowex AG1X8 anion exchange resin, 200-400 mesh) ) in 900 mM formate, pH 3.0, were added to each of the wells to stop the reaction.The resin was allowed to settle for one hour, and 50 μ of the supernatant was removed and taken to a flat bottom Micolite-2 plate. (Dynex.) To each well, 150 μ? Of scintillation fluid (Microscint 49) (Packard) was added.The incorporation of [? "33?] ??? was measured using a Top Count NXT (Packard) counter.

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - A compound of Formula I wherein A is (CH2) m; wherein each CH2 can be independently substituted with one or more substitutions selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, ayanyl and alkynyl; m is from 0 to 8; Q is a 5- or 6-membered heteroaryl, or an aryl, optionally saturated, or optionally substituted with R1, R2 or R12; B is an aromatic heterocyclic radical; X is selected from the group consisting of: N and C; Y and Z are independently selected from the group consisting of: N, C, CH, CR3, S and O; R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, aikenyl, alkynyl, haloalkyl, CN, N02, OR5, OCOOR5, C02R7, CON (R6) R7, COR6, SR6, SOR6, S02R6, NR6R7 , NR6COR7, NR6CONHR7, NR6S02R7, NR6S02NHR7 and S02N (R6) R7 in which R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from the group constituted by: S, SO, S02, O and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optionally substituted with hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, N02, OR5, OCOOR5, C02R7, CON (R6) R7 , COR6, SR6, SOR6, S02R6, NR6R7, NR6COR7, NR6CONHR7, NR6S02R7, NR6S02NHR7 and S02N (R6) R7 in which R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing 1 to 3 heteroatoms substituted or unsubstituted, selected from the group consisting of: S, SO, S02, O and NR6; R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl OR6, CN, N02, SR6, NHR6, CON (R6) R7, NHCONHR6, C02H and haloalkyl; R1 and R2 can go together to form a saturated or unsaturated carbocyclic ring, of 5 to 7 members, optionally containing from 0 to 3 heteroatoms selected from the group consisting of: N, O, or S, and wherein said ring is optionally substituted with R; R3 is selected from the group consisting of: amidine, alkylamino, aminoalkyl, CONHR16, NH2, NHCOR6 and CH2NHCOR6, substituted or unsubstituted; R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic radical, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, S02N (R8) R8 ', NHR9, NHCOR9, NR9C0R9, NHCO (OR9), NR9C0 (0R9), NR8S02R1 °, NHSO2N (R10) R10', NR6CON (R10) R10 ', COR9, C02R8, CON (R8) R8', wherein R8 and R8 can go together to form a 3- to 7-membered carbocyclic ring, bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, S02, O, N and NR6, and wherein R10 and R10 they can go together to form a 3- to 7-membered carbocyclic ring, bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, S02, O, N and NR6, wherein said aryl, heterocyclic radical, heteroaryl or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of group consisting of: OR14, N (R14) R14 and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haioaikyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclic alkyl and heterocyclic radical; R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haioaikyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclic alkyl and heterocyclic radical; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haioaikyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haioaikyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R9 is independently selected from the group consisting of: hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclic radical, cycloalkyl, heterocyclic alkyl, haloalkyl, arylalkylamino, amino, aminoalkyl, aminoacyl, nitro, azido and heteroarylalkyl, wherein alkyl, aryl, heteroaryl, aminoalkyl or arylalkyl are optionally substituted with one or more radicals selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanate, socyanate, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl , dialkylammoalkyloxy and heterocyclic radical option onally substituted with alkyl, alkylamino, aminoalkyl, hydroxyalkyl and alkylaminoalkyl; R 0 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyl, phenoxy, benzyloxy, dialkylaminoalkyloxy, and heterocyclic radical; R 0 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy and heterocyclic radical; R1 is selected from the group consisting of: hydrido, halogen, haloalkyl, CN, C02R5, lower alkyl, lower alkenyl, lower alkynyl, alkoxy and CONH2; R 12 is selected from the group consisting of: hydrido, halogen, alkyl and alkoxy; R13 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of group consisting of: OR14, N (R14) R14 'and glycols; R14 is independently selected from the group consisting of: hydrido and lower alkyl; R14 is independently selected from the group consisting of: hydrido and lower alkyl; R 5 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic radical, alkylalkene, alkylaquin, hydroxy, hydroxyalkyl, alkylhydroxy, amine, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano , alkylthio, alkylisulfinyl and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic radical; and R16 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy and alkoxyalkyl; or their isomers, tautomers, vehicles, esters and prodrugs, and their pharmaceutically acceptable salts. 2. A compound of Formula II: wherein A is (CH2) m; wherein each CH2 can be independently substituted with one or more substitutions selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl and alkynyl; m is from 0 to 8; Q is a 5- or 6-membered heteroaryl, or an aryl, optionally saturated, or optionally substituted with R1, R2 or R12; B is an aromatic heterocyclic radical; R is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, N02, OR5, OCOOR5, C02R7, CON (R6) R7, COR6, SR6, SOR6, S02R6, NR6R7 , NR6COR7, NR6CONHR7, NR6S02R7, NR6S02NHR7 and S02N (R6) R7 in which R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from the group constituted by: S, SO, SO2, O and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optionally substituted with hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN,? 02, OR5, OCOOR5, CO2R7, CON (R6) R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2R7, NR6SO2NHR7 and SO2N (R6) R7 in which R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing 1 to 3 heteroatoms of 1 to 3 substituted or unsubstituted heteroatoms, selected from the group consisting of: S, SO, SO2, O and NR6; R2 is selected from the group constituted by. halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, NO2, SR6, NHR6, CON (R6) R7, NHCONHR6, CO2H and haloalkyl; R1 and R2 can go together to form a saturated or unsaturated carbocyclic ring, of 5 to 7 members, optionally containing from 0 to 3 heteroatoms selected from the group consisting of: N, O, or S, and wherein said ring is optionally substituted with R; R3 is selected from the group consisting of: amidine, alkylamino, aminoalkyl, CONHR16, NH2) NHCOR6 and CH2NHCOR6, substituted or unsubstituted; R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic radical, nitro, acylamine, aryl, heteroaryl, and alkenyl, OR13, SR8, SO2N (R8) R8 ', NHR9, NHCOR9, NR9COR9, alkenyl, OR13, SR8, SO2N (R8) R8', NHR9, NHCOR9, NR9COR9, NHCO (OR9), NR9CO (OR9), NR8SO2R10, NHSO2N (R10) R10 ', NR6CON (R 0) R10 ', COR9, CO2R8, CON (R8) R8', wherein R8 and R8 can go together to form a 3- to 7-membered carbocyclic ring, carrying from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, S02, O, N and NR6, and wherein R10 and R10 'can go together to form a 3- to 7-membered carbocyclic ring, bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, S02, O, N and NR6, wherein said aryl, heterocyclic radical, heteroaryl or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of group consisting of: OR14, N (R1) R14, and glycols; R6 is independently selected from the group consisting of; hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclic alkyl and heterocyclic radical; R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclic alkyl and heterocyclic radical; R8 is independently selected from the group consisting of; hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R9 is independently selected from the group consisting of; hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclic radical, cycloalkyl, heterocyclic alkyl, haloalkyl, arylalkylamino, amino, aminoalkyl, amino acid, nitro, azido and heteroarylalkyl, wherein alkyl, aryl, heteroaryl, aminoalkyl or arylalkyl are optionally substituted with one or more radicals selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl, alkylthio, alkylsulfinyl, alkylsulfonium, alkylamino, aminoalkyl, alkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanate, isothiocyanate, aicyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy and heterocyclic radical optionally substituted by alkyl, alkylamino , aminoalchiio, hydroxyalqui it, and alkylaminoalkyl; R10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, and heterocyclic radical; R10 'is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, and heterocyclic radical; R11 is selected from the group consisting of: hydrido, halogen, haloalkyl, CN, CO2R5, lower alkyl, lower alkenyl, lower alkynyl, alkoxy and CONH2; R 12 is selected from the group consisting of: hydrido, halogen, alkyl and alkoxy; R13 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of group constituted by; OR14, N (R14) R14 and glycols; R14 is independently selected from the group consisting of: hydrido and lower alkyl; R 4 is independently selected from the group consisting of: hydrido and lower alkyl; R 5 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic radical, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano , alkylthio, alkylsulfinyl and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic radical; and R16 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy and alkoxyalkyl; or their isomers, tautomers, vehicles, esters and prodrugs, and their pharmaceutically acceptable salts. 3. The compound according to claim 2, further characterized by wherein A is (CH2) m; wherein each CH2 can be independently substituted with one or more substitutions selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl and alkynyl; m is from 0 to 8; Q is a 5- or 6-membered heteroaryl, or an aryl, optionally saturated, or optionally substituted with R1, R2 or R12; B is an aromatic heterocyclic radical; R is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, N02, OR5, OCOOR5, C02R7, CON (R6) R7, COR6, SR6, SOR6, S02R6, NR6R7 , NR6COR7, NR6CONHR7, NR6S02R7 and S02N (R6) R7 where R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing 1 to 3 substituted or unsubstituted heteroatoms, selected from the group constituted by: S, SO, S02 O and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optionally substituted with hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, N02, OR5, OCOOR5, C02R7, CON (R6) R7 , COR6, SR6, SOR6, S02R6, NR6R7, NR6COR7, NR6CONHR7, NR6S02R7, NR6S02NHR7 and S02N (R6) R7 in which R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing 1 to 3 heteroatoms from 1 to 3 substituted or unsubstituted heteroatoms, selected from the group consisting of: S, SO, S02 O and NR6; R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, N02, SR6, NHR6, CON (R6) R7, NHCONHR6, C02H and haloalkyl; R and R2 can go together to form a saturated or unsaturated carbocyclic ring, of 5 to 7 members, optionally containing from 0 to 3 heteroatoms selected from the group consisting of: N, O, or S, and wherein said ring is optionally substituted with R1; R3 is CONHR 6; R4 is selected from the group consisting of; halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic radical, nitro, acylamino, aryl, heteroaryl and alkenyl, OR13, SR8, S02N (R8) R8 \ NHR9, NHCOR9, NR9COR9, NHCO (OR9), NR9CO (OR9), NR8S02RQ, NHS02N (R10), NR6CON (R10) R10 ', COR9, C02R8, CON (R8) R8', wherein R8 and R8 'can go together to form a carbocyclic ring from 3 to 7 members, carrying from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, S02, O, N and NR6, wherein R 0 and R 10 can go together to form a carbocyclic ring of 3 to members carrying from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, SO2, O, N and NR6, wherein said aryl, heterocyclic radical, heteroaryl or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of group consisting of: OR 4, N (R) R 14 and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclic alkyl, and heterocyclic radical; R7 is independently selected from the group consisting of; hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclic alkyl and heterocyclic radical; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R8 is independently selected from the group consisting of; hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R9 is independently selected from the group consisting of; hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclic radical, cycloalkyl, heterocyclic alkyl, haloalkyl, arylalkylamino, amino, aminoalkyl, amino acid, nitro, azido and hetroarylalkyl, wherein alkyl, aryl, heteroaryl, aminoalkyl or arylalkyl are optionally substituted with one or more radicals selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanate, isothiocyanato, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy and heterocyclic radical optionally substituted by alkyl, alkylamino , aminoalkyl, hydroxyalq uilo, and alkylaminoalkyl; R10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, and heterocyclic radical; R 0 'is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halogen, haioalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, and heterocyclic radical; R1 is independently selected from the group consisting of: hydrido, halogen, haioalkyl, CN, CO2R5, lower alkyl, lower alkenyl, lower alkynyl, alkoxy and CONH2; R 12 is selected from the group consisting of: hydrido, halogen, alkyl and alkoxy; R13 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of group constituted by; OR14, N (R14) R14 'and glycols; R14 is independently selected from the group consisting of: hydrido and lower alkyl; R14 'is independently selected from the group consisting of: hydrido and lower alkyl; R15 is independently selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic radical, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano , alkylthio, alkylsulfinyl and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic radical; and R 6 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy and alkoxyalkyl; or their isomers, tautomers, vehicles, esters and prodrugs, and their pharmaceutically acceptable salts. 4 - The compound according to claim 3, further characterized by wherein A is (CH2) m; wherein each CH2 can be independently substituted with one or more substitutions selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl and alkynyl; m is from 0 to 8; Q is a 5- or 6-membered heteroaryl, or an aryl, optionally saturated, or optionally substituted with R1, R2 or R12; B is an aromatic heterocyclic radical; R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, N02, OR5, OCOOR5, C02R7, CON (R6) R7, COR6, SR6, SOR6, S02R6, NR6R7 , NR6COR7, NRBCONHR7, NR6S02R7, NR6S02HNR7 and S02N (R6) R7 in which R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from the group constituted by: S, SO, S02, O and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optionally substituted with hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3 CN, N02, OR5, OCOOR5, C02R7, CON (R6) R7, COR6, SR6, SOR6, S02R6, NR6R7, NR6COR7, NR6CONHR7, NR6S02R7, NR6S02HNR7 and S02N (R6) R7 in which R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing 1 to 3 substituted heteroatoms or unsubstituted, selected from the group consisting of: S, SO, S02, O and NR6; R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, N02, SR6, NHR6, CON (R6) R7, NHCONHR6, C02H and haloalkyl; R1 and R2 can go together to form a saturated or unsaturated carbocyclic ring, of 5 to 7 members, optionally containing from 0 to 3 heteroatoms selected from the group consisting of: N, O, or S, and wherein said ring is optionally substituted with R1; R3 is CONHR16; R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic radical, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, S02N (R8) R8 ', NHR9, NHCOR9, NR9COR9, NHCO (OR9), NR9CO (OR9), NR8S02R10, NHSO2N (R10) R10', NR6CON (R10) R10 ', COR9, C02R8, CON (R8) R8', wherein R8 and R8 can go together to form a 3- to 7-membered carbocyclic ring, bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, S02, O, N and NR6, and wherein R1D and R10, can go together to form a 3- to 7-membered carbocyclic ring, bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, S02, O, N and NR6, wherein said aryl, heterocyclic, heteroaryl or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of group consisting of: OR14, N (R14) R14 and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclic alkyl and heterocyclic radical; R7 is independently selected from the group consisting of; hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclic alkyl and heterocyclic radical; R8 is independently selected from the group consisting of; hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R8 'is independently selected from the group consisting of; hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R9 is independently selected from the group consisting of; hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclic radical, cycloalkio, heterocyclic alkyl, haloalkyl, arylalkylamino, amino, aminoalkyl, aminoacyl, nitro, azido and heteroarylalkyl, wherein alkyl, aryl, heteroaryl, aminoalkyl or arylalkyl are optionally substituted with one or more radicals selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanate, isothiocyanate, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy and heterocyclic radical optionally substituted by alkyl, alkylamino , aminoalkyl, hydroxyalqui it, and alkylaminoalkyl; R10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, and heterocyclic radical; R10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more selected radicals between alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, and heterocyclic radical; R 1 is selected from the group consisting of: hydrido, halogen, haloalkyl, CN, C02R5, lower alkyl, lower alkenyl, lower alkynyl, alkoxy and CONH2; R12 is hydrous; R13 is independently selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group constituted by; OR14, N (R14) R14 and glycols; R 4 is independently selected from the group consisting of: hydrido and lower alkyl; R 4 is independently selected from the group consisting of: hydrido and lower alkyl; R15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic radical, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic radical; and R16 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy and alkoxyalkyl; or their isomers, tautomers, vehicles, esters and prodrugs, and their pharmaceutically acceptable salts. 5. The compound according to claim 3, further characterized by wherein A is (CH2) m; wherein each CH2 can be independently substituted with one or more substitutions selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl and alkynyl; m is from 0 to 8; n is independently selected from 0, 1 or 2; Q is a 5- or 6-membered heteroaryl, or an aryl, optionally saturated, or optionally substituted with R1, R2 or R12; B is an aromatic heterocyclic radical; R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, N02, OR5, OCOOR5, C02R7, CON (R6) R7, COR6, SR6, SOR6, S02R6, NR6R7 , NR6COR7, NR6CONHR7, NR6S02R7, NR6S02NHR7 and S02N (R6) R7 in which R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from the group constituted by: S, SO, S02, O and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optionally substituted with hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, N02, OR5, OCOOR5, C02R7, CON (R6) R7 , COR6, SR6, SOR6, S02R6, NR6R7, NR6COR7, NR6CONHR7, NR6S02R7, NR6S02NHR7 and S02N (R6) R7 in which R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing 1 to 3 heteroatoms from 1 to 3 substituted or unsubstituted heteroatoms, selected from the group consisting of: S, SO, S02 O and NR6; R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, N02, SR6, NHR6, CON (R6) R7, NHCONHR6, C02H and haloalkyl; R and R2 can go together to form a saturated or unsaturated carbocyclic ring, of 5 to 7 members, optionally containing from 0 to 3 heteroatoms selected from the group consisting of: N, O, or S, and wherein said ring it is optionally substituted with R1; R3 is CONHR 6; R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic radical, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, S02N (R8) R8 ', NHR9, NHCOR9, NR9COR9, alkenyl, OR13, SR8, S02N (R8) R8', NHR9, NHCOR9, NR9COR9, NHCO (OR9), NR9CO (OR9), NR8S02R10, NHSO2N (R0) R10 ', NR6CON ( R10) R10 ', COR9, C02R8, CON (R8) R8', wherein R8 and R8 'can go together to form a 3- to 7-membered carboxyl ring, carrying from 1 to 3 substituted or unsubstituted heteroatoms, selected between S, SO, SO2, O, N and NR6, and wherein R10 and R0 can go together to form a 3- to 7-membered carbocyclic ring, carrying from 1 to 3 substituted or unsubstituted heteroatoms, selected from S , SO, SO2, O, N and NR6, wherein said aryl, heterocyclic radical, heteroaryl or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl arylalkyl, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group constituted by: OR14, N (R14) R14 'and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, aicylaminoalkyl, akoxy, aikoxychiol, heterocyclic alkyl and heterocyclic radical; R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, aicylaminoalkyl, akoxy, aikoxychiol, heterocyclic alkyl and heterocyclic radical; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, aicylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, aicylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R9 is independently selected from the group consisting of. hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclic radical, cycloalkyl, heterocyclic alkyl, haloalkyl, arylalkylamino, amino, aminoalkyl, aminoacyl, nitro, azido and heteroarylalkyl, wherein alkyl, aryl, heteroaryl, aminoalkyl or arylalkyl are optionally substituted with one or more radicals selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanate, isothiocyanate, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy and heterocyclic radical optionally substituted by alkyl, alkylamino , aminoalkyl, hydroxyalk ilo and alkylaminoalkyl; R10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more selected radicals between alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy and heterocyclic radical; R10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more selected radicals between alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy and heterocyclic radical; R11 is hydrous; R 12 is selected from the group consisting of: hydrido, halogen, alkyl and alkoxy; R13 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of group consisting of: OR 4, N (R 14) R 14 and glycols; R 4 is independently selected from the group consisting of: hydrido and lower alkyl; R 4 'is independently selected from the group consisting of: hydrido and lower alkyl; R15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic radical, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic radical, and R16 is independently selected among the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy and alkoxyalkyl; or their isomers, tautomers, vehicles, esters and prodrugs, and their pharmaceutically acceptable salts. 6. The compound according to claim 3, further characterized by wherein A is (CH2) m; wherein each CH2 can be independently substituted with one or more substitutions selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkenyl and alkynyl; m is from 0 to 8, Q is a 5 or 6 membered argonary, or an aryl, optionally saturated, or optionally substituted with R1, R2 or R12¡ B is an aromatic heterocyclic radical; R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, N02, OR5, OCOOR5, C02R7, CON (R6) R7, COR6, SR6, SOR6, S02R6, NR6R7 , NR6COR7 'NR6CONHR7, NR6S02R7, NR6S02NHR7 and S02N (R6) R7 in which R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from the group constituted by: S, SO, S02, O and NR6, wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optionally substituted with hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, N02l OR5, OCOOR5, C02R7, CON (R6) R7, COR6, SR6, SOR6, S02R6, NR6R7, NR6COR7 'NRsCONHR7, NR6S02R7, NR6S02NHR7 and S02N (R6) R7 in which R6 and R7 can go together to form a carbocyclic ring of 3-7 members carrying from 1 to 3 substituted or unsubstituted heteroatoms, selected from the group consisting of: S, S O, S02, O and NR6, R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR5, CN, N02, SR6, NHR6, CON (R6) R7, NHCONHR6, C02H and haloalkyl; R and R2 can go together to form a saturated or unsaturated carbocyclic ring, of 5 to 7 members, optionally containing from 0 to 3 heteroatoms selected from the group consisting of: N, O, or S, and wherein said ring is optionally substituted with R; R3 is CONHR16; R4 is selected from the group consisting of: halogen, alkylsuifinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic radical, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, S02N (R8) 8 ', NHR9, NHCOR9, NR9COR9' NHCO (OR9), NR9CO (OR9), NR8S02R1 °, NHSO2N (R10) R10 ', NR6CON (R10) R10', COR9, C02R8, CON (R8) R8 ', wherein R8 and R8 can go together to form a 3 to 7 membered carbocyclic ring, bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, S02, O and NR6, and wherein R 0 and R 10 can go together to form a 3 to 7 membered carbocyclic ring, bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, S02, O and NR6, wherein said aryl, heroic, heteroaryl or alkenyl radical are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl arylalkyl, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group constituted by: OR14, N (R14) R14 and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heteroacyclic alkyl, and heterocyclic radical; R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heteroacyclic alkyl, and heterocyclic radical; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclic alkyl; R9 is independently selected from the group consisting of: hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclic radical, cycloalkyl, heterocyclic alkyl, haloalkyl, arylalkylamino, amino, aminoalkyl, aminoacyl, nitro, azido and heteroarylalkyl, wherein alkyl, aryl, heteroaryl, aminoalkyl or arylalkyl are optionally substituted with one or more radicals selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxy, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanate, isothiocyanate, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl , dialkyaminoalkyloxy and heterocyclic radical optional substituted with alkyl, alkylamino, aminoalkyl, hydroxyalkyl and alkylaminoalkyl; 10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more selected radicals between alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxy, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy and heterocyclic radical; R10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more selected radicals between alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxy, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy and heterocyclic radical; R11 is hydrous; R 2 is hydride; R13 is selected from the group consisting of: hydrido, alkyl, aryl, arylaryl, heteroaryl, heterocyclic alkyl or heteroarylalkyl wherein aryl, alkyl, arylaryl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group constituted by: OR14, N (R14) R14 and glycols; R 4 is independently selected from the group consisting of: hydrido and lower alkyl; R14 is independently selected from the group consisting of: hydrido and lower alkyl; R15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic radical, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl and alkylsulfonyl; wherein aryl or arylaikyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic radical, and R16 is independently selected among the group consisting of: hydrido, aryl, arylaikyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy and alkoxyalkyl; or their isomers, tautomers, vehicles, esters and prodrugs, and their pharmaceutically acceptable salts. 7. The compound according to claim 4, further characterized in that A is (CH2) m; wherein each CH2 can be independently substituted with one or more substitutions selected from the group consisting of: hydroxy, halo, alkoxy, alkyl, lower, amino, aminoalkyl, alkylamino, alkenyl and alkynyl; m is 1 or 2; B is a 5- or 6-membered aromatic heterocyclic radical; Q is a 5 or 6 membered heteroaryl, or an aryl, optionally saturated, or optionally substituted with R, R2 or R12; B is an aromatic heterocyclic radical; R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, N02, OR5, OCOOR5, C02R7, CON (R6) R7, COR6, SR6, SOR6, S02R6, NR6R7 , NR6COR7 'NR6CONHR7, NR6SO2R7, NR6S02NHR7 and SO2N (R6) R7 in which R6 and R7 can go together to form a 3-7 membered carbocyclic ring bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from the group constituted by: S, SO, SO2, O and NR6, wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optionally substituted with hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, NO2 , OR5, OCOOR5, CO2R7, CON (R6) R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7 and SO2N (R6) R7 in which R6 and R7 can go together to form a carbocyclic ring of 3-7 members carrying from 1 to 3 substituted or unsubstituted heteroatoms, selected from the group consisting of: S, S O, SO2, O and NR6, R2 is hydrous; R3 is CONHR16; R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydroid, hydroxyalkyl, haloalkoxy, heterocyclic radical, nitro, acylamino, aryl, heteroaryl and alkenyl, OR 3, SR8, S02N (R8 ) 8 ', NHR9, NHCOR9, NR9COR9, NHCO (OR9), NR9CO (OR9), NR8S02R1 °, NHSO2N (R10) R10', NR6CON (R10) R10 ', COR9, CO2R8, CON (R8) R8', in the that R8 and R8 'can go together to form a 3- to 7-membered carbocyclic ring, carrying from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, SO ?, O and NR5, and wherein R10 and R1Q can go together to form a 3 to 7 membered carbocyclic ring, bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, SO2, O and NR6, wherein said aryl, heroic, heteroaryl or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl arylalkyl, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group constituted by: OR14, N (R14) R14 and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heteroacyclic alkyl, and heterocyclic radical; R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heteroacyclic alkyl, and heterocyclic radical; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkion, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroalkyl, and heterocyclic alkyl; R9 is independently selected from the group consisting of: hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclic radical, cycloalkyl, heterocyclic alkyl, haloalkyo, arylalkylamino, amino, aminoalkyl, aminoacyl, nitro, azido and heteroarylalkyl, wherein alkyl, aryl, heteroaryl, aminoalkyl or arylalkyl are optionally substituted with one or more radicals selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyo, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl , thioalkyl, aminoacyloxy, thiocyanate, isothiocyanate, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy and heterocyclic radical optionally substituted by alkyl, alkylamino, aminoalkyl, hydroxyalkyl and alkylaminoalkyl; R10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkion, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more selected radicals between alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy and heterocyclic radical; R10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more selected radicals between alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy and heterocyclic radical; R11 is selected from the group consisting of hydrido, halo, CF3, CN, C02R5 and CONH2; R12 is hydrous; R 13 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclic alkyl or heroarylalkyl wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group constituted by: OR 4, N (R 4) R 14 'and glycols; R 4 is independently selected from the group consisting of: hydrido and lower alkyl; R14 is independently selected from the group consisting of: hydrido and lower alkyl; R15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic radical, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amine, aminoalkyl, alkylamino, alkylaminealkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halo, haloaikyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic radical, and R16 is independently selected among the group consisting of: hydrido, aryl, arylalk, lower alkyl, haloaicyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy and alkoxyalkyl; or their isomers, tautomers, vehicles, esters and prodrugs, and their pharmaceutically acceptable salts. 8. The compound according to claim 7, further characterized in that A is (CH2) m; wherein each CH2 can be independently substituted with one or more substitutions selected from the group consisting of: hydroxy, halo, alkoxy, alkyl, lower, amino, aminoalkyl, alkylamine, alkenyl and alkynyl; m is 2; B is a 5- or 6-membered aromatic heterocyclic radical; R1 is selected from the group consisting of S02NH2, SO2N (R6) 2 and S02R6; R2 is CONH2; R 4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloaicyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic radical, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, S02N (R8) 8 ', NHR9, NHCOR9' NR9COR9 'NHCO (OR9), NR9CO (OR9), NR8S02R1 °, NHSO2N (R10) R10', NR6CON (R10) R10 ', COR9, C02R8, CON (R8) R8', wherein R8 and R8 can go together to form a 3- to 7-membered carbocyclic ring, bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, SO2, O, N and NR6, and wherein R 0 and R10 'can go together to form a 3- to 7-membered carbocyclic ring, carrying from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, SO2, O, N and NR6, wherein said aryl, heroic radical , heteroaryl or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl arylalkyl, heteroaryl, heterocyclic alkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group constituted by: OR14, N (R14) R14 'and g! icos; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heteroacyclic alkyl, and heterocyclic radical; R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heteroacyclic alkyl, and heterocyclic radical; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R9 is independently selected from the group consisting of: hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclic radical, cycloalkyl, heterocyclic alkyl, haloalkyl, arylalkylamino, amino, aminoalkyl, aminoacyl, nitro, azido and heteroarylalkyl, wherein alkyl, aryl, heteroaryl, aminoalkyl or arylaikyl are optionally substituted with one or more radicals selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanate, isothiocyanate, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkeniio, alkynyl, dialkylaminoalkyloxy and optional heterocyclic radical substituted with alkyl, alkylamino, aminoalkyl, hydroxyalkyl and alkylaminoalkyl; R 0 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylaryl, wherein aryl, heteroaryl, heterocyclic radical or arylaikyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy and heterocyclic radical; R10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylaryl, wherein aryl, heteroaryl, heterocyclic radical or arylaikyl are optionally substituted with one or more selected radicals between alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy and heterocyclic radical; R11 is selected from the group consisting of: hydrido, halo, CF3, NC, C02R5 and CONH2; R12 is hydrous; R13 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of group consisting of: OR14, N (R14) R14 'and glycols; R 4 is independently selected from the group consisting of: hydrido and lower alkyl; R14 is independently selected from the group consisting of: hydrido and lower alkyl; R15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic radical, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamine, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl and alkylsuifonyl; wherein aryl or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic radical, and R 6 is selected independently from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy and alkoxyalkyl; or their isomers, tautomers, vehicles, esters and prodrugs, and their pharmaceutically acceptable salts. 9. - The compound according to claim 6, further characterized by the formula wherein A is (CH2) m; m is 1 or 2; B is a 5- or 6-membered aromatic heterocyclic radical; R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic radical, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, S02N (R8) 8 ', NHR9, NHCOR9, NR9COR9, NHCO (OR9), NR9CO (OR9), NR8S02R10, NHSO2N (R10) R10', NR6CON (R0) R10 ', COR9, C02R8, CON (R8) R8', wherein R8 and R8 'can go together to form a 3- to 7-membered carbocyclic ring, bearing from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, S02, O, N and NR6, and wherein R10 and R10 'can go together to form a 3- to 7-membered carbocyclic ring, carrying from 1 to 3 substituted or unsubstituted heteroatoms, selected from S, SO, S02, O, N and NR6, wherein said aryl, heroic radical , heteroaryl or alkenyl are optionally substituted with R9; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic radical, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclic alkyl; R9 is independently selected from the group consisting of: hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclic radical, cycloalkyl, heterocyclic alkyl, haloalkyl, arylalkylamino, amino, aminoalkyl, aminoacyl, nitro, azido and heteroarylalkyl, wherein alkyl, aryl, heteroaryl, aminoalkyl or arylalkyl are optionally substituted with one or more radicals selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanate, isothiocyanate, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, aikinylamino, alkenyl, alkynyl, dialkylaminoalkyloxy and optional heterocyclic radical substituted with alkyl, alkylamino, aminoalkyl, hydroxyalkyl and alkylaminoalkyl; R 0 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy and heterocyclic radical; R10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic radical, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclic radical or arylalkio are optionally substituted with one or more selected radicals between alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy and heterocyclic radical; R 3 is independently selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclic alkyl or heroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclic alkyl or heteroarylalkyl are optionally substituted with one or more selected radicals between the group consisting of: OR14, N (R) R14 'and glycols; R14 is independently selected from the group consisting of: hydrido and lower alkyl; R14 'is independently selected from the group consisting of: hydrido and lower alkyl; R15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic radical, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radicals selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic radical, and R16 is independently selected among the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy and alkoxyalkyl; or their isomers, tautomers, vehicles, esters and prodrugs, and their pharmaceutically acceptable salts. 10. The compound according to claim 3, 4, 5, 6 or 7, further characterized in that R3 is CONH2. 11. The compound according to claim 3, 4, 5, 6, 7, 8 or 9, further characterized in that B is selected from the group consisting of: thiophene, pyrrole, imidazole, pyrazole, pyridazine, primidine, and pyrazine . 12. The compound according to claim 10, further characterized in that B is selected from the group consisting of: thiophene, pyrrole, imidazole, pyrazole, pyridazine, primidine, and pyrazine. 13. The compound according to claim 9, further characterized in that it is selected from the group consisting of: 1- [4- (aminosulfonyl) pheny] -6-benzyl-1, 4,5,6-tetrahydropyrrolo [2, 3-g] indazole-3-carboxylic acid ethyl ester; 1- [4- (aminosulfonyl) phenyl] -6-benzyl-1, 4,5,6-tetrahydropyrrolo [2,3-g] indazole-3-carboxamide; 1- [4- (Aminosulfonyl) pheny] -6-benzyl-1, 4,5,6-tetrahydropyrazolo [3,4-e] indazole-3-carboxylic acid ethyl ester; 1- [4- (aminosulfonyl) pheny] -6-benzyl-1, 4,5,6-tetrahydropyrazolo [3,4-e] indazole-3-carboxamide; 1 - [4- (Aminosulfonyl) phen]] -1, 4,5,6-tetrahydropyrazolo [3,4-e] indazole-3-carboxylic acid ethyl ester; 1 - [4- (aminosulfonyl) pheni] -1,4,5,6-tetrahydropyrazolo [3,4- e] indazole-3-carboxamide; 1- [4- (Aminosulfonyl) pheni] -4,5-dihydro-1 H-thieno [2,3-g] indazole-3-carboxylic acid ethyl ester; 1 - [4- (aminosulfonyl) pheni] -4,5-dihydro-1 H-thieno [2,3-g] indazole-3-carboxamide; 1 - [4- (aminosulfonyl) pheny] -4,5-dihydro-1 H -pyrazolo [4,3-f] isoquinoline-3-carboxamide; 1- [4- (aminosulfonyl) pheny] -1,4,5,8-tetrahydropyrazolo [4,3-g] indazole-3-carboxamide, 8-amino-1- [4- (aminosulfonyl) phenyl]) - 4 , 5-dihydro-1 H -pyrazolo [4,3-h] quinazoline-3-carboxamide, 8-chloro-1- [4- (fluorophenyl) -4,5-dihydro-1 H-pyrazolo- [4,3] -h] quinoline-3-carboxamide, 1- (4-fluorophenyl) -N- (4-methoxybenzyl) -8 - [(4-methoxy-benzyl) amino] -4,5-dihydro-1 H-pyrazolo [4] , 3-h] quinoline-3-carboxamide; 8 - [(3-chloroisonicotinoyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-1 H -pyrazolo [4,3-h] quinoline-3-carboxamide, 8-. { [(2-chloropyridin-3-yl) carbonyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1 H -pyrazolo [4,3-h] quinolin-3-carboxamide, and 8-. { [5-chloro-2- (4-methylpiperzin-1-yl) isonicotinoyl] amino} -1- (4-fluoropheni1) -4,5-dihydro-1 H-pyrazolo [4,3-h] quinolm carboxamide. 14. A composition comprising the compound of the Claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 13, and at least one pharmaceutically acceptable carrier. 15. A composition comprising the compound of Claim 10, and at least one pharmaceutically acceptable carrier. 16. A composition comprising the compound of the Claim 1 1, and at least one pharmaceutically acceptable carrier. 17. A composition comprising the compound of Claim 12, and at least one pharmaceutically acceptable carrier. 18. The use of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 13, for preparing a medicament for treating cancer, inflammation or inflammatory disease in a subject. 19. The use of a compound of Claim 10, for preparing a medicament for treating cancer, inflammation or an inflammatory disease in a subject. 20. The use of a compound of claim 11, for preparing a medicament for treating cancer, inflammation or an inflammatory disease in a subject. 21. The use of a compound of Claim 12, for preparing a medicament for treating cancer, inflammation or an inflammatory disease in a subject. 22. Use as claimed in Claim 21, for use in the treatment of cancer. 23. Use as claimed in Claim 21, for use in the treatment of inflammation. 24. - The use as claimed in Claim 2, for use in the treatment of an inflammatory disease. 25. - The use as claimed in Claim 24, wherein the inflammatory disease is arthritis. 26. - The use as claimed in Claim 24, wherein the inflammatory disease is a pain. 27. - The use as claimed in Claim 24, wherein the Inflammatory disease is fever.