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MXPA04010952A - Substituted pyrazolyl compounds for the treatment of inflammation. - Google Patents

Substituted pyrazolyl compounds for the treatment of inflammation.

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Publication number
MXPA04010952A
MXPA04010952A MXPA04010952A MXPA04010952A MXPA04010952A MX PA04010952 A MXPA04010952 A MX PA04010952A MX PA04010952 A MXPA04010952 A MX PA04010952A MX PA04010952 A MXPA04010952 A MX PA04010952A MX PA04010952 A MXPA04010952 A MX PA04010952A
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MX
Mexico
Prior art keywords
alkyl
amino
group
hydroxy
hydrido
Prior art date
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MXPA04010952A
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Spanish (es)
Inventor
Lennon Patrick
Original Assignee
Pharmacia Corp
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Publication date
Priority claimed from PCT/US2002/029774 external-priority patent/WO2003024935A2/en
Application filed by Pharmacia Corp filed Critical Pharmacia Corp
Publication of MXPA04010952A publication Critical patent/MXPA04010952A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

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

Description

PIRAZOLYL COMPOUNDS REPLACED FOR THE TREATMENT OF INFLAMMATION FIELD OF THE INVENTION The present invention generally relates to the field of anti-inflammatory pharmaceutical agents and specifically relates to substituted pyrazolyl derivatives, to compositions comprising them and to methods for treating cancer, inflammation and disorders associated with inflammation, such as arthritis. BACKGROUND OF THE INVENTION The following description of the background of the invention is provided to aid in the understanding of the invention, but it is not and does not describe the prior art to the invention. The NF-? is a ubiquitous transcription factor that has an important role in the activation of the immune system and in the stress responses regulating the transcription of many inducible premature genes including proinflammatory cytokines, adhesion molecules, growth factors, enzymes and receptors (Ghosh S. , May, MJ ,, and ????,? (1998) Annu., Rev. Immunol., 16, 115-260; Zandi, E., and Karin, M. (1999) Mol. Cell. Bbl. 19, 4547-4551; Karin, M. (1999) J. Biol. Chem. 274, 27339-27342). The specificity of the expression of the gene is determined at the cellular level by a set of external stimuli such as bacterial products including LPS, as well as cytokines, the most important being the tumor a necrosis factor (TNFa) and the terothieuquina-β (? ? 1 ß). By synergistic interaction with other transcription factors, additional 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 homo- and heterodimers of the Reí family of proteins and is sequestered in an inactive form in the cytoplasm by family members ??? of inhibitory proteins (Ghosh S., May, MJ, and opp E (1998) Annu Rev. Immunol., 16, 115-260; Zandi, E., and Karin, M. (1999) Mol. Cell. Biol. 19, 4547-4551; Karin, M. (1999) J. Biol. Chem. 274, 27339-27342). The kB mask the nuclear localization signal in NF - ??, avoiding the nuclear translocation and therefore the DNA binding to the promoter regions of the response genes. The stimulation of the cells with an agonist that activates NF-KB results in a series of biochemical signals that have as a final result the phosphorylation, ubiquitinylation and degradation of the IKB, thus releasing NF-? for nuclear translocation (Ghosh S., May, MJ, and Kopp. E (1998) Annu., Rev. Immunol., 16, 115-260; Zandi, E., and Karin, M. (1999) Mol. Cell. Biol. 19, 4547 ^ 551; Karin, M. (1999) J. Biol. Chem. 274, 27339-27342). Recently, two kinases ??? (IKKI or IKKa and IKK2 or ??? ß), which phosphorylate the kB and therefore initiate its degradation, have been cloned and characterized in several laboratories (Ghosh S., May, MJ, and Kopp. E (1998) Annu. Rev. Immunol., 16, 115-260; 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 as well as enzymatically and exist as a heterodimer in a large protein complex called signaling IKK (Regnier, C, Song, H., Gao, X., Goeddel, 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, Shevchenko, 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,., Hayadawa, M and Karin,. (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 a regulatory adapter protein necessary for the activation of IKK and 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, BW, Shevchenko, A., Bennet, B. L, Young, DB, Li, JW, Pascual, G., Motiwala, A., Zhu, H., Mann, and Manning, AM ( 1999) Mol. Cell. Biol. 2, 1526-1538). IKKI and IKK2 are co-expressed in most adult human tissues as well as in different stages of mouse embryo development (Regnier, C, Song, H., Gao, X., Goeddel, D., Cao , Z. and Rothe, M. (1997) Cell 90, 373-383; DiDonato, J A., Hayakawa, M., Rothwarf, DM, Zandi, E. and Karin, M. (1997) Nature 388, 548- 554; Mercury, F., Zhu, H., Murray, BW, Shevchenko, 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. (1998) Gene 222, 31-40). This kinase complex appears to represent a critical co denominator in the activation of NF-B in several signal transduction pathways stimulated by a variety of agonists including cytokines, such as TNF-α and IL1 p, 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 Kopp. E (1998) Annu., Rev. Immunol., 16, 115-260; Zandi, E., and arin,. (1999) Mol. Cell. Biol. 19, 4547-4551; Karin, M. (1999) J. Biol. C em. 274, 27339-27342). IKK1 (also referred to as ??? a, Regnier, C, Song, H., Gao, X., Goeddel, D., Cao, Z. and Rothe,. (1997) Ce // 90, 373-383; DiDonato, JA, Hayaka a, M., Rothwarf, DM, Zandi, E. and Karin, M. (1997) Nature 388, 548-554, Mercury, F., Zhu, H., Murray, BW, Shevchenko, 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 conventional biochemical puration of the kinase activity of kB of HeLa S3 cells stimulated with TNF-a and its interaction with MAP3K, a kinase that induces NF-? (NIK), in a selection with double hybrid yeast. IKK1 was identd as the previously cloned serine / threonine kinase, CHUK (Connelly, M. and Marcu, K. (1995) Cell, Mol. Biol. Res. 41, 537-549). IKK1 (also called IKKa) is an 85 kDa protein with 745 amino acids that contains an N-terminal serine / threonine kinase catalytic domain, an antipathetic zipper leucine helix and a C-terminal helix-loop-helix domain. IKK2 (also called ??? ß) was also cloned by conventional biochemical puration, copurd with IKK1 from HeLa S3 cells stimulated with TNFa as well as being identd in the public databases starting from an EST clone with sequence homology to IKK1 (Mercury, F., Zhu, H., Murray, BW, Shevchenko, 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). IKK2 is an 87-kDa protein of 756 amino acids that has the same general topology as IKK1 except for the addition of a 1-amino acid extension at the C-terminus. IKK1 and IKK2 are 52% identical in general with an identity of 65% in the kinase domain and a 44% identity in the C-terminal protein interaction domains. The data obtained using analysis by mammalian time expression, by in vitro translation experiments and by coexpression in a baculoviral system reveal that IKK1 and IKK2 are preferably associated in the heterodimer form for their leucine zipper motifs. Although homodimers have also been described in these systems, it is believed that the heterodimer is the physiological form of the kinase in the cells of mammals (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 IKKy) contains three a-helical regions that include a leucine zipper, preferably interacts with IKK2 and is needed for the activation of the heterodimeric kinase complex possibly by bringing other proteins to the signalosome complex (Yamaoka, S., Courtois, G., Bessia, C, Whiteside, ST, Weil, R., Agou, F., Kirk, HE, Kay, RJ, and Ireal, A. (1998) Ce // 93, 1231-1240; Rothwarf, DM, Zandi, E., Natoli, G., Karin, M. (1998) Nature 395, 297, Mercury, F., Murray, BW, Shevchenko, A., Bennet, BL, Young, DB, Li, JW, Pascual, G., Motiwala, A., Zhu, H., Mann, M and Manning, A. M (1999) Mol Cell Cell Biol. 2, 1526-1538). The kinase activities of IKKI and IKK2 are regulated by phosphorylation and require an intact leucine zipper (LZ) for dimerization as well as an intact helix-loop-helix domain (HLH), which can exert a positive regulatory effect on kinase activity even when expressed in the trans position with respect to the rest of the IKK protein (Regnier, C, Song, H., Gao, X., Goeddel, 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, Shevchenko, 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) Ce // 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). Both IKK subunits contain a canonical motif of MAPKK activation loop near the N-terminus which is the target for phosphorylation and activation of MAP3K kinase activity such as NIK and MEKK1, although physiological regulation by these two upstream kinases awaits characterization Additional (Zandi, E., and Karin, M. (1999) Mol. Cell. Biol. 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, phosphorylation of serines at the C-terminus of IKK2 results in a reduction in the activity of IKK and is postulated to be responsible for the temporal kinase activity observed after stimulation of cells with an agonist (Dehase, M., Hayakawa , M., Chen, Y., and Karin, M. (1999) Science 284, 309-313). IKK2 demonstrates a more potent kinase activity compared to IKKI using IkBa or IkBp as substrate (Mercurio, F., Zhu, H., Murray, BW, Shevchenko, 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; Dehase, M., Hayakawa, M., Chen, Y., and Karin, M. (1999) Science 284, 309-313). Mutations of the serine phospho-acceptor moieties in the activation loop MAPKK alter the kinase activity IKK2; substitutions of serine for alanine results in lower kinase activity while substitutions of serine for glutamic acid result in a constitutively active kinase. Other similar mutations of alanine in IKK1 do not result in a lower stimulation of total IKK activity in response to TNFα or γ1β (Dehase, M., Hayakawa, M., Chen, Y., and Karin, M. (1999 Science 284, 309-313). The fact that IKK2 is the dominant kinase activity in the IKK complex is further supported by the analysis of fibroblasts from mice with deficiencies of IKK1 or IKK2. Fibroblasts lacking IKK1 retain complete IKK activity in response to cytokines and could activate NF-γ. In contrast, fibroblasts lacking IKK2 do not show IKK activity when stimulated with cytokines or activate NF-α. In addition, the phenotypes of each of the IKK deficiencies are unique, resulting in the lack of IKK1 in skin and skeletal defects, with the lack of IKK2 lethal for the embryo due to hepatocyte apoptosis. (Li, Q., Antwerp, DV, Mercury, F., Lee, K., and Verma, IM (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., H ang, JY, Buscher, D., Lee, K., Izpisua-Belmonte, J. C, and Verma, IM (1999) Gene and Development 13, 1322-1328; Tanaka, M., Fuentes, ME , Yamaguchi, K., Dumin, MH, Dalrymple, SA, Hardy, K.L, and Goeddel, DV (1999) Immunity 10, 421-429). It is known that NF- ?? it has a key role in the regulated expression of a large number of pro-inflammatory mediators including cytokines such as IL-6 and IL-8, cell adhesion molecules, such as ICAM and VCAM, and inducible nitric oxide synthase (NOS). It is known that such mediators have a key role in the recruitment of leukocytes at sites of inflammation and in the case of NOS., can lead to the destruction of the organ in some inflammatory and autoimmune diseases. The importance of NF- ?? in inflammatory disorders it is further reinforced with studies of inflammation in the respiratory tract including asthma, in which it has been shown that NF-γ is activated. This activation may be behind the increased production of cytokines and the infiltration of leukocytes characteristic of these disorders. In addition, it is known that inhaled steroids reduce the hypersensitivity of the respiratory tract and suppress the inflammatory response in the asthmatic airways. In view of the recent discoveries regarding the glucocorticoid inhibition of NF-KB, it can be speculated that these effects are mediated by the inhibition of NF-γ. Additional evidence of the role of NF- ?? in inflammatory disorders comes from studies of the rheumatoid synovium. Although NF- ?? It is normally present as an inactive cytoplasmic complex, recent immunohistochemical studies have indicated that NF-KB is present in the nucleus, and therefore active, in cells comprising rheumatoid synovium. In addition, it has been shown that NF-? it is activated in human synovial cells in response to stimulation with TNF-a. Such distribution may be the mechanism underlying the increased production of cytokines and eicosanoids characteristic of this tissue. See Roshak, A. K., et al., J. Biol. Chem., 271, 31496-31501 (1996). It is also likely that the NF-xB / Rel and kB proteins have a key role in the neoplastic transformation. Members of the family are associated with cell transformation in vitro and in vivo due to overexpression, gene amplification, gene rearrangement or translocations (Gilmore TD, Trends Genet 7: 318-322, 1991; Gillmore TD, Oncogene 18: 6925-6937, 1999; Rayet B. et al., Oncogene 18: 6938-6947, 1991). In addition, the rearrangement and / or amplification of the genes encoding these proteins are observed in 20-25% of certain human lymphoid tumors. In addition, a role of NF- has been reported? 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 shown that the inhibition of NF- ?? potentiates TNF and cancer therapy through increased apoptosis (Wang C-Y et al., Science 274: 784-787, 1996; Wang C-Y et al., Nat Med 5: 412-417, 1999). It has also been shown that in cells infected with the human type 1 lymphocyte leukemia virus (HTLV1) (the etiologic agent of an aggressive CD4 + activated T lymphocyte cancer), IKKa and ßβ are constitutively expressed, that they normally function temporarily (Chu ZL et al., J of Biological Chemistry 273: 15891-15894, 1998). It has been shown that the transformation and transactivation protein of HTLV 1 (Tax) binds to MEKK1 and increases the activity of ??? to increase the phosphorylation of serine residues 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 to Matsuo et al discloses that the 1,5-diarylpyrazoles and specifically 1- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -3-trifluoromethylpyrazole have anti-inflammatory activity . U.S. Patent No. 3,940,418 to R. Hamilton describes Tricyclic 4,5-dihydrobenzo [g] indazoles as anti-inflammatory agents. In addition, R. Hamilton [J. Heterocyclic Chem., 13. 545 (1976)] describes tricyclic 4,5-dihydrobenzo [g] indazoles as anti-inflammatory agents. U.S. Patent No. 5,134,155 discloses condensed tricyclic pyrazoles having a saturated ring linking pyrazole and a phenyl radical as inhibitors of HMG-CoA reductase. European publication EP 477 049, published on March 25, 1992, discloses that [4,5-dihydro-1-phenyl-1 H-benzo [g] indazol-3-yl] amides have antipsychotic activity. European publication EP 347,773 published on December 27, 1989 discloses [4,5-dihydro-1-phenyl-1 H-benzo [g] indazol-3-yl] propanamides as immunostimulants. M. Hashem et al [J. Med. Chem., 19, 229 (1976)] describes condensed tricyclic pyrazoles having a saturated ring linking the pyrazole and a phenyl radical, as antibiotics. Certain substituted pyrazolyl benzenesulfonamides have been described in the literature as synthetic intermediates. Specifically, 4- [5- (4-chlorophenyl) -3-phenyl-1 H-pyrazol-1-yl] benzenesulfonamide has been prepared from a pyrazoline compound as intermediate for compounds with hypoglycemic activity [R. Solimán et al, J. Pharm. Sci., 76, 626 (1987)]. 4- [5- [2- (4-Bromophenyl) -2H-1, 2,3-triazol-4-yl] -3-methyl-1 H -pyrazol-1-yl] benzenesulfonamide has been prepared from a composed of pyrazoline and has been described as having potentially hypoglycemic activity [H. okhtar, 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-1 H-pyrazole-1 has been prepared. -yl] benzenesulfonamide [H. Mokhtar et al, Pak J. Sci. Ind. Res., 34, 9 (1991)]. //. Farmaco-Ed. Sci., 40, 272 (1985)], specifically for 1 - [4- (aminosulfonyl) phenyl] -5-phenyl-1 H-pyrazole-3,4-dicarboxylic acid. The use of styrylpyrazole esters for antidiabetes drugs [H. Mokhtar et al, Pharmazie, 33. 649-651 (1978)]. The use of styrylpyrazole carboxylic acids for antidiabetes drugs has been described [R. Soliman et al, Pharmazie, 33. 184-5 (1978)]. The use of 4- [3,4,5-trisubstituted-pyrazol-1-yl] benzenesulfonamides as intermediates for anti-diabetes agents of sulfonylurea and specifically, 1 - [4- (aminosulfonyl) phenyl] -3- acid has been described. 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 for anti-diabetes agents and, more specifically, 4- [3-methyl-5- phenyl-1 H-pyrazol-1-yl] benzenesulfonamide [H. Feid-Allah, Pharmazie, 36. 754 (1981)]. In addition, 1- (4- [aminosulfonyl] phenyl) -5-phenylpyrazole-3-carboxylic acid has been prepared from the 4- [3-methyl-5-phenyl-1H-pyrazol-1-yl] benzenesulfonamide described above [. Solimán et al, J. Pharm. Sci., 70, 602 (1981)]. WO 00/27822 describes tricyclic pyrazole derivatives, WO 00/59901 describes dihydroindene pyrazoles, WO 99/17769 discloses indene [1,2-c] -, naphtho [1, 2-c] - and benzo [6,7] cyclohepta [1,2-c] pyrazole, US 5,196,445 describes heteroaryl-3-oxo-propanenitrile derivatives useful in the treatment of rheumatoid arthritis, WO 97/10210 describes tricyclic derivatives of pyrrolidine as calcium channel antagonists, WO 95/15315 discloses diphenylpyrazole compounds, WO 95/15317 discloses triphenylpyrazole compounds, WO 95/15318 discloses tri-substituted pyrazole compounds and WO 96 / 09293 describes benzo [g] indazolyl derivatives. WO 95/15316 describes substituted pyrazolylbenzenesulfonamide derivatives and WO 01/32663 discloses tricyclic pyrazolecarboxylic acid derivatives as CB-i cannabinoid receptor inhibitors. DETAILED DESCRIPTION OF THE INVENTION A class of compounds, which are useful in the treatment of cancer, inflammation and disorders related to inflammation, is defined by Formula I: wherein A is (CH2) m; wherein each CH2 can be independently substituted with one or more substituents selected from the group consisting of: aryl, heteroaryl, alkanoyl, hydroxy, halogen, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl and alkynyl; m is from 1 to 4; B is a 5- or 6-membered heteroaryl, aryl, saturated or unsaturated heterocyclyl, wherein said aryl, heteroaryl, or heterocyclyl are optionally substituted with R1, R2 and R12; X is selected from the group consisting of: N and C; Y and Z are independently selected from the group consisting of: N, CH, CR3, S and O; R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, N02, OR5, OCOOR5, CO2R7, CON (R6) R7, COR6, SR6, SOR6, S02R6, NR6R7 , NR6COR7, NR6CONHR7, NR6S02R7, NR6S02NHR7 and S02N (R6) R7 wherein R6 and R7 may be taken together to form a carbocyclic ring of 3-7 members having 1 to 3 heteroatoms substituted or unsubstituted selected from the group consisting of: S , SO, S02, O and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR 5 are optionally substituted, hydrido, halo, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, N02, OR5, OCOOR5, C02R7, CON (R6) R7, COR6, SR6, SOR6, S02R6, NR6R7, NR6COR7, NR6CONHR7, NR6S02R7, NR6S02NHR7 and SOzN (R6) R7 wherein R6 and R7 may be taken together to form a carbocyclic ring of 3-7 members having 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 may be taken 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 selected from the group consisting of: amidine, alkylamino, aminoalkyl, CONHR7, 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, heterocyclyl, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, S02N (R8) R8 ', NHR 9, NHCOR9, NR9COR9, NHCO (OR 9), NR9CO (OR9), NR8S02R10, NHSO2N (R10) R'10", NR6CON (R'10) R10', COR9, COzR8, CON (R8) R8 ', where R8 and R8 can be taken together to form a 3-7 membered carbocyclic ring having from 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, S02, O, N, and NR6 and where R 0 and R 0 can taken together to form a 3-7 membered carbocyclic ring having from 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, S02, O, N and NR6 where said aryl, heterocyclyl, heteroaryl or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: I hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclylalkyl and heteroarylalkyl, where aryl, alkyl, arylalkyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of OR14 , N (R14) R1 and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclylalkyl, and heterocyclyl; R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclylalkyl, and heterocyclyl; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclyl, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclylalkyl; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclyl, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclylalkyl; R9 is independently selected from the group consisting of: I hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclyl, cycloalkyl, heterocyclylalkyl, 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, alquildioxi, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy, and heterocyclic optionally substituted with alkyl, alkylamino, aminoalkyl, hydroxyalkyl, and alkylaminoalkyl; R10 is independently selected from the group consisting of: I hydrido, lower alkyl, heteroaryl, heterocyclyl, haloalkyl, arylalkylamino, heteroarylalkyl, aryl and arylalkyl, where anlo, heteroaryl, heterocyclyl, 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 heterocyclyl, R10 is independently selected from the group consisting of: I hydrido, lower alkyl, heteroaryl, heterocyclyl, haloalkyl, arylalkylamino, heteroarylalkyl , aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclyl, 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 heterocyclyl, R11 is selected and Among the group consisting of: hydride, 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; R 3 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclylalkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclylalkyl, or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of by OR14, N (R14) R14 'and glycols; R14 is independently selected from the group consisting of hydrido and lower alkyl; and R1 is independently selected from the group consisting of hydrido and lower alkyl; or isomers, tautomers, vehicles, esters, prodrugs and pharmaceutically acceptable salts thereof. Another class of compounds is defined by Formula II wherein A is (CH2) m; wherein each CH2 can be independently substituted with one or more substituents selected from the group consisting of: aryl, heteroaryl, alkanoyl, hydroxy, halogen, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl and alkynyl; m is from 1 to 4; B is a 5 or 6 membered saturated or unsaturated heteroaryl, aryl, heterocyclyl, wherein said aryl, heteroaryl or heterocyclyl are optionally substituted with R1, R2 and R12; 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, where R6 and R7 can be taken together to form a 3-7 membered carbocyclic ring having from 1 to 3 substituted or unsubstituted heteroatoms selected from the group consisting of: 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 where R6 and R7 can be taken together to form a 3-7 membered carbocyclic ring has 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; R1 and R2 can be taken together to form a 5-7 membered saturated or unsaturated carbocyclic ring 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 selected from the group consisting of: amidine, alkylamino, substituted or unsubstituted aminoalkyl, CONHR7, NH2, NHCOR6 and CH2NHCOR6; R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclyl, 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', where R8 and R8 ' they can be taken together to form a 3-7 membered carbocyclic ring having from 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, S02, O, N and NR6 and where R10 and R10 can be taken together to form a carbocyclic ring 3-7 members having from 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N and NR6, wherein said aryl, heterocyclyl, heteroaryl, or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclylalkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclylalkyl, or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of OR 14, N (R 4) 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, heterocyclylalkyl and heterocyclyl; R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclylalkyl, and heterocyclyl; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclyl, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclylalkyl; R8 'is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclyl, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl and heterocyclylalkyl; R9 is independently selected from the group consisting of: hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclyl, cycloalkyl, heterocyclylalkyl, haloalkyl, arylalkylamino, amino, aminoalkyl, aminoacyl, nitro, azido and heteroarylalkyl, where 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 heterocyclyl optionally substituted with alkyl, alkylamino, aminoalkyl, hydroxyalkyl and alkylaminoalkyl; R10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclyl, haloalkyl, arylalkylamino, heteroarylalkyl, aryl, and arylalkyl, wherein aryl, heteroaryl, heterocyclyl, 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 heterocyclyl, R10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclyl, haloalkyl, arylalkylamino, heteroarylalkyl , aryl and arylalkyl, wherein aryl, heteroaryl, heterocyclyl, 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 heterocyclyl, R11 is selected between 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, heterocyclylalkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclylalkyl, or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of OR14, N (R14) R14'y glycols; R14 is independently selected from the group consisting of hydrido and lower alkyl; and R1 'is independently selected from the group consisting of hydrido and lower alkyl; or isomers, tautomers, vehicles, esters, prodrugs and pharmaceutically acceptable salts thereof. Another class of compounds is defined by Formula III wherein B is a 5- or 6-membered heteroaryl, aryl, saturated or unsaturated heterocyclyl, wherein said aryl, heteroaryl, or heterocyclyl are optionally substituted with R1, R2 and R12; W is a 5- or 6-membered heteroaryl, aryl, saturated or unsaturated heterocyclyl; 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 where R6 and R7 can be taken together to form a 3-7 membered carbocyclic ring having from 1 to 3 substituted or unsubstituted heteroatoms selected from the group consisting of: 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 where R6 and R7 can be taken together to form a carbocyclic ring of 3-7 members having 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, N02I SR6, NHR6, CON (R6) R7, NHCONHR6, C02H and haloalkyl; R1 and R2 can be taken together to form a 5-7 membered saturated or unsaturated carbocyclic ring 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; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclylalkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclylalkyl, or heteroarylalkyl are optionally substituted with one or more radicals selected from the 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, heterocyclylalkyl, and heterocyclyl; R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclylalkyl, and heterocyclyl; R 12 is selected from the group consisting of: hydrido, halogen, alkyl and alkoxy; R15 is selected from the group consisting of: alkylsulfonamide, sulfamyl, and alkyl, wherein said alkyl is optionally substituted with a carbocyclyl or heterocyclyl, wherein said carbocyclyl or heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alqu¡lamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl and heteroaryl, wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R' where n is from 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R') R 'where n is from 0 to 4 and each R' is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR 'where n is 0 to 4 and R' is selected from gr upo composed of hydrido, hydroxy, amino and alkyl; alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanate, isothiocyanate, alquildioxi, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy, and heterocyclyl, wherein said heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl , hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R' where n is 0 to 4 and each R 's and independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R ') R' where n is from 0 to 4 and each R 'is independently selected from the group consisting of hydrido , hydroxy, amino and alkyl, (CH2) nNHC (0) OR 'where n is from 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino and alkyl, R17 is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4 ], C02 (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; and R18 is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4], C02 (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; or isomers, tautomers, vehicles, esters, prodrugs and pharmaceutically acceptable salts thereof. Definitions The present invention includes the use of all hydrates, solvates, complexes and prodrugs of the compounds of this invention. Prodrugs are covalently linked compounds that release the active parental drug according to Formula I, Formula II or Formula III in vivo. If a chiral center or other form of isomeric center is present in a compound of the present invention, it is intended herein to include all forms of such isomer or isomers, including enantiomers and diastereomers. Compounds containing a chiral center can be used as a racemic mixture, enantiomerically enriched mixture or the racemic mixture can be separated using known techniques and a separate single enantiomer can also be used. In cases where the compounds have unsaturated carbon-carbon double bonds, the cis (Z) and trans (E) isomers are within the scope of this invention. In cases where compounds may exist in tautomeric forms, such as the keto-enol tautomers, each tautomeric form is contemplated as included in this invention whether it exists in equilibrium or primarily in one form. The meaning of any substituent in any case of the Formula I, Formula II or Formula III or any sub-formula thereof is independent of its meaning, or any other meaning of substituent, of any other case, unless otherwise specified.
The term "alkyl" is used, either alone or with other terms, such as "haloalkyl" and "alkylsulfonyl"; and includes linear or branched radicals having from one to about twenty carbon atoms or, preferably, from one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having from one to about ten carbon atoms. Most preferred are lower alkyl radicals having from one to about five carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tere-butyl, pentyl, isoamyl, hexyl, octyl and the like. The term "hydrido" refers to a single hydrogen atom (H). This radical hydrido can be bound, for example, to an oxygen atom forming a hydroxyl radical or two hydrido radicals can be attached to a carbon atom forming a methylene radical (-CH 2 -). The term "halo" refers to halogens such as fluorine, chlorine and bromine or iodine atoms. The term "haloalkyl" includes radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically include monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for example, may have a bromine, chlorine or fluoro atom within the radical. The dihalo radicals can have two or more of the same halo atom or a combination of different halo radicals and the polyhaloalkyl radicals can have more than two of the same halo atoms or a combination of different halo radicals. The term "hydroxyalkyl" includes linear or branched alkyl radicals having from one to about ten carbon atoms any of which may be substituted with one or more hydroxyl radicals. The terms "alkoxy" and "alkoxyalkyl" include linear or branched oxy-containing radicals, each having alkyl portions of one to about ten carbon atoms, such as methoxy. The term "alkoxyalkyl" also includes alkyl radicals having two or more alkoxy radicals attached to the alkyl radical, ie, forming monoalkoxyalkyl and dialkoxyalkyl radicals. The "alkoxy" or "alkoxyalkyl" radicals may be further substituted with one or more halo atoms such as fluoro, chloro, or bromo, to provide "haloalkoxy" or "haloalkoxyalkyl" radicals. Examples of "alkoxy" radicals include methoxy, butoxy and trifluoromethoxy. The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings, wherein such rings may be attached in a pendent manner or may condense. The term "aryl" includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. The term "heterocyclyl" includes ring-shaped radicals containing saturated, partially saturated and unsaturated heteroatoms, wherein the atoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclyl radicals include pyrrolidyl and morpholinyl. The term "heteroaryl" includes unsaturated heterocyclyl radicals. Examples of unsaturated heterocyclyl radicals, also referred to as "heteroaryl" radicals, include thienyl, pyrrolyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl and tetrazolyl. The term also includes radicals in which the heterocyclyl radicals are fused with aryl radicals. Examples of such condensed bicyclic radicals include benzofuran, benzothiophene and the like. The term "heterocyclic alkyl" includes alkyl attached to the heterocyclyl. The term "sulfonyl", used alone or linked to other terms such as alkylsulfonyl, refers respectively to divalent radicals -SO2-. The term "alkylsulfonyl" includes alkyl radicals attached to a sulfonyl radical, wherein alkyl is defined as above. The term "arylsulfonyl" includes sulfonyl radicals substituted with an aryl radical. The terms "sulfamyl" or "sulfonamidyl", alone or used with other terms such as "N-alkylsulfamyl", "N-arylsulfamyl". "?,? - dialkylsulfamyl" and "N-alkyl-N-arylsulfamyl", refers to a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-SO2-NH2). The terms "N-alkylsulfamyl" and "α, β-dialkylsulfamyl" refer to sulfamyl radicals substituted, respectively, with an alkyl radical, a cycloalkyl ring or two alkyl radicals. The terms "N-arylsulfamyl" and "N-alkyl-N-arylsulfamyl" refer to sulfamyl radicals substituted, respectively, with an aryl radical and an alkyl radical and an aryl radical. The terms "carboxy" or "carboxyl", used alone or with other terms, such as "carboxyalkyl", refer to -C02H. The term "carboxyalkyl" includes radicals having a carboxyl radical as defined above, attached to an alkyl radical. The term "carbonyl", used alone or with other terms, such as "alkylcarbonyl", refers to -. { C = O) -. The term "alkylcarbonyl" includes radicals having a carbonyl radical substituted with an alkyl radical. An example of an "alkylcarbonyl" radical is CH3- (C = O) -. The term "alkylcarbonylalkyl" refers to an alkyl radical substituted with an "alkylcarbonyl" radical. The term "alkoxycarbonyl" means a radical containing an alkoxy radical, as described above, linked by an oxygen atom to a carbonyl radical (C = O). Examples of such "alkoxycarbonyl" radicals include (CH3) 3CO-C = O) - and - (O =) C-OCH3. The term "alkoxycarbonylalkyl" includes radicals having "alkoxycarbonyl", as defined above, substituted with an alkyl radical. Examples of such "alkoxycarbonylalkyl" radicals include (CH3) 3COC (= O) (CH2) 2-y- (CH2) 2 (0 =) COCH3. The term "amido" when used alone or with other terms such as "amidoalkyl", "N-monoalkylamido", "N-monoarylamido", "?,? - dialkylamido", "N-alkyl-N-arylamido", " N-alkyl-N-hydroxyamido "and" N-alkyl-N-hydroxyamidoalkyl ", includes a carbonyl radical substituted with an amino radical. The terms "N-alkylamido" and "?,? - dialkylamido" refer to 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" refer to amido-substituted radicals, respectively, with an aryl radical and an alkyl radical and an aryl radical. The term "N-alkyl-N-hydroxyamido" includes amido radicals substituted with a hydroxyl radical and with an alkyl radical. The term "N-alkyl-N-hydroxyamidoalkyl" includes alkyl radicals substituted with an N-alkyl-N-hydroxyamido radical. The term "amidoalkyl" includes alkyl radicals substituted with amido radicals. The term "aminoalkyl" includes alkyl radicals substituted with amino radicals. The term "alkylaminoalkyl" includes aminoalkyl radicals having the nitrogen atom substituted with an alkyl radical. The term "amidino" refers to a radical -C (= NH) -NH2. The term "cyanoamidino" refers to a radical -C (= NCN) -NH2. The term "heterocycloalkyl" includes alkyl radicals substituted with a heterocyclyl, such as pyridylmethyl and thienylmethyl. The term "aralkyl" includes alkyl radicals substituted by aryl, such as benzyl, diphenylmethyl, triphenylmethyl, phenethyl, and diphenethyl. The terms benzyl and phenylmethyl are interchangeable. The term "cycloalkyl" includes radicals having from three to ten carbon atoms, such as cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "cycloalkenyl" includes unsaturated radicals having from three to ten carbon atoms, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The term "alkylthio" includes radicals containing a linear or branched alkyl radical of one to ten carbon atoms, attached to a divalent sulfur atom. An example of "alkylthio" is methylthio, (CH3-S-). The term "alkylsulfinyl" includes radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a -S (= 0) -divalent atom. The terms "N-alkylamino" and "N, N-dialkylamino" refer to amino groups that have been substituted with an alkyl radical and with two alkyl radicals, respectively. The term "acyl", used alone or within a term such as "acylamino", refers to a radical provided by the moiety after removing a hydroxyl from an organic acid. The term "acylamino" includes an amino radical substituted with an acyl group. An example of "acylamino" radical is acetylamino (CH3C (= 0) -NH-). Compounds of Formula I, Formula II or Formula III would be useful, but not limited, in the treatment of inflammation in a subject and for the treatment of other disorders associated with inflammation, such as, as an analgesic in the treatment of pain. and of headaches or as an antipyretic in the treatment of fever. For example, compounds of Formula I, Formula II or Formula III would be useful for treating arthritis, including but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Such compounds of Formula I, Formula II or Formula III would be useful in the treatment of asthma, bronchitis, dysmenorrhea, tendinitis, bursitis and skin-related conditions such as psoriasis, eczema, burns and dermatitis. The compounds of Formula I, Formula II or Formula III would also be useful for treating gastrointestinal conditions 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, Formula II or Formula III would be useful in the treatment of inflammation in diseases such as vascular diseases such as vascularitis, migraine, headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, scleroderma, fever. rheumatic, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet syndrome, polymyositis, gingivitis, hypersensitivity, conjunctivitis, swelling after a wound, myocardial ischemia and the like. The compounds of the present invention can also be used for pain. The compounds are useful as anti-inflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects. Compounds of Formula I, II or III are useful as agents for treating cancer or anti-cancer agents. The compounds of Formula I, II or III can be proapoptotic, antiapoptotic, cell cycle antiprogressive, anti-invasive, 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 a variety of cancers including, but not limited to, carcinoma such as carcinoma of the bladder, breast, colon, kidney, liver, lung including small cell lung cancer, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute Hnfocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, ciliated cell lymphoma, and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukaemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, follicular thyroid cancer, and Kaposi's sarcoma. Due to the major role of PK in the regulation of cell proliferation, these compounds are also useful in the treatment of a variety of cell proliferative disorders such as, for example, benign prostatic hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, psoriasis, proliferation of vascular smooth cells associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical stenosis and restenosis. The compounds of Formula I, II or III can be used as an antiviral agent. 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, ??? a / ??? ß, TBK or IKK heterodimer. The compounds of the invention may also be useful as inhibitors of other protein kinases such as, for example, protein kinase C in different isoforms, cyclin-dependent kinase (cdk), Met, PAK-, PAK-5, ZC-1, STLK -2, DDR-2, Aurora 1, Aurora 2, Bub-1, PLK, Chkl, Chk2, HER2, rafl, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, IGF-R, VEGF-R , PI3K, Weel kinase, Src, Abl, Akt, ILK, MK-2, IKK-2, Cdc7, Nek and thus be effective in the treatment of diseases associated with other protein kinases. The present invention preferably includes compounds, which selectively inhibit IKK2 on IKK1. Preferably, the compounds have an IC50 of IKK2 of less than 1 μ? and have a selectivity ratio of inhibition of IKK2 on inhibition of IKK1 of at least 50 and more preferably at least 100. Even more preferably, the compounds have a Cl50 of IKK1 greater than 10 μ? and more preferably greater than 100 μ ?. The compounds of Formula I, II or III can also be used to treat cardiovascular disorders associated with angiogenesis, ophthalmology and osteoporosis. The compounds of the present invention can also be used for the treatment of knee injuries such as sports injuries. Although it is possible to administer an active ingredient only as the crude chemical compound, it is preferable to present it in the form of a pharmaceutical formulation.
The present invention comprises a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention together with at least one pharmaceutically acceptable carrier, adjuvant or diluent. The present invention also comprises a method for treating inflammation or disorders related to inflammation in a subject, the method comprising administering to the subject having such inflammation or such disorders a therapeutically effective amount of a compound of the present invention. The pharmaceutically acceptable salts thereof are also included in the family of compounds of the present invention. The term "pharmaceutically acceptable salts" includes salts commonly used to form alkali metal salts and to form addition salts of free acids or bases. The nature of the salt is not critical, as long as it is pharmaceutically acceptable. The pharmaceutically acceptable acid addition salts of the compounds of the present invention can be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric. Suitable organic acids can be selected from the classes of organic acids aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric acid , citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulphanilic, stearic, cyclohexylaminosulfonic, algenic, beta-hydroxybutyric, salicylic, galactolic and galacturonic. The pharmaceutically acceptable base addition salts of compounds of the present invention include metal salts made of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made with α, β '- dibenzylethylenediamine, 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 included within this invention are pharmaceutical compositions comprising one or more compounds of the present invention together with one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants and / or excipients (collectively referred to herein. as "vehicle" materials) and, if desired, other active ingredients. Accordingly, 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 as described hereinabove can be formulated as lyophilized solutions or powders for parenteral administration. The powders can be reconstituted by adding a suitable diluent or other pharmaceutically acceptable carrier before use. The liquid formulation can be an isotonic aqueous solution with buffer. The compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route and in a dose effective for the treatment intended to be provided. The compounds and compositions may 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, a 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 isotonic saline, conventional 5% dextrose in water or a solution of ammonium acetate or sodium acetate with buffer as a suitable vehicle can be used. Such a formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in an inhaler or nebulizer with metered dose for insufflation. It may be desirable to add excipients such as polyvinyl pyrrolidone, gelatin, hydroxy cellulose, gum arabic, polyethylene glycol, mannitol, sodium chloride or sodium citrate. The pharmaceutical composition is preferably manufactured in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The amount of therapeutically active compound that is administered and the dosage regimen for treating a disease with the compounds and / or compositions of this invention depend on a variety of factors, including the subject's age, weight, sex and health status, the The severity of the disease, the route and frequency of administration, and the particular compound employed, and in this way, can vary widely. The pharmaceutical compositions may contain active ingredient in the range of about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mg and most preferably between about 1 and 100 mg. A daily dose of about 0.01 to 100 mg / kg of body weight, preferably between about 0.1 and about 50 mg / kg of body weight and most preferably between about 1 to 20 mg / kg of body weight, may be appropriate The daily dose can be administered from one to four doses per day. For therapeutic purposes the compounds of this invention are usually combined with one or more adjuvants appropriate for the indicated route of administration. If administered orally, the compounds can be mixed with lactose, sucrose, starch powder, alkanoic acid cellulose esters, cellulose alkyl esters, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acid, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol and then form tablets or encapsulate for convenient administration. Such capsules or tablets may contain a controlled release formulation such as may be provided in a dispersion of active compound in a sustained 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 isotonic aqueous or non-aqueous solutions or suspensions. These solutions and suspensions may be prepared with sterile powders or granules having 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. The pharmaceutical preparations are manufactured following conventional pharmacy techniques which involve crushing, mixing, granulating and compressing, when necessary, for tablet forms.; or crush, mix and fill for forms in hard gelatin capsules. When a liquid carrier is used, the preparation will be in the form of an aqueous or non-aqueous syrup, elixir, emulsion or suspension. Such a liquid formulation can be administered orally or introduced into a soft gelatin capsule. For rectal administration, the compounds of the present invention can also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into suppositories. 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 and the instillation of such compound in the ear, eye and nose, where the compound does not enter significantly in the blood flow. The term "systemic administration" means oral, intravenous, intraperitoneal and intramuscular administration. The amount of a compound of the present invention (hereinafter referred to as the active ingredient) required to exert a therapeutic or prophylactic effect after topical administration will, of course, vary with the compound chosen, the nature and severity of the condition being treated and the animal that undergoes the treatment and, ultimately, is the doctor's decision. The topical formulations of the present invention, both for veterinary and medical use, comprise an active ingredient together with one or more acceptable carriers and therefor and optionally any other therapeutic ingredient. The vehicle must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not be detrimental to the recipient thereof. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin at the site where treatment is required such as: liniments, lotions, creams, ointments, or pastes and drops suitable for administration in the eye, ear or nose. The active ingredient may comprise, for topical administration, 0.01 to 5.0% by weight of the formulation. The drops according to the present invention can comprise sterile aqueous or oily solutions or suspensions and can be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and / or fungicidal agent and / or any other suitable preservative and preferably including a surfactant. . The resulting solution can be clarified by filtration, transferred to a suitable container which is then sealed tightly and autoclaved or kept at 90-100 ° C for half an hour. Alternatively, the solution can be sterilized by filtration and transferred to the container with an aseptic technique. Examples of suitable bactericidal and fungicidal agents for inclusion in the drops are nitrate or phenylmercuric acetate (0.00217c), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, dilute alcohol and propylene glycol. Lotions according to the present invention include those 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 procedures similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent for accelerating drying and refreshing the skin such as an alcohol or acetone, and / or a moisturizer such as glycerol or an oil such as castor oil or peanut oil. The creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They can be manufactured by mixing the active ingredient in finely divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous liquid, with the aid of suitable 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 oil or olive oil; wool fat or its derivatives or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol or macrogols. The formulation can incorporate any suitable surfactant such as an anionic, cationic or nonionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof. Suspending agents may also be included such as natural gums, cellulose derivatives or inorganic materials such as siliceous silicas and other ingredients, such as lanolin. Other adjuvants and modes of administration are known in the pharmaceutical art. Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be understood as limitations. GENERAL SYNTHETIC PROCEDURES The starting materials used in this document are commercially available or prepared by routine procedures well known to those skilled in the art and which can be found in conventional reference texts such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wíley-Interscience). The compounds of the invention can be synthesized according to the following procedures of Schemes I-XI, where the substituents R1-R14 are as defined for Formula I, Formula II or Formula III, above, except where specifically indicated. SCHEME I 2 3 Synthetic Scheme I illustrates the procedure used to prepare the anti-inflammatory pyrazoles of the present invention. The 1,3-dicarbonyl compounds such as 1, or the enol form shown to be in equilibrium with the 1,3-diketone, are allowed to react with a substituted hydrazine hydrochloride 2 in methanol or ethanol or hot acetic acid to provide the pyrazoles 3 by a condensation reaction. When A = -CH2CH2-, the central ring can be flavored to provide A = -CH = CH-, using an antioxidant such as DDQ, Pd or Pt on carbon with cyclooctadiene or another H2 or sulfur acceptor in an appropriate solvent or without solvent . SCHEME II 4 1 Synthetic scheme II illustrates the process for the preparation of substituted diketones 1. An appropriately substituted ketone 4 including, but not limited to, 1-indanones, 1 -tetralones and 1-benzosuberones, is 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 dimethyl or diethyl oxalate, in an appropriate solvent such as methanol, diethyl ether or tetrahydrofuran, to provide 1,3-dicarbonyl compounds which are suitable for transformation into anti-inflammatory pyrazoles as illustrated in Scheme I. Alternatively, the dicarbonyl compounds 1 can be prepared directly from commercially available cyclic ketones.
SCHEME III 8 1 Synthetic scheme III illustrates a three-step process used for the preparation of substituted 1-tetralones. In step one, an appropriate substituted benzene is condensed with succinic anhydride and a catalyst such as aluminum chloride in the corresponding 4-phenyl-4-ketobutanoic acid derivatives 6. In step two, the keto group of the acids phenyl-4-ketobutanoic acids are reduced using catalytic hydrogenation or Wolff-Kishner type reductions, to thereby provide the 4-phenylbutanoic acids 7. In addition, the ketone reductions can be carried out using metallic amalgams. In step three, the 4-phenylbutanoic acids are treated with a mixture of trifluoroacetic anhydride and trifluoroacetic acid to effect an intramolecular Friedel-Crafts acylation which produces the selected tetralones 8. Alternatively, Friedel-Crafts acylation may be affected with other strong acids such as polyphosphoric acid, sulfuric acid or aluminum chloride.
SCHEME IV Synthetic scheme IV describes an alternative synthetic route to 1-tetralones 8. In step one, the addition of allylmagnesium bromide in a suitable solvent such as THF or diethyl ether, to an appropriate substituted benzoate 9, yields 1-phenylbutyl -3-en-1-ones 10. In step two, the 1-phenylbut-3-en-1-ones 10 can be cyclized under Friedel-Crafts alkylation conditions, provided that R4 is a substituent that activates the ring, using catalysts such as aluminum chloride producing the 1-tetralones 8. SCHEME V 8 Scheme V describes the direct modification of 1-tetrane on substituted tetralones. The commercially available 1-tetratramine can be treated with a variety of electrophilic reagents such as bromine, ammonium nitrite or vinylsilanes, represented by E +, with or without a catalyst directly generating tetraion 8, which contains bromine, nitro or vinyl groups. Such tetralones 8 can be further improved to provide the desired substitution pattern. The mixtures can be easily separated using chromatographic techniques.
SCHEME VI An alternative to Scheme V is Scheme VI wherein an appropriately substituted decalin is subjected to electrophilic addition generating substituted decalins 11. Substituted decalins can also be prepared by Friedel-Crafts alkylation of substituted benzenes. Then, the substituted decalins 11 can be oxidized to give the tetralones 8 using oxidants such as Mn04 or SeCfe. SCHEME VII Scheme VII describes the modification of existing tetralones in analogues containing different functional groups that can also be further modified. For example, the hydroxy tetralone (8a when R 4 = OH) can be transformed into triflate 8b by treatment with trifluoromethanesulfonic anhydride. Triflate 8b can be subjected to Pd (OAc) 2, an appropriate phosphine and CO in the presence of methanol generating tetralone 12 containing a carboxymethyl group. The triflates can be used in a variety of palladium coupling reactions to introduce additional functional groups.
SCHEME VIII I) JÍ2 / ftJC ¾ NaOH Synthetic Scheme VIII illustrates a three-step process used for the preparation of substituted 1-indanones 16. In step one, an appropriate substituted benzaldehyde 13 is condensed with methyl acetate and a catalyst such as triethylamine in the corresponding cinnamate derivatives of methyl 14. In addition, commercially available cinnamates can also be used in the following stages. In step two, the olefin group of cinnamate 14 is reduced using catalytic hydrogenation and the ester is hydrolyzed with a base, such as NaOH, to thereby provide 3-phenylpropanoic acid 15. In step three, the 3-phenylpropanoic acid they are treated with a mixture of trifluoroacetic anhydride and trifluoroacetic acid to effect Friedel-Crafts intramolecular acylation producing selected 1-indanones 16. Alternatively, Friedel-Crafts acylation can be carried out with other strong acids such as sulfuric acid or aluminum chloride.
SCHEME IX Synthetic Scheme IX illustrates a two-step route for the preparation of substituted 1-indanones 16. Commercially available methyl benzoate 9 or other alkyl esters can be treated with a lithium vinyl reagent producing the phenylvinyl ketones 17. As Alternatively, dimethylamides or N-methyl-O-methylhydroxamides can be used in place of the esters. In addition, other vinyl metals, such as vinylmagnesium bromide, can be used in place of the vinyl lithium reagent. The resulting phenylvinyl ketones can be cyclized using Friedel-Crafts alkylation catalysts such as aluminum chloride. SCHEME X Synthetic Scheme X illustrates a three-step process used for the preparation of substituted 1-benzosuberones 20. In step one, an appropriately substituted benzene 5 is condensed with glutaric anhydride and a catalyst such as aluminum chloride in the corresponding acid derivatives 5-phenyl-5-ketopentanoic 18. In step two, the keto group of 5-phenyl-5-ketopentanoic acids 18 is reduced using catalytic hydrogenation or Wolff-Kishner-type reductions, to thereby provide 5-phenyl-5-ketopentanoic acids. phenylpentanoic 19. In addition, ketone reductions can also be performed using metal amalgams. In step three, the 5-phenylpentanoic acids are treated with a mixture of trifluoroacetic anhydride and trifluoroacetic acid to effect Friedel-Crafts intramolecular acylation producing selected benzosuberones 20. Alternatively, Friedel-Crafts acylation can be carried out with other strong acids such as polyphosphoric acid, H2S0 or AICI3. Alternatively, 5-phenyl-5-ketopentanoic acids 18 can be prepared with glutaric acid and an appropriately substituted phenyl lithium or phenyl Grignard reagent compatible with the reaction conditions Scheme XI R = 3- or 4-benzyloxy Scheme XI describes the synthesis of pyrazoles with phenols in the N-position. In step one; 3- or 4-benzyloxy phenylhydrazine was refluxed with (7-nitro-1-oxo-1, 2,3,4-tetrahydronaphthaien-2-yl) (oxo) ethyl acetate 1 in acetic acid to give pyrazole. Then, the nitro group was reduced to amine using tin (II) chloride in ethanol. In the next step, the transformation of ester to amide was performed by reaction with liquid ammonia in a pressurized tube at high temperature. The resulting compound can be reacted with acid and HATU in DMF or with acid chloride in pyridine to give the desired amide. The benzyl group was deprotected by stirring with TFA at room temperature.
The complete contents of all publications, patents and patent applications cited in this description are incorporated by reference in this document as if the incorporation of each publication, patent or individual patent application would have been indicated individually and specifically by reference. Although the above invention has been described in some detail by way of illustration and examples for purposes of clarity of understanding, it will be apparent to those skilled in the art with the description 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 solely for purposes of exemplification and are not intended to limit the scope of the invention, which has been described in broad terms above.
EXAMPLES Example 1 1-. { 4 - [(aminothio) peroxy] phenyl} -8-nitro-4,5-dihydro-1H-benzo [g] indazole-3-carboxamide Stage 1 To 7-nitro-1-tetralone (4.6 g, 0.024 mol) and ethyl oxalate (3.5 ml, 0.026 mol) in ether (100 ml) was added dropwise bis (trimethylsilyl) lithium amide ( 1M in THF, 26 ml). The suspension was stirred overnight and filtered to give the product as an olive green solid, 6.2 g (87% yield). 1 H NMR (DMSO-300 MHz) 8.45 (d, 1 H); 8.05 (d of d, 1H); 7.42 (d, 1 H); 4.08 (c, 2H); 2.82-2.72 (m, 2H); 2.51-2.43 (m, 2H); 1, 21 (t, 3H). Stage 2 1-. { 4 - [(Aminothio) peroxy] phenyl} -8-Nitro-4,5-dihydro-1 H-benzo [g] indazole-3-carboxylate ethyl The material from Step 1 (6.2 g, 0.021 mol) and 4-sulfonamidophenylhydrazine hydrochloride (5.1 g, 0.023 mol) was stirred in methanol (100 ml) overnight. HCl conc. (2 ml) was added to the slurry and the contents were heated in a steam bath for 1 hour. The contents were allowed to cool and filtered to give an off-white solid, 6.9 g. The NMR and LC / MS analyzes show that the solid contains two components, the desired pyrazole and the hydrated one. TFA (60 mL) and TFAA (20 mL) were added to the solid and heated in a steam bath for 1 hour. The contents were concentrated in vacuo leaving the product as a solid, 6.4 g (69% yield). FABHRMS m / z 443.1020 (M + H, C2oHi9N406S requires 443.1025). 1 H NMR (DMSO-de / 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, 1H); 7.50 (d, 1 H); 4.33 (c, 2H); 3.20-2.95 (m, 4H); 1.33 (t, 3H). Anal. Calculated for C2oHi8N406S: C, 54.29; H, 4.10; N, 12.66. Found: C, 54.49; H, 4.00; N, 12.52. Step 3 The material from Step 2 (718 mg, 0.0016 mol), conc. Ammonium hydroxide. (30 ml) and methanol (15 ml) were stirred in a stoppered flask for 72 hours. The contents were filtered giving a light amber solid (606 mg). The solid was recrystallized from acetonitrile to give the product as a light amber solid, 450 mg (68% yield). FABHRMS m / z 414.0902 (M + H, C18Hi6N505S requires 414.0872). 1 H NMR (300 MHz DMSO) 8.15-7.95 (m, 3H); 7.83 (d, 2H); 7.80-7.40 (m, 6H); 3.20-2.95 (m, 4H). Anal. Calculated for Ci8H15 505S: C, 52.30; H, 3.66; N, 16.94. Found: C, 52.04; H, 3.64; N, 16.61. Example 2 8-amino-1-. { 4 - [(aminothio) peroxy] phenyl} -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide The compound was prepared in a similar manner to Example 1 in 70% yield. FABHRMS m / z 384.1136 (M + H, C18H18 503S requires 384.1 30). 1 H NMR (DMSO-de / 300 MHz) 7.95 (d, 2H); 7.75 (d, 2H); 7.53 (br s, 1 H); 7.43 (s a, H); 7.32 (s a, 1H); 7.01 (d, 1H); 6.44 (d of d, 1 H); 6.03 (s, 1H); 4.81 (s, 2H); 2.93-2.65 (m, 4H). Anal. Calculated for CieHíyNsCbS. C, 56.38, H, 4.47; N, 18.27. Found: C, 56.31; H, 4.42; N, 18.31. Example 3 8- (acetylamino) -1-. { 4 - [(aminothio) peroxy] phenyl} -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide To the material of Example 2 (1.0 g, 0.0026 mol) in DMF (15 mL) was added dropwise a mixture of acetic anhydride (0.283 mL, 0.003 mol) and pyridine (0.243 mL, 0.003 mol) in DMF (5 mi). The contents were stirred overnight, diluted with water (75 ml) and filtered to give the desired compound as a white solid, 1.0 g (90% yield). FABHRMS m / z 426.1235 (M + H, C20H20N5O4S requires 426.1236). 1 H NMR (DMSO-de / 300 MHz) 9.80 (s, 1 H); 8.00 (d, 2H); 7.75 (d, 2H); 7.60 (s, 1 H); 7.48 (s, 2H); 7.39 (s, 1 H); 7.30 (d, 1 H); 7.15 (s, 1H); 2.90 (s, 4H); 1, 92 (s, 3H). Anal. Calculated for CzoHigNsC S (1H20): C, 54.17; H, 4.77; N, 15.79. Found: C, 54.20; H, 4.97; N, 15.77. Example 4 1-. { 4 - [(aminothio) peroxy] phenyl} -8-. { [(methylthio) peroxy] amino) -4,5-dihydro-1 H-benzo [g] indazol-3-car oxamide To the material of Example 2 (1.2 g, 0.003 mol) and triethylamine (0.278 ml, 0.0035 mol) in DMF (10 ml) at 0 ° C, methanesulfonyl chloride (0.278 ml, 0.5 mmol) was added dropwise. , 0035 mol) in CH2Cl2 (2 ml). The contents were stirred overnight, slowly reaching room temperature. The content was diluted with water (50 ml) and filtered to give the product as an off-white solid, 524 mg (37% yield). FABHRMS m / z 462.0917 (M + H, Ci9H2oN505S2 requires 462.0906). 1 H NMR (DMSO-d 6/300 MHz) 9.60 (s, 1 H); 7.98 (d, 2H); 7.80 (d, 2H); 7.60 (s, 1 H); 7.50 (s, 2H), 7.40 (s, 1H); 7.37 (d, 1 H); 7.02 (s, 1 H); 6.75 (s, 1 H); 2.93 (s, 4H); 2.75 (s, 3H). Anal. Calculated for C, 49.45; H, 4.15; N, 15.17. Found: C, 49.19; H, 3.77; N, 15.53. Examples 5-40 Synthesis of the sulfonamide / amide / urea library Scheme XII Sulfonamides, amides and urea were synthesized in library format using a Bohdan reaction block. The starting materials are the product of Example 2 (8-amino-1- {4 - [(aminothio) peroxy] phenyl} -4,5-dihydro-1H-benzo [g] indazol-3 carboxamide) and the sulfonyl chlorides, acyl chlorides, and appropriate isocyanates. Thirty-five reactions constituted this library. The general procedure is as follows: 48 mg of the product of Example 2 (8-amino-1- {4 - [(aminothio) peroxy] phenyl} -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide) in 1 ml pyridine were introduced into each reaction vessel, then 1.2 eq. of sulfonyl chloride and the mixture was stirred overnight. Then 3 ml of methylene chloride and 300 mg of PS-trisamine resin were added and then stirred overnight. After filtration and washing with 2 ml of methanol twice, the filtrates were combined and the solvents were evaporated. The residue was dissolved in 2 ml of dimethylformamide and MS-TsOH resin (450 mg) was added and stirred for 48 hours. After filtering and washing with 2 ml of DMF, the combined filtrate was analyzed by LC-MS and LC. Then, the filtrate was evaporated in a SpeedVac apparatus and the residue was suspended in 2 ml of H20 / tBuOH and lyophilized for 2 days. All the compounds were obtained in solid form and most of the compounds are approximately 90% pure. Table 1 shows the substitutions, compound identification and IKK heterodimer assay values for the compounds of the sulfonamide library. The structures of the compounds of Examples 5-40 were confirmed by Mass Spectroscopy and / or NMR analysis. Synthesis of Compounds of Examples 41-45 Scheme XIII Example 2 Example 41 1- [4- (Aminosulfonyl) phenyl] -8- (benzylamino) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide To a mixture of the product of Example 2 (8-amino-1- {4- [(aminothio) peroxy] phenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide) (76 mg, 0.20 mmol), acetic acid (0.3 mL) and sodium triacetoxyborohydride (213 mg, 1.00 mmol) in DMF (3 mL) was added benzaldehyde (64 mg, 0.60 mmol). The resulting mixture was stirred at room temperature for 18 hours, water (10 mL) was added, extracted with EtOAc (3x10 mL). The combined organic phases were washed with water (3x10 mL), dried over MgSO4, filtered through a pad of silica gel with EtOAc and concentrated. The crude product was triturated with diethyl ether to give 1- [4- (aminosulfonyl) phenyl] -8- (benzylamino) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide as a yellow solid ( 66 mg, 70%). Its structure was confirmed by H NMR and MS (474, +1). C25HZ3N503S, Cale: C: 63.41, H: 4.90, N: 14.79; Found, C: 63.11, H: 4.70, N: 13.54. Example 42 1- [4- (Aminosulfonyl) phenyl] -8 - [(4-methylbenzyl) amino] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide 1- [4- (Aminosulfonyl) phenyl] -8 - [(4-methylbenzyl) aminoH, 5-dihydro-1H-benzo [g] indazole-3-carboxamide (32 mg, 65%) was synthesized by the same procedure than in Example 41, starting from the product of Example 2 (8-amino-1- {4 - [(aminothio) peroxy] phenyl} -4,5-dihydro-1H-benzo [g] indazole- 3-carboxamide) (38.3 mg, 0.10 mmol) and p-Tolualdehyde (36 mg, 0.30 mmol). Its structure was confirmed by 1 H NMR and MS (488, M + 1). C 26 H 25 N 5 O 3 S, Cale: C: 64.05, H: 5.17, N: 14.36; Found, C. 63.78, H: 4.99, N: 14.22. Example 43 1- [4- (Aminosulfonyl) phenyl] -8 - [(4-methoxybenzyl) amino] -4,5-dihydro-1 H -benzo [g] ndazole-3-carboxamide The title compound (36 mg, 71%) was synthesized by the same procedure as in Example 41 starting from the product of Example 2 (8-amino-1- {4 - [(aminothio) peroxy] phenyl}. 4,5-dihydro-1H-benzo [g] indazole-3-carboxamide) (38.3 mg, 0.10 mmol) and p-anisaldehyde (38 mg, 0.30 mmol). Its structure was confirmed by 1 H NMR and MS (504, M + 1). C26H25N504S (Et20) or, 6, Cale: C: 62.24, H: 5.70, N: 12.78; Found, C: 61.68, H: 5.43, N: 12.54. Example 44 1- [4- (Aminosulfonyl) phenyl] -8 - [(4-chlorobenzyl) amino] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide The title compound (37 mg, 74%) was synthesized by the same procedure as in Example 41 starting from the product of Example 2 (8-amino-1- {4 - [(aminothio) peroxy] phenyl}. 4,5-dihydro-1H-benzo [g] indazole-3-carboxamide) (38.3 mg, 0.10 mmol) and p-chlorobenzaldehyde (42 mg, 0.30 mmol). Its structure was confirmed by 1 H NMR and MS (508, M + 1). CzsH ^ NsOaSCI. Calc .: C: 59.11, H: 4.37, N: 13.79; Found, C: 58.78, H: 4.25 N: 13.18. Example 45 1- [4- (Aminosulfonyl) phenyl] -8- (isobutylamino) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The title compound (27 mg, 61%) was synthesized by the same procedure as in Example 41 starting from the product of Example 2 (8-amino-1- {4 - [(aminothio) peroxy] phenyl} -4,5-dihydro-H-benzo [g] indazole -3-carboxamide) (38.3 mg, 0.10 mmol) and isopropyl aldehyde (22 mg, 0.30 mmol). Its structure was confirmed by 1 H NMR and MS (440, M + 1). C22H25N503S.H20. (Et20) or, 2: Cale: C: 57.97, H: 6.19, N: 14.83; Found, C: 57.63, H: 5.76 N: 14.04. Procedures for the synthesis of Compounds of Examples 46 and 47 Scheme XIV Example ? R = CH3 Example 46 R = C¾CH- = CH2 Example 47 Example 46 8-amino-1-. { 4 - [(dimethylamino) sulfonyl] phenyl} -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide To a stirred solution of the product of Example 2 (8-amino-1- {4 - [(aminothio) peroxy] phenyl} -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide ) (38 mg, 0.10 mmol) in DMF (1 mL) at room temperature under Ar atmosphere was added sodium hydride in mineral oil (60%, 8 mg, 0.20 mmol). After 2 hours, iodomethane (28.4 mg, 0.20 mmol) in DMF (10 mL) was added and the resulting mixture was stirred at room temperature for 18 hours, water (10 mL) was added, extracted with EtOAc (3x10 ml). The combined organic phases were washed with water (3x10 ml), dried over MgSO 4, filtered through a pad of silica gel with EtOAc and concentrated. The crude product was triturated with diethyl ether to give 8-amino-1-. { 4 - [(dimethylamino) sulfonyl] phenyl} -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide as a yellow solid (29 mg, 70%). Its structure was confirmed by 1 H NMR and MS (412, M +). C2oH2i 503S (H20) o.3. (Et20) or, 3 Cale: C: 57.99, H: 5.65, N: 15.95; Found, C: 57.31, H: 5.18, N: 15.26. Example 47 8-amino-1 -. { 4 - [(diallylamino) sulfonyl] phenyl} -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure used for Example 46 except that the iodomethane was replaced with allyl bromide (24.2 mg, 0.20 mmol). The title compound is a yellow solid (28 mg, 61%). Its structure was confirmed by 1 H NMR and MS (464, M + 1). C 24 H 25 N 503 S, Cale: C: 62.18, H: 5.44, N: 15.11; Found, C: 61.76, H: 5.10, N: 14.77. Synthesis of Examples 48 and 49 Scheme XV Example 2 Example 49 EXAMPLE 48 8- (L-alanylamino) -1- [4- (aminosulfonyl) phenyl] -4,5-dichloro-1 H -benzo [g] indazole-3-carboxamide To a stirred solution of 8-amino-1-. { 4 - [(aminothio) peroxy] phenyl} -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide (Example 2) (153 mg, 0.40 mmol) in DMF (6 mL) was added N-Boc-L-alanine (90 mg, 0.48 mmol), EDC (88 mg, 0.46 mmol), HOBt (60 mg, 0.44 mmol) and triethylamine (0.06 mL, 0.44 mmol). The reaction mixture was allowed to stir overnight at room temperature. The DMF was then removed under reduced pressure and the resulting residue was purified by reverse phase preparative HPLC to beige powder (83 mg, 38%). The powder was then dissolved in dioxane / water (2 ml, 1: 1) and 5M HCl (1 mL) was added at room temperature. After stirring for 3 hours, the solvent was removed under reduced pressure to give an oily residue. The residue was dissolved in a minimum amount of methanol and ether was added. The resulting precipitate was filtered to give the title compound as a pale yellow solid (66 mg, 90%). 1 H NMR (400 Hz, d 6 -DMSO): 1.33 (d, 3 H, J = 6 Hz), 2.88-2.97 (m, 4 H), 3.92 (m, 1 H), 7.24 -8.15 (7H, m) ¡+1 = 456, Anal. Calculated for C21H23N604SCI containing MeOH (1) and CH2CI2 (1): C, 45.44; H, 4.83; N, 13.82. Found C, 45.37; H, 4.83; N, 13.60. Example 49 8- (D-alanylamino) -1- [4- (aminosulfonyl) phenyl] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide To a stirred solution of 8-amino-1-. { 4 - [(aminothio) peroxy] phenyl] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide (Example 2) (156 mg, 0.40 mmol) in DMF (6 ml) N-Boc-D-alanine (81 mg, 0.43 mmol), EDC (85 mg, 0.44 mmol), HOBt (58 mg, 0.43 mmol) and triethylamine (0.06 ml, 0.degree. 44 mmol). The reaction mixture was allowed to stir overnight at room temperature. The DMF was subsequently removed under reduced pressure and the resulting residue was purified by reverse phase preparative HPLC to give a beige powder (122 mg, 56%). The powder was then dissolved in dioxane / water (2 ml, 1: 1) and 5M HCl (1 ml) was added at room temperature. After stirring for 3 hours, the solvent was removed under reduced pressure to give the title compound as a light orange solid (92 mg, 87%). 1 H NMR (400 MHz, d6-DMSO): 1.35 (d, 3H, J = 6 Hz), 2.80-2.94 (m, 4H), 3.91 (m, 1H), 7.13 -8.14 (7H, m); M + 1 = 456. EXAMPLE 50 8 - [(2-Chlorobenzoyl) amino] -1-. { 4 - [(dimethylamino) sulfonyl] phenyl} -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide Example 46 Example 50 To a stirred solution of 8-amino-1-. { 4 - [(dimethylamino) sulfonyl] phenyl} -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide (Example 46) (1.52 g, 3.70 mmol) in pyridine (25 ml) at room temperature was added 2 -chlorobenzoic acid (970 mg, 5.55 mmol). After 14 hours, tnsamine (1 g) was added and the mixture was stirred for 2 hours. The mixture was filtered through a pad of silica gel with EtOAc and concentrated. Column chromatography (silica gel, EtOAc) gave the title compound as a yellow solid (900 mg, 1.63 mmol, 44%). Its structure was confirmed by 1 H NMR and MS (551, M + 1). C27H24CIN5O4S, Cale: C 58.96, H: 4.40, N: 12.73; Found, C: 58.66, H: 4.65, N: 12.58. Examples 51-91 Synthesis of the sulfonamide / amide / urea library The sulfonamides, amides and ureas of Examples 51-91 were synthesized in library format as described in Examples 5-40. The starting materials are the product of Example 4 (8-amino-1- {4 - [(aminothio) peroxy] phenyl} -4,5-dihydro-1H-benzo [g] indazol-3. carboxamide) and suitable sulfonyl chlorides, acyl chlorides and isocyanates. Table 1 shows the identification of the compound, the compound, the test values in IKK resin, weight of the formula and characterization by mass spectroscopy of the compounds of this library.
Table 1 COMPOSITE STRUCTURE EXAMPLE Resin- Weight Mass IKK2 Spec. 1- [4- or .0 Example 10 = 508.00 509 (aminosulfonyl) pheny] -8- 44 100 μ? [(4-chlorobenzyl) amino] -4,5-dihydro-1 H- a benzo [g] ndazole-3-carboxamide 1- [4- O.. Example 10 < 439.54 440 (aminosulfonyl) phenyl] -8-45 100 μ? (Butynylamino) -4,5-dihydro-1H-benzo [g] indazol-3-carboxamide 8-amino-1-. { 4- O .0 Example 1 < 10 411, 48 412 [(dimethylamino) sulfonyl] fe 46 μ? nil } -4,5-dihydro-1 H- benzo [g] indazol-3-carboxamide 8-amino-1-. { 4- V Example 1 < 10 463.56 464 [(diallylamino) sulfonyl] phenyl] 5-dihydro-1H-7o ,. 47 μ? benzo [g] indazole-3-carboxamide Hydrochloride of 8- (L- Example 1 < 10 490.97 492 alanylamino) -1- [4-48 μ? (aminosulfonyl) phenyl] -4,5-dihydro-1 H- benzo [g] indazole-3-carboxamide COMPOSITE STRUCTURE EXAMPLE Resin- Weight Mass IKK2 Spec. 1- [4- Example 1 < 10 465.53 466 (aminosulfonyl) pheny] -8- 54 μ? [(cyclobutylcarbonyl) amin or] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide 1- [4- Example 1 < 10 45151 452 (aminosulfonyl) pheny] -8- 55 μ? [(cyclopropylcarbonyl) ami] -4,5-dihydro-1H-benzo [g] indazol-3-carboxamide 1- [4- Example 1 < 10 453.52 454 (aminosulfonyl) phenyl] -8- 56 μ? (butylamino) -4,5- d -hydro-1 H- benzo [g] ndazole-3-carboxamide 1- [4- Example 1 10 501, 57 502 (amnosulfonyl) phenyl] -8-57 μ? [(phenylacetyl) amino] -4,5-dihydro-1H-benzo [g] ndazole-3-carboxamide 1- [4- Example 1 < 10 455.49 456 (aminosulfonyl) pheny] -8- 58 μ? [(methoxyacetyl) am no] -, 5-dihydro-1H-benzo [g] indazole-3-carboxamide COMPOSITE STRUCTURE EXAMPLE Resin- Weight Mass IKK2 Spec. 1- [4- Example < 1 μ? 501, 57 502 (aminonosulfonyl) phenyl] -8- 71 [(3-methy1benzoyl) amino] -4,5-dihydro-1H-benzo [g] ndazole-3-carboxamide 1- [ 4- Example < 1 μ? 566.43 567 (aminosulfonyl) phenyl] -8-72 [(3-bromobenzoyl) amino] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide 1- [4- Example 1 < 10 531, 59 532 (aminosulfonyl) phenyl] -8- 73 μ? . { [(3-methoxyphenyl) acetyl] amino} -4,5-dihydro-1 H- benzo [g] indazole-3-carboxamide 1 - [4 (anesulfonyl) phenyl] - Example < 1 μ? 488.53 489 8 - [(pyridin-3- (4-carbonyl) amino] -4,5-dhydro-1H-benzo [g] indazole-3-carboxamide COMPOSITE STRUCTURE EXAMPLE Resin- Weight Mass IKK2 Spec. 1- [4- Example 10 < 537.62 538 (amnosulfonyl) phenyl] -8-. { 79 100 μ? [(3-methylphenyl) sulfonyl] ami no} -4,5-dihydro- 1 H-benzo [g] indazole-3-carboxamide 1- [4- Example < 1 μ? 517.56 518 (aminosulfonyl) phenyl] -80 8 - [(3-methoxybenzoyl) amino] -4,5-d, 1-d-1-H-benzo [g] indazole-3-carboxamide 1- [4- Example < 1 μ? 521, 98 522 (aminosulfonyl) phenyl] -8- 81 [(3-chlorobenzoyl) l amno] -, 5-dihydro-1 H- benzo [g] indazole-3-carboxamide 1- [4- Example 10 < 517.56 518 (aminosulfonyl) phenyl] - 82 100 μ? 8 - [(2-methoxy-benzoyl) amino] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide COMPOSITE STRUCTURE EXAMPLE ResinWeight Mass the Formula spec. 1- [4- Example < 1 μ? 556.43 557 (aminosulfonyl) phenyl] -8- 87 [(2,3-dichlorobenzoyl) amino] -4,5-dihydro-1 H- benzo [g] indazole-3-carboxamide 1- [4- Example < 1 μ? 505.53 506 (aminosulfonyl) phenyl] -8- 88 [(2-fluorobenzoyl) amino] -4,5-dihydro-1 H- benzo [g] indazole-3-carboxamide 1- [4- Example 1 μ? 522.97 523 (aminosulfonyl) phenyl] -8-89. { [(2-chloropyridin-3-yl) carbonyl] amino} -4,5- d -hydro-1 H- benzo [g] indazole-3-carboxamide 1- [4- Example 10 < 558.04 558 (amnosulfonyl) phenyl] -8-90 100μ? . { [(2-chlorophenyl) sulfonyl] amino} -4,5-D-Hydro-1 H- Benzo [g] indazole-3-carboxamide Examples 92-125 Examples 92-125 shown in Table 2 were synthesized using the following synthetic procedures similar to Scheme I wherein R9 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl or appropriate cycloalkyl. Scheme XV Example 92 8-amino-1- [4- (Methylsulfonyl) phenyl] -4,5-dihydro-H-benzo [g] indazole-3-carboxamide hydrochloride Stage 1 A mixture of (17.2 mmol) of diketo ester and (17.2 mmol) of 4- (methylsulfonyl) -phenylhydrazine in 100 mL of acetic acid was heated to reflux with stirring for 3 hours and then cooled. The mixture was concentrated and the residue was triturated with ethyl acetate to yield a brown solid, which was filtered, washed with ethyl acetate and dried to give the title compound. The structure was confirmed by 1 H NMR. Stage 2 A solution of the title product of Step 1 in acetic acid was treated at room temperature with 5% palladium on carbon in a hydrogen gas atmosphere at 5 psi (34.48 kPa). The reaction was followed by LC-MS. Upon completion of the conversion, the mixture was filtered and concentrated to give the title compound as a brownish oil which was used directly for the next step. Step 3 8-amino-1 - [4- (Methylsulfonyl) phenyl] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide hydrochloride The title product of Step 2 was dissolved in anhydrous ethanol and then an approximately equal volume of liquid ammonia was added. The resulting mixture was sealed in a pressure vessel and stirred overnight at 100 ° C. After cooling, the mixture was concentrated. The residue was taken up in dichloromethane-methanol and chromatographed on silica gel using ethyl acetate as eluent to give the title compound, as an oil which crystallized on standing. Table 2 Example 126 8-. { [2-chloro-5- (4-methylpiperazin-1-yl) benzoyl] amino} -1- [4- (Methylsulfonyl) phenyl] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide Example 126 was synthesized using the following scheme. VXI scheme R = 4-F, 4-S02Ma, 3,4-MDO, etc. To a mixture of 2-chloro-5- (4-methylpiperazin-1-yl) benzoic acid (0.9 g, 0.0035 mol), the title compound of Example 92 (0.0024 mol) and 1 ml of diisopropylethylamine in 25 ml of DMF was added HATU (1.3 g, 0.0035 mol) in one portion. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed and the residue was purified by preparative HPLC to give the product as a pale white solid (89% yield); mp: 94-95 ° C; 1HR N (D SO + TFA-d, 400 MHz) d: 10.29 (s, 1H), 8.10 (d, J = 8.7 Hz, 2H), 7.86 (d, J = 8, 7 Hz, 2H), 7.64 (s, 1H), 7.43 (dd, J = 2.1, 8.2 Hz, 1H), 7.41 (s, 1 H), 7.37 (dd) , J = 2.0, 8.2 Hz, 1H), 7.35 (d, J = 8.2Hz, 1 H), 7.08 (dd, J = 3.0, 8.9 Hz, 1H) , 7.04 (d, J = 3.0 Hz, 1 H), 3.89 (d, J = 12.8 Hz, 2H), 3.51 (d, J = 12.8 Hz, 2H), 3.23 (s, 3H), 3.11 (m, 2H), 2.95 (m, 4H), 2.86 (m, 2H). The bioactivity in the IKK 2 Resin test of the compound of Example 126 is shown in Table 2. Examples 127-158 shown in Table 3 were synthesized with the following synthesis scheme in which R 9 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl or cycloalkyl. Scheme XVII Resin 3 Example 127 1- [4- (Rethylsulfonyl) phenyl] -8-nitro-4,5-dihydro-1H-benzo [g] indazole-3-carboxylic acid A 5.0 g (11.3 mmol) of Example 92 (1- [4- (Methylsulfonyl) phenyl] -8-nitro-4,5-dihydro-H-benzo [g] indazole-3-carboxylic acid ethyl ester) in 115 ml of THF was added 115 ml of NaOH 1 N and the mixture was allowed to stir overnight at room temperature. The solution was acidified with 2N HCl and extracted three times with ethyl acetate. The combined extracts were washed with aq. to 10%, brine, dried with Na 2 SO and concentrated to yield 4.97 g (100%) of a yellow solid: 1 H NMR (de-DMSO) 3.00 (m, 2H), 3.11 (m, 2H ), 3.31 (s, 3H), 7.39 (d, 1H), 7.67 (d, 1H), 7.90 (d, 2H), 8.07 (dd, 1H), 8.16 (d, 1H); MS (ESI +) 414 (M + 1). Example 128: Resin 1 and 1- [4- (methylsulfonyl) phenyl] -8-nitro-4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide. Commercially available Rink amide resin was sequentially washed ( 10 g, NovaBiochem No. 01-64-0013, mesh 100-200, 0.61 mmol / g) with dichloromethane (DCM) and dimethylformamide (DMF). The resin was filtered, treated twice with 50% piperidine in DMF for 15 minutes and subsequently washed three times each with DMF, DCM and anhydrous DMF. To the resin was added 4.65 g of Example 127, 1.52 g of HOBt and 1.75 ml of DIC in 35 ml of anhydrous DMF. After 3 hours at room temperature, the reagents were removed by filtration and the resin was washed three times each with DMF, methanol and DCM. The resin was used directly in the next step. A small portion (approximately 100 mg) of resin was cleaved by treatment with 20% TFA in CH2Cl2 for 30 minutes. The resin was washed twice with CH2Cl2 and the collected filtrates were concentrated in vacuo. The product was purified by chromatography on silica to give the title compound as a light yellow solid: 1 H NMR (CDCl 3) 9.03 (s, 2H), 8.20 (d, J = 8.4Hz, 2H), 8 , 10 (dd, J = 2Hz, 8.4Hz, 1H), 7.79 (d, J = 8.4Hz, 2H), 7.53 (d, J = 8.4Hz, 1H), 7, 51 (d, J = 2 Hz, 1 H), 3.25 (s, 3 H), 3.16 (m, 4 H); MS (ESI +) 413 (M + 1, 100). Example 129 Resin 2 and 8-amino-1- [4- (methylsulfonyl) phenyl] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide, trifluoroacetic acid salt To resin 2 (6, 0 mmol) was added 50 ml of 2M SnCl2-2H20 in wet DMF. After stirring the mixture overnight, the reagents were removed by filtration and the resin was washed three times each with DMF, THF and DCM. The resin was filtered and dried giving 10.96 g of resin 2. A 92.1 mg portion of the resin was treated twice with 20% TFA in CH2Cl2 and washed three times with CH2Cl2. The combined filtrates were concentrated in vacuo and the resin loading was determined by direct NMR cleavage of the title compound: resin loading 0.46 meq / g; H NMR (CDCl 3 / TFA) 3.14 (sa, 4H), 3.31 (s, 3H), 6.78 (d, 1H, 2.0 Hz), 7.33 (dd, 1H), 7, 54 (d, 1 H, 8.0 Hz), 7.83 (d, 2H), 8.16 (d, 2H); MS (ESI +) 383 (M + 1, 100). Resin 3 Resin 2 (0.45 mmol / g, 0.200 g, 90 pmol) was washed three times with anhydrous NMP and subsequently treated with 0.45 mmol of carboxylic acid R9COOH in 0.5 ml of anhydrous NMP, 0, 45 mmol of PyBrop in 0.5 ml of anhydrous NMP and 0.9 mmol of DIEA. The resin was stirred at room temperature under an N2 atmosphere for 2 hours. Subsequently, the reagents were removed by filtration, the resins were re-treated with the appropriate carboxylic acid, PyBrop and DIEA in the same manner as described above. After stirring the reaction vessels overnight at room temperature, the reagents were removed by filtration and the resin was washed three times each with NMP, DMF, methanol and DCM. The products were separated from the resins by adding 0.5 ml of 20% TFA / DCM and stirring the mixture for 15 minutes. The filtrate was collected and the resin was again treated with more TFA / DCM for 15 minutes. The resin was washed twice with DCM and the filtrates were combined and concentrated in vacuo to produce the final products. EXAMPLE 130 8 - [(Cyclobutylcarbonyl) amino] -1- [4- (methylsulfonyl) phenyl] -4, 5-dihydro-1H-benzo [g] indazole-3-carboxamide Using the procedure described with resin 3, the product was obtained in 57% yield as a light yellow solid: 1 H NMR (CDCl 3 / CD 3 OD). 8.13 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 1.6 Hz, 1 H), 7 , 24 (d, J = 8 Hz, 1H), 6.97 (dd, J = 2 Hz, 8 Hz, 1 H), 6.88 (s, 1 H), 3.23 (8, 3H), 3.10 (m, 2H), 3.02 (m, 1 H), 2.95 (m, 2H), 2.16 (m, 4H), 1.95 (m, 1H), 1.82 ( m, 1 H). 13 C NMR (CDCl 3 / CD 3 OD): 165.0, 144.2, 142.9, 140.4, 137.1, 133.0, 129.3, 129.2, 126.4, 126.0, 123, 3, 119.4, 114.8, 114.7, 60.7, 44.8, 40.6, 31, 7, 29.6, 25.3, 22.8, 20.1, 18.1, 14,3. High Resolution Mass: M + H + = 465.1591 (observed), 465.1608 (theoretical). Example 131 8 - [(2-Chloro-4,5-dimethoxybenzoyl) amino] -1- [4- (methylsulfonyl) phenyl] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide Using The procedure described with resin 3, the product was obtained with a 62% yield as a light yellow solid: 1 H NMR (CDCl 3). 8.14 (d, J = 8.8Hz, 2H), 8.03 (s, 1H), 7.79 (d, J = 8.8Hz, 2H), 7.40 (d, 1H), 7, 29 (m, 1 H), 7.21 (s, 1H), 7.16 (m, 1 H), 6.81 (s, 1H), 3.89 (s, 3H), 3.88 (s) , 3H), 3.14 (m, 2H), 3.13 (s, 3H), 2.99 (m, 2H). 13 C NMR (CDCl 3): 171.4, 164.4, 163.7, 151, 7, 148.4, 144.3, 143.1, 140.8, 140.2, 136.4, 134.0, 129.6, 129.4, 126.7, 126.4, 126.1, 123.3, 122.4, 119.7, 115.3, 113.2, 113.0, 60.6, 45, 0, 29.8, 21, 3, 20.2. Mass High Resolution: M + H + = 581, 1277 (observed), 581, 1256 (theoretical). Examples 132-158 The compounds of Examples 132-158 were prepared as previously described for Example 130 using the aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl or cycloalkyl and are listed in Table 3 Example 159 8-. { [2-chloro-5- (methylsulfonyl) benzoyl] amino} -1- [4- (Methylsulfonyl) phenyl] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide Scheme XVIII To 0.30 g of amino resin 2 (pretreated in DCM for two hours and washed with dry NMP) was added PyBrop (0.42g, 0.90 mmol), 2-chloro-5-methylthiobenzoic acid (182mg, 0, 9 mmol), DIEA (314 μl, 1.8 mmol) and dry NMP (2 ml). The resin was stirred for two hours. Excess reagents were drained and the resin was washed with DMF (x3), methanol (x3) and DCM (x3) and treated with a mixture of 20% TFA / DCM containing 1% triisopropylsilane (2 x 12 min. x 3 ml). The resin was washed with DMC (2 x 4 ml). The combined filtrate and washings were evaporated to a solid, which was subsequently dissolved in 10 ml of DCM. To the resulting solution was added MCPBA (440 mg, 77% pure, 1.96 mmol). After 3 hours, the reaction was quenched with 30 ml of ethyl acetate. The organic phase was washed with sat. Sodium bicarbonate. (x3) and brine (x2), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica with 8: 2 EtOAc / hexane. The product was isolated as a light yellow solid, 37 mg (34%): H NMR (CDCl3 / CD3OD) 8.00 (d, J = 8.8 Hz, 2H), 7.83 (s, 1 H), 7.81 (dd, 1 H), 7.68 (d, J = 8.4Hz, 2H), 7.51 (d, J = 8.4 + Hz, 1H), 7.34 (s, 1 H) ), 7.25-7.17 (m, 2H), 3.02 (s, 3H), 2.98 (s, 3H), 2.96 (m, 2H), 2.88 (m, 2H) . LC-MS: 599.0 (M + H +). High Resolution Mass: M + NH4 + = 616.1077 (observed), 616, 1086 (theoretical). Example 160 8- (L-histidylammon) -1 - [4- (methylsulfonyl) phenyl] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide SCHEME XIX Amino resin 3 (0.402 mmol / g, 0.0804 mmol, 0.200 g) was pretreated in DCM for one hour followed by washing using anhydrous NMP. To this resin, 5.0 equiv. of Fmoc-His-OH (0.402 mmol, 152 mg) followed by addition of PyBroP (NovaBiochem, 0.402 mmol, 187 mg). To this mixture was added 10.0 equiv. of DIEA (0.804 mmol, 140 μ) followed by addition of anhydrous NMP (1 mL). The reaction vessel was capped and stirred under a nitrogen atmosphere for two hours. The reagents were removed by filtration and the resin was washed as follows: NMP (x3), DMF (x3), DCM (x3) and anhydrous NMP (x1). The resin was re-treated as described above and allowed to stir under a nitrogen atmosphere overnight. The vessel was drained and washed as follows: NMP (x3), DMF (x3), MeOH (x3), DCM (x3) and DMF (x1). The Fmoc group was deprotected using 50:50 piperidine / DMF (x2, 2ml) 40 minutes each. The resin was washed as follows: DMF (x3), MeOH (x3) and DCM (x3). The resin was allowed to air dry for about one hour. The resin was subsequently treated with 20:80 TFA / DCM containing 1% triisopropylsilane (x2, 1 ml, 45 minutes). The filtrates were collected and the resin was washed with DCM (x3, 1 mL). All washes were collected and volatile materials were removed under a nitrogen atmosphere yielding 17.2 mg of an orange solid. MS + +1 (C25H25N7O4S): 520 (measured). Table 3 Examples 161-206 Examples 161-206 shown in Table 4 were synthesized using the following synthetic procedure similar to that of Scheme I wherein R9 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl or cycloalkyl. appropriate. The detailed synthesis of 1- (1,3-benzodioxol-5-yl) -8- is described below. { [(2-chloropyridin-3-yl) carbonyl] amino} -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide (Example 161) and is illustrative for the compounds of Table 4 SCHEME XX (7-nitro-1-oxo-l, 2,3-4-te1rahdronaphthalen-2-yl) (oxo) ethyl acetate 1 . Pyridine Example 161 1- (1,3-benzodioxol-5-yl) -8-. { [(2-chloropyridin-3-yl) carbonyl] amino} -4,5-Clihydro-1 H-benzo [g] indazol-3-carboxamide Stage 1 The title compound of Step 1 was prepared by the procedure described by T. Komatsu et al, Azneim.-Forsch. (1972) 22 (12), 2099-104.
Stage 2 A mixture of 5.00 g (17.2 mmol) of diketo ester and 3.24 g (17.2 mmol) of the title product of Step 1 in 100 ml of acetic acid was heated to reflux with stirring for 3 hours and then He cooled. The mixture was concentrated and the residue was triturated with ethyl acetate to yield a brown solid which was filtered, washed with ethyl acetate and dried to give the title compound, 4.79g. The structure was confirmed by 1 H NMR. Stage 3 A solution 4.79 g of the title product of Step 2 in acetic acid was treated at room temperature with 5% palladium on carbon under a hydrogen gas atmosphere at 5 psi (34.48 kPa). The reaction was followed by LC-MS. At the end of the conversion, the mixture was filtered and concentrated to give the title compound as a brownish oil which was used directly for the next step. Step 4 8-amino-1- (1,3-benzodioxol-5-yl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The title product of Step 3 was dissolved in anhydrous ethanol and then an approximately equal volume of liquid ammonia was added. The resulting mixture was sealed in a pressure vessel and then stirred overnight at 100 ° C. After cooling, the mixture was concentrated. The residue was taken up in dichloromethane-methanol and chromatographed on silica gel using ethyl acetate as eluent to give the title compound, 890mg, as an oil which crystallized on standing. Anal, for C19Hi6N403 0.75 H20 (P 361, 87): Caled .: C, 63.06, H, 4.46, N, 15.48. Found: C, 63.24; H, 4.70, N, 14.58. Stage 5 A mixture of the title product of Example 4 (3.6 g, 0.01 mol) and 2-chloronicotinyl chloride (1.8 g, 0.01 mol) in 50 ml of pyridine was stirred at room temperature overnight . The solvent was removed and the residue was triturated with a mixture of acetonitrile and methanol (20: 1) to give 2.6 g of the title compound as a light brown solid. The stock solution was concentrated and purified in the same way giving another 0.69 g of product (yield 68%); mp: 165-166C. Anal. Caled, for C25Hi8CIN5O40.5H2O: C, 60.43; H, 3.85; 14.09. Found: C, 60.27; H, 3.59; N, 14.14. Table 4 Structure Weight Name Compound IC50 Resin - Example olec. IKK lo 487.90 1- (1, 3-benzodioxol-5-yl) -8. { [(2-1 μ? 161 chloropyridin-3-yl) carbonyl] amino} 4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide 522,35 1- (1,3-benzodioxol-5-yl) -8-. { [(2,5- < 1 μ 162 dichloropyridin-3-yl) carbonyl] amino} 4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide 565.01 1- (1,3-benzodioxol-5-yl) -8-. { [2- < 1 μ? 163 Chloro-4- (methylsulfonyl) benzoyl] amino} -, 5-dihydro-1 H -benzo [g] indazole-3-carboxamide 504,91 1- (1,3-benzodioxol-5-yl) -8 - [(2- <1 μ? 164 chlorine-4 -fluorobenzoyl) amino] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide 486.92 1 - (1,3-benzodioxol-5-yl) -8 - [(2- <1μ 165 chlorobenzoyl) amino] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide 522.90 1- (1,3-benzodioxol-5-yl) -8 - [(2-1 μ? 166 ..X «¼ L Chloro-4,5-difluorobenzoyl) amino] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide Structure Weight Name Compound CI» Resin - Molec. IKK lo 501, 93 1- (1, 3-benzodoloxol-5-yl) -8-. { [(2- <1 μ? 167 chloro-6-methylpyridin-3-l) carbonyl] amino} -4,5-dihydro-1 H- benzo [g] indazole-3-carboxamide 530.93 1 - (1,3-benzodoloxol-5-yl) -8-. { [(6- <1 μ? 168 chloro-1, 3-benzodoloxol-5-yl) carbonyl] amino} -, 5-dihydro-1H-benzo [g] indazole-3-carboxamide < x 501, 93 8 - [(2-amino-6- <1 μ 169 chlorobenzoyl) amino] -1 - (1,3-benzodioxol-5-yl) -, 5-dihydro-1 H-benzo [g] indazole-3-carboxamide r- or 487.91 1 - (1,3-benzodioxol-5-yl) -8- < 1 μ? 170 [(3-chloroisonicotinyl) amino] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide 538.39 Hydrochloride of 8 - [(3-amino-2- < 1 μ? 171 chlorobenzoyl) amino] -1- (1,3-benzodioxol-5-H) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide 501, 93 8 - [(5-amino -2- < 1 μ? 172 chlorobenzoyl) amino] -1- (1,3-benzodioxol-5-yl) -4,5-d? Idro-a ???? | ? 1 1 or 1 H-benzo [g] ndazole-3-carboxamide 531, 92 1- (1,3-benzodioxol-5-yl) -8 - [(2- = 1 μ? 173 chloro-5-n) trobenzoyl) amino] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide Structure Weight Name Compound Cl5o Resin- Molecular IKK Example 442.44 1 - (1,3-benzodioxol-5- il) -8- (3-1 <10 μ? 200 furoylamino) -4,5-dihydro-1 H- benzo [g] indazole-3-carboxamide 501, 93 8 - [(3-amino -4- 1 < 10 μ? 201 chlorobenzoyl) amino] -1 - (1,3-benzodioxol-5-yl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide or. 467.49 1 - (1,3-benzodioxol-5-yl) -8-. { [(2-1 <; 10 μ? 202 methy1pyridin-3-yl) carbonyl] amine} 4,5-D-Hydro-1H-benzo [g] indazole-3-carboxamide 587.04 1- (1,3-benzodioxol-5-yl) -8- (. {2-1 < 10 μ? 203 Chloro-4- '(N, Md.methylglycol) amino] benzoyl.] amino) -4,5-d.hydro-1H-benzo [g] ndazole- 3-carboxamide 536.46 1 - (1,3-benzodioxol-5-yl) -8- 1 < 10 μ? 204 ([2- (trifluoromethoxy) benzoyl] amino} -4,5-dihydro-1 H -benzo [g] ndazole-3-carboxamide 469.46 1 - (1,3-benzodoxox- 5-yl) -8- { [(6-1 <10 μ 205 hydroxy-pyridin-2-yl) carbonyl] amino.} - 4,5-dhydro-1 H-benzo [ g] ndazole-3-carboxamide 477.48 1- (1,3-benzodioxol-5-yl) -8 - [(4-1 <10 μ? 206 cyanobenzoyl) amino] -4 , 5-diethyl-1H-benzo [g] indazole-3-carboxamide SCHEME XXI EXAMPLE 207 1- (1,3-Benzodioxol-5-yl) -8- ( { [2- (methylamino) pyridin-3-yl] carbonyl.} Amino) -4, 5-dihydro-1 H-benzo [g] indazole-3-carboxamide A mixture of the title product of Example 161 (1.4 g, 0.0028 mol) and methylamine (0.014 mol) in 6 ml of EtOH was heated in a sealed tube at 100 ° C for 48 hours. The whitish precipitate that formed in the crude reaction mixture was filtered and washed with EtOH and Et20 yielding 1.05 g of the title compound (75% yield). mp: 273-275 ° C. 1 H NMR (300 MHz, d 6 -DMSO): 8 2.88-2.95 (m, 4H + 3H), 6.12 (s, 2H), 6.57-6.61 (dd, 1H, J = 7.6 Hz, 4.7 Hz), 6.95-6.98 (dd, 1 H, J = 8 Hz, 2 Hz), 7.07 (d, 1 H, J = 8 Hz), 7 , 13 (d, 1 H, J = 2 Hz), 7.25-7.34 (m, 3H), 7.45-7.50 (m, 2H), 7.82-7.83 (m, 1 H), 7.91-7.95 (dd, 1 H, J = 7.6 Hz, 1.7 Hz), 8.18-8.20 (dd, 1H, J = 4.8 Hz, 1 , 8 Hz), 10.02 (s, 1 H). + 1 = 483. EXAMPLE 208 1- (1,3-benzodioxol-5-yl) -8 - [(. {2 - [(2-hydroxyethyl) amino] pyridin-3-yl} carbonyl) ami no] -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 207 starting from the product of Example 161 (1 g, 0.0020 mol ) and ethanolamine (0.626 g, 0.010 mol) in 4 ml of EtOH yielding 0.475 g of the title compound (yield: 46%). Mp: 250-253 ° C. 1 H NMR (300 MHz, d 6 -DMSO): d 2.86-2.93 (m, 4H), 3.43-3.47 (m, 2H), 3.53-3.54 (m, 2H) , 4.76 (s, 1 H), 6, 12 (s, 2H), 6.56-6.59 (dd, 1H, J = 7.5 Hz, 4.8 Hz), 6.95-6 , 97 (dd, 1 H, J = 8 Hz, 2 Hz), 7.05 (d, 1 H, J = 8 Hz), 7.1 1 (d, 1 H, J = 2 Hz), 7, 26-7.37 (m, 4H), 7.51 (s, 1 H), 7.89-7.91 (dd, H, J = 7.6 Hz, 1.5 Hz), 7.97- 7.99 (t, 1 H, J = 5 Hz), 8.14-8, 15 (dd, 1 H, J = 4, 7 Hz, 1.6 Hz), 10.02 (s, 1 H) . Anal. Caled, for C27H24 6O5: C, 63.27; H, 4.72; N, 16.40. Found: C, 63.38; H, 4.7; N, 16.34 M + 1 = 513 Example 209 1- (1,3-Benzodioxol-5-yl) -8 - [(. {2 - [(4-methoxybenzyl) amino] pyridin-3-yl}. carbonyl) amino] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 207 starting from the product of Example 161 (2 g, 0.0040 mol) and p-methoxybenzylamine (2.8 g, 0.020 mol) in 10 ml of EtOH with a yield of 1.96 g of the title compound (yield: 60%). Mp: 181-182 ° C. 1H RN (300 MHz, d6-DMSO): d 2.88-2.94 (m, 4H), 3.71 (s, 3H), 4.56 (d, 2 H, J = 5.6 Hz) , 5.98 (s, 2H), 6.60-6.64 (dd, 1 H, J = 7.5 Hz, 4.7 Hz), 6.88 (d, 2H, J = 8.4 Hz ), 6.96 (s, 2H), 7.11 (s, 1H), 7.23-7.35 (m, 5 H), 7.39 (s, 1H), 7.49 (s, 1H) ), 7.95 (d, 1H, J = 7.45 Hz), 8.17 (d, 1H, J = 4.7 Hz), 8.23 (t, 1 H, J = 5.6 Hz) , 0.06 (s, H). Anal. Cale, for CasHze eOg: C, 67.34; H, 4.79; N, 14.28. Found C, 67.08; H, 4.78; N, 14.19. M + 1 = 589. Example 210 8-. { [(2-aminopyridin-3-yl) carbonyl] amino} -1- (1,3-benzodioxol-5-yl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide The title compound of Example 209 (1.96 g, 0.0033 mol) was dissolved in 6 ml CH2Cl2 and reacted with 5 ml of TFA at room temperature for 36 hours. The crude reaction mixture was diluted with CH2Cl2 and basified with a saturated aqueous solution of Na2CO3. The phases were separated and the organic phase was dried over gS04. The residue obtained after removal of the solvent in vacuo was triturated with EtOH yielding 0.503 g of the title compound (32% yield). Mp: 265-267 ° C. 1 H NMR (300 MHz, drDMSO): d 2.88-2.95 (m, 4H), 6.12 (s, 2H), 5.58-6.62 (dd, 1 H, J = 7.6 Hz, 4.7 Hz), 6.97-7.08 (m, 4H), 7.17 (d, 1H, J = 1.9 Hz), 7.28 (s, 1H), 7.32 ( s, 2H), 7.55 (s, 2H), 7.95-7.98 (dd, 1H, J = 7.7 Hz, 1.7 Hz), 8.11-8.13 (dd, 1 H, J = 4.7 Hz, 1.7 Hz), 9.99 (s, 1 H). M + 1 = 469. SCHEME XXII Example 211 1- (1,3-Benzodioxol-5-yl) -8 - [(2,5-dichloroisonicotinoyl) amino] -4,5-dihicyl-1H-benzo [g] indazole -3-carboxamide 2,5-Dichloroisonicotinic acid (1.65 g, 0.0086 mol), HATU (3.27 g, 0.0086 mol) and finally Et3N (2.32 mL, 0.0166 mol) were added to a solution of the compound of title of Step 4 of Example 161 (2g, 0.00574 mol) in 29 ml of DMF. The reaction mixture was stirred at room temperature for 3 hours. The end of the reaction was confirmed by monitoring the disappearance of the title compound from Step 4 of Example 161 in LC / MS. The crude reaction mixture was concentrated to approximately 10 ml of DMF. After adding water to this residue with DMF, a white solid formed. This white solid was triturated in water for 20 minutes and filtered. The solid was collected, dissolved in THF and dried with MgSO4. Removal of the solvent produced a brown solid which was triturated in hot CH3CN (80 ° C) to give 2.2 g of the title compound (73% yield). Mp: 292-293 ° C. 1 H NMR (300 MHz, cfe-DMSO): d 2.90-2.92 (m, 4H), 6.09 (s, 2H), 6.94-7.04 (m, 2H), 7.12. (d, 1H, J = 2 Hz), 7.26-7.38 (m, 4H), 7.51 (s, 1H), 7.81 (s, 1H), 8.61 (s, 1H) 10.54 (s, 1H). M + 1 = 523. EXAMPLE 212 1- (1,3-Benzodioxol-5-yl) -8 - [(5-chloro-2-morpholin-4-ylisoncarcinoyl) amino] -4,5-dihydro -1 H-benzo [g] indazole-3-carboxamide Stage 1 5-chloro-2-morfo! N-4-ilisonicotinic acid 2,5-dichloroisonicotinic acid, prepared with the procedure of E. arzi, A. Bigi, M. Schlosser, Eur. J. Org. Chem. 2001, 1371-1376, (1, 6g, 0.0083 mol) and morpholine (10.9g, 0.125 mol) in 4 ml of N, N-dimethylacetamide were heated at 80 ° C for 4 days. The volatile components were removed in vacuo and the resulting yellow solid was partitioned between water and Et2Ü. The aqueous phase was acidified to pH = 1.5 using an aqueous solution of HCl and extracted once with Et20 (25 mL) and three times with CH2Cl2 (25 mL). The organic extracts were combined and the solvents removed in vacuo. The resulting yellow solid crystallized from MeOH yielding the title compound 1. 07 g (yield, 34%). 1 H NMR (300 Hz, c / rDMSO): d 3, 3.45 (t, 4 H, J = 4.8 Hz), 3.67 (t, 4 H, J = 4, B Hz), 7.06 (s) , 1 H), 8.21 (s, 1 H), 13.79 (s (broad), 1 H). 13 C NMR (100 MHz, cfe-DMSO): d 45.6, 66.4, 107.3, 116.1, 141, 3, 148.3, 158.5, 166.8. M + 1 = 243.
Step 2 1- (1,3-Benzodioxol-5-yl) -8 - [(5-chloro-2-morpholin ^ -ilyisonicotinoyl) arnino] -4,5-dihydro-1H-benzo [g] ndazole -3-carboxamide The title compound was synthesized by the same procedure as in Example 211 starting from the title material of step 1 (0.35 g, 0.00144 mol), the title compound of Step 4 of Example 161 (0.333 g) , 0.00096 mol), HATU (0.54 g, 0.00142 mol) and Et3N (0.39 ml, 0.00279 mol) in DMF (8 ml) with a yield of 0.487 g of the title compound (yield : 88%). Mp: 269-271 ° C. 1 H NMR (300 MHz, oVDMSO): d 2.88-2.93 (m, 4H), 3.46 (t, 4H, J = 4.6 Hz), 3.66 (t, 4H, J = 4.6 Hz), 6.09 (s, 2H), 6. 94 (s, 1H), 6.97 (d, 1 H, J = 2 Hz), 7.02 (d, 1 H, J = 8.2 Hz), 7.11 (d, 1H, J = 1 , 9 Hz), 7.25 (s, 1 H), 7.29-7.32 (m, 2H), 7.39-7.42 (dd, 1 H, J = 8.2 Hz, 2 Hz ), 7.5 (s, 1H), 8.19 (s, 1H), 10.36 (s, 1H). M + 1 = 574. EXAMPLE 213 1- (1,3-Benzodioxol-5-yl) -8- ( { [5-chloro-2- (methylthio) pyrimidin-1-yl] c-rbonyl}. ) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 211 starting from 5-chloro-2- (methyl-thio) pyrimidine-4-carboxylic acid (1.76 g, 0.00861 mol), the compound from the title of Step 4 of Example 161 (2 g, 0.00574 mol), HATU (3.27 g, 0.00857 mol) and Eta (2.32 ml, 0.0166 mol) in DMF (29 ml) with a yield of 1.3, g of the title compound (yield: 42%). 1 H NMR (300 MHz, de-DMSO): d 2.52 (s, 3H), 2.88-2.93 (m, 4H), 6.08 (s, 2H), 6.94-6.97 (dd, 1 H, J = 8.2 Hz, 1.9 Hz), 7.01 (d, 1H, J = 8.2 Hz), 7.11 (d, 1 H, J = 1, 9 Hz ), 7.25-7.33 (m, 3H), 7.38-7.41 (dd, 1 H, J = 8.2 Hz, 1.9 Hz), 7.5 (s, 1 H) , 8.88 (s, 1H), 10.59 (s, 1H). M + 1 = 536. SCHEME XXIII Example 214 1- (1,3-benzodioxol-5-yl) -8-. { [5-chloro-2- (4-methyl-piperazin-1-yl) isonicotinoyl] amino} -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide A mixture of the title compound of Example 211 (1.2g, 0.0023 mol) and N-methylpiperazine (4.6 ml, 0.046 mol) was heated at 100 ° C in a sealed tube for 24 hours. The completion of the reaction was checked by HPLC. After removing the volatile components in vacuo, the residue was partitioned between water and CH2Cl2. The organic phase was washed once more with water and dried over MgSO4. The product of the crude mixture was purified by chromatography on silica gel using CH2Cl2 / MeOH: 12/1 to 10/2 giving 0.62 g of the title product, yield: 46%. Mp: 305-307 ° C. H NMR (400 MHz, de-DMSO): d 2.18 (s, 3H), 2.34-2.35 (d, 2H, J = 5 Hz), 2.89-2.91 (m, 4H) ), 3.49 (d, 2H, J = 5 Hz), 6.08 (s, 2H), 6.91-7.03 (m, 3H), 7.1 (d, 1H, J = 2 Hz ), 7.24-7.3 (m, 3H), 7.38-7.41 (dd, 1H, J = 8.3 Hz, 2 Hz), 7.49 (s, 1H), 8.13 (s, 1H), 10.33 (s, 1H). M + 1 = 587. EXAMPLE 215 1- (1,3-Benzodioxol-5-yl) -8 - [(5-chloro-2-piperazin-1-yl-sonicotinoyl) amino] -4,5-dihydro-1H -benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 214 starting from the title compound of Example 211 (1g, 0.0018 mol) and piperazine (3 g, 0.036 mol) in EtOH (4 mL). The reaction was carried out at 95 ° C for 24 hours. After allowing the reaction mixture to cool, the volatile components were removed in vacuo. The residue was triturated with H20 and finally with EtOH in a yield of 0.572 g of the title compound (yield: 55%). 1 H NMR (300 MHz, cfe-DMSO): d 2.71 (s, broad, 4H), 2.86-3.30 (m, 4H), 3.39 (s, broad, 4H), 6.07 (s, 2H), 6.85 (s, 1H), 6.93-6.95 (dd, 1H, J = 8.2 Hz, 1.9 Hz), 7.00 (d, 1H, J = 8.2 Hz), 7.09 (d, 1 H, J = 1.9 Hz), 7.24-7.30 (m, 3H), 7.38-7.41 (dd, 1H, J = 8.2 Hz, 1.74 Hz), 7.49 (s, 1 H), 8.12 (s, 1H), 10.32 (s, 1H). M + 1 = 573.
EXAMPLE 216.sup.-S-benzodioxol-S-yl-S-yl-e-dichloropyridin-1-carbonyl-yamino ^. S-d -hydro-1 H -benzo [g] indazole-3-carboxamide The title compound was synthesized with 1, 653 g of 3,6-dichloro-2-pyridinecarboxylic acid (CP92740, prepared by the method of E. Marzi, A. Bigi, M. Schlosser, Eur. J. Org. Chem. 2001, 1371-1376) and the title compound of Step 4 of Example 161 (2.0 g) by the same procedure used for Example 21 1. The title compound is a brown solid (2.4 g, 80 %), pf 263-265 ° C Its structure was confirmed by 1 H NMR and LC / MS: 1 H NMR (de-DMSO): d 2,82-3.01 (m, 4 H)), 6, 1 1 (s, 2 H), 6.97-7.07 (m, 2H), 7.38 (d, 1 H, J = 1 Hz), 7.81 (s, 1 H), 7.33-7.42 (m, 3H) , 7.52 (s, 1 H), 7.51 (d, 1 H, J = 9 Hz), 8, 15 (d, 1 H, J = 9 Hz), 10.57 (s, 1 H) . ESI mass spectrum for C25H18CI2N5O: 522 (M + 1). Example 217 1- (1,3-benzodioxol-5-yl) -8- ( { [3-chloro-6- (4-methyl-piperazin-1-yl) -pyridin-2-yl] -carbonyl} -amino) -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide Step 1 Potassium 3-chloro-6- (4-methylpiperazin-1-yl) pyridin-2-carboxylate Potassium-3-chloro-6- (4-methylpiperazin-1-yl) pyridin-2-carboxylate was synthesized with the reaction used in Example 250, step 1 starting with 3,6-dichloro-2-pyridinecarboxylic acid (0.60 g, 3.125 mmol), N-methylpiperazine (7.2 g, 72 mmol). The reaction was carried out at 95 ° C for 3 days. The volatile components were removed in vacuo. The resulting residue was washed with a saturated solution of K2CO3 and with CH2Cl2. Three phases were formed. The medium layer was separated, dried and the solvent was removed under reduced pressure to give 0.89 g of potassium 3-chloro-6- (4-methylpiperazin-1-yl) pyridine-2-carboxylate (96%). Its structure was confirmed by 1H RN and LC / MS: 1H NMR (D20): d 2.18 (s, 3H), 2.43 (s, broad, 4H), 3.37 (s, broad, 4H), 6.77 (d, 1H, J = 9 Hz), 7.58 (d, 1 H, J = 9 Hz). ESI mass spectrum for C11H15CIN302 +: 256 (M + 1) in the presence of TFA. Step 2 1- (1,3-Benzodioxol-5-yl) -8- ( { [3-chloro-6- (4-methyl-piperazin-1-yl) -pyridin-2-yl] -carbonyl) amino) -4 , 5-dihydro-1H-benzo [g] ndazole-3-carboxamide The title compound was synthesized with 0.30 g of 3-chloro-6- (4-methyl-piperazin-1-yl) -2-pyridinecarboxylic acid, obtained by acidification of its K salt of step 1 and the title compound of Step 4 of Example 161 (0.217 g) by the same procedure used for example 260. The title compound is a brown solid (0.23 g, 61%), mp. 264-266 ° C (decomposition). Its structure was confirmed by 1 H NMR and LC / MS: 1 H NMR (cfe-DMSO): d 2.70 (s, 3 H), 2.72-4.30 (m, 12 H), 6.02 (s, 2 H) ), 6.92-7.12 (m, 4H), 7.22-7.36 (m, 3H), 7.42-7.53 (m, 2H), 7.77 (d, 1H, J = 9 Hz), 10.32 (s, 1H). ESI mass spectrum for CaoHkgCINyC: 586 (M + 1). Example 218 1- (1,3-benzodioxol-5-yl) -8-. { [(3-chloro-6- { [2- (dimethylamino) ethyl] thio}. Pyridin-2-yl) carbonyl] amino} -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The title compound was synthesized with 0.36 g of the title compound of Step 1 of Example 262 and the title compound of Step 4 of Example 161 (0.35 g) by the same procedure used for Example 260. The title compound is a white solid (0.51 g, 86%). Its structure was confirmed by 1 H NMR and LC / MS: 1 H NMR (cfe-DMSO): d 2.18 (s, 6 H), 2.55 (m, 2 H), 2.85 (m, 4 H), 3, 24 (m, 2H), 6.10 (s, 2H), 6.90-7.08 (m, 2H), 7.14 (s, 1H), 7.22-7.35 (m, 2H) , 7.36-7.47 (m, 3H), 7.52 (s, 1 H), 7.84 (d, 1 H, J = 9 Hz), 10.40 (s, 1H). ESI mass spectrum for C29H28CIN604S +: 591 (M + 1). Example 219 1- (1,3-benzodioxol-5-yl) -8-. { [(3-chloro-6-morpholin-4-ylpyridin-2-yl) carbonyl] amino} -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The title compound was synthesized with 0.27 g of morpholine and the title compound of Example 216 (0.522 g) by the same procedure used for example 207 except that the EtOH was replaced with 0.5 ml of DMA. The reaction was carried out at 80 ° C for 36 hours. The title compound, isolated by preparative HPLC, is a white solid (0.30 g, 52%), m.p. 260-262 ° C (decomposition). Its structure was confirmed by 1 H NMR and LC / MS: 1 H NMR (CDCl 3) d 2.96 (m, 2 H), 3.15 (m, 2 H)), 3.48 (m, 4 H), 3.86 ( m, 4H), 5.41 (s, 1 H), 6.74-6.86 (m, 2H), 6.90-7.04 (m, 2H), 7.16 (d, 1H, J = 1 Hz), 7.28-7.35 (m, 2H), 7.54-7.22 (m, 2H), 9.32 (s, 1 H). ESI mass spectrum for C29H26CIN605 +: 573 (M + 1). EXAMPLE 220 1- (1,3-benzodioxol-5-yl) -8- ( { [3-chloro-6- (methylamino) pyridin-2-yl] carbonyl} amino) -4,5-dihydro -1 H-benzo [g] indazole-3-carboxamide The title compound was synthesized with N-methylamine (6 ml of 33% by weight solution in EtOH) and the compound of Example 216 (1.04 g) by the same procedure used for example 207 except that 1 ml was added. of DMA. The reaction was carried out at 82 ° C for 5 days. The title compound, isolated by preparative HPLC, is a white solid (0.29 g, 52%), M.p. 269-270 ° C (decomposition). Its structure was confirmed by 1H NMR and LC / MS: 1H NMR (oVDMSO): d 2.76 (d, 3H, J = 5.5 Hz), 2.84-3.99 (m, 4H), 6, 16 (s, 2H), 6.57 (d, 1 H, J = 9 Hz), 6.91-7.04 (m, 3H), 7.12 (d, 1H, J = 1Hz), 7, 22-7.34 (m, 3H), 7.46-7.54 (m, 3H), 10.19 (s, 1H). ESI mass spectrum for C26H22CIN604 +: 517 (M + 1). Example 221 SCHEME XXIV R = -F, 4-S0Me, 3,4-DO, etc.
Step 1: A solution of 2-chloro-5-bromobenzoic acid (23.6 g, 0.1 mol), conc. Sulfuric acid. (5 ml) and condensed isobutene (400 ml) was prepared in a pressure vessel and stirred at room temperature under a pressure of 12 psi (82.74 kPa) for 2 days. The container was opened and the excess isobutene was released. The remaining liquid was treated with a sat solution. of NaHCC > 3 and extracted with methylene chloride. The organic phase was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to give 20.5 g of the crude product as a brown oil, which was used without further purification (70%).
Step 2: A mixture of tere-butyl 2-chloro-5-bromobenzoate (2.95 g, 0.01 mol), N-methylpiperazine (1.5 g, 0.015 mol), Na'BuO (1.5 g) , 0.015 mol), Pd2 (dba) 3 (0.18 g, 0.0002 mol) and BINAP (0.2 g, 0.0003 mol) in toluene was heated at 100 ° C under a nitrogen atmosphere for 16 hours . The solution was cooled to room temperature and filtered through a pad of Celite®. The filtrate was concentrated and the residue was partitioned between methylene chloride and water. The organic phase was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to give 3.0 g of the crude product as a dark brown oil (97%). The NMR and MS were consistent with the proposed structure. Step 3: To a solution of tere-butyl 2-chloro-5- (4-methylpiperazin-1-yl) benzoate (7.3 g, 0.023 mol) in methylene chloride (150 ml) was added dropwise Trifluoroacetic acid (62 ml, 0.8 mol) at 0-5 ° C. The reaction mixture was stirred overnight while allowing to warm to room temperature. The solvent and excess TFA was removed and the residue was triturated with ether to give 7.5 g of acid as a light brown solid; 1 H NMR (DMSO, 400 Hz) d: 10.11 (s, 1 H), 7.39 (d, J = 8.9 Hz, 1H), 7.33 (d, J = 3.1 Hz, 1H ), 7.16 (dd, J = 3.1, 8.9 Hz, 1 H), 3.90 (d, J = 12.2 Hz, 2H), 3.52 (d, J = 11, 1Hz) , 2H), 3.15 (m, 2H), 2.98 (m, 2H), 2.87 (s, 3H); Anal. Caled, for C 12 H 15 Cl 2 O 2 + 1, 0 TFA: C, 45.60; H, 4.37; N, 7.60. Found: C, 45.99; H, 4.62; N, 7.21. Step 4: To a mixture of 2-chloro-5- (4-methylpiperazin-1-yl) benzoic acid (0.9 g, 0.0035 mol), the title compound of Step 4 of Example 161 (0, 82 g, 0.0024 mol) and 1 ml of diisopropylethylamine in 25 ml of DMF was added HATU (1.3 g, 0.0035 mol) in one portion. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed and the residue was purified by preparative HPLC to give 1.25 g of the product as a pale white solid (89% yield); mp: 185-187 ° C; HRMN (DMSO + TFA-d, 400 MHz) d: 10.26 (s, 1H), 9.81 (sa, 1H), 7.52 (sa, 1H), 7.44 (dd, J = 2, 0, 8,1Hz, 1H), 7,37 (d, J = 8,6 Hz, 1H), 7,33 (d, J = 2,1Hz, 1H), 7,31 (d, J = 8, 4 Hz, 1H), 7.30 (s, 1H), 7.12 (d, J = 2.0 Hz, 1H), 7.09 (m, 2H), 7.03 (d, J = 8, 2 Hz, 1H), 6.98 (dd, J = 2.1, 8.2 Hz, 1H), 6.11 (s, 2H), 3.90 (m, 2H), 3.50 (m, 2H), 3.14 (m, 2H), 2.96 (m, 6H), 2.86 (s, 3H). The bioactivity in the IKK2 Resin test of the compounds of Examples 207-221 is shown in Table 5. Table 5 Examples 222-243 Examples 222-243 shown in Table 6 were synthesized with the corresponding starting compounds using the following synthesis procedure similar to Scheme I where R 9 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, heteroarylalkyl substituted or appropriate cycloalkyl. SCHEME XXV (7-ntr-1 -oxo-1, 2,3-4-tetrahydronaphthalen-2-yl) (oxo) ethyl acetate 1 B'coa. Pyridine Table 6 Example 244 8-amino-1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] ndazole-3-carboxamide This material was prepared with 4-fluorophenyl hydrazine by the procedure described for Example 92. Example 245 1- (4-fluorophenyl) -8-. { [(2-piperazin-1-ylpyridin-3-yl) carbonyl] amino} -4,5-dihydro- 1 H-benzo [g] ndazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 207 starting from the title compound of Example 225 (0.81 g, 0.017 mol) and piperazine (3 g, 0.0348 mol) in 4 ml of EtOH yielding 0.523. g of the title compound (yield: 58%). Mp: 156-157 ° C. 1 H-NMR (300 MHz, dg-D SO): d 2.63 (t, 4H, J = 4.5 Hz), 2.86-2.93 (m, 4H), 3.08 (t, 4H , 4.5 Hz), 6.86-6.90 (dd, 1 H, J = 7.4 Hz, 4.8 Hz), 7.23 (s, 1 H), 7.28 (s, 1 H), 7.32 (d, 1H, 8.3 Hz), 7.40 (t, 2H, J = 8.7 Hz), 7.54-7.6 (m, 4H), 7.63- 7.66 (dd, 1 H, J = 7.4 Hz, 1.7 Hz), 8.22-8.25 (dd, 1 H, J = 4.8 Hz, 1.9 Hz), 10, 25 (5, 1 H). M + 1 = 512. Example 246 8-. { [(6-chloro-4-methylpyridin-3-yl) carbonyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide A modification of the procedure of Weglinski and Talik (Rocz, Chem. 1977, 51, 2401) was used. Powdered potassium carbonate (-325 mesh) was dried under vacuum at 200 ° C overnight before use. A layer of dry potassium carbonate (28.56 g, 0.207 mol) was placed on the bottom of a 300 mL Hastelloy-B autoclave followed by a layer of 2-hydroxy-4-methylpyridine (28.51 g, 0.2612). mol) mixed with dry potassium carbonate (28.70 g, 0.208 mol). The vessel was sealed, carefully purged with dry carbon dioxide (5 x 80 psig (551.6 kPa)), pressurized with dry carbon dioxide at 800 psig (5516 kPa) and heated to 130 ° C for 18 hours. hours. After cooling and carefully ventilating, the product mixture was dissolved in water (560 ml) and added to 132 ml of 6N HCl with vigorous stirring for approximately 20 minutes. The pH of the resulting suspension was 2.43 and potassium carbonate (ca. 0.25 g) was added until pH = 2.53. After stirring the suspension for 1 hour at 25 ° C, the precipitate was recovered by vacuum filtration, washed with water (3 x 35 ml) and dried under vacuum at 100 ° C yielding 7.11 g of a chestnut powder . The 1 H NMR analysis of the chestnut powder was consistent with a mixture of approximately 5.6% by mole of 2-hydroxy-4-methylpyridine and 94.4% by mole of the desired 2-hydroxy-4-methyl-5-pyridinecarboxylic acid. The yield was estimated at 17.0% based on the NMR test of the recovered product. 1 H NMR (400 MHz, dg-DMSO) d 2.36 (d, J = 1 Hz, 3 H), 6.19 (apparent s, 1 H), 7.99 (s, 1 H), 12.2 ( s wide, 2H). 1 C NMR (100 MHz, dg-DMSO) d 21, 6, 109.1, 1 19.5, 141, 1, 151, 8, 161, 8, 165.8. Stage 2 4-Methyl-6-chloronicotinic acid 6-Hydroxy-4-methylnicotinic acid (10 g, 65.3 mmol) and phosphorus oxychloride (33 mL) were combined and heated to reflux for 3 hours. The reaction solution was poured into 300 ml of ice and then 600 ml of water was added. The solution boiled for 30 minutes before cooling and extracting the product in ether. The solvent was removed and the residue recrystallized from 900 ml of hot water. Solid yellow, 9.06g (81% yield). Mp 170-172 ° C. 1 H NMR (CD 3 OD): d 2.61 (s, 3 H), 7.41 (s, 1 H), 8.80 (s, 1 H). LC-MS, M + 1 = 172. Step 3: 8- [(6-Chloro-4-methylpyridin-3-yl) carbonyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The compound of example 244 (3.872 mmol), 4-methyl-6-chloronicotinic acid from step 2 (5.828 mmol) and HATU (5.844 mmol) were dissolved in 20 ml of DMF followed by the addition of 1.9 ml of triethylamine. . The mixture was stirred at room temperature overnight. The solvent was removed by distillation and the residue was suspended in water, filtered and washed with water. The solid was recrystallized from acetonitrile, then redissolved in acetonitrile, decolorized with decolorizing carbon and dried over anhydrous MgSO 4. The solvent was distilled to give a solid. Mp: 280-284 ° C. 1 H NMR (cfe-DMSO, 400 Hz): d 2.28 (s, 3H); 2.84-2.98 (m, 4H); 7.25-7.44 (m, 6H); 7.49 (s, 1H); 7.51-7.62 (m, 3H); 8.35 (s, 1H); 10.31 (s, 1H). 13 C NMR (DMSO, 100 MHz): d 19.13, 20.35, 29.67, 115.01, 117.07, 117.30, 120.08, 121.34, 126.19, 126.60, 128.72, 128.81, 129.58, 132.80, 133.42, 136.81, 136.84, 137.64, 139.71, 143.19, 148.42, 149.96, 151, 59, 161, 44, 163.88, 164.47, 164.78. M + 1 = 476. Example 247 1- (4-fluorophenyl) -8-. { [(4-methyl-6-morpholin-4-ylpyridm ^ dihydro-1 H -benzo [g] indazole-3-carboxamide] The title compound of Example 246 (1.47 mmol) and morpholine (23.1 mmol) were dissolved in 10 ml of?,? - dimethylacetamide. The reaction mixture was then introduced under a nitrogen atmosphere and stirred in an oil bath at 100 ° C for 27 hours. The solvent was partially distilled from the mixture and then added to water, filtered and washed with water. The solid was recrystallized from acetonitrile, then dissolved in acetonitrile and dried over MgSC > 4 anhydrous. The solvent was distilled to give a solid. Mp: 301 ° C (decomp.) 1 H R N (de-DMSO, 400 MHz): d 2.22 (s, 3H); 2.80-2.94 (m, 4H); 3.46 (t, 4H, J = 4.8 Hz); 3.62 (t, 4H, J = 4.8 Hz); 6.67 (s, 1H); 7.22-7.27 (m, 3H); 7.31-7.38 (m, 2H); 7.42 (dd, 1 H, J = 1.9 Hz, 8.2 Hz) 7.49-7.57 (m, 3H); 8.11 (s, 1H); 9.92 (s, 1H). 1 C NMR (oVDMSO, 100 MHz): d 20.35, 20.38, 29.63, 45.55, 66.54, 108.46, 114.91, 117.02, 117.25, 119.91 , 121.23, 122.78, 126.42, 128.64, 128.73, 129.36, 132.60, 136.82, 136.85, 138.38, 139.82, 143.15, 147 , 70, 148.03, 160.04, 161.39, 163.84, 164.47, 166.18. M + 1 = 527 Example 248 8 - [(2,5-Dichloroisonicotinoyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide 2 , 5-dichloroisonicotinic acid (1.65 g, 0.0086 mol), HATU (3.27 g, 0.0086 mol) and Et3N (2.32 ml, 0.0166 mol) were added to a solution of the title compound of Example 244 ( 1.85 g, 0.00574 mol) in 29 ml of DMF. The reaction mixture was stirred at room temperature for 3 hours. The completion of the reaction was confirmed by monitoring the disappearance of the title compound of Example 246 step 2 in LC / MS. The crude reaction mixture was concentrated to approximately 10 ml of DMF. After adding water to this residue in DMF, a white solid formed. This white solid was triturated in water for 20 minutes and filtered. The solid was collected, dissolved in THF and dried with MgSO4. Removal of the solvent produced a brown solid which crystallized from CH3CN to give 2.1 g of the compound as white needles (73% yield). 1 H NMR (300 MHz, cfe-DMSO): 2.86-2.91 (m, 4H), 7.18 (d, 1 H, J = 1.2 Hz), 7.25 (s, 1H), 7.32-7.36 (m, 4H), 7.52-7.56 (m, 3H), 7.75 (s, 1H), 8.57 (s, 1H), 10.49 (s, 1 HOUR). M + 1 = 497. EXAMPLE 249 8 - [(5-Chloro-2-morpholin-4-ylisonicotinoyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-H-benzo [g] indazole -3-carboxamide The title compound of Example 244 (0.757 mmol), 5-chloro-2-morpholin-4-ylisonicotinic acid (1.38 mmol) and HATU (1.57 mmol) were dissolved in 5 mL of DMF followed by the addition of 0.4 ml of triethylamine. The mixture was stirred at room temperature for 3 hours and the DMF was partially removed by distillation. Water was then added to the reaction mixture, filtered and washed with water. The solid was dissolved in THF, decolorized with decolorizing carbon and dried over anhydrous MgSO4. The THF was distilled off and the solid was triturated in diethyl ether three times, then triturated in ethanol and twice more with acetonitrile, filtered and dried under vacuum. Mp: 309-313 ° C. 1 H NMR (cfe-DMSO, 400 MHz): d 2.80-2.95 (m, 4H); 3.42 (t, 4H, J = 5 Hz); 3.62 (t, 4H, J = 5 Hz); 6.88 (s, 1 H); 7.17-7.21 (m, 1 H); 7.23-7.41 (m, 5H) 7.49-7.58 (m, 3H); 8.14 (s, 1 H); 10.31 (s, 1 H). 13 C NMR (cfe-DMSO, 100 MHz): d 20.34, 29.70, 45.74, 66.50, 106.55, 114.97, 115.87, 117.09, 117.32, 120, 05, 121, 41, 126.67, 128.64, 128.73, 129.62, 133.47, 136.80, 136.82, 137.48, 139.64, 143.21, 145.28, 147.54, 158.30, 161, 39, 163.85, 164.45. M + 1 = 547. Example 250 8-. { [5-chloro-2- (4-methylpiperazin-1-yl) isonicotinoyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide Stage 1 5-Chloro-2- (4-methyl-piperazin-1-yl) isonicotinic acid hydrochloride 5-Chloro-2- (4-methyl-piperazin-1-yl) isonicotinic acid hydrochloride was synthesized with the same procedure as in Example 212 step 1 starting from 2,5-dichloroisonicotinic acid (3 g, 0.0156 mol), N-methylpiperazine (30.7 g, 0.30 mol) in 10 ml of α, β-dimethylacetamide. The reaction was carried out at 100 ° C for 8 days. The volatile components were removed in vacuo. The resulting residue was washed with a saturated solution of K2CO3 and with CH2Cl2. The solvents were removed in vacuo and the resulting residue dissolved in a minimum amount of water, acidified to pH = 1 with an aqueous solution of HCl (1 N) and washed with CH 2 Cl 2. After standing at room temperature, the aqueous acidic faso produced 2 g (yield: 44%) of the title compound. 1 H NMR (300 Hz, D20): d 2.85 (s, 3 H), 3.13 (t, 2 H, J = 12.28 Hz), 3.34 (t, 2 H, J = 14.3 Hz) , 3.56 (d, 2H, J = 12.28 Hz), 4.18 (d, 2H, J = 14.3 Hz), 7.08 (s, 1 H), 8.00 (s, 1 H). 1JC NMR (75 MHz, D20): 8.1.13, 43.4, 52.54, 109.5, 117.6, 142.3, 147.9, 154.4, 169.5. Stage 2 8-. { [5-chloro-2- (4-methylpiperazin-1-yl) isonicotinoyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 21 1 starting from 5-chloro-2- (N-methyl-piperazinyl) isonicotinic acid hydrochloride from step 1 (0.59 g, 0.00202 mol) , the title compound of Example 244 (0.432 g, 0.00134 mol), HATU (0.755 g, 0.00198 mol) and E¾3N (1.09 ml, 0.0078 mol) in DMF (8 ml) with a yield of 0.305 g of the title compound (yield: 40%). H NMR (300 Hz, de-DMSO): d 2.17 (s, 3H), 2.33 (t, 4H, J = 4.8 Hz), 2.87-2.93 (m, 4H), 3.47 (t, 4H, J = 4.8 Hz), 6.87 (s, 1 H), 7.2 (d, 1 H, J = 1, 9 Hz), 7.27 (s, 1 H), 7.29-7.41 (m, 5H), 7.53-7.58 (m, 3H), 8.13 (s, 1 H), 10.31 (s, 1 H). M + 1 = 561. Example 251 1- (4-fluorophenyl) -8-. { [2- (4-methyl-piperazin-1-yl) isonicotinoyl] amino} -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide Step 1 8 - [(2-chloro-sonicotinoyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide This material was prepared with Example 244 (8-amino-1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide) and 2-chloroisonicotinic acid with the procedure described for Example 246 step Step 2 The material of step 1 (2.17 mmol) and N-methyl piperazine (32.9 mmol) were dissolved in 5.0 ml of?,? - dimethylacetamide. The reaction mixture was then introduced under a nitrogen atmosphere and stirred in an oil bath at 100 ° C for 88 hours. The solvent was partially removed by distillation and then added to water, filtered and washed with water. The solid was dissolved in acetonitrile, decolorized with decolorizing carbon and dried over anhydrous MgSO 4. The solvent was distilled, then the solid residue was recrystallized from acetonitrile. Mp: 277-279 ° C. 1 H NMR (400 MHz, cfe-DMSO): S 2.17 (s, 3H); 2.35 (t, 4H, J = 5 Hz) 2.82-2.95 (m, 4H); 3.47 (t, 4H, J = 5 Hz); 6.85 (d, 1 H, J = 5 Hz); 7.01 (s, 1 H) 7.21-7.44 (m, 6H); 7.50-7.59 (m, 3H); 8, 16 (d, 1 H, J = 5 Hz); 10.10 (s, 1H). 13 C NMR (DMSO-d 6, 100 Hz): d: 20.32, 29.69, 45.20, 46.46, 55.00, 105.43, 11, 23, 115.50, 1 17.07, 117.30, 120.66, 121, 37, 126.54, 128.60, 128.69, 129.48, 133.36, 136.82, 136.85, 137.70, 139.71, 143.19, 144.36, 148.89, 159.88, 161, 37, 163.81, 164.44, 165.15. M + 1 = 526. Example 252 8-. { [5-chloro-2- (4-methyl-1,4-diazepan-1-yl) isonicotinoyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 214 starting from the title compound of Example 248 (1 g, 0.0020 mol) and 1-methylhomopiperazine (4.6 g, 0.040 mol). The reaction was carried out at 95 ° C for 24 hours. After allowing the reaction mixture to cool, the volatile components were removed in vacuo. The residue was triturated with H2O yielding 0.899 g of the title compound as a tetrahydrate (yield: 71%). 1 H NMR (300 MHz, oVDMSO): d 1, 81-1, 83 (m, 2H), 2.21 (s, 3H), 2.41 (t, 2H, J = 5.5 Hz), 2, 53 (t, 2H, J = 4.56 Hz), 2.87-2.93 (m, 4H), 3.53 (t, 2H, J = 5.5 Hz), 3.63-3.67 (m, 2H), 6.62 (s, 1 H), 7.19 (d, 1 H, J = 1, 9 Hz), 7.27-7.38 (m, 4H), 7.42- 7.45 (dd, 1 H, J = 8.12 Hz, 1.88 Hz), 7.53-7.58 (m, 3H), 8.07 (s, 1 H), 10.31 (s) , 1 HOUR). M + 1 = 575. Example 253 8 - [(5-Chloro-2-piperazin-1-ylisonicotinoyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole- 3-carboxamide The title compound was synthesized by the same procedure as in Example 214 starting from the title compound of Example 248 (1g, 0.0020 mol) and piperazine (3.44g, 0.040 mol) in 5 ml of EtOH. The reaction was carried out at 100 ° C for 24 hours. The whitish precipitate that formed in the crude reaction mixture was filtered and washed with EtOH yielding 0.579 g of the title compound (yield: 53%). 1 H NMR (300 MHz, cfe-DMSO): 2.67 (t, 4H, J = 4.9 Hz), 2.85-2.90 (m, 4H), 3.36 (t, 4H, J = 4.9 Hz), 6.80 (s, 1 H), 7.18-7.19 (m, 1 H), 7.25 (s, 1 H), 7.27-7.35 (m, 3H), 7.37-7.39 (dd, 1 H, J = 8 Hz, 2Hz), 7.51 -7.55 (m, 3H), 8.09 (s, 1 H), 10.28 (s, 1 H). M + 1 = 547 Example 254 8- ( {5-Chloro-2 - [[2- (dimethylamino) ethyl] (methyl) amino] isonicotinoyl}. Amino) -1- (4-fluorophenyl) -4, 5-dihydro-1 H-benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 214 starting from the title compound of Example 248 (0.8 g, 0.0016 mol) and?,?,? '- trimethylethylenediamine (3.3 g, 0.032 mol). The reaction was carried out at 100 ° C for 24 hours. After removal of the volatile components in vacuo, the residue was partitioned between water and CH2Cl2. The organic phase was washed once more with water and dried over MgSO4. The crude product mixture was purified by preparative HPLC to give 0.424 g of the title product, yield: 47%. 1H RN (400 MHz, d < r DMSO): 2.13 (s, 6H), 2.34 (t, 2H, J = 6.7 Hz), 2.87-2.95 (m, 4H) , 2.96 (s, 3H), 3.59 (t, 2H, J = 6.7 Hz), 6.58 (s, 1 H), 7.2 (d, 1 H, J = 2Hz), 7.27 (s, 1H), 7.29-7.37 (m, 3H), 7.41-7.44 (dd, 1 H, J = 8 Hz, 2 Hz), 7.53-7, 58 (m, 3H), 8.13 (s, 1 H), 10.36 (s, 1 H). M + 1 = 563. Example 255 8-. { [(3-chloro-6-morpholin-4-ylpyridin-2-yl) carbonyl] amino) -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide Stage 1 3-Chloro-6-morpholinyl-2-pyridine carboxylic acid 3,6-Dichloropyridine-2-carboxylic acid (0.55 g, 2.86 mmol), morpholine (1.37 g, 15.7 mmol) and N, N-dimethylacetamide (1.37 ml) were combined and stirred for 24 hours. hours at 80 ° C. An additional volume of morpholine (1.39 g, 15.7 mmol) was added and heating continued for a further 40 hours. After cooling, the DMA was removed in the presence of toluene. The residue was dissolved in water and extracted with ether by removing excess morpholine. The aqueous phase was acidified to pH = 2 and the product was extracted into ether. Crystallization from water gave a white solid, 369 mg (53% yield). 1 H NMR (CD 3 OD): d 3,52 (t, 4 H), 3.78 (t, 4 H), 6.97 (d, 1 H), 7.65 (d, 1 H). LC-MS, M + H: 243. Stage 2 8-. { [(3-chloro-6-morpholin-4-ylpyridin-2-yl) carbonyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide The title compound was synthesized with 0.294 g of 3-chloro-6-morpholinyl-2-pyridine carboxylic acid (from step 1) and (0.258 g) of the title compound of example 244 by the same procedure used for example 211 except that HATU was replaced by HBTU (BF4). The title compound is a brown solid (0.37 g, 84%), m.p. 252-254 ° C. Its structure was confirmed by 1 H NMR and LC / MS: 1 H NMR (CDCl 3): d 2.95 (m, 2 H), 3, 12 (m, 2 H), 3.48 (m, 4 H), 3.88 (m, 4H), 5.39 (s, 1 H), 6.65-6.82 (m, 3H), 7.16, 7.18-7.23 (m, 3H), 7.43-7 , 56 (m, 3H), 7.62 (m, 1 H), 9.18 (s, 1 H). ESI mass spectrum for C28H25CIFN6: 547 (M + 1). EXAMPLE 256 8- ( { [3-Chloro-6- (4-methyl-piperazin-1-yl) -pyridin-2-yl] -carbonyl} -amino) -1- (4-fluorophenyl) -4,5-dihydro -1 H-benzo [g] indazole-3-carboxamide The title compound was synthesized with 0.501 g of 3-chloro-6-piperazinyl-2-pyridine carboxylic acid, obtained by acidification of its K salt (from step 1 of Example 217) and with the title compound of Example 244 ( 0.37 g) by the same procedure used for Example 217. The title compound is a brown solid (0.56 g, 88%), mp. 218-220 ° C. Its structure was confirmed by 1 H NMR and LC / MS. 1 H NMR (cfe-DMSO): d 2.19 (s, 3 H), 2.38 (m, 4 H), 2.85 (m, 4 H), 3.45 (m, 4 H), 6.95 (d , 1 H, J = 9 Hz), 7.20 (d, 1 H, J = 2 Hz), 7.26-7.40 (m, 4H), 7.49-7.62 (m, 4H) , 7.63 (d, 1H, J = 9 Hz), 10.20 (s, 1 H). ESI Mass Spectrum for 560 (M + 1) Example 257 8-. { f (3-chloro-6- { [2- (dimethylamino) ethyl] thio.} pyridin-2-yl) carbonyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide Step 1 Chloride of 2 - [(6-carboxy-5-chloropyridin-2-yl) thio] -N, N-dimethylethanaminium 3,6-Dichloropyridine-2-carboxylic acid (1.0 g, 5.23 mmol), sodium hydroxide (1.64 g, 15.7 mmol) and anhydrous THF (10 mL) were combined before slowly adding N, N-dimethylaminoethanethiol (1.9 g, 18.3 mmol). After stirring for several hours in a nitrogen atmosphere, two aliquots of DMF (10 ml each) were added. Several hours later, more DMF (10 ml) and more dimethylaminoethanethiol (1.9 g, 18.3 mmol) were added. The reaction was stirred overnight at room temperature. The solution was diluted with water and extracted three times with methylene chloride. The aqueous phase was acidified to pH 5 and extracted four times with methylene chloride. The aqueous phase was acidified to pH 1, the solvent was removed and the residue recrystallized in hot water. Yellow solid, 0.786 g (51% yield). 1 H NMR (300 MHz, CD 3 OD): d 2.98 (s, 6 H), 3.53 (m, 4 H), 7.50 (d, 1 H), 7.85 (d, 1 H). 13 C NMR (75 MHz, CD 3 OD): d 24.4, 42.8, 58.2, 125.7, 128.1, 140.0, 147.3, 158.2, 166.0. Stage 2 8-. { [(3-chloro-6-. {[[2- (d-methylamino) ethyl] thio} pyridin-2-yl) carbonyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The title compound was synthesized with 0.355 g of the title compound of Step 1 and the title compound of Example 244 (0.32 g) by the same procedure used in Example 255. The title compound is a white solid ( 0.49 g, 87%). Its structure was confirmed by 1 H NMR and LC / MS: 1 H NMR (CD 3 CN): d 2.18 (s, 6 H), 2.57 (m, 2 H), 2.85 (m, 4 H), 3.00 ( m, 4H), 3.26 (m, 2H), 5.88 (s, 1H), 6.94 (d, 1 H), 7.27-7.38 (m, 5H), 7.47- 7.62 (m, 3H), 7.69 (d, 1 H, J = 9 Hz), 9.40 (s, 1H). ESI mass spectrum for C28H27CIFN602S +: 565 (M + 1). Example 258 This compound was synthesized using the same procedure described for Example 221; mp: 194-195 ° C; 1 HNMR (DMSO + TFA-d, 400 MHz) d: 10.24 (s, 1H), 9.69 (s, 1 H), 7.60 (m, 2H), 7.46 (d, J = 4 , 2 Hz, 1H), 7.38 (m, 4H), 7.10 (dd, J = 2.6, 8.9 Hz, 1 H), 7.06 (s, 1H), 3.90 ( d, J = 13.0 Hz, 2H), 3.50 (d, J = 12.0 Hz, 2H), 3.12 (m, 2H), 2.95 (m, 4H), 2.91 ( s, 3H), 2.86 (s, 2H). The bioactivity IKK2 of examples 245-257 is shown in Table 7. Table 7 Examples 259-263 Examples 259-263 were synthesized with the corresponding starting materials using the following synthetic procedures similar to Scheme I where R9 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl or appropriate cycloalkyl. SCHEME XXVI (7-Nitro-1-oxo-1, 2,3-4-tetrahydronaphthalen-2-yl) (oxo) ethyl acetate 1 OOjH, HATU ROOCI. Pyridine SCHEME XXVII Example 259 1- [4- (benzyloxy) phenyl] -8 - [(2-chlorobenzoyl) amino] -4,5-dihydro-1-benzo [g] indazole-3-carboxamide Step 1: A mixture of 4- hydrochloride benzyloxy phenyl hydrazine (6.42 g, 0.03 mol) and (7-nitro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl) (oxo) ethyl acetate 1 (9.2 g, , 03 mol) in 200 ml of acetic acid was heated to reflux for 16 hours, then cooled to room temperature. The precipitate was collected by filtration and dried in air to give 8.5 g of product as a light green solid (60% yield); 1 HNMR (DMSO, 400 Hz) d: 8.07 (dd, 1H), 7.66 (d, 1 H), 7.35-7.53 (m, 8H), 7.24 (dd, 2H), 5.26 (s, 2H), 4.32 (c, 2H), 3.11 (m, 2H), 3.30 (m, 2H), 1.32 (t, 3H). Step 2: A mixture of the product of step 1 (15.0 g, 0.032 mol) and tin chloride (21.6 g, 0.096 mol) in 400 ml of ethanol was heated to reflux overnight. Two more equivalents of tin chloride were added and stirred for 6 hours. The reaction mixture was cooled to room temperature and the precipitate was filtered and washed with ether to give 13.5 g of the amine as light yellow solid (96% yield); 1HR N (DMSO, 400 MHz) d: 8.07 (dd, 1H), 7.66 (d, 1H), 7.35-7.53 (m, 8H), 7.24 (dd, 2H), 5.26 (s, 2H), 4.32 (c, 2H), 3.11 (m, 2H), 3.30 (m, 2H), 1.32 (t, 3H). Step 3: A tightly closed reaction vessel containing the product of step 2 (6.2 g, 0.014 mol) and 40 ml of liquid ammonia in 200 ml of pure alcohol was heated to 120 ° C and 600 psi (4137 kPa) ) for 24 hours. After cooling, the solvent was removed and the residue was purified by chromatography on silica gel (ethyl acetate / hexane, 6: 4) to give 4.0 g of product as a pale yellow solid (70% yield); 1HR N (CDCl 3, 400 MHz) d: 7.35-7.47 (m, 7?), 7.07 (m, 3?), 6.81 (s, 1H), 6.50 (dd, 1 H), 6.07 (d, 1 H), 5.49 (s, 1 H), 5.15 (s, 2H), 3.37 (s, 2H), 3.08 (m, 2H), 2.86 (m, 2H). Step 4: To a solution of the product of step 3 (7.08 g, 0.017 mol) in 100 ml of pyridine was added 2-chlorobenzoyl chloride (3.4 g, 0.019 mol) in one portion and the mixture of The reaction was stirred at room temperature overnight. The solvent was removed and the residue was stirred with water. The precipitate was collected by filtration and dried in the air to give 7.5 g of product as a white solid (80% yield); 1 HNMR (DMSO, 400 MHz) d: 10.29 (s, 1H), 7.15-7.51 (m, 18 H), 5.16 (s, 2H), 2.90 (m, 4H); Anal. Caled, for C32H25CIN403: C, 70.01; H, 4.59; N, 10.20. Found: C, 69.62; H, 4.44; N, 10.24. Example 260 1- [4- (benzyloxy) phenyl] -8-. { [(2-chloropyridin-3-yl) carbonyl] amino} -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide This compound was synthesized following the same procedure as in Example 259 except that 2-chloronicotinyl chloride was used in step 4; 1 HNMR (DMSO, 400 Hz) d: 10.42 (s, 1 H), 8.50 (d, 1H), 7.96 (d, 1H), 7.16-7.54 (m, 15H), 5.16 (s, 2H), 2.93 (m, 4H); Anal. Caled, for C31 H24CIN5O3: C, 67.70; H, 4.40; N, 12.73. Found: C, 66.75; H, 4.17; N, 12.41. Example 261 8 - [(2-Chlorobenzoyl) amino] -1- (4-hydroxyphenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide The final product of Example 259 (7.5 g , 0.014 mol) was dissolved in TFA (120 ml) and the dark brown solution was stirred at room temperature for 84 hours. The solvent was removed and the residue was taken up in 200 ml of water. The solid was collected and dried in air to give 6.5 g of product as a pale white solid (83% yield); 1 H NMR (DMSO, 400 MHz) d: 10.29 (s, 1 H), 9.84 (s, 1 H), 7.24-7.51 (m, 11 H), 6.87 (d, 2 H), 2.90 (m, 4H); Anal. Caled, for CasH ^ CI ^ C + 1, 0 HzO: C, 62.96; H, 4.44; N, 11.75. Found: C, 62.92; H, 4.28; N, 11, 76. EXAMPLE 262 8 - [(2-Chlorobenzoyl) amino] -1- (3-hydroxyphenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide This compound was synthesized following the same procedure as in Example 261 except for the use of 3-benzyloxyphenylhydrazine hydrochloride in step 1; 1 HNMR (DMSO, 400 MHz) d: 10.31 (s, 1H), 7.27-7.54 (m, 10H), 6.89 (m, 3H), 2.92 (m, 4H); Anal. Caled, for C25H19CIN4O3 +0.5 H20: C, 64.17; H, 4.31; N, 11, 97. Found: C, 64.29; H, 4.36; N, 11.63. EXAMPLE 263 8 - [(2-Chloropyridin-3-yl) carbonyl] amino} -1- (4-hydroxyphenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide This compound was synthesized following the same procedure as in Example 261 except for the use of 2-chloronicotinyl chloride in stage 4; 1 HNMR (DMSO, 400 MHz) d: 10.31 (s, 1 H), 7.27-7.54 (m, 10H), 6.89 (m, 3H), 2.92 (m, 4H); Anal. Caled, for C24H18CIN503: C, 62.68; H, 3.95; N, 15.23. Found: C, 62.03; H, 3.89; N, 14.83. The bioactivity in the IKK2 resin assay of Examples 259-263 is shown in Table 8.
Table 8 Example 264 8 - [(2-Chlorobenzoyl) amino] -1 - [4- (2-morpholin-4-ylethoxy) phenyl] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide To a suspension of the product of Example 261 (0.6 g, 0.001 mol) and cesium carbonate in 10 ml of DMF was added 4- (2-chloroethyl) morpholine hydrochloride (0.19 g, 0.001 mol) in a portion. The reaction mixture was stirred at room temperature overnight. After removal of the solvent, the residue was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. This crude product was purified by HPLC to give 0.15 g of product as light yellow (26% yield); 1 HNMR (DMSO, 400 MHz) d: 1 1, 49 (br s, 1 H), 10.33 (s, 1 H), 7.14-7.54 (m, 10 H), 4.53 (s, 2 H) ), 3.82 (m, 2H), 3.58 (m, 8H), 3.08 (m, 2H), 2.93 (m, 4H); Anal. Caled. for C3i H3oCIN5041, 0 H20, 1.0 HCl: C, 59.43; H, 5.31; N, 11, 18. Found: C, 59.58; H, 5.26; N, 10.92. EXAMPLE 265 8 - [(2-Chlorobenzoyl) amino] -1-. { 4 - [(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] phenyl} -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide This compound was synthesized following the same procedure as in Example 264 except for the use of 2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate (yield 78%); 1 H NMR (CDCl 3, 400 Hz) d: 7.69 (d, 1 H), 7.59 (m, 2 H), 7.44 (d, 2 H), 7.30-7.40 (m, 3 H), 7.05 (d, 2H), 6.83 (d, 2H), 4.52 (m, 1H), 4.13 (m, 2H), 4.02 (m, 2H), 3.93 (m , 2H), 3.14 (m, 2H), 2.98 (m, 2H), 1.46 (s, 3H), 1.26 (s, 3H); Anal. Caled, for C31 H29CIN4O5: C, 64.98; H, 5.10; N, 9.78. Found: C, 64.56; H, 4.97; N, 9.68. Example 266 8 - [(2-Chlorobenzoyl) amino] -1- [4- (2,3-dihydroxypropoxy) phenyl] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide To a suspension of the product of Example 265 (0.36 g, 0.00063 mol) methanol was added 1N HCl and the mixture was heated to reflux for 16 hours. The solvent was removed and the crude product was recrystallized from water and methanol giving 0.24 g of the desired product as a white solid (72%).; 1 H NMR (DMSO, 400 MHz) d: 10.30 (s, 1 H), 7.36-7.57 (m, 6H), 7.33 (d, 1H), 7.28 (s, 1 H ), 7.18 (d, 1H), 7.09 (d, 2H), 4.98 (d, 1H), 4.68 (t, 1 H), 4.10 (c, 1 H), 4 , 05 (dd, 1H), 3.92 (dd, 1 H), 3.83 (m, 1 H), 3.45 (t, 1 H), 3.16 (d, 2H), 2.94 (m, 4H); Anal. Caled, for C2aH25Cl 405: C, 63.10; H, 4.73; N, 10.51. Found: C, 62.81; H, 4.45; N, 10.16. The compounds of Examples 267-275 were synthesized as described in Example 264 using the appropriate substituted aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl or cycloalkyl. The bioactivity in the IKK2 resin assay of the compounds of Examples 264-275 is shown in Table 9. Table 9 EXAMPLE 276 8 - [(2-Chlorobenzoyl) amino] -1- (4-cyanophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide Step 1: The product (45.0 g, 0.096 mol) of step 1 of Example 261 was hydrogenated in 400 ml of acetic acid with Pd (OH) 2 / C as catalyst for 17 hours in a 15 psi atmosphere (103 , 43 kPa) on a Parr shaker. After removal of the solvent, the residue was triturated with a mixture of methanol and ether (1: 2) to give 23.0 g of the desired product as a white solid (yield 68%); 1 H NMR (DMSO, 400 MHz) d : 10.06 (s, 1H), 7.27 (d, 2H), 6.98 (d, 1H), 6.92 (d, 2H), 6.43 (dd, 1H), 6.02 (d, 1 H), 4.82 (sa, 2H), 4.29 (c, 2H), 2.75 (m, 2H), 1.30 (t, 3H). Step 2: A tightly closed reaction vessel containing the product of step 1 (25.0 g, 0.072 mol) and 40 ml of liquid ammonia in 250 ml of pure alcohol was heated to 120 ° C and 600 psi (4137 kPa) ) for 30 hours. After cooling, the precipitate was collected by filtration to give 16.7 g of the product as a pale yellow solid (73% yield); 1 HNMR (CDCl 3, 400 MHz) d: 7.44 (s, 1 H), 7.27 (d, 2 H), 7.20 (s, 1 H), 6.97 (d, 1 H), 6.91 (d , 2 H), 6.40 (d, 1H), 6.03 (s, 1H), 4.77 (sa, 2H), 2.85 (m, 2H), 2.72 (m, 2H). Step 3: To a solution of the product of step 1 (5.25 g, 0.016 mol) and TBDMSCI (3.0 g, 0.02 mol) in 100 ml of DMF was added imidazole (2.72 g, 0.degree. , 04 mol) in one portion. The reaction mixture was stirred at room temperature for 36 hours. The solvent was removed and the residue was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. This crude product was purified by chromatography on silica gel (ethyl acetate / hexane, 1: 1) to give 4.0 g of product as a white solid (57% yield). The NMR was consistent with the proposed structure. Step 4: To a mixture of the product of step 3 (1.05 g, 0.0024 mol) and 2-chloro-4,5-methylenedioxanylbenzoic acid (0.73 g, 0.0036 mol) in 25 ml of DMF 1 ml of diisopropylethylamine was added, followed by the addition of HATU (1.37 g, 0.0036 mol). The reaction was stirred at room temperature for 16 hours and concentrated. The residue was partitioned between water and ethyl acetate and the organic phase was concentrated. This crude product was then dissolved in 20 ml of THF and treated with 10 eq of TBAF for 1 hour at room temperature. After removal of the solvent, the residue was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and triturated with a mixture of acetonitrile to give 1.04 g of desired product as an off-white solid (86% yield); 1 H NMR (SO, 400 MHz) d: 10.17 (s, 1 H), 9.85 (s, 1 H), 7.47 (m, 2H), 7.27 (m, 5H), 7, 14 (s, 1 H), 7.04 (s, 1 H), 6.88 (d, 2H), 6, 12 (s, 2 H), 2.92 (m, 4H). Example 277 8-. { [(6-chloro-1,3-benzodioxol-5-yl) carbonyl] amino} -1- (3-hydroxyphenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide This compound was synthesized following the same procedure as in Example 276 except for the use of 3-benzyloxyphenylhydrazine hydrochloride in step 1; 1 HNMR (DMSO, 400 MHz) d: 10.19 (s, 1 H), 9.86 (s, 1 H), 7.51 (m, 2 H), 7.31 (m, 3 H), 7.24 (d, 1 H), 7.14 (s, 1 H), 7.04 (s, 1 H), 6.88 (m, 3 H), 6, 12 (s, 2 H), 2.91 ( m, 4H); Anal. Caled, for C26H19CIN405: C, 62.10; H, 3.81; N, 1, 14. Found: C, 61, 52; H, 3.53; N, 11, 11 Example 278 8 - [(2-Chloro-5-nitrobenzoyl) amino] -1- (4-hydroxyphenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide This compound was synthesized following the same procedure as in Example 276 except for the use of 2-chloro-5-nitrobenzoic acid in step 4; Anal. Caled, for C25Hi8CIN505-1.5 H20: C, 56.56; H, 3.99; N, 13.19. Found: C, 56.89; H, 4.45; N, 12.81. Example 279 8-. { [2-chloro-5- (methylsulfinyl) benzoyl] amino} -1- (4-hydroxy-phenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide This compound was synthesized following the same procedure as in Example 276 except for the use of 2-chloro-5- (methylthio) benzoic acid in step 4 and then oxidizing the desired product with mCPBA; 1 H NMR (DMSO, 400 MHz) d: 10.43 (s, 1 H), 9.85 (s, 1 H), 7.26-7.79 (m, 10 H), 6.88 (d, J = 8 , 5 Hz, 2H), 2.92 (m, 4H), 2.80 (s, 3H); Anal. Caled, for C26H21CIN4O4S: C, 59.94; H, 4.06; N, 10.75; S, 6.15. Found: C, 59.48; H, 4.09; N, 10.54; S, 6.18. Example 280 8 - [(5-amino-2-chlorobenzoyl) amino] -1- (4-hydroxyphenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide This compound was synthesized following the same procedure than in Example 276 except for the use of 5 - [(tert-butoxycarbonyl) amino] -2-chlorobenzoic acid in step 4 and then deprotecting with 4N HCl in dioxane; 1 H NMR (DMSO, 400 MHz) d: 10.19 (s, 1 H), 9.84 (s, 1 H), 7.49 (d, 1 H), 7.46 (d, 1 H), 7 , 28-7.31 (m, 5H), 7.12 (d, 1 H), 6.88 (d, 2H), 6.64 (m, 2H), 2.90 (m, 4H), 2 , 80; Anal Caled, for C2sH20CIN5O3 3.0 H20: C, 56.87; H, 4.96; N, 13.26. Found: C, 56.18; H, 5, 10; N, 13.09. The compounds of Examples 281-287 listed in Table 10 were prepared according to the procedure of Example 276 using the appropriate acylating agent. The bioactivity in the IKK2 resin assay of the compounds of Examples 276-287 is shown in Table 10. Table 10 Example 288 8-. { [(2-chloropyridin-3-yl) carbonyl] amin ^ ^ benzo [g] indazole-3-carboxamide This compound was synthesized in a manner analogous to Example 3 by substituting 4-morpholinylphenylhydrazine hydrochloride and 2-chloronicotinyl chloride; 1 H NMR (DMSO, 400 MHz) d: 10.39 (s, 1H), 8.50 (d, 1 H), 7.94 (d, 1 H), 7.05-7.53 (m, 10H) , 3.74 (m, 4H), 3.18 (m, 4H), 2.92 (m, 4H); Anal. Caled, for C28H25CI 6O3: C, 63.57; H, 4.76; N, 15.89. Found: C, 63.19; H, 4.61; N, 15.48. Cl50 resin IKK-2 < 10 μ ?. EXAMPLE 289 8 - [(2-Chlorobenzoyl) amino] -1-. { 4 - [(1 E) -3-hydroxy-3-methylbut-1-enyl] phenol} -4.5-dihydro-1 H-benzo [g] ndazole-3-carboxamide A 50 ml round bottom flask with a magnetic stir bar was charged with 1- (4-bromophenyl) -8 - [(2-chlorobenzoyl) amino] -4,5-dihydro-1 H -benzo [g] indazole- 3-carboxamide (987 mg, 1.89 mmol), palladium (II) acetate (44 mg, 0.19 mmol), 1,1'-biphenyl-2-yl [di (tert-butyl)] phosphine ( 254 mg, 0.822 mmol) and dimethylformamide (20 mL). The resulting solution was sprayed with argon for 10 minutes. To the solution was added 2-methyl-3-buten-2-ol (823 mg, 6.07 mmol) and triethylamine (614 mg, 6.07 mmol). The solution was sprayed with argon for 2 more minutes. The flask was sealed with a rubber septum and heated to 100 ° C in an oil bath for 90 minutes. The reaction was allowed to cool to room temperature and water was added. The resulting precipitate was collected and purified by chromatography on silica gel (100% hexane to 100% ethyl acetate). The pure fractions were combined, concentrated to dryness, triturated with diethyl ether and dried in vacuo to give 215 mg of 8 - [(2-chlorobenzoyl) amino] -1-. { 4 - [(1 E) -3-hydroxy-3-methylbut-1-enyl] phenyl} -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide (0.408 mmol, 21% yield) as a solid. 1H RN (400 MHz, DMSO-d6) d 1.29 (s, 6 H), 2.88-2.98 (m, 4 H), 4.76 (s, 1 H), 6.48 (d , 1 H), 6.58 (d, 1 H), 7.23 (d, 1 H), 7.30-7.50 (m, 8 H), 7.53-7.59 (m, 3 H), 10.28 (s, 1 H); MS (ESI +) for C30H27CIN4O3 m / z 527 (M + H) +. The compounds of Examples 290-308 listed in Table 11 were prepared according to the procedure of Example 289 using the appropriate alkene. The bioactivity in the IKK2 resin assay of the compounds of Examples 289-308 is shown in Table 11.
Table 11 EXAMPLE 309 8 - [(2-Chlorobenzoyl) amino] -1- (4- {(1 E) -3 - [(2-methoxyethyl) amino] -3-oxoprop-1-enyl} phenyl) -4 , 5-dihydro-1 H-benzo [g] indazole-3-carboxamide To a 50 ml cylindrical syringe equipped with a frit disk was added 2.02 g of PS-MBCHO (Argonaut Technologies, loading 1.46 mmol / g). The resin was washed with?,? - dimethylformamide. To the resin was added a solution of sodium triacetoxyborohydride (3.20 g, 15.1 mmol), disodium in trimethyl orthoformate (1.5 ml), acetic acid (1.5 ml) and N, N-dimethylformamide (12 ml). my). To the mixture was added 2-methoxyethylamine (1.11 g, 14.8 mmol). The mixture was allowed to stir on an orbital shaker for 16 hours. The solution was drained from the resin and washed with a solution of 8 parts of?,? - dimethylformamide per 1 part of trimethyl orthoformate per 1 part of acetic acid. The resin was subsequently washed with N, N-dimethylformamide, 1 part N, N-dimethylformamide per 1 part triethylamine, N, N-dimethylformamide, dichloromethane and diethyl ether. The resin was dried under vacuum. To a 4 ml peptide flask was added 100 mg of the resin.
A solution of HBTU (127 mg, 0.336 mmol), -hydroxybenzotriazole (52 mg, 0.38 mmol), triethylamine (34 mg, 0.34 mmol) and acid (2E) -3- (4-. {3- (aminocarbonyl) -8 - [(2-chlorobenzoyl) amino] -4,5-dihydro-1H-benzo [g] indazol-1-yl}. phenyl) prop-2-enoic (172 mg, 0.335 mmol ) in 2 ml of N, N-dimethylformamide was added to the resin. The peptide flask was agitated on an orbital shaker for 16 hours, after which the solution was drained and the resin was washed with DMF, dichloromethane and diethyl ether. The resin was dried under vacuum. The resin was suspended in 2 ml of 90% aqueous trifluoroacetic acid and stirred for 30 minutes. The solution was filtered. The resin was washed with 2 ml of 90% aqueous trifluoroacetic acid, picking up the washing. The TFA solutions were combined, diluted to 15 ml with water and concentrated to dryness. The resulting oil was triturated with methanol yielding the title compound. MS (ESI +) for C31 H28CIN5O4 m / z 570.2 (M + H) +. The compounds of Examples 310-315 listed in Table 12 were prepared according to the procedure of Example 309 using the appropriate amine. The bioactivity in the IK 2 resin test of the compounds of Examples 309-315 is shown in Table 12. Table 12 EXAMPLE 316 8 ^ [(2-chloropyridin-3-yl) carbonyl] amino} -1- [4- (3-Hydroxypropyl) phenyl] -4,5-chloro-1-H-benzo [g] indazole-3-carboxamide Using conventional hydrogenation conditions 8- [(2-chloropyridin-3-yl) carbonyl] amino was transformed} -1-. { 4 - [(1Z) -3-hydroxyprop-1-enyl] phenol} -4,5-D-Hydro-1 H-benzo [g] ndazole-3-carboxamide in 8-. { [(2-chloropyridin-3-yl) carbonyl] arnino} -1- [4- (3-Hydroxypropyl) phenyl] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide. MS (ESI +) for m / z 502 (M + H) +. CI5o resin IKK-2 < 1 μ ?. Example 317 8 - [(2-Chlorobenzoyl) amino] -1- [4- (3-furyl) phenyl] -4,5-dihydro-1 H -benzo [g] ndazole-3-carboxamide Step 1: A suspension of ethyl 1- (4-bromophenyl) -8-nitro-4,5-dihydro-1H-benzo [g] indazole-3-carboxylate (4.4 g) in THF (80 ml) was treated with NaOH aq. 1 (80 ml) and stirred vigorously overnight. The reaction mixture was diluted with ethyl acetate and acidified to pH = 2 with aq HCl. 1 N. The organic phase was separated and the aqueous fraction was extracted with EtOAc (3x). The combined extracts were washed with brine, dried over Na 2 SO 1, filtered and concentrated in vacuo yielding 4.0 g (97%) of 1- (4-bromophenyl) -8-nitro-4,5-dihydro-1H acid. -benzo [g] indazole-3-carboxylic acid as a solid: MS (ESI +) 414 [M + H] +. 1 H NMR (400 MHz, cy-DMSO) d 8.07 (dd, 1 H), 7.83 (d, 2 H), 7.66 (d, 1 H), 7.56 (d, 2 H), 7 , 42 (d, 1H), 3.10 (m, 2H), 2.99 (m, 2H). Step 2: A suspension of Rink amide resin (5.3g, 2.5 mmol, 0.47 meq / g, NovaBiochem), in 30% piperidine / DMF was prepared in a solid phase reactor equipped with a top stirrer . The mixture was stirred for 15 minutes, filtered and treated a second time with 30% piperidine / DMF for 15 minutes. The solvent was removed by filtration and the resin was washed with DMF (3x), MeOH (3x) and DCM (4x). A solution of 1- (4-bromophenyl) -8-nitro-4,5-dihydro-1H-benzo [g] indazole-3-carboxylic acid (2.07 g) in 1: 1 DCM / DMF (10 ml) ) was prepared and added to the resin, followed by 1M HOBt in DMF (5 mL) and 1M DIC in DMF (5 mL). The resin was stirred at room temperature. After stirring for 16 hours, the resin was washed with DMF (3x), MeOH (3x), DCM (4x) and filtered to yield the charged resin. The loading of the resin was determined by 1 H NMR with direct cleavage: 0.569 mmol / g. Evaporation of the NMR sample with direct excision of the resin gave an oil: MS (ESI +) 413 [M + H] +. 1 H NMR (400 MHz, 10% TFA / CDCl 3): d 8,10 (dd, 1 H), 7.76 (d, 2 H), 7.63 (d, 1 H), 7.53 (d, 1 H ), 7.41 (d, 2H), 3.16 (m, 4H). Step 3: In a solid phase reactor equipped with an overhead stirrer, to a resin suspension of step 2 (7.8 g, 4.43 mmol) in NMP (15 mL) was added 2M SnCl2 in NMP (15 g). my). The mixture was stirred for 1 hour, filtered and re-treated with 2M SnCl2 in NMP (15 mL). After stirring overnight the resin was filtered, washed with DMF (3x), MeOH (3x), DCM (4x), filtered and air dried to yield the intermediate amine resin. The loading of the resin was determined by 1 H NMR with direct cleavage: 0.414 mmol / g. In a solid phase reactor equipped with an overhead stirrer, a suspension of 0.4 g of the amine resin in NMP was prepared. Step 4: The resin was allowed to stir for 5 minutes and was subsequently treated with a solution of 2-chlorobenzoic acid (126 mg) in NMP (1 ml). The mixture was treated with HATU (307 mg), DIEA (0.28 ml) and stirred for 1 hour. The resulting resin was filtered, subjected to a second treatment with 2-chlorobenzoic acid, HATU and DIEA in NMP and allowed to stir. After stirring overnight, the resin was filtered, washed with DMF (3x), MeOH (3x) and DCM (4x). The resin was filtered and dried in the air producing the resin. The loading of the resin was determined by 1 H NMR with direct cleavage: 0.702 mmol / g. Step 5: To a reaction vessel was added resin from step 4 (0.20 g, 0.09 mmol) in a toluene / EtOH (2: 1) suspension. The vessels were purged with argon for 5 minutes and subsequently treated with Pd (PPh3) (41, 6 mg, 0.036 mmol), a 3-furylboric acid (0.2 mmol) and a 2CÜ3 2M (200 μ ?, 0.4 mmol). The vessels were heated to 100 ° C and allowed to stir for 30 hours. Each vessel was quenched with 25% NH4OH for 30 min, filtered and washed three times with DMF, MeOH, MeOH: H20 (1: 1), 0.2 N HCl, MeOH: H20 (1: 1), MeOH and DCM . The resins were allowed to dry and were separated with 10% TFA / DCM (2 mL) for 30 minutes. The resins were washed twice with 0.5 ml of DCM and the combined filtrates were concentrated to produce the desired final product. The compounds of Examples 318-323 listed in the Table 13 were prepared according to the procedure of Example 317 using the appropriate boric acid in step 5. The bioactivity in the IKK2 resin assay of the compounds of Examples 316-323 is shown in Table 13.
Table 13 The compounds of Examples 324-366 of Table 14 were prepared analogously to Example 3 using the appropriate hydrazine and an acylating or sulfonation agent. The bioactivity in the IKK2 resin assay of the compounds of Examples 324-366 is shown in Table 14.
Table 14 EXAMPLE 367 8 - [(2-Chlorobenzoyl) amino] -1- [5- (methysulfonyl) pyridn-2-yl] -4,5-dih dro-1 H-benzo [g] indazole-3-carboxamide Stage 1 To a suspension of 2,5-dibromopyridine (12.0 g, 0.05 mol) in ether was added dropwise "BuLi (32 ml of 1.6 N in hexane, 0.05 mol) at -78 °. C. The purple suspension was stirred for 1 hour and then treated with dimethyl disulfide.The reaction mixture was kept at this temperature for 1 h and a half hour at 0 ° C. The reaction was quenched with a mixture of concentrated HCl and ether. The organic phase was washed with brine, dried over MgSC and filtered The filtrate was concentrated giving 10.3 g of the crude product as a brown oil, which was used without purification, to a solution of this crude product ( 10.0 g, 0.05 mol) in methanol (200 ml) was added a solution of OXONE® in 300 ml of water.The reaction was stirred at room temperature for 72 hours.The solvent was removed and the residue was basified with a 50% NaOH solution The precipitate was collected by filtration, dried in the air to give 8.2 g of product in the form of white crystal (yield). 72% in two stages.) The NMR spectrum was consistent with the proposed structure. Stage 2 A mixture of the product of stage 1 (8.0 g, 0.034 mol) and hydrazine (2.3 g, 0.068 mol) in 100 ml of ethanol was heated to reflux for 2 hours, cooled to room temperature and the solid was collected by filtration, washed with NaHCC > 3 saturated, water, dried in air giving 4.0 g of crude product as a pale white solid (63% yield); The NMR spectrum was consistent with the proposed structure. Stage 3 A mixture of the product from step 2 (1.4 g, 0.007 mol) and ethyl (7-nitro-1, 2,3,4-tetrahydronaphthalen-2-yl) (oxo) acetate (2.03 g, 0.007 mol) in 75 ml of acetic acid was heated to reflux in a nitrogen atmosphere for 3 hours. The solvent was removed and the residue was treated with a mixture of methanol / ethyl acetate / ether to give 1.67 g of the product as a yellow solid (54% yield); 1 HNMR (DMSO, 400 MHz) d: 8.98 (dd, 1H), 8.68 (dd, 1H), 8.21 (d, 1H), 8, 13 (dd, 1H), 7.95 (d , 1H), 7.68 (d, 1H), 4.37 (c, 2H), 3.42 (s, 3H), 3.11 (m, 2H), 3.00 (m, 2H), 1 , 35 (t, 3H); Anal. Caled, for C2oH18N406S: C, 54.29; H, 4.10; N, 12.66; S. 7.23. Found: C, 53.71; H, 4.41; N, 12.56; S, 7.14. Stage 4 The product from step 3 (1.6 g, 0.0036 mol) was hydrogenated on a Parr shaker with 20% Pd (OH) 2 / C in acetic acid for 2 hours at 5 psi (34.48 kPa). After removal of the solvent, the residue was triturated with a mixture of methanol and ether to give 1.0 g of the product as a white solid (67% yield): 1 H NMR (DMSO, 400 MHz) d: 9.01 (dd) , 1 H), 8.62 (dd, 1H), 8.07 (dd, 1H), 7.01 (d, 1 H), 6.46 (dd, 1 H), 6.12 (d, 1H) ), 4.90 (sa, 2H), 4.33 (c, 2H), 3.42 (s, 3H), 2.87 (m, 2H), 2.78 (m, 2H), 1.33 (t, 3H); Anal. Caled, for C20H20N4O4S: C, 58.24; H, 4.89; N, 13.58; S, 7.77. Found: C, 57.70; H, 4.68; N, 13.43; S, 7.60. Stage 5 To a suspension of the product from step 4 (0.95 g, 0.0023 mol) in 25 ml of methanol was added liquid ammonia by a dry ice condenser. The solution was sealed with a septum and stirred at room temperature for 48 hours. The solvent was removed and the solid was triturated with methanol to give 0.68 g of product as a yellow solid (77% yield): 1 H NMR (CDCl 3, 400 MHz) d: 8.99 (d, 1 H), 8, 63 (ddd, 1 H), 8.10 (d, 1H), 7.66 (s, 1 H), 7.43 (s, 1 H), 7.00 (d, 1 H), 6.45 (d, 1 H), 6.22 (s, 1H), 4.89 (s, 2H), 3.41 (s, 3H), 2.86 (m, 2H), 2.74 (m, 2H) ); Anal. Caled, for Ci8Hi7N503S: C, 56.39; H, 4.47; N. 18.27; S, 8.36. Found: C, 55.48; H, 4.29; N, 17.84; S, 8.19. Stage 6 To a suspension of the product from step 5 (0.62 g, 0.0016 mol) in 10 ml of pyridine was added 2-chlorobenzoyl chloride (0.29 g, 0.0016 mol) in one portion and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate) to give 0.6 g of the product as a yellow solid (72% yield); 1 HNMR (DMSO, 400 MHz) d: 10.36 (S, 1H), 9.00 (d, 1H), 8.62 (dd, 1 H), 8.15 (d, 1H), 7.74 ( s, 1 H), 7.39-7.54 (m, 7 H), 7.34 (d, 1 H), 3.32 (s, 3H), 2.93 (m, 4H); Anal. Caled, for C25H20CIN5O4S: C, 57.53; H, 3.86; N, 13.42; S, 6.14. Found: C, 56.69; H, 4.37; N, 12.82; S, 5.86. Cl50 resin IKK-2 < 1 μ ?. Example 368 8 - [(2-Chlorobenzoyl) amino] -1- [6- (methylsulfonyl) pyridin-3-yl] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide Step 1 A mixture of 2-chloro-5-nitropyridine (20.5 g, 0.13 mol) and sodium thiomethoxide (10.9 g, 0.16 mol) in DMS was heated at 100 ° C under a nitrogen atmosphere for 3 hours. hours. It was cooled to room temperature and water was added. The precipitate was collected, dried in air giving 14.5 g of product as a brown solid. To a solution of this solid (16.5 g, 0.097 mol) in 100 ml of acetone was added 170 ml of a 2N sulfuric acid solution. Then, a solution of KMnO_i (20.0 g, 0.126 mol) in 375 ml of water was added dropwise to the above suspension. The reaction mixture was stirred at room temperature overnight and then filtered. The solid was stirred with 400 ml of hot ethanol, then cooled and filtered. The filtrate was concentrated to half the volume and the precipitate was collected and dried in air to give 12.5 g of the desired product as a pale yellow solid, which was used without further purification. The R N and MS were consistent with the proposed structure. Stage 2 A mixture of the product of step 1 (12.3 g, 0.061 mol), iron (6.5 g, 0.11 mol) and 1 ml of acetic acid in 250 ml of water was heated to reflux for 4 hours. It was cooled to room temperature, 400 ml of a saturated solution of NaHCC * 3 was added and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated to give 3.5 g of the crude product as a dark brown solid. To a solution of this raw product in HCI. conc. at -10 ° C a solution of NaN02 was added dropwise. The mixture was stirred at this temperature for 2 hours and then a solution of tin chloride in HCl conc. keeping the temperature below -5 ° C. The reaction was stirred overnight while allowing to warm to room temperature. A solution of NaOH was added to adjust the pH to 9 and filtered through a pad of Celite®. The aqueous phase was extracted with THF and the organic phase was washed with brine, dried over gSO4 and concentrated. The crude product was triturated with methanol giving the hydrazine as a yellow solid. The NMR and MS were consistent with the proposed structure. Stages 3-6 The title compound was synthesized using the same procedure from step 3 to step 6 of example 367 except for the use of the above hydrazine; 1 H NMR (DMSO, 400 MHz) 10.38 (s, 1H), 9.08 (s, 1H),, 1H), 8.41 (d, 1H), 8.25 (d, 1H), 7, 71 (s, 1 H), 7.35-7.53 (m, 8H), 3.28 (s, 3H), 2.96 (m, 4H); Anal. Caled, for C25H2oCI 504S: C, 57.53; H, 3.86; N, 13.42; S, 6.14. Found: C, 56.62; H 4.09; N, 13.09; S, 5.99. Cl50 resin IKK-2 < 1 μ ?. Example 369 8 - [(2-Chlorobenzoyl) amino] -1- (4-cyanophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide 1- (4-Bromophenyl) -8 - [(2-chlorobenzoyl) amino] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide (5.2g) and Zn (CN) 2 ( 0.9 g) in 100 ml of DMF in an atmosphere of N2. Then Pd (Ph3P) 4 (1.38g) was added. The reaction mixture was heated to 100 ° C under N2 for 12 hours. After the end of the reaction according to HPLC, the solvent was evaporated and the residue was suspended in ethyl acetate and water. After filtering and washing with water and ethyl acetate, the filtrate from the organic phase was separated and dried with Na 2 SO 4. After filtration and evaporation of the solvent, the residue was triturated with ether. The solid obtained was filtered and washed with ether, then dried under vacuum. The desired compound (3.4g) was obtained and characterized by 1 H NMR, LC-MS (468, M + 1) and CHN analysis. Cl50 resin IKK-2 <; 1 μ ?. The compounds of Examples 370-380 of Table 15 were prepared by reduction and / or acylation or sulfonation of Example 324 or Example 325 using standard conditions. The bioactivity in the IKK2 resin test of the compounds of Examples 370-380 is shown in Table 15. Table 15 Compound No, Weight Structure. Compound Name (s) MS Clone Molec Example. Resin- (M + H) IKK2 Example 381 1- (6-aminopyridin-3-yl) -8 - [(3-chloroisonicotinoyl) amino] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide Step 1: A 3-neck 100 ml flask was charged (in order) with Cul (300 mg, 1.6 mmol), 1,10-phenanthroline (350 mg, 1.94 mmol) and 25 ml of DMF. A dark cherry-red solution was obtained as a result. To this solution was added (in order) 2-chloro-5-iodopyridine (2.0 g, 8.4 mmol), t-butyl carbamate (1.33 g, 10.1 mmol), 25 mL of DMF and Cs2C03 (4.75 g, 14.6 mmol). A reflux condenser with a nitrogen inlet, a thermometer and a glass stopper was attached to the flask. The suspension was heated at 70 ° C for 3 hours with stirring. The reaction was allowed to cool to room temperature. The crude reaction mixture was poured into 200 ml of water to give an oxide-colored solid. The product was extracted from this aqueous suspension using 2 x 200 ml of diethyl ether. The ether phases were extracted with 200 ml of water, dried over MgSO 4, filtered and then concentrated to give a dark oil. The oil was chromatographed on silica gel (25g) using 20% EtOAc / 80% hexane to give 0.9 g (3.7 mmol, 44%) of product (light yellow oil which slowly solidified). The NMR and MS were consistent with the proposed structure. Step 2: To a mixture of the product from step 1 (6.35 g, 0.023 mol) and (7-nitro-1-oxo-1, 2,3,4-tetrahydronaphthalen-2-yl) (oxo) acetate from Ethyl (6.6 g, 0.023 mol) in 200 ml of ethanol was added with 10 ml of 1 N HCl and the reaction mixture was heated to reflux under a nitrogen atmosphere for 6 hours. After cooling the solution, the precipitate was collected by filtration and dried in the air to give 7.5 g of the product as a yellow crystal (83% yield); 1 HNMR (DMSO, 400 MHz) d: 8.76 (dd, 1 H), 8.22 (dd, 1H), 8.12 (dd, 1 H), 7.85 (dd, 1 H), 7, 71 (d, 1H), 7.44 (d, 1H), 4.35 (c, 2H), 3.14 (m, 2H), 3.03 (m, 2H), 1.33 (t, 3H ); Anal. Caled, for C19H15CIN404. C, 57.22; H, 3.79; N, 14.05; Cl, 8.89. Found. C, 57.03; H, 3.95; N, 13.71; Cl, 9.04.
Step 3: The product of step 2 (7.5 g, 0.019 mol) was hydrogenated on a Parr shaker with 5% Pt / C in acetic acid for 2 hours at 5 psi (34.48 kPa). After removal of the solvent, the residue was triturated with a mixture of methanol and ether to give 6.5 g of the product as a pale yellow solid (94% yield): 1 H NM (DMSO, 400 MHz) d: 8.64 (dd, 1H), 8.09 (dd, 1 H), 7.75 (dd, 1 H), 7.02 (d, 1 H), 6.45 (dd, 1 H), 6.03 ( d, 1 H), 4.99 (sa, 2H), 4.31 (c, 2H), 2.88 (m, 2H), 2.78 (m, 2H), 1.31 (t, 3H); Anal. Caled, for Ci9Hi7CIN402: C, 61.88; H, 4.65; N, 15.19; Cl, 9.61. Found: C, 60.97; H, 5.06; N, 14.65; Cl, 9.50. Step 4: To a mixture of the product of step 3 (0.96 g, 0.0026 mol) and 3-chloroisonicotinic acid (0.65 g, 0.004 mol) in 25 ml of DMF was added 1 ml of diisopropylethylamine, followed by the addition of HATU (1.50 g, 0.004 mol). The reaction was stirred at room temperature for 16 hours and concentrated. The residue was triturated with methanol and acetonitrile to give 1.08 g of product as a pale yellow solid (82% yield); HRMN (DMSO, 400 MHz) d: 10.56 (s, 1 H), 8.76 (s, 1 H), 8.69 (d, 1 H), 8.63 (d, 1 H), 8 , 14 (dd, 1 H), 7.76 (d, 1H), 7.56 (d, 1 H), 7.53 (dd, 1 H), 7.40 (d, 1 H), 7, 26 (d, 1H), 4.32 (c, 2H), 2.97 (s, 4H), 1.31 (t, 3H). Step 5: A sealed reaction vessel containing the product of step 4 (0.8 g, 0.0016 mol) and 10 ml of liquid ammonia in 50 ml of pure alcohol was heated to 120 ° C and 600 psi ( 4137 kPa) for 24 hours. After cooling, the solvent was removed and the residue was triturated with a mixture of methanol and acetonitrile to give 0.38 g of product as a pale yellow solid (52% yield); HRMN (DMSO, 400 MHz) d: 10.57 (s, 1 H), 8.75 (s, 1 H), 8.63 (d, 1 H), 8.02 (d, 1 H), 7 , 47-7.56 (m, 3H), 7.35 (d, 1 H), 7.32 (d, 1 H), 7.27 (s, 1H), 6.54 (d, 1 H) , 6.36 (s, 2H), 2.92 (m, 4H); Anal. Caled, for C23H18CIN702: C, 60.07; H, 3.95; N, 21, 32 Found: C, 59.26; H, 3.99; N, 20.85. Example 382 8 - [(3-Chloroisonicotinoyl) amino] -1-thien-2-yl-4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide Step 1: To a mixture of tere-butyl 1-thien-2-l, 2-hydrazincarboxylate (3.9 g, 0.016 mol, synthesized using the same procedure as in the previous example) and (7-nitro-1-oxo-1) Ethyl 2,3,4-tetrahydronaphthalen-2-yl) (oxo) acetate (4.6 g, 0.016 mol) in 100 ml of ethanol was added with 5 ml of 1N HCl and the reaction mixture was heated to reflux in a nitrogen atmosphere for 6 hours. After cooling the solution, the precipitate was collected by filtration and air dried to give 2.6 g of the product as a brown solid (44% yield). This solid was heated to reflux with 3 eq of tin chloride in ethanol under a nitrogen atmosphere for 3 hours. The solvent was removed and the residue was partitioned between THF and sat. of NaHCO3. The organic phase was washed with brine, dried over gSO 4 and concentrated to give 1.4 g of the crude product as a yellow solid, used without further purification. The S and NMR were consistent with the proposed structure. Step 2: A tightly closed reaction vessel containing the crude product of step 1 (1.3 g, 0.004 mol) and 10 ml of liquid ammonia in 50 ml of pure alcohol was heated to 120 ° C and 600 psi ( 4137 kPa) for 24 hours. After cooling, the solvent was removed and the residue was triturated with a mixture of methanol and acetonitrile to give 1.0 g of product as a pale yellow solid. To a mixture of this solid (0.56 g, 0.0018 mol) and 3-chloroisonthinic acid (0.39 g, 0.0027 mol) in 20 ml of DMF was added 1 ml of dilsopropylethylamine, followed by the addition of HATU (1.03 g, 0.0027 mol). The reaction was stirred at room temperature for 16 hours and concentrated. The residue was triturated with methanol and water to give 0.31 g of product as a pale yellow solid (38% yield); 1 H NMR (DMSO, 400 MHz) d: 10.55 (s, 1 H), 8.75 (s, 1 H), 8.62 (d, 1 H), 7.67 (d, 1H), 7, 62 (s, 1 H), 7.55 (d, 1H), 7.44 (s, 3H), 7.42 (s, 1H), 7.35 (m, 3H), 7.12 (m, 1H), 2.93 (m, 4H); Anal. Caled, for C ^ eCINsOaS: C, 58.73; H, 3.58; N, 15.57. Found: C, 58.26; H, 3.62; N, 15.48. Example 383 8 - [(3-Chloroisonicotinoyl) amino] -1-thien-3-yl-4,5-dihydro-1H-benzo [g] indazole-3-carboxamide This compound was synthesized using the same procedure as previously described in Example 381. 1 HNMR (DMSO, 400 MHz) d: 10.54 (s, 1H), 8.75 (s, 1H), 8.62 (d, 1 H), 7.85 (dd, 1H), 7.75 (dd, 1H), 7.58 (s, 1H), 7.54 (d, 1H), 7.38 (m, 3H), 7 , 31 (s, 1H), 7.28 (dd, 1H), 2.92 (m, 4H); Anal. Caled, for C22H16CI 5O2S: C, 58.73; H, 3.58; N, 15.57. Found: C, 58.65; H, 3.77; N, 15.59. Example 384 1- (4-amino-3,5-difluorophenyl) -8 - [(3-chloroisonicotinoyl) amino] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide Step 1: L-bromo-3,4,5 trifluorobenzene (5 g, 24 mmol) was added to a suspension of Pd (OAc) 2 (0.269 g, 5 mol%), bisdiphenylphosphino-ferrocene (1.0 g, 7 g). mol%) in anhydrous toluene (50 ml) at room temperature. Benzophenone hydrazone (4.9 g) was added, stirred for 5 minutes followed by addition of dry cesium acetate (9.33 g) and toluene (40 ml). The flask was removed from a glove box and heated at 86 ° C for 72 hours. The reaction was controlled by the disappearance of bromotrifluorobenzene by LC (210 nm) or 19 F NMR. The reaction mixture was cooled to room temperature and filtered through a sintered glass funnel. The solvent was removed in vacuo. The orange solid residue was re-dispersed in ether (15 ml) and hexane (150 ml) and heated to 58 ° C, stirred for 20 minutes. The hot solution was filtered rapidly, the solid discarded and the solution allowed to cool to room temperature, stirred for 30 minutes, then 1 hour at 4 ° C. The formed suspension was filtered, washed with cold hexane (2x25 ml). The crystals were air-dried and then under vacuum at 80 ° C for 1 hour giving 5 g of diphenylmethanone (3,4,5-trifluorophenyl) hydrazone (64% yield) as a yellowish solid. Step 2: The product of the step 1 (1.9 g) and (7-nitro-1-oxo-1), 2,3,4-tetrahydronaphthalen-2-yl) (oxo) ethyl acetate (1.66 g) were dispersed in 1M HCl in ethanol (125 ml), heated to reflux and stirred until the starting material disappeared (overnight) The solution was cooled to 4 ° C and stirred for 2 hours. The cold suspension was filtered, the solid was washed with anhydrous ethanol (2x25 ml), dried in the air and in the vacuum oven at 70 ° C for 1 hour to give 1.4 g of 8-nitro-1- (3, 4,5-trifluorophenyl) -4,5-dhydro-1 H -benzo [g] indazole-3-carboxamide as a brown powder (yield 58%). Step 3: The product from step 2 (1.17 g, 0.0028 mol) was hydrogenated on a Parr shaker with 5% Pt / C in acetic acid for 4 h at 5 psi (34.48 kPa). After removal of the solvent, the residue was triturated with a mixture of methanol and ether to give 1.0 g of the product as a pale yellow solid. A sealed reaction vessel containing this solid and 10 ml of liquid ammonia in 50 ml of pure alcohol was heated at 120 ° C and 600 psi (4137 kPa) for 24 hours. After cooling, the solvent was removed and the residue was triturated with a mixture of methanol and acetonitrile to give 0.8 g of 8-amino-1- (4-amino-3,5-difluorophenyl) -4.5- dihydro-1 H-benzo [g] indazole-3-carboxamide as a pale yellow solid (80% yield in two steps); The NMR spectrum was consistent with the proposed structure. Step 4: To a mixture of the product of step 3 (0.75 g, 0.0021 mol) and 3-chloroisonicotinic acid (0.33 g, 0.0023 mol) in 20 ml of DMF was added 1 ml of diisopropylethylamine, followed by the addition of HATU (0.9 g, 0.0023 mol). The reaction was stirred at room temperature for 16 h and concentrated. The crude product was purified by reverse phase HPLC to give 0.15 g of 1- (4-amino-3,5-difluorophenyl) -8 - [(3-chloroisonicotinoyl) amino] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide as a pale white solid (yield 15%); 1HR N (DMSO, 400 MHz) d: 10.56 (s, 1 H), 8.76 (s, 1 H), 8.63 (d, 1 H), 8.56 (s, 1H), 7 , 54 (d, 1 H), 7.49 (dd, 1 H), 7.35 (m, 2H), 7.31 (s, 1H), 6.71 (m, 2H), 5.88 ( s, 2H), 2.92 (m, 4H), Anal. Caled, for C24Hi7FCIN602 + 0.5 H20: C, 57.21; H, 3.60; N, 16.68. Found: C, 56.91; H, 3.70; N, 16.64. Example 385 1- (4-amino-2,5-difluorophenyl) -8 - [(3-chloroisonicotinoyl) aminoH, 5-dihicyl-1 H -benzo [g] indazole-3-carboxamide This compound was synthesized using the same procedure as in Example 384; mp: 289-290 ° C; HRMN (DMSO, 400 Hz) d: 10.55 (s, 1 H), 8.75 (s, 1 H), 8.63 (d, 1 H), 7.57 (d, 1 H), 7 , 55 (s, 1 H), 7.39 (m, 4H), 7.29 (s, 1 H), 6.70 (m, 1 H), 5.90 (sa, 2H), 2.89 (s, 4H); Anal. Caled, for C24H17FCIN602: C, 58.25; H, 3.46; N, 16.98. Found: C, 57.65; H, 3.73; N, 16.82. Other analytical data for the compounds of Examples 381-385 are presented in Table 16.
Table 16 Example 386 8-. { [(2-chloropyridin-3-yl) carbonyl] amino} -1- [4- (3-hydroxyprop-1-ynyl) phenyl] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The following Scheme was used for the synthesis of the title compound of Example 386. SCHEME XXVIII Example 386 To a stirred solution of 8-amino-1- (4-bromophenyl) -, 5-dihydro-1H-benzo [g] indazole-3-carboxamide (2.30 g, 6 mmol) and tert-butyldimethyl - (2-propynyl-oxy) silane (1.12 g, 6.6 mmol) in DMF-triethylamine (6 ml-6 ml) was added Cul (114 mg, 0.6 mmol) and tetrakis (triphenylphosphine) palladium (346 mg, 0.3 mmol) and the resulting mixture was heated at 100 ° C for 14 h before cooling to room temperature. The mixture was filtered through a pad of silica gel, washed with EtOAc and concentrated. The crude material was taken up in pyridine (20 ml), treated with 2-chloronicotinyl chloride (1.23 g, 7 mmol) at room temperature for 14 hours. Tetrabutylammonium fluoride (25 ml of a 1 M solution in THF, 25 mmol) was added at room temperature and stirred overnight. Aqueous ammonium chloride was added, the mixture was extracted with EtOAc (5x30 ml). The organic portions were combined, dried over MgSO4, filtered and separated on a column of silica gel (EtOAc). This gave 8 - ([(2-chloropyridin-3-yl) carbonyl] amino) -1- [4- (3-hydroxyprop-1-ynyl) phenyl] -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide as a pale yellow solid (1.19 g, 40% in 3 steps). The H NMR was consistent with its structure. EXAMPLE 387 8 - ([(2-chloropyridin-3-yl) carbonyl] amino.} -1- [4- (5-hydroxypent-1-ynyl) phenyl] -4,5-dihydro-H-benzo [g ] indazole-3-carboxamide The compound was prepared in a manner similar to Example 386. The NMR was consistent with its structure. Example 388 8-. { [(2-chloropyridin-3-yl) carbonyl] amino} -1- (4-ethynylphenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide To a stirred solution of 8-amino-1- (4-bromophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide (5.74 g, 15 mmol) and fer-butyldimethylsilylacetylene (2). , 31 g, 16.5 mmol) in DMF-triethylamine (20 ml-10 ml) was added Cul (285 mg, 1.5 mmol) and tetrakis (triphenylphosphine) palladium (870 mg, 0.75 mmol) and the The resulting mixture was heated at 100 ° C for 14 h before cooling to room temperature. The mixture was filtered through a pad of silica gel, washed with EtOAc and concentrated. The crude material was taken up in pyridine (30 ml), treated with 2-chloronicotinyl chloride (2.90 g, 16.5 mmol) at room temperature for 14 hours. Tetrabutylammonium fluoride (25 mL of a 1M solution in THF, 25 mmol) was added at room temperature and stirred overnight. Aqueous ammonium chloride was added, the mixture was extracted with EtOAc (5x30 mL). The organic portions were combined, dried over MgSO4, filtered and separated on a column of silica gel (EtOAc). This gave the product as a pale yellow solid (3.5 g, 49% in 3 steps). The 1 H NMR was consistent with its structure. CNH calculated for C26Hi8N502CI (H20) 1, 3: C (63.5%), H (4.2%), N (14.3%) Found: C (63.6%), H (4.0 %), N (14.3%). Example 389 8-. { [(2-chloropyridin-3-yl) carbonyl] amino} -1- (4-vinylphenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide A solution of 8-. { [(2-chloropyridin-3-yl) carbonyl] amino} -1- (4-ethynylphenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide (557 mg, 1.19 mmol) in DMF-DMSO (20 mL - 1 mL) was treated room temperature with H2 (5 psi (34.48 kPa)) and Pd-CaS04 (5%, 100 mg) for 12 minutes. The mixture was filtered through a pad of celite, concentrated and water added. The solid product was collected by filtration, washed with water and ether and dried to give the product (262 mg, 47%). The 1H NMR was consistent with its structure. Example 390 1- (4-acetylphenyl) -8-. { [(2-chloropyridin-3-yl) carbonyl] amino} -4,5-dihydro-1l-l-benzo [g] indazol-3-carboxamide A mixture of 8-. { [(2-chloropyridin-3-yl) carbonyl] amino} -1- (4-ethynylphenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide (442 mg, 1.2 mmol), water (65 mg, 3.6 mmol) and triflic acid ( 270 mg, 1.8 mmol) in dioxane (10 mL) was heated at 100 ° C for 18 hours. The mixture was cooled to room temperature, aqueous NaHCO 3 was added and filtered. The product was washed with water and ether and dried. This gave the product (293 mg, 67%). The 1H NMR was consistent with its structure. Example 391 8-. { [(2-doropyridin-3-yl) carbonyl] amino) -1- [4- (1-hydroxyethyl) phenyl] -4,5-dihydro-1H-benzo [g] ndazole-3-carboxamide To a mixture of 1- (4-acetylphenyl) -8-. { [(2-chloropyridin-3-yl) carbonyl] amino} -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide (200 mg, 0.41 mmol) in MeOH (3 mL) and water (0.3 mL) was added NaBH 4 (10 mg, 0.25 mmol) at room temperature and stirred for 14 hours. The mixture was separated on a column of silica gel (EtOAc) to give the product (100 mg, 50%). The 1H NMR was consistent with its structure. Other analytical data of the compounds of Examples 386-391 are presented in Table 17. Table 17 Example 392 8-. { [5- (acetylamino) -2-chlorobenzoyl] amin ^ 1 H -benzo [g] indazole-3-carboxamide Stage 1 To a stirred solution of NaOH (11.26 g, 281.6 mmol) in water (500 mL) was added dropwise a solution of 4-fluorothiophenol (25 mL, 234.6 mmol) in methanol (50 mL). ). After 15 minutes ethyl bromide (14.4 ml, 281.6 mmol) was added. After 6 hours more NaOH (1 g) was added and the reaction mixture was extracted with ether (3 X 300 mL). The combined organic extracts were treated with brine followed by MgSO4 then concentrated to give 1- (ethylthio) -4-fluorobenzene (29 g, 80%) as a liquid with a slightly yellow color. Stage 2 To a solution of the crude product from Step 1 in CH2Cl2 (500 mL) was added m-CPBA (82 g of 77% max powder, 368 mmol) in portions with vigorous stirring. After 5 hours, the reaction mixture was concentrated and ethyl acetate (750 ml) was added. The organic phase was subsequently washed with 4% aqueous NaOH (2 X 100 mL), water (100 mL), then brine (75 mL) and finally dried over gSO4. The solution was concentrated yielding a white solid (17.9 g) which was used in the next step without purification. Stage 3 The crude product from Step 2 was dissolved in ethanol (200 ml) and hydrazine (24 ml, 758 mmol) was added. The reaction mixture was heated to reflux for 6 hours and then left at room temperature overnight. The ethanol was concentrated to a smaller volume and then water was added. A white precipitate formed and was collected (12.87 g, 68%). The desired compound (1- [4- (ethylsulfonyl) phenyl] hydrazine) was used in the next step without purification. Stage 4 The title compound was prepared analogously to Example 3 using 1- [4- (ethylsulfonyl) phenyl] hydrazine and the appropriate acylating agent. The desired product crystallizes in the reaction medium in an 81% yield. Anal. Calculated for C29H26CIN5O5S (MW = 591.13): C, 58.83; H, 4.43; N, 11, 83. Found: C, 58.69; H, 4.46; N, 12.16. Example 393 8 - [(2-Chlorobenzoyl) amino] -1- [4- (isopropylsulfonyl) phenyl] -4,5-dihydro-1 H -benzo [g] ndazole-3-carboxamide Stage 1 Into a round bottom 250 ml flask was added KH (35% by weight in mineral oil) (1.64 g, 14.35 mmol). The solid was washed with hexane (2 X 10 mL) in a nitrogen atmosphere. THF (50 mL) was added and the suspension was cooled to 0 ° C. Iodomethane (0.89 mL, 14.35 mmol) was added followed by a solution of 4-fluorophenylmethylsulfone (1.25 g, 7.17 mmol) in THF (10 mL). The reaction mixture was stirred at 0 ° C for 1 hour then allowed to warm to room temperature overnight. A mixture of ethyl and isopropyl sulfone was observed, so that LiHMDS (7.2 ml, 14.35 mmol) and iodomethane (0.45 ml, 14.35 mmol) were added thereto. After 2.5 hours water was added to the reaction mixture and the aqueous phase was extracted with ether (3 X 150 mL). The combined organic extracts were treated with brine and dried over gS04. The ether solution was concentrated to give the desired compound as a yellow solid. The crude material was used in the next step without further purification. Stage 2 The product of Step 1 (640 mg, 3.15 mmol) was dissolved in pure ethanol (12 mL), the system was purged with N2 and hydrazine (404 mg, 12.6 mmol) was added and the reaction was heated to reflux overnight. HPLC showed 78% product and 21% starting material. To complete the reaction, 2 more equivalents of hydrazine were added and the reaction was heated to reflux for a further 5 hours, at this time HPLC indicated 95% product. The reaction mixture was concentrated and the residue was stirred with water. A white solid was isolated, 390 mg (58%). HPLC indicated 86% product and 14% starting material. The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The organic phase was dried over MgSO4 and concentrated in a yield of 258 mg (38%) of 1- [4- (isopropylsulfonyl) phenyl] hydrazine with 99% purity. MH + = 215. The 390 mg were re-dissolved in 10 ml of ethanol and treated again with more hydrazine obtaining more product with the desired purity. Stage 3 The title compound was prepared analogously to Example 3 using 1- [4- (isopropyl sulfonyl) phenyl] hydrazine and the appropriate acylating agent. The desired compound was recovered in 86% yield. HPLC indicated that the compound had a purity of 94%. Anal. Calculated for C28H2sCIN404S + 1H20 (MW = 550.05): C, 61, 05; H, 4.61; N, 10.17. Found: C, 60.67; H, 4.44; N, 10.14. Example 394 Hydrochloride of 1 -. { 4 - [(3-aminopropyl) sulfonyl] phenyl} -8-. { [(2-chloropyridin-3-yl) carbonyl] amino} -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide Stage 1 Bf '^^ s HBoc Hydrogen-3-bromopropylamino bromide commercially available (10 g, 45.7 mmol) was suspended in CH2Cl2 (125 mL). Triethylamine (10 mL, 98 mmol) was added followed by (Boc) 20 (11 g, 50 mmol) as a solid. After stirring overnight at room temperature the reaction mixture was diluted with CH2Cl2 (100 mL). The organic phase was washed with 1M HCl (100 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL), then dried over MgSO4. Evaporation under reduced pressure afforded the desired compound as a slightly yellow liquid. (10.55g, 97%) and no purification was necessary. Stage 2 BocHN To a stirred solution of NaOH (624 mg, 15.6 mmol) in water (20 ml) was added dropwise a solution of 4-fluorobenzenethiol (2 g, 15.6 mmol) in methanol (5 ml) at room temperature. After 30 minutes a solution of the product of Step 2 (3.71 g, 15.6 mmol) in methanol (5 ml) was added dropwise and the reaction mixture was allowed to stir at room temperature overnight. Ether (450 ml) was added and the aqueous phase was separated. The organic phase was subsequently washed successively with 1 N NaOH (75 ml), concentrated aqueous NH 4 Cl (75 ml) and brine (50 ml). The solution was dried over MgSO4 and concentrated to give the desired compound as a colorless liquid (3.2 g, 72%). The compound was used in the next step without further purification. Stage 3 BocHN To a stirring solution of the product of Step 2 (3.2 g, 11.2 mmol) in CH2Cl2 (150 mL) was added m-CPBA (77% max powder) (9.56 g, mmol) in portions at room temperature. The reaction was left overnight, then concentrated and ethyl acetate (750 ml) was added. The organic phase was subsequently washed with 4% aqueous NaOH (2 X 100 mL), water (100 mL), then brine (75 mL) and finally dried over MgSO4. The solution was concentrated to yield a white solid which was used in the next step without purification. Stage 4 All crude material from step 3 was dissolved in ethanol (30 ml) and hydrazine (2.4 ml, 75 mmol) was added. The reaction mixture was heated to reflux overnight then concentrated to a volume of 5 ml and added to water. The resulting precipitate was collected yielding tere-butyl 3 - [(4-hydrazinophenyl) sulfonyl] propylcarbamate as a white solid (1.88 g, 51%). The compound was used in the next step without further purification. Stage 5 The title compound was prepared analogously to Example 3 using tere-butyl 3 - [(4-hydrazinophenyl) sulfonyl] propylcarbamate and the appropriate acylating agent. The title compound was isolated as chestnut HCl salt after conventional Boc deprotection using 4N HCl in dioxane. The compounds of Examples ^ 395-409 of Table 18 were prepared analogously to Examples 392, 393 and 394 using the appropriate hydrazine and acylating agent. The bioactivity in the IKK2 resin assay of the compounds of Examples 392-409 is shown in Table 18. Table 18 EXAMPLE 410 8 - [(2-Dorobenzoyl) amino] -1- [4- (methylthio) phenyl] -4,5-dihicyl-1 H-benzo [g] indazole-3-carboxamide Stage 1 4-Methylthiol-aniline (10.0 g, 7.2 mmol) was suspended in 6N HCl (50 mL). The solution was cooled to 0 ° C and sodium nitrite (5.26 g, 7.6 mmol) dissolved in water (20 ml) was added dropwise maintaining the temperature at 0 ° C. When the addition is complete, the reaction mixture is homogeneous and has changed from a dark brown to an orange co After stirring this for one hour, SnCb ^ HbO (42.5 g, 18.8 mmol) dissolved in conc. HCl was added. (35 ml) to the cold solution for a period of 15 minutes. The reaction was allowed to stir for 2 hours allowing the temperature to reach room temperature. The white solid was filtered and suspended in a mixture of water and ice (300 ml). A 50% NaOH solution was added until the reaction mixture becomes basic (pH ~ 12). Any undissolved solid was removed by filtration and the aqueous phase was extracted with ethyl ether (3 x 300 mL). The organic phase was dried over MgSO4 and concentrated to a yellow solid (7.8 g, yield 71%). HPLC analysis indicated that the product is 64% pure and has +1 = 155 (the other impurity was the starting material); 1 H NMR (CDCl 3) d 2.44 (s, 3 H), 6.78 (m, 2 H), 7.23 (m, 2 H). Stage 2 The title compound was prepared analogously to Example 3 using 1- [4-methylsulfonyl) phenyl] hydrazine and the appropriate acylating agent.
The compounds of Examples 411-414 of Table 19 were prepared analogously to Example 410 using the appropriate acylating agent. The bioactivity in the IK 2 resin test of the compounds of Examples 410-414 is shown in Table 19. Table 19 Compound No., Structure Weight Name Compound Cl MS MS Example Molec. Resin- (+ H) KK2 'O 489.00 8-1 (2-1 = 10 489 410 chbenzoyl) amine] -1 - μ? [4- (methylthio) phenyl] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide 428.54 8 - [(methylsulfonyl) amino] - < 1 μ? 429 411", 1- [4- (methylthio) phenyl] -4,5-dihydro-1H-benzo [g] ndazole-3-carboxamide 526.45 Hydrochde of 8 - [(3- <1 μ? 490 412 na chisoncarcinyl) amino] -1- [4- (methylthio) phenyl] -hydro-1H-benzo [g] indazole-3-carboxamide The compounds of Examples 415-420 of Table 20 were prepared by oxidation with m-CPBA with the appropriate sulfide. The bioactivity in the IKK2 resin assay of the compounds of Examples 415-420 is shown in Table 20. Table 20 Example 421 1-. { 4 - [(allylamino) sulfonyl] phenyl} -8 - [(2-chbenzoyl) amino] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide To a stirred solution of 1- [4- (aminosulfonyl) phenyl] -8 - [(2-chbenzoyl) amino] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide (2967 mg, , 7 mmol) in THF (120 mL) was added DMAP (348 mg, 2.8 mmol), then triethylamine (0.95 mL, 6.8 mmol), followed by acetic anhydride (1.62 mL, 17%). 1 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated. To the residue was added 5% aqueous NaHCO3 (100 mL). All the compounds were dissolved. The aqueous phase was washed with EA (100 ml x 2), CH 2 Cl 2 (100 ml).
The aqueous phase was separated. To the aqueous phase, 1 N HCl was added until pH = 6. A white precipitate formed. It was filtered and washed with ether to give a white solid. The solid was dried under reduced pressure at 45 ° C giving 1-. { 4 - [(acetylamino) sulfonyl] phenyl} -8 - [(2-chbenzoyl) amino] -4l5-dihydro-1 H -benzo [g] indazole-3-carboxamide (2255.4 mg, 70%). Stage 2 To a stirred solution of 1-. { 4 - [(acetylamino) sulfonyl] phenyl} -8 - [(2-Chbenzoyl) amino] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide (563 mg, 1 mmol) in H20 (5 mL) was added cesium carbonate (163 mg, 0.5 mmol). The suspension was stirred at room temperature overnight. All the compounds were dissolved dried to give the salt Cs + (650 mg, 93%). Stage 3 To a stirred solution of the Cs + salt of 1-4 - [(acetylamino) sulfonyl] phenyl} -8 - [(2-Chbenzoyl) amino] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide (637 mg, 0.92 mmol) in DMF (8 mL) was added a solution of allyl bromide (111 mg, 0.92 mmol). The solution was stirred at room temperature over a weekend and concentrated. MeOH-1-kO (2: 1) was added to the mixture. A precipitate formed. It was filtered giving a yellow solid of 1- (4- [acetyl (allyl) amino] sulfonyl) phenyl) -8 - [(2-chbenzoyl) amino] -4,5-dihydro-1H-benzo [g] indazol-3 -carboxamide (360 mg, 65%) Stage 4 A solid of 1- (4- { [Acetyl (allyl) amino] sulfonyl) phenyl) -8 - [(2-chlorobenzoyl) amino] -4,5-dihydro-1 H -benzo [g] indazol-3 -carboxamide (360 mg, 0.6 mmol) was dissolved in a 0.5N solution of NaOH in EtOH (10 mL) and stirred at room temperature overnight. The mixture was concentrated. Purified by HPLC to give the desired compound (210 mg, 62%.) Cl50 resin IKK-2 < 1 μ. Example 422 8 - [(2-Chlorobenzoyl) amino] -1-. { 4 - [(methylamino) sulfonyl] phenyl} -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide Stage 1 To a stirred solution of 1-. { 4 - [(acetylamino) sulfonyl] phenyl} -8 - [(2-Chlorobenzoyl) amino] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide (563 mg, 1 mmol) in DMF (20 ml) was added Nahb (40 mg, 1 mmol). The mixture was stirred at room temperature for 1 hour. A solution of iodomethane (170.3 mg, 1.2 mmol) in DMF (1 mL) was added to the mixture. The solution was stirred at room temperature for 4 hours and concentrated. Purified by HPLC to give a solid of the desired compound 1- (4- {[[acetyl (methyl) amino] sulfonyl} phenyl) -8 - [(2-chlorobenzoyl) amino] -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide (155 mg, 27%.) Step 2 A solid of 1- (4. {[[Acetyl (methyl) amino] sulfonyl] phenyl) -8 - [(2-chlorobenzoyl) amino] -4,5-dihydro-1H-benzo [g] indazole- 3-carboxamide was dissolved in a 0.5N solution of NaOH in EtOH (3 mL) and stirred at room temperature for 2 hours. A suspension formed. It was filtered and washed to give the desired compound (29 mg, 53%.) CI5o resin IKK-2 < 1 μ ?. The compounds of Examples 423-433 of Table 21 were prepared analogously to Example 46 using the appropriate alkylating agent and, if appropriate, the acylating or sulfonation agent. Table 21 Compound No. Structure Weight Name Compound IC50 Resin MS Example Molec. IKK (M + H) 435.51 8-amino-1- [4- (2,5-1 <10 μ? 436 423 c 0 dihydro-1 H-pyrrol-1-ylsulfonyl) phenyl] -4.5 - dihydro-1 H-benzo [g] indazol-3-carboxamide The following scheme was used for the synthesis of the EXAMPLE XXIX EXAMPLE 434 1- (1,3-Benzodolox-5-yl) -8 ^ [(2-chloropyridin-3-yl) carbonyl] amino) -5,5-dimethyl-5-dihydro- 1 H-benzo [g] indazole-3-carboxamide Step 1: 4,4-Dimethyl tetralone (6g) was suspended in 120 ml of conc. H2SO4. to 0 ° C, then a solution of KN03 (3.8g) / H2SO4 (15ml) was added dropwise at 0 ° C. The reaction mixture was stirred at 0 ° C for three hours until the starting material disappeared, then poured into about 100 g of ice. After cooling, the mixture was filtered and the solid obtained washed with water, hexane and then dried under vacuum. 5.6 g of the desired product were obtained. It was used like this without further purification. Its structure was confirmed by LC-S (220, M + 1), HPLC, 1HRMN. Step 2 The title compound of Step 1 (5.6g) was dissolved in 100 ml of THF, then (COOEt) 2 (5.6g) was added. The mixture was cooled to -40 ° C and then a solution of LiHMDS / THF 1 (40ml) was slowly added.
The reaction mixture was slowly warmed to room temperature, then stirred overnight and then neutralized with aq. 2N. The mixture was extracted with EA (3x200ml). The EA solution was dried over NajSCy After filtration and evaporation of the solvent, the residue was purified by HPLC (50% CH3CN to 90% CH3CN in 30 minutes). 1.3 g of the desired product were obtained. The structure was confirmed by LC-MS (320, M + 1) and HPLC. Step 3 The title compound of Step 2 (1.3g) and 3,4-methylenedioxyphenylhydrazine hydrochloride (0.85g) were suspended in 100 ml of HOAc. The mixture was heated to reflux for 3 hours and then the solvent was evaporated and the residue was purified by HPLC (50% CH3CN / H2O to 90% CH3CN / H2O in 30 minutes). 0.65 g of the desired product was obtained and characterized by LC-MS analysis (436, M + 1), 1 H NMR, HPLC. Step 4 The title compound of Step 3 (0.65g) was suspended in 100 ml of EtOH and then added with SnCl2 (1.2g). The reaction mixture was heated to reflux overnight. Then the solvent was evaporated and the residue was dissolved in 15 ml of CH 3 CN and filtered. The solution was purified by HPLC (40% CH3CN / H2O to 90% CH3CN / H20 in 30 minutes). 0 were obtained, 25g of the desired product and was characterized by HPLC and LC-MS (406, M + 1). Step 5 The title compound of Step 4 (0.25g) was dissolved in EtOH and liquid ammonia and heated at 100 ° C with a pressure of 600 psi (4137 kPa) for 36 hours. After releasing the pressure and evaporating the solvent, the residue is purified by HPLC (5% CH3CN / H20 to 60% CH3CN / H20 in 30 minutes). 200 mg of desired product were obtained and characterized by LC-MS (376, M + 1) and HPLC analysis. Step 6 The title compound of Step 5 (90 mg) was dissolved in pyridine (5 ml), then 2-chloro-nicotinoyl chloride (52 mg) was added. The reaction mixture was stirred overnight and then the solvent was evaporated. The residue was purified by HPLC (30% CH3CN / H2O to 90% CH3CN / H20 in 30 minutes). 49 mg of the desired compound 1- (1,3-benzodioxol-5-yl) -8- were obtained. { [(2-chloropyridin-3-yl) carbonyl] amino} -5,5-dimethyl-4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The resulting compound was obtained and analyzed by 1 H NMR analysis, LC-MS (516, M + 1), HPLC and CHN. Example 435 1- (1,3-benzodioxol-5-yl) -8 - [(3-chloroisonicotinoyl) amino] -5,5-dimethyl-4,5-dihydro-1 H -benzo [g] indazol-3 carboxamide The title compound of Example 332 (90mg) was dissolved in 5ml of DMF, then 2-chloroisonicotinic acid (100mg), HATU (150mg) and diisopropylethylamine (0.5 ml) were added. The reaction mixture was stirred at room temperature for two days. After completion of the reaction, the solvent was evaporated and the residue was purified by HPLC (30% CH3CN / H2O to 90% CH3CN / H2O in 30 minutes). 100mg of product was obtained and characterized by 1HR N, LC-MS (516, M + 1), HPLC, CHN analysis. The compounds of Examples 436-443 of Table 22 were prepared analogously to Examples 434 and 435. The bioactivity in the IKK2 resin assay of the compounds of Examples 434-443 is shown in Table 22.
Table 22 nd = not determined Example 444 1- (1,3-benzodioxol-5-yl) -8 - [(N-isopropylglycyl) amino] -4,5-dihydro-1 H- benzo [g] indazole-3-carboxamide Step 1 To a solution of 8-amino-1- (1,3-benzodioxol-5-yl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide (1.00 g, 2.87 mmol) ) in DMA (5.0 mL) was added chloroacetyl chloride (0.27 mL, 3.44 mmol) and triethylamine (0.48 mL, 3.44 mmol) and the mixture was stirred at room temperature overnight . The reaction mixture was triturated with distilled water (3x40 ml) and the solid product precipitated once the water was added. The mixture was filtered and the solid was dried in vacuo overnight to give 8 - [(chloroacetyl) amino] -1- (4-phlorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide . MS (ESI +) for CziH ^ CI ^ m / z 425 (M + H) +. Step 2 To a solution of product from step 1 (0.10 g, 0.24 mmol) dissolved in DMA (2.0 ml) was added isopropylamine (3.0 eq) followed by the PS-DIEA resin (2). , 0 eq). The mixture was stirred and heated at 100 ° C overnight. The reaction mixture was cooled to room temperature and the solution was filtered. The filtrate was subsequently evaporated in a stream of nitrogen overnight. The sample was purified on the silica SPE column. The clean fractions were combined and concentrated giving the title material. 1 H NMR (CD 3 OD) d 7.38 (dd, 1 H), 7.28 (d, 1 H), 7.18 (d, 1 H), 7.0 (t, 1 H), 6.96 ( d, 2H), 6.12 (s, 2H), 3.29 (s, 2H), 3.04 (m, 2H), 2.95 (m, 2H), 2.79 (m, 1 H) , 1.08 (d, 6H); MS (ESI +) for C24H25N504 miz 448 (M + H) + The compounds of Examples 445-452 listed in the table below were prepared according to the procedure of Example 444 using the appropriately substituted aniline and the appropriate amine.
The bioactivity in the IK 2 resin test of the compounds of Examples 444-452 is shown in Table 23 Table 23 Example 453 8-. { [5-Chloro-2- (4-methyl-piperazin-1-yl) isonicotinoyl] amino} -1- [4- (Methylsulfonyl) phenyl] -4,5-dihydro-1 H-benzo [g] ndazole-3-carboxamide Stage 1 8 - [(2,5-dichloroisonicotinoyl ) amino] -1- [4- (methylsulfonyl) phenyl] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide The product of Example 92 (8-amino-1 - [4- (methylsulfonyl) phenyl] -4,5-d, hr-1-H-benzo [g] ndazole-3-carboxamide hydrochloride) ( 1.20 mmol), 2,5-dichloroisonicotinic acid (1.83 mmol), HATU (1.83 mmol) and 0.7 ml of triethylamine were dissolved in 10 ml of D F. The mixture was stirred at room temperature for one night before adding more triethylamine (0.4 ml), HATU (1.29 mmol) and 2,5-dichloroisonicotinic acid (2.24 mmol) to complete the reaction. After another 2.5 hours, the mixture was added to water, forming a precipitate, which was filtered and washed with water. After trituration with water, the product was dissolved in tetrahydrofuran, decolorized with activated carbon, dried over MgSO4 and the solvent was removed. The solid was dissolved in anhydrous acetonitrile, filtered and the acetonitrile was removed. The residue was purified by recrystallizations from pure ethanol followed by triturations with anhydrous acetonitrile. Mp: 215-222 ° C. Mass Spectrum: M + 1 = 556. 1 H NMR (d, d ^ DMSO, 400 MHz): 2.87-2.98 (m, 4H); 3.18 (s, 3H); 7.29-7.38 (m, 4H) 7.60 (s, 1 H) 7.76 (s, 1 H); 7.80-7.85 (m, 2H); 8.06-8, 11 (m, 2H); 8.58 (s, 1 H); 10.56 (s, 1 H). Stage 2 8-. { [5-Chloro-2- (4-methyl-piperazin-1-yl) isonicotinoyl] amino} -1- [4- (rethylsulfoni phenyl ^ .S-dihydro-I H-benzolglindazole-S-carboxarnide The product of Step 1 (0.92 mmol) and N-methylpiperazine (9.0 mmol) were combined with 2.6 mL of DMA. The reaction mixture was introduced under a nitrogen atmosphere and stirred in an oil bath at 100 ° C for 15 hours. The mixture was subsequently added to water, forming a precipitate, which was filtered and washed with water. The solid was dissolved in acetonitrile, dried over MgSC and the solvent was distilled. Mass Spectrum: M + 1 = 620. Example 454 1- (1,3-Benzodioxol-5-yl) -8-. { [(6-chloro-4-methylpyridin-3-yl) carbonyl] amino} -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide The product of Example 161, Step 4 (5.93 mmol), 6-chloro-4-methylnicotinic acid (Example 246, Step 1) (8.91 mmol), HATU (8.73 mmol) and 3.0 ml of triethylamine were dissolved in 30 ml of DMF. The mixture was stirred at room temperature for 5.4 hours. Then, the solvent was partially distilled and the residue was suspended in water, filtered and washed with water. The solid was dissolved in tetrahydrofuran, decolorized with activated carbon, dried over MgSO4 and the solvent was distilled. The product was purified by recrystallizations from tetrahydrofuran and trituration in ethanol / water. Mp: 303 ° C (decomp). Mass Spectrum: M + 1 = 502.1H NMR (d, ck-DMSO, 400 MHz): 2.28 (s, 3H); 2.81-2.96 (m, 4H); 6.06 (s, 2H); 6.90-6.94 (m, 1H); 6.97-7.01 (m, 1H); 7.08 (d, 1 H, J = 2.0 Hz) 7.20-7.39 (m, 4H) 7.45-7.49 (m, 2H); 8.34 (s, 1 H); 10.30 (s, 1H) Examples 455, 456 and 457 were synthesized with the following general synthetic procedure, illustrated for Example 455: Example 455 8- ( { [6- (Aminomethyl) -3-chloropyridin-2-yl] carbonyl}. Amino) -1- (1,3-benzodioxol-5-yl) -4,5-di hydro-1H-benzo [g] indazole-3-carboxamide Step 1 1- (1,3-Benzodioxol-5-yl) -8-. { [(3-chloro-6-cyanopyridin-2-yl) carbonyl] amino) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The product of Example 216 (1- (1,3-benzodioxol-5-yl) -8-. {[[(3,6-dichloropyridin-2-yl) carbonyl] amino.} -4,5-dihydro- 1 H-benzo [g] indazole-3-carboxamide) (1.045 g, 2 mmol), Zn (CN) 2 (0.138 g, 1.2 mmol), Pd2 (dba) 3 (0.0904 g, 0 , 1 mmol) (dba = dibenzylidenacetone) and dppf (dppf = bs [diphenylphosphino] pheirocene) (0.121 g, 0.22 mmol) were mixed in a flask containing a stir bar. The mixture was placed under vacuum and then nitrogen three times to remove oxygen. Degassed anhydrous solvents (9 ml of DMF and 3 ml of benzonitrile) were added under an atmosphere of N2 and the flask was placed in an oil bath at 90 ° C for 6 hours. After 6 hours, the solvent was removed in vacuo, 50 ml of ether was added and the mixture was stirred for 3 hours. The ether was removed by filtration and the solid was triturated with 50 ml of water for 3 hours, dried and purified by HPLC. The title compound is a yellow solid (0.234 g, 23%). 1 H NMR (oVDMSO): d 2.82-3.01 (m, 4H), 6.09 (s, 2H), 6.97-7.07 (m, 2H), 7, 14 (d, 1 H , J = 3 Hz), 7.27 (s, 1H), 7.33-7.40 (m, 3H), 7.52 (s, 1 H), 8.21 (d, 1 H, J = 8 Hz), 8.39 (d, 1 H, J = 8 Hz), 10.60 (s, 1H). ESI mass spectrum for C26HIBCIN60 +: 513 (M + 1). Step 2 8- ( { [6- (Aminomethyl) -3-chloropyridin-2-yl] carbonyl}. Amino) -1- (1,3-benzodioxol-5-yl) -4,5-dihydro- 1 H-benzo [g] indazole-3-carboxamide The product of Step 1 (0.24 g, 0.47 mmol) was dissolved in a mixture of anhydrous solvents, containing glyme (3 mL), methanol (9 mL) and a 1.2 M solution of HCl in methanol ( 3 mi). The mixture was introduced under an atmosphere of N2 in a Fisher-Potter vessel containing a magnetic stirring bar and 0.02 g of 5% Pd / C catalyst (Degussa-Frankfurt, Germany). Previously, the catalyst was dried and pre-activated (H2, 50 psi (344.75 kPa), 30 minutes). The hydrogenation was carried out at a pressure of 3 psi (20.69 kPa) for 3 hours at room temperature. The catalyst was removed by filtration and the filtrate was purified by HPLC to give 0.152 g of the TFA salt of 8- ( { [6- (Aminomethyl) -3-chloropyridin-2-yl] carbonyl} amino) -1. - (1,3-benzodolox-5-yl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, which was ground in a water-triethylamine mixture (2: 1) ) for 30 minutes. The title compound (0, 12 g, 49%) was obtained as a free base (a white solid) after filtration and drying. 1 H NMR (rfe-DMSO): d 2.03 (s, 2H), 2.82-3.00 (m, 4H)), 3.80 (s, 2H), 6.09 (s, 2H), 6.92-7.03 (m, 2H), 7.15 (d, 1H, J = 2 Hz), 7.25 (s, 1 H), 7.28-7.44 (m, 3H), 7.49 (s, 1 H), 7.58 (d, 1 H, J = 8.5 Hz), 7.96 (d, 1H, J = 8.5 Hz), 10.40 (s, 1 H). ESI mass spectrum for C26H22CIN604 +: 517 (M + 1). Example 456 8-. { [2- (Aminomethyl) -5-chloroisonicotinoyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide Step 1 8 - [(5-Chloro-2-cyanoisonicotinoyl) amino] -1- (4-fluorophenyl) ) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The compound of Step 1 was synthesized by the same procedure as in step 1 of Example 455 for 1- (1,3-benzodioxol-5-yl) -8-. { [(3-chloro-6-cyanopyridin-2-yl) carbonyl] amino} -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide starting from the compound of Example 248 (8 - [(2,5-dichloroisonicotinoyl) amino] -1- (4-fluorophenyl) -4 , 5-dihydro-1H-benzo [g] indazole-3-carboxamide) (1.67 g, 3.2 mmol), Zn (CN) 2 (0.230 g, 2 mmol), Pd2 (DBA) 3 (0.203 g , 0.22 mmol) and DPPF (0.121 g, 0.52 mmol), in a mixture of DMF (6 mL) and benzonitrile (2 mL). The mixture was heated at 90 ° C for 6 hours. The solvents were removed under reduced pressure. The residue was triturated with 50 ml of ether overnight and filtered to give 2.2 g of a brown solid. The title compound, isolated from 0.8 g of the crude reaction mixture by preparative HPLC, is a white solid (0.30 g), P.f. 275-276 ° C. 1 H NMR (CD 3 OD): d 2,94-3.17 (m, 4H)), 7.20-7.48 (m, 9H), 8.01 (s, 1 H), 8.82 (s, H). ESI mass spectrum for C25H17CIF 6O2 +: 487 (M + 1). Stage 2 8-. { [2- (Aminomethyl) -5-chloroisonicotinoyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in step 2 of Example 455 for 8- ( { [6- (aminomethyl) -3-chloropyridin-2-yl] carbonyl} amino) -1- (1,3-benzodioxol-5-yl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide starting from 1.2 g of the crude reaction mixture containing the compound of Step 1 and 0.4 g of 10% Pd / C (Aldrich) in a mixture of glyme (3 mL), methanol (14 mL) and a 1.2 M solution of HCl in methanol (6 mL). Hydrogenation was performed at a pressure of 5 psi (34.48 kPa) for 8 hours at room temperature. The catalyst was removed by filtration and the filtrate was purified by HPLC to give 0.43 g of the TFA salt of 8-. { [2- (aminomethyl) -5-chloroisonicotinoyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, which was triturated in 2N HCl for 3 hours. The title compound (0.35 g) as an HCl salt (white solid) was obtained after filtration and drying. P.f., 312-314 ° C. H NMR (CD3OD): d 2.91-3.15 (m, 4H), 4.33 (s, 2H), 6.09 (s, 2H), 7.22-7.42 (m, 5H) , 7.38-7.52 (m, 3H), 8.78 (s, 1 H). ESI mass spectrum for C25H2iCIFN602 +: 491 (M + 1).
Example 457 8-. { [2- (Amomethyl) -5-chloroisonicotinyl] amino} -1- (1,3-benzodolox-5-yl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide Step 1 1- (1,3-Benzodolox-5-) L) -8 - [(5-Chloro-2-cyanoisonicotinyl) amino] -4,5-dhydro-1 H -benzo [g] indazole-3-carboxamide The compound of Step 1 was synthesized by the same procedure as in step 1 of Example 455 for 1- (1,3-benzodioxol-5-yl) -8- [(3-chloro-6-cyanopyridin-2- il) carbonyl] amino} -4.5-dihydro-1H-benzo [g] indazole-3-carboxamide starting from the compound of Example 211 (1- (1,3-benzodioxol-5-yl) -8 - [(2,5-dichloroisonicotinyl)) amino] -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide) (2.16 g, 4.1 mmol), Zn (CN) 2 (0.287 g, 2.5 mmol), Pd2 ( DBA) 3 (0.203 g, 0.24 mmol) and DPPF (0.121 g, 0.55 mmol), in a mixture of DMF (9 mL) and benzonitrile (3 mL). The mixture was heated at 90 ° C for 6 hours. The solvents were removed under reduced pressure. The residue was triturated with 50 ml of ether overnight and filtered to give 2.8 g of a brown solid. The product, isolated from 0.9 g of the crude reaction mixture by preparative HPLC, is a white solid (0.35 g), P.f. 321-322 ° C. 1 H NMR (cfe-DMSO): d 2.82-3.01 (m, 4H)), 6.10 (s, 2H), 6.94-7.06 (m, 2H), 7.1 (d , 1H, J = 2 Hz), 7.24-7.38 (m, 4H), 7.52 (s, 1 H), 8.38 (s, 1 H), 8.97 (s, 1 H ). ESI mass spectrum for 513 (M + Step 2: 8 ^ [2- (Aminomethyl) -5-chloroisonicotinoyl] amino} -1- (1,3-benzodioxol-5-yl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in step 2 of Example 455 for 8- ( { [6- (aminomethyl) -3-chloropyridin-2-yl] carbonyl} amino) -1- (1,3-benzodioxol-5-yl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide starting from 1.4 g of the crude reaction mixture containing the compound of Step 1 and 0, 6 g of 10% Pd / C (Aldrich) in a mixture of glyme (20 ml), methanol (30 ml) and a 1.2 M solution of HCl in methanol (10 ml). Hydrogenation was performed at a pressure of 5 psi (34.48 kPa) for 8 hours at room temperature. The catalyst was removed by filtration and the filtrate was purified by HPLC to give 0.52 g of the TFA salt of the title compound, which was triturated in 1 N HCl (2: 1) for 3 hours. The title compound (0.40 g) as an HCl salt (a white solid) was obtained after filtration and drying. P.f. , 125-130 ° C. 1 H NMR (CD 3 OD): d 2.90-3.16 (m, 4H), 4.34 (s, 2H), 6.09 (s, 2H), 6.92-7.03 (m, 3H) , 7.38 (s, 2H), 7.40 (s, 1 H), 7.57 (s, 1H), 8.78 (s, 1 H). ESI mass spectrum for C26H23CIN604 +: 518 (M + 1). Examples 458 and 459 were synthesized with the following synthesis procedures, illustrated for Example 458.
SCHEME XXX Example 458 8- ( { [3-Chloro-6- (morpholin ^ -ylmethyl) pyridin-2-yl] carbonyl] amino) -1- (4-fluorophenyl) -4.5 -dihydro-1 H-benzo [g] indazole-3-carboxamide Stage 1 ethyl 2,5-dichloroisonicotinate 2,5-Dichloroisonicotinic acid (7.2 g, 37.5 mmol) and 180 mL of anhydrous C2H5OH were introduced into a flask containing a magnetic stir bar in an N2 atmosphere. The mixture was cooled to 0 ° C and 5.6 ml of SOCI2 (38 mmol) was added dropwise. The solution was heated to reflux overnight. The volatile components were partially evaporated reducing the volume to 30 ml. The residue was partitioned between an aqueous solution of Na 2 CO 3 with pH = 8.5 (75 ml) and CH 2 Cl 2 (75 ml). The organic phase was separated The aqueous phase was extracted with CH2Cl2 (2 x 25 mL). The organic phase was combined, dried over MgSO4 and concentrated in vacuo to give 7.8 g of the product (yield 97.5%). NMR (CDCl 3): d 1.42 (t, 3H, J = 7 Hz), 4.44 (c, 2H, J = 7 Hz), 7.68 (s, 1. 8.50 (s, 1 H) ESI mass spectrum for 220 (M + 1) Stage 2 Ethyl 2- (aminomethyl) -5-chloroisonicotinate hydrochloride All dry reagents (7.8 g (35.45 mmol) of ethyl 2,5-dichloroisonicotinate, 4.5 g (3.5 mmol) of Zn (CN) 2, 0.226 g (0.41 mmol) of dppf (dppf = bis [diphenylphosphino] ferrocene) and 0.170 g (0.19 mmol) of Pd2 (dba) 3) (dba = dibenzylideneacetone) were mixed in a flask containing a bar to stir. Degassed anhydrous solvents (10 ml of DMF and 3.3 ml of benzonitrile) were added under an N 2 atmosphere and the flask was placed in an oil bath at 90 ° C for 6 hours. After 6 hours, the solvents were removed in vacuo, then 100 ml of water was added and the residue was triturated for 3 hours. After filtration, the solid was dried under reduced pressure to give about 7 g of product mixture, which was used for the reduction without further purification. Starting material and ethyl dicyanoisonicotinate were detected. This product mixture (7 g) was introduced into a Fisher-Porter vessel with 1.8 g of 10% Pd / C (Aldrich) in 120 ml of EtOH and 30 ml of Et20-HCl (2M solution) in one atmosphere of hydrogen (2-3 psi) (13.79-20.69 kPa) and stirred at room temperature for 3 hours. After removing the solvent, the oil was triturated with ether to give a brownish solid which, after filtration, was triturated with 10 ml of CH3CN to give 4.2 g of the title compound as an HCl salt (47% yield). 1 H NMR (CD 3 OD): d 1, 41 (t, 3 H, J = 7 Hz), 4.38 (s, 2 H), 4.46 (c, 2 H, J = 7 Hz), 7.80 (s, 1 H), 8.78 (s, 1H). ESI mass spectrum for CeHi2Cl2N202 +: 215 (M + 1). Stage 3 5-Chloro-2- (morpholin-4-ylmethyl) trifluoroacetate ethyl sonicotinate The product of step 2 (1.77 g, 7 mmol), 2-bromoethyl ether (2.18 g, 9.5 mmol) and ethyldiisopropylamine (2.5 g, 19 mmol) in 10 ml of acetonitrile were introduced into the reaction mixture. a flask containing a magnetic stir bar. The reaction mixture was stirred for 8 days at room temperature. The volatile components were removed under reduced pressure and the desired product (solid, 1.3 g, 65% yield) was isolated by preparative HPLC in the form of TFA salt. 1 H NMR (CD 3 OD): S 1, 42 (t, 3 H, J = 7 Hz), 3.41 (s, broad, 4 H), 4.46 (c, 2 H, J = 7 Hz), 4.58 ( s, 2H), 4.88 (s, broad, 4H), 7.90 (s, 1H), 8.83 (s, 1H). ESI mass spectrum for C13H18CIN203 +: 285 (+ 1). Step 4 5-Chloro-2- (morpholin-4-ylmethyl) isonicotinic acid hydrochloride The compound of Step 3 (2.69 g, 10.3 mmol) as a suspension in 3N HCl (15 mL) was heated to reflux for 3 hours. The volatile components were removed under reduced pressure yielding 1.88 g (95% yield) of the title compound. 1 H NMR (CD3OD): d 3.30 (s, broad, 2H), 3.41 (s, broad, 2H), 3.83 (s, broad, 2H), 4.05 (s, broad, 2H) , 4.58 (s, 2H), 7.92 (s, 1 H), 8.83 (s, 1 H). ESI mass spectrum for CnH ^ CI zOa *: 257 (M + 1). Step 5 8- ( { [3-Chloro-6- (morpholin-4-methyl) pyridin-2-yl] carbonyl} amino) -1- (4-fluorophenyl) - 4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide The title compound was synthesized with 0.94 g (3.2 mmol) of 5-chloro-2- (morpholin-4-ylmethyl) isonicotinic acid hydrochloride (step 4) and the compound of Example 244 (8-amino) 1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide) (0.69 g, 2.1 mmol) by the same procedure used for Example 255 except that the DF it was replaced with DMSO (4 ml). The title compound is a brownish solid (0.31 g, 26%), P.f., 310-315 ° C (decomp.). 1 H NMR (CD 3 OD): d 2.78-2.82 (m, 4H), 2.92-3, 12 (m, 4H), 3.76-3.80 (m, 4H), 3.98 ( s, 2H), 7.21-7.42 (m, 5H), 7.50-7.63 (m, 3H), 8.63 (s, 1 H). ESI mass spectrum for CasHzyCIFNeC. 561 (M + 1). Example 459 1- (1,3-Benzodioxol-5-yl) -8- ( { [3-chloro-6- (morpholin-4-ylmethyl) pyridin-2-yl] carbonyl} amino) -4 , 5-dihydro-1 H-benzo [g] indazole-3-carboxamide The title compound was synthesized with 1.0 g (3.4 mmol) of 5-chloro-2- (morpholin-4-ylmethyl) isonicotinic acid hydrochloride (step 4 of Example 458) and the product of Example 161, Step 3 (0.78 g, 2.2 mmol) by the same procedure used for Example 255 except that the DMF was replaced with DMSO (5 mL). The title compound was initially isolated in the form of TFA salt by preparative HPLC. After triturating with 2N HCl (2 x 20 mL) it was filtered and dried under reduced pressure to give the product as bis (hydrochloride) tetrahydrate (0.35 g, 22% yield), P., 231-235 ° C. (decomp.) H NMR (CD3OD): d 2.50-2.54 (m, 4H), 2.92-3.12 (m, 4H), 3.76-3.80 (m, 6H), 6.09 ( s, 2H), 6.90-7.10 (m, 3H), 7.38-7.42 (m, 3H), 7.58 (s, 1H), 8.60 (s, 1H). ESI mass spectrum for CaoFbsCINe: 587 (M + 1). Examples 460 and 461 were synthesized with the following synthesis procedure, illustrated for the synthesis of Example 461. SCHEME XXXI Example 460 1- (1,3-Benzodioxol-5-yl) -8-. { [5-chloro-2- (2-morpholin-4-ylethyl) isonicotinoyl] amino} - 4,5-dihydro-1 H-benzo [g] indazol-3-carboxamide Stage 1 2,5-Dichloroisonicotinate methyl Thionyl chloride (9.13 g, 5.6 mL, 76 mmol) was added at 0 ° C to a suspension of 2,5-dichloroisonicotinic acid (7.3 g, 38 mmol) in 170 mL of MeOH. The reaction mixture was heated to reflux overnight. The volatile components were evaporated and the resulting residue was basified (pH = 9) with a saturated aqueous solution of Na 2 CO 3 and extracted with CH 2 Cl 2. The organic extract was dried over MgSO4. Purification by chromatography on silica gel (hexanes / EtOAc: 4/1) afforded the title compound as a white solid, 89% yield. H NMR (300 MHz, CDCl 3): d 3.98 (s, 3 H), 7.7 (s, 1 H), 8.49 (s, 1 H), 13 C NMR (300 MHz, CDCl 3): d 53.4 , 125.2, 129.2, 139.3, 150.1, 151, 1, 163.4. Mass Spectrum, M + 1 = 207. Stage 2 Methyl 2-vinyl-5-chloroisonicotinate Pd (PPh3) 4 (263 mg, 0.6%) was added to a degassed mixture of methyl 2,5-dichloroisonicotinate (step 1) (8.39 g, 40.7 mmol) and tributyl (vinyl) tin ( 15.4 g, 14.24 mL, 48.5 mmol) in 100 mL of THF. The reaction mixture was stirred at 60 ° C for 4 days. The solvent was evaporated and the resulting residue was partitioned between CH2Cl2 and a saturated aqueous solution of KF. The CH2Cl2 extract was washed with H20 and dried over MgSO4. Purification by chromatography on silica gel (hexanes / EtOAc: 20/1 to 10/1) afforded the title compound as a colorless oil, yield 74%. 1 H NMR (300 MHz, CDCl 3): d 3.96 (s, 3H), 5.55 (d, 1 H, Jcis = 10.8 Hz), 6.24 (d, 1H, Jtrans = 17.5 Hz), 6.78 (dd, 1H, Jt ns = 17.5 Hz, Jes = 10.8 Hz), 7.65 (s, 1 H), 8.62 (s, 1 H), 13 C NMR (300 Hz, CDCl 3): d 53.2, 120.2, 121, 9, 128.6, 135.3, 137.2, 151, 1, 154.7, 164.8. Correlation spectroscopy of H-13C and 1H-15N (ghmbc) confirmed the structure. Stage 3 2- (Morpholin-4-ylethyl) -5-chloroisonicotinic acid hydrochloride A mixture of the material of step 2 (1.5 g, 7.5 mmol), morpholine (0.97 g, 0.97 ml, 11 mmol) and acetic acid (0.66 g, 0.63 ml, 11 mmol) in 7 mL of EtOH was heated to reflux for 2 days. The reaction mixture was concentrated in vacuo and the resulting residue basified to pH = 8 to 9 with a saturated aqueous solution of Na 2 CO 3 and extracted with CH 2 Cl 2. The organic extracts were dried over MgSO4. The raw product, consisting of a mixture of methyl and ethyl esters of 5-chloro-2- (morpholinoethyl) -isonicotinic acid and was stirred with NaOH (1 mol / l, 7.5 ml, 7.5 mmol) in 20 ml of EtOH, at room temperature for 2 hours. The volatile components were removed and the basic aqueous residue was washed once with CH2Cl2. The aqueous phase was acidified to pH = 3 with an aqueous solution of HCl (1 N) and washed with CH 2 Cl 2 before concentrating in vacuo to yield a white solid, which was washed with MeOH to give the title product, yield 49%. 1 H NMR (300 MHz, cfe-DMSO): d 2.47-2.48 (m, 2H), 2.82-2.87 (m, 4H), 2.96-3.015 (m, 2H), 3 , 6-3.3-63 (m, 2H + H20), 7.49 (s, 1 H), 8.53 (s, 1 H), 13 C NMR (300 MHz, D20): d 30.3, 52.0, 56.1, 63.9, 121, 4, 125.6, 147.9, 149.0, 154.9, 172.6. Mass Spectrum, M + 1 = 271. Step 4 1- (1,3-Benzodioxol-5-yl) -8 - ([5-chloro-2- (2-morpholin-4-ylethyl) isonicotinoyl] amino) - 4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The product from Step 4 was synthesized by the same procedure as in Example 211, starting from 8-amino-1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide ( 0.3 g, 0.86 mmol), 2- (morpholin-4-ylethyl) -5-chloroisonicotinic acid hydrochloride (step 2) (0.399 g, 0.86 mmol), HATU (0.48 g, 1, 28 mmol) and EtaN (0.511 g, 0.70 ml, 5.05 mmol) in 6 ml of DMF. Purification by chromatography on silica gel (CH2Cl2 / MeOH: 11/1) afforded the title compound as a yellow solid, 41% yield. 1H RN (300 MHz, oVDMSO): d 2.38 (s (broad), 4H), 2.62 (t, 2H, J = 7.12 Hz), 2.87-2.92 (m, 4H + 2H), 3.52 (t, 4H, J = 3.23), 6.07 (s, 2H), 6.94 (dd, 1 H, J = 8.2 Hz, 1.88 Hz), 6 , 99-7.01 (m, 1H), 7.09 (d, 1H, J = 1.88 Hz), 7.24 (s, 1H), 7.27-7.31 (m, 2H), 7.38 (dd, 1H, J = 8.2 Hz, 1.88 Hz), 7.43 (s, 1 H), 7.49 (s, 1H), 8.58 (s, 1H), 10 , 44 (s, 1 H). Mass Spectrum, M + 1 = 262. EXAMPLE 461 8- [5-Chloro-2- (2-morpholin-4-ylethyl) isonicotinoyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 211, starting from 8-amino-1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide (0.489 g, 1.52 mmol), 2- (Morpholin-4-ylethyl) -5-chloroisonicotinic acid hydrochloride (step 3 of Example 460) (0.7 g, 2.27 mmol), HATU (0.852 g, 2.24 mmol) and EtsN (0.885 g, 1.22 mL, 8.75 mmol) in 10 mL of DMF . Purification by preparative reverse phase HPLC afforded the title compound as a white solid, 25% yield. 1 H NMR (300 MHz, de-DMSO): d 2.35 (s (broad), 4H), 2.58 (t, 2H, J = 7.58 Hz), 2.84-2.90 (m, 4H + 2H), 3.54 (t, 4H, J = 4.36 Hz), 7.18 (s, 1 H), 7.25 (s, 1 H), 7.28-7.37 (m , 4H), 7.39 (s, 1 H), 7.53-7.56 (m, 3H), 8.55 (s, 1 H), 10.41 (s, 1 H). Mass Spectrum, M + 1 = 576. Example 462 was prepared using a synthetic procedure similar to that of Example 460 and 461, differing only in the amine added to the methyl 2-vinyl-5-chloropyridine. SCHEME XXXII Example 462 8- (. {5-Chloro-2- [2- (dimethylamino) ethyl] isonicotinoyl}. Amino) -1- (4-fluorophenyl) -4,5-dihydro-1 H-benzo [g] indazol-3-carboxamide Stage 1 Methyl 5-chloro-2- [2- (d.methylamino) ethyl] isonicotinate A mixture of methyl 2-vinyl-5-chloroisonicotinate (step 2 of Example 460) (2.48 g, 12.5 mmol), methylamine (2M solution in MeOH) (11.5 ml, 23 mmol) and acetic acid (1.38 g, 1.32 mL, 23 mmol) in 3 mL of MeOH was heated at 78 ° C in a sealed tube for 3 days. The reaction mixture was concentrated in vacuo and the resulting residue basified to pH = 8 to 9 with a saturated aqueous solution of Na 2 CO 3 and extracted with CH 2 Cl 2. The organic extracts were dried over MgSO4. Purification by chromatography on silica gel (CH2Cl2) afforded the title compound in 37% yield. 1 H NMR (400 MHz, CDCl 3): d 2.29 (s, 6 H), 2.71 (t, 2 H, J = 7.36 Hz), 2.97 (t, 2 H, J = 7.36 Hz) , 3.9 (s, 3H), 7.5 (s, 1H), 8.56 (s, 1H), 13C NMR (300 MHz, CDCl3). d 35.5, 45.4, 53.1, 59.0, 123.8, 127.8, 137.1, 150.8, 159.3, 164.9. Mass Spectrum, M + 1 = 243. Step 2 5-Chloro-2- [2- (dimethylamino) ethyl] isonicotinic acid hydrochloride An aqueous solution of NaOH (1 mol / L) (5.8 ml, 5.8 mmol) was added to a solution of methyl 5-chloro-2- [2- (dimethylamino) ethyl] isonicotinate (step 1) ( 1.41 g, 5.8 mmol) in 15 ml of MeOH. The reaction mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The basic aqueous residue was washed once with CH 2 Cl 2. The aqueous phase was acidified to pH = 3 with an aqueous solution of HCl (1N) and washed with CH 2 Cl 2 before concentration in vacuo yielding a white solid, which was washed with MeOH giving the title product, 40% yield. 1 H NMR (300 MHz, D20): d 2.76 (s, 6H), 3.12 (t, 2H, J = 7.24 Hz), 3.38 (t, 2H, J = 7.24 Hz) , 7.30 (s, 1 H), 8.40 (s, 1 H). Mass Spectrum, M + 1 = 229. Step 3 8- ( {5-Chloro-2- [2- (dimethylamino) ethyl] isonicotinoal.] Amino) -1- (4-fluorophenyl) -4 , 5-dihydro-1 H-benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 211, starting from 8-amino-1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide ( , 3 g, 0.86 mmol) (0.478 g, 1.48 mmol), 2- (morpholin-4-ylethyl) -5-chloroisonicotinic acid hydrochloride (step 3 of Example 460) (0.59 g, 2, 22 mmol), HATU (0.833 g, 2.19 mmol) and EtaN (0.871 g, 1.2 mL, 8.6 mmol) in DMF (8 mL). Purification by preparative reverse phase HPLC afforded the title compound as a white solid in 33% yield. H NMR (300 MHz, cfe-DMSO): d 2.10 (s, 6H), 2.54 (t, 2H, J = 7 Hz), 2.81-2.90 (m, 6H), 7, 18 (s, 1 H), 7.26-7.37 (m, 6H), 7.52-7.56 (m, 3H), 8.54 (s, 1 H), 10.42 (s, 1 HOUR). Mass Spectrum, M + 1 - 534 EXAMPLE 463 B-IIS-Chloro ^^ '- bipyridin ^ -i carbonyljaminoJ-l ^ -fluorophenylH.S-dihydro-1 H -benzo [g] indazole-3-carboxamide Step 1 -Chloro-2,4'-bipyridine-4-carboxylic acid methyl The product of Step 1 was synthesized by the same procedure as for the methyl 2-vinyl-5-chloroisonicotinate (step 2 of Example 461) starting from methyl 2,5-dichloroisonicotinate (step 1 of Example 460) (1, 4 g, 6.8 mmol), 4-tributylstannilpyridine (2.5 g, 6.8 mmol) and Pd (PPh3) 4 (45 mg) in 20 ml of dioxane. The reaction mixture was heated to reflux for 7 days. Purification by chromatography on silica gel (CH2Cl2 / MeOH: 18/1) afforded the title compound as a colorless oil, yield 44%. 1 H RN (300 MHz, CDCl 3): d 4.02 (s, 3 H), 7.89-7.91 (m, 2 H), 8.17 (s, 1 H), 8.76 (d, broad, 2H, J = 6.0 Hz), 8.81 (s, 1 H). Mass Spectrum, M + 1 = 249. Stage 2 5-Chloro-2,4'-bipyridine-4-carboxylic acid hydrochloride The compound of Step 2 was synthesized by the same procedure as for 5-chloro-2- [2- (dimethylamino) ethyl] isonicotinic acid hydrochloride (step 2 of Example 462) starting from the product of Step 1 (0.755 g, 3 mmol) and NaOH (1 mol / L) (4.5 mL, 4.5 mmol) in 5 mL of MeOH. The reaction mixture was stirred at room temperature for 1 hour before acidification to pH = 2 with an aqueous solution of HCl (1 N). The acid mixture was washed once with CH2Cl2. In the acidic aqueous phase, white needles crystallized. These needles were filtered and washed with water to give the title compound in 36% yield. 1 H NMR (300 MHz, CDCl 3): d 8.1 (dd, 2 H, J = 4.6 Hz, 1.6 Hz), 8.4 (s, 1 H), 8.72 (dd, 2 H, J = 4.6 Hz, 1.6 Hz), 8.9 (s, 1H). Mass Spectrum, M + 1 (-HCl) = 235. Stage 3 8-. { [(5-Chloro-2,4'-bipyridin-4-yl) carbonyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 211 starting from 8-amino-1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide (0.3 g, 0.86 mmol) (0.227 g, 0.7 mmol), the product of Step 2 (0.287 g, 1.0 mmol), HATU (0.395 g, 1 mmol) and ¼? (0.413 g, 1.2 mL, 4 mmol) in DMF (6 mL). Crystallization from CH3CN afforded the title compound as a white solid, yield 45%. 1 H NMR (400 MHz, de-DMSO): d 2.9-2.95 (m, 4H), 7.26 (d, 1H, J = 2 Hz), 7.28 (s, 1 H), 7 , 34-7.42 (m, 4H), 7.55 (s, 1H), 7.57-7.6 (m, 2H), 8.07 (dd, 2H, J = 4.6 Hz, 1 , 5 Hz), 8.3 (s, 1H), 8.7 (dd, 2H, J = 4.6 Hz, 1.5 Hz), 8.86 (s, 1H), 10.5 (s, 1 HOUR). Mass Spectrum, M + 1 = 539. Example 464 was synthesized with the following synthesis procedure. The first two bicyclic compounds were not isolated in pure form but subjected to successive reactions as described in step 3 giving e ^ S-chloro-r-methyl-l '. .S'.e'-tetrahydro ^. ^ - bipyridin ^ -yl) carbonyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide.
Stage 1 1-Methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate LiHMDS (1M, THF) (48.6 mL, 48.6 mmol) was added to a solution of 1-methyl-4-piperidone (5 g, 5.43 mL, 44.2 mmol) in 80 mL of THF a -75 ° C. The mixture was stirred at this temperature for 2 hours and heated to -50 ° C. A solution of N-phenyltrifluoro-methanesulfonimide (17, 36 g, 48.6 mmol) in 55 ml of THF was added to the reaction mixture, which was then allowed to warm to room temperature over a period of 3 hours. The volatile components were removed in vacuo. Purification of the resulting residue by chromatography on silica gel (EtOAc / hexanes: 7/3) afforded the title compound in 73% yield. 1 H NM (300 MHz, CDCl 3): d 2.36 (s, 3 H), 2.43-2.45 (m, 2 H), 2.65 (t, 2 H, J = 5.8 Hz), 3, 05-3.07 (m, 2H), 5.68-5.70 (m, 1H).
Step 2 1-Methyl-4- (trimeth! Lestannyl) -1, 2,3,6-tetrahydropyridine Pd (PPh3) 4 (0.31 g, 0.26 mmol) was added to a degassed mixture of 1-methyl-1, 2,3,6-tetrahydropyridyl-4-yl trifluoromethanesulfonate or (step 1) ( 3.28 g, 13.3 mmol), hexamethylditin (4.60 g, 14 mmol), LiCl (1.73 g, 40 mmol) and a few crystals of 2,6-di-tert-butyl-4-methylphenol. in 60 ml of dioxane. The reaction mixture was heated at 98 ° C for 4 hours. After cooling, the reaction mixture was poured into an aqueous KF solution and extracted with Et20. The organic extracts were washed once with H20 and once with brine before being dried over gS04. The residue obtained after removal was purified by chromatography on silica gel (CH2Cl2 / MeOH: 10/1) yielding the title compound in 41% yield. 1 H NMR (300 MHz, CDCl 3): d 0.0 (t, 9H, Jsn.H = 26.4 Hz), 2.21 (s, 3H), 2.23-2.27 (m, 2H), 2.39 (t, 2H, J = 5.6 Hz), 2.82-2.85 (m, 2H), 5.70-5.72 (m, 1 H). Stage 3 S-EIIS-chloro-l-methyl-r ^ '. S'.e'-tetrahydro ^^' - bipyridin ^ -i carbonyl-amino-J- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide Pd (PPh3) (30 mg, 0.025 mmol) was added to a degassed mixture of the product from Step 2 (1.82 g, 7 mmol) and methyl 2,5-dichloroisonicotinate (step 1 of Example 460) (0, 96 g, 4.66 mmol) in 10 ml of dioxane. The reaction mixture was maintained at 98 ° C overnight. After cooling, the reaction mixture was poured into an aqueous KF solution and extracted with EtOAc. The organic extracts were washed once with H20 and once with brine before being dried over MgSO4. The residue, obtained after removal of the solvents, was purified by chromatography on silica gel (CH2Cl2 / MeOI-I: 15/1) yielding 0.606 g of a 2/1 mixture of the 5-c? O-V-met \\ - V, 2 ', 3', 6'-tetrahydro- [2,4 '] - bipyridinyl-4-carboxylic acid methyl ester and the product of Step 2 which was dissolved in 5 ml of MeOH and made reacting at room temperature with an aqueous solution of NaOH (1M) (2.5 ml, 2.5 mmol) for 1.5 hours. The reaction mixture was acidified to pH = 2 with an aqueous solution of HCl (1 N) and concentrated to give a white solid residue. This residue was reacted with 8-amino-1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide (0.52 g, 1.6 mmol) in 10 ml. of DMF in the presence of Et3N (0.94 g, 1.3 ml, 9.3 mmol) and HATU (0.906 g, 2.38 mmol). After stirring for 1.5 hours, the mixture was concentrated and a white solid precipitated after the addition of water. The solid was filtered, dissolved in THF and dried over gS04. Preparative HPLC afforded the title compound in 36% yield. 1 H NMR (400 MHz, cfe-DMSO): d 2.25 (s, 3 H), 2.51-2.53 (m, 4 H), 2.86-2.91 (m, 4 H), 3.04 (s, broad, 2H), 6.73 (s, broad, 1 H), 7.19 (t, 1 H, 3 = 2.5 Hz), 7.25 (s, 1 H), 7.29 -7.38 (m, 4H), 7.52-7.56 (m, 3H), 7.59 (s, 1 H), 8.59 (s, 1 H), 10.4 (s, 1 H). Mass Spectrum, M + 1 = 558 Example 465 1- (4-Fluorophenyl) -8 - [(2-morpholin-4-ylisonicotinoyl) amino] -4,5-dihydro-1 H -benzo [g] indazol-3 -carboxamide Stage 1 8 - [(2-Chloro-6-phenyl) -amino] -1- (4-fluorophenyl) -4,5-dihicyl-1 H -benzo [g] indazole-3-carboxamide The product of Example 244 (8-amino-1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide) (8.46 mmol), acid 2 -chloroisonicotinic (12.70 mmol), HATU (12.63 mmol) and 4.2 ml of triethylamine were dissolved in 42 ml of DMF. The mixture was stirred at room temperature for 4 hours. The solvent was partially distilled and the residue was suspended in water, filtered and washed with water. The solid was triturated in water, dissolved in acetonitrile, decolorized with activated carbon, dried over MgSO4 and recrystallized from acetonitrile. Mp: 258-262 ° C. Mass Spectrum: M + 1 = 462. 1 H NMR (d, o VDMSO, 400 MHz): 2.83-2.95 (m, 4H); 7.26 (s, 1H); 7.30-7.42 (m, 5H); 7.50-7.58 (m, 3H) 7.65-7.68 (m, 1 H); 7.78 (s, 1 H); 8.53 (d, 1 H, J = 5.1 Hz); 10.36 (s, 1 H). Step 2 1- (4-Fluorophenyl) -8 - [(2-morpholin-4-ylisonicotinoyl) amino] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide The product of Step 1 (2.17 mmol) and morpholine (32.7 mmol) were dissolved in 10 ml of?,? - dimethylacetamide. The reaction mixture was introduced under a nitrogen atmosphere and stirred in an oil bath at 80 ° C for 160 hours thereafter at 100 ° C for 172 hours. The solvent was partially distilled from the mixture, then added to water to form a precipitate, filtered and washed with water. The solid was recrystallized from acetonitrile and triturated from diethyl ether, ethyl acetate, acetonitrile and ethanol. The product was dissolved in tetrahydrofuran, dried over MgSO4 and the solvent was distilled. Finally, the product was dissolved in ethanol followed by distillation by removing the trapped solvents. Mp: 269-274 ° C (decomp.). Mass Spectrum: M + 1 = 513. 1 H NMR (d, cfe-DMSO, 400 MHz): 2.56-2.59 (m, 4H); 3.44 (t, 4H, J = 4.8 Hz); 3.66 (t, 4H, J = 4.8 Hz); 6.88-6.92 (m, 1 H); 7.02 (s, 1 H); 7.24-7.43 (m, 6H); 7.50-7.58 (m, 3H); 8.19 (d, IH, J = 5.1 Hz); 10,12 (s, 1 H). EXAMPLE 466 8 - ([5-chloro-2- (1,4-diazepan-1-yl) isonicotinoyl] amino.} -1- (4-fluorophenyl) -4,5-dihydro-1 H-benzo [g ] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 214 starting from 8 - [(2,5-dichloroisonicotinoyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide (Example 248) (1 g, 2 mmol) and homopiperazine (4 g, 40 mmol) in 5 ml of EtOH. The reaction was carried out at 100 ° C for 24 hours. The white precipitate that formed in the crude reaction mixture was filtered and washed with EtOH yielding the title product, yield: 82%. 1 H NMR (400 MHz, cfe-DMSO): d 1, 68-1, 72 (m, 2H), 2.63 (t, 2H, J = 5.84 Hz), 2.79 (t, 2H, J = 5 Hz), 2.91-2.93 (m, 4H), 3.59 (t, 2H, J = 5 Hz), 3.64 (t, 2H, J = 5.84 Hz), 6, 62 (s, 1H), 7.2 (d, 1 H, J = 2 Hz), 7.28-7.4 (m, 4H), 7.44 (dd, 1 H, J = 8.2 Hz , 2 Hz), 7.55-7.60 (m, 3H), 8.08 (s, H), 10.32 (s, 1 H). Mass Spectrum, M + I = 561. Example 467 8- (. {5-Chloro-2- [4- (2-hydroxyethyl) piperazin-1-yl] isonicotinoyl}. Amino) -1- (4- fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 214 starting from 8 - [(2,5-dichloroisonicotinoyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-1 H-benzo [g ] indazole-3-carboxamide (Example 248) (0.8 g, 1.6 mmol) and 1- (2-hydroxyethyl) piperazine (4.19 g, 3.94 mL, 32 mmol). The reaction was carried out at 100 ° C for 24 hours. The white precipitate that formed in the crude reaction mixture was filtered and washed with EtOH and finally triturated with CHCl3 to yield the title product, yield: 66%. 1 H NMR (400 MHz, cfe-DMSO): d 2.38 (t, 2 H, J = 6.2 Hz), 2.44 (t, 4 H, J = 4.7 Hz), 2.87-2.93 (m, 4H), 3.45-3.52 (m, 4H + 2H), 4.39 (t, 1H, J = 5.3 Hz), 6.87 (s, 1 H), 7.2 (d, 1 H, J = 2 Hz), 7.27 (s, 1 H), 7.29-7.38 (m, 3H), 7.4 (dd, 1 H, J = 8.2 Hz , 2 Hz), 7.54-7.58 (m, 3H), 8.12 (s, 1 H), 10.31 (s, 1 H). Mass Spectrum, M + 1 = 591. EXAMPLE 468 8- ( {5-Chloro-2- [4- (2-methoxyethyl) piperazin-1-yl] isonicotinoyl}. Amino) -1- (4- fluorophenyl) -4,5-dihydro-1H-benzo [g] indazoI-3-carboxamide The title compound of Example 248 (8 - [(2,5-dichloroisonicotinoyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide ) (1.61 mmol) and 1- (2-methoxyethyl) -piperazine (16.25 mmol) were combined with 4.0 mL of DMA. The reaction mixture was introduced under a nitrogen atmosphere and stirred in an oil bath at 100 ° C for 25 hours. The mixture was added to water to form a precipitate, filtered and washed with water. The product was dissolved in tetrahydrofuran, dried over MgSO4 and the solvent was distilled. The product was purified by practically dissolving in ethanol, adding acetonitrile, the solid was triturated in the solvent mixture, the solvent was partially distilled and the suspension was filtered. Elemental Analysis: 61, 65% C, 5.22% H, 16.04% N (theory: 61.64% C, 5.17% H, 16.23% N). Mp: 238-240 ° C. Mass Spectrum: M + 1 = 604. EXAMPLE 469 8 - [(5-Chloro-2 { [2- (dimethylamino) ethyl] amino.} Isonicotinoyl) amino] -1- (4-fluorophenyl) - 4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 214 starting from 8 - [(2,5-dichloroisonicotinoyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [ g] ndazole-3-carboxamide (Example 248) (1 g, 2 mmol) and N, Nd-methylethylenediamine (3.55 g, 4.42 ml, 40 mmol). The reaction was carried out at 100 ° C for 24 hours. The white precipitate that formed in the crude reaction mixture was filtered and washed with EtOH and finally purified by preparative reverse phase HPLC yielding the title product, yield: 14%. H NM (400 MHz, cfe-DMSO): d 2.13 (s, 6H), 2.34 (t, 2H, J = 6.5 Hz), 2.87-2.92 (m, 4H), 3.29-3.30 (m, 2H), 6.49 (s, 1 H), 6.78 (t, 1 H, J = 5.3 Hz), 7.2 (d, 1 H, J = 2 Hz), 7.27 (s, 1 H), 7.29-7.40 (m, 4H), 7.53-7.58 (m, 3H), 7.99 (s, 1 H) , 10.3 (s, 1H). Mass Spectrum, M + 1 = 549. EXAMPLE 470 8- ( {5-Chloro-2 - [(3R) -3-methyl-piperazin-1-yl] -isonicotinoyl}. Amino) -1- (4-fluorophenyl) ) -4,5-dihydro-H-benzo [g] indazole-3-carboxamide compound of the title of Example 248 dichloroisonicotinoyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide) (2.62 mmol) and (R) -2 methylpiperazine (25.6 mmol) were combined with 6.5 ml of DMA. The reaction mixture was introduced under a nitrogen atmosphere and stirred in an oil bath at 100 ° C for 15.5 hours. The mixture was subsequently added to water, forming a precipitate, which was filtered and washed with water. The solid was dissolved in acetonitrile, dried over MgSO4 and the solvent was distilled. Pf., 275-278 ° C (decomp.). Mass Spectrum: M + 1 = 560. EXAMPLE 471 8- (. {5-Chloro-2 - [(3S) -3-methyl-piperazin-1-yl] ison-phenyl-1-yl. ) -1- (4-fluorophenyl) -4,5-clihydro-1 H -benzo [g] inclazole-3-carboxamide The title compound of Example 248 (8 - [(2,5-dichloroison-tacinyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazol-3 carboxamide) (2.63 mmol) and (S) -2-methylpiperazine (25.1 mmol) were combined with 6.5 ml of?,? - dimethylacetamide. The reaction mixture was introduced under a nitrogen atmosphere and stirred in an oil bath at 100 ° C for 15.5 hours. The mixture was subsequently added to water to form a precipitate, which was filtered and washed with water. The solid was dissolved in acetonitrile, dried over MgSO4 and the solvent was distilled. Mp: 275-278 ° C (decomp.). Mass Spectrum: M + 1 = 560. EXAMPLE 472 8- ( {5-Chloro-2 - [(3R, 5S) -3,5-dimethylpiperazin-1-yl] isonicotinoyl}. Amino) -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide The title compound of Example 248 (8 - [(2,5-dichloroisonicotinoyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide) (2 , 62 mmol) and cis-2,6-dimethyl piperazine (26.2 mmol), were combined with 6.5 ml of DMA. The reaction mixture was introduced under a nitrogen atmosphere and stirred in an oil bath at 100 ° C for 24 hours. The mixture was subsequently added to water, forming a precipitate, which was filtered and washed with water. The solid was dissolved in acetonitrile, dried over MgSO4 and the solvent was distilled. Mp: 250 ° C (decomp.). Mass Spectrum: M + 1 = 574. Examples 473, 474, 475 were synthesized with the following synthesis procedure, illustrated for 473. SCHEME XXXIII Example 473 8- ( {5-Chloro-2 - [(3R, 5S) -3,4,5-trimethylpiperazin-1-yl] isonicotinoyl}. Amino) -1- (4-fluorophenyl) -4, 5-dihydro-1H-benzo [g] indazole-3-carboxamide Stage 1 (3R, 5S) -3,5-Dimethyl-piperazine-1-carboxylic acid benzyl ester Benzyl chloroformate (9.7 g, 8.12 ml, 54.1 mmol) was slowly added to a mixture of 2,6-dimethylpiperazine (6.25 g, 54.7 mmol) and? ¾? (5.53 g, 7.6 mL, 54.7 mmol) in 100 mL of CHCI3. The reaction mixture was stirred at room temperature for 4 hours. Water was added and the organic phase was separated and dried over MgSQ 4. Purification by chromatography on silica gel (CH2Cl2 / eOH: 12/1) afforded the title compound in 60% yield. 1 H NMR (300 MHz, CDCl 3): d 1, 04 (d, 6H, J = 6.2 Hz), 1.46 (s, broad, 1H), 2.38 (m, broad, 2H), 2, 78 (s, broad, 2H), 3.99-4.03 (m, broad, 2H), 5.12 (s, 2H), 7.34-7.36 (m, 5H), 13C NMR (300 MHz, CDCl 3): d 19.5, 50.9, 67.3, 128.1, 128.2, 128.7, 137.0, 155.3. Stage 2 (3R, 5S) -3,4,5-trimethylpiperazine-1-carboxylic acid benzyl ester NaBH (OAc) 3 (2.96 g, 14 mmol) was added to a mixture of the product from Step 1 (2.34 g, 10 mmol) and formaldehyde (0.86 g, 0.79 mL, 10 mmol). in 35 ml of dichloroethane. The reaction mixture was stirred at room temperature for 1 hour and 40 minutes and quenched by adding a saturated aqueous solution of NaHCC > 3. The product was extracted with EtOAc and dried over MgSO 4. Evaporation of the volatile components yielded the title compound in 76% yield. 1 H NMR (300 MHz, CDCl 3): d 1, 09 (d, 6H, J = 6.1 Hz), 2.16-2.17 (m, 2H), 2.25 (s, 3H), 2, 65 (m, broad, 2H), 3.95 (m, broad, 2H), 5.13 (s, 2H), 7.33-7.36 (m, 5H). Mass Spectrum, M + 1 = 263. Stage 3 (2R, 6S) -1, 2,6-Trimethylpiperazine A mixture of the product of Step 2 (2.75 g, 10 mmol) and Pd / C (5%, 1.1 g) in 20 ml of MeOH was reacted for 2 h at room temperature in an atmosphere of H2 (15 psi). (103.43 kPa)). The mixture was filtered through Celite and the filtrate was evaporated yielding the title compound in 80% yield. 1 H NMR (400 MHz, CDCl 3): d 1.0 (d, 6H, J = 6.1 Hz), 1.78 (m, broad, 1H), 2.0-2.05 (m, 2H), 2.21 (s, 3H), 2.5 (t, 2H, J = 10.7), 2.82 (dd, 2H, J = 12.5 Hz, 1.8 Hz). Mass Spectrum, M + 1 = 129. Step 4 8- ( {5-Chloro-2 - [(3R, 5S) -3,4,5-trimethylpiperazin-1-yl] isonicotinoyl}. Amino) - 1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 214 starting from 8 - [(2,5-dichloroisonicotinoyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-1 H-benzo [g ] indazole-3-carboxamide) (0.49 g, 1.0 mmol) and (2R, 6S) -1, 2,6-trimethylpiperazine (step 3) (1.03 g, 8.0 mmol) in 5 ml. of EtOH. The reaction was carried out at 100 ° C for 5 days. The whitish precipitate that formed in the crude mixture was filtered and washed with EtOH yielding the title compound in a 77% yield. 1 H NMR (400 MHz, oVDMSO): d 1, 01 (d, 6H, J = 12.3 Hz), 2.05 (m, broad, 2H), 2.13 (s, 3H), 2.47- 2.53 (2H, m, overlapped with DMSO), 2.88-2.93 (m, 4H), 4.11 (d, 2H, J = 12.3 Hz), 6.92 (s, 1 H ), 7.21 (d, 1 H, J = 2.0 Hz), 7.27 (s, 1 H), 7.3-7.38 (m, 3H), 7.41 (dd, 1H, J = 8.2 Hz, 2.0 Hz), 7.54-7.58 (m, 3H), 8.11 (s, 1H), 10.32 (s, 1H). HRMS cale, for C31H32CIFN7O2 588.2285, Found 588.2212. EXAMPLE 474 8- ( {5-Chloro-2 - [(3) -3,4-dimethylpiperazin-1-yl] isonicotinoyl}. Amino) -1- (4-fluorophenyl) -4,5-dihydro- 1 H-benzo [g] indazole-3-carboxamide Stage 1 (3R) -3-methylpiperazin-1-carboxylic acid benzyl ester The product of Step 1 was synthesized by the same procedure as for the compound of Step 1 of Example 473 starting from 2- (R) -methylpiperazine (6 g, 59.9 mmol), triethylamine (6.04 g, , 32 mL, 59.7 mmol) and benzyl chloroformate (10.62 g, 59.2 mmol) in 100 mL of CHCl3. Purification by chromatography on silica gel (CH2Cl2 / eOH: 12/1) afforded the title compound in 30% yield. 1 H NMR (300 MHz, CDCl 3): d 1, 05 (d, 3 H, J = 6.2 Hz), 1.59 (s, 1 H), 2.47 (s, broad, 1 H), 2, 71-2.9 (m, 4H), 4.02 (s, broad, 1 H), 5.13 (s, 2H), 7.30-7.36 (m, 5H). Stage 2 (3R) -3,4-Dimethylpiperazine-1-carboxylate benzyl The title compound of step 2 was synthesized by the same procedure as for the compound of Step 2 of Example 473 starting from the compound of Step 1 (3.77 g, 16 mmol), formaldehyde (1.46 g, 1 , 34 ml, 16 mmol) and NaHB (OAc) 3 (4.98 g, 23 mmol) in 60 ml of dichloroethane afforded the title compound in 95% yield. 1 H NMR (300 MHz, CDCl 3): d 1, 05 (d, 3 H, J = 6.24 Hz), 2.02-2.08 (m, 1H), 2.13-2.21 (m, 1 H), 2.28 (s, 3H), 2.72-2.76 (m, 2H), 3.08 (t, 1H, J = 1.2 Hz), 3.95-3.99 (m , 2H), 5.12 (s, 2H), 7.32-7.36 (m, 5H). Stage 3 (2R) -1, 2-Dimethylpiperazine The title compound of Step 3 was synthesized by the same procedure as in step 3 of Example 473 starting from the compound of Step 2 (3.78 g, 15.2 mmol), (Pd / C (5%, 1 , 6g) in 30 ml of MeOH in an atmosphere of H2 (15 psi (103.43 kPa)) The reaction mixture was stirred for 4 hours yielding the title compound in 53% yield.1H NMR (300 Hz , CDCl 3): d 1, 03 (d, 3 H, J = 6.24 Hz), 1, 96-2.03 (m, 1 H), 2.12-2.21 (m, 1 H), 2 , 27 (s, 1 H), 234 (s, broad, 1 H), 2.45-2.52 (m, 1 H), 2.73-2.92 (m, 4H), Mass Spectrum, M + 1 = 115. HRMS cale, for C6Hi5N2 115.1230, Found 115.1199. Stage 4 8- ( {5-Chloro-2 - [(3R) -3,4-dimethylpiperazin-1-yl) sonicotinoyl .}. amino) -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 214 starting from 8 - [(2,5-dichloroisonicotinoyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-1 H-benzo [g ] indazole-3-carboxamide (Example 248) (0.434 g, 0.87 mmol) and (2R) -1,2-dimethylpiperazine (step 3) (0.9 g, 7.8 mmol) in 5 mL of EtOH. The reaction was carried out at 100 ° C for 4 days. The whitish precipitate that formed in the crude reaction mixture was filtered and washed with EtOH yielding the title compound in 55% yield. 1 H NMR (400 MHz, de-DMSO): d 1.0 (d, 3H, J = 6.17 Hz), 1.96-2.0 (m, 1H), 2.05-2.06 (m , 1H), 2.15 (s, 3H), 2.48-2.54 (m, 1H), 2.74 (d, broad, 1H, J = 11.5 Hz), 2.85-2, 93 (m, 4H), 4.01-4.09 (m, 2H), 6.89 (s, 1H), 7.21 (d, 1H, J = 2.0 Hz), 7.27 (s) , 1H), 7.29-7.38 (m, 2H), 7.41 (dd, 1 H, J = 8.2 Hz, 2.0 Hz), 7.53-7.58 (m, 2H) ), 8.11 (s, 1H), 10.33 (s, 1H). HRMS cale, for C3oH3oCIFN702 574.2128, Found 574.2094. EXAMPLE 475 8- (. {5-Chloro-2 - [(3S) -3,4-dimethyl-piperazin-1-yl] -sonicotinyl} -amino) -1- (4-fluorophenyl) -4.5- dihydro-1H-benzo [g] indazol-3-carboxamide Stage 1 (3S) -3-methylpiperazine-1-carboxylic acid benzyl ester The compound of Step 1 was synthesized by the same procedure as for step 1 of Example 473 starting from 2- (S) -methylpiperazine (6 g, 59.9 mmol), triethylamine (6.04 g, 8.32 ml 59.7 mmol) and benzyl chloroformate (10.62 g, 59.2 mmol) in 100 ml of CHCl3. Purification by chromatography on silica gel (CH2Cl2 / eOH: 12/1) afforded the title compound in 22% yield. 1 H NMR (300 MHz, CDCl 3): d 1, 05 (d, 3 H, J = 6.2 Hz), 1.89 (s, H), 2.48 (s, broad, H), 2.7- 2.97 (m, 4H), 4.02 (s, broad, 1H), 5.12 (s, 2H), 7.32-7.35 (m, 5H). Stage 2 (3S) -3,4-Dimethyl-piperazine-1-carboxylate benzyl The compound of Step 2 was synthesized by the same procedure as for step 2 of Example 473 starting from the compound of Step 1 (3.1 g, 13 mmol), formaldehyde (1.2 g, 1.1 ml, mmol) and NaHB (OAc) 3 (4.09 g, 19 mmol) in 50 ml of dichloroethane yielding the title compound in 96% yield. 1 H NMR (300 MHz, CDCl 3): d 1.05 (d, 3 H, J = 6 Hz), 2.02-2.05 (m, 1 H), 2.13-2.21 (m, 1 H ), 2.28 (s, 3H), 2.71-2.75 (m, 2H), 3.08 (t, 1 H, J = 1.5 Hz), 3.95-3.99 (m , 2H), 5.12 (s, 2H), 7.32-7.36 (m, 5H). Stage 3 (2S) -2-Meti I pi perazine ?? ^ N- (2S) -2-methylpiperazine was synthesized by the same procedure as for step 3 of Example 473 starting from the material of step 2 (3.1 g, 12.4 mmol), (Pd / C (5%, 1 , 37g) in 25 ml MeOH in an atmosphere of H2 (15 psi (103.43 kPa)) The reaction mixture was stirred for 4 hours yielding the title compound in 55% yield.1H NMR (300 MHz, CDCl 3): d 1.03 (d, 3H, J = 6.24 Hz), 1.97-2.03 (m, 1 H), 2.12-2.21 (m, 1 H), 2, 27 (s, 1H), 2.42 (s, broad, 1 H), 2.45-2.52 (m, 1 H), 2.73-2.92 (m, 4H), Mass Spectrum, M + 1 = 115. Step 4 8- ( {5-Chloro-2 - [(3S) -3,4-dimethylpiperazin-1-yl] isonicotinoyl}. Amino) -1- (4-fluorophenyl) ) -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 214 starting from 8 - [(2,5-dichloroisonicotinoyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-1 H-benzo [g ] indazole-3-carboxamide (Example 248) (0.380 g, 0.76 mmol) and (2S) -2-methylpiperazine (step 3) (0.79 g, 6.8 mmol) in 3 ml of EtOH. The reaction was carried out at 100 ° C for 3 days. The whitish precipitate that formed in the crude reaction mixture was filtered and washed with EtOH yielding the title compound in 55% yield. 1 H NMR (400 MHz, oVD SO): d 1, 0 (d, 3 H, J = 6.17 Hz), 1.96-1.98 (m, 1 H), 2.02-2.09 (m , 1 H), 2.16 (s, 3 H), 2.48-2.54 (m, 1 H), 2.74 (d, broad, 1 H, J = 11, 7 Hz), 2.85- 2.93 (m, 4H), 4.02-4.09 (m, 2H), 6.89 (s, 1 H), 7.21 (d, 1 H, J = 2.0 Hz), 7 , 27 (s, 1 H), 7.29-7.38 (m, 2H), 7.41 (dd, 1H, J = 8.2 Hz, 2.0 Hz), 7.54-7.58 (m, 2H), 8.11 (s, 1 H), 10.33 (s, 1 H). HRMS cale, for CaoHaoCIFNyOz 574.2128, Found 574.2098. Example 476 8-. { [5-Chloro-2- (4-ethylpiperazin-1-yl) isonicotinoyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The title compound of Example 248 (8 - [(2,5-dichloroisonicotinoyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide) (1 81 mmol) and 1-ethyl piperazine (18.1 mmol) were combined with 4.5 ml of DMA. The reaction mixture was introduced under a nitrogen atmosphere and stirred in an oil bath at 100 ° C for 21 hours. The mixture was added to water, forming a precipitate, which was filtered and washed with water. The solid was dissolved in acetonitrile, dried over MgSO4, filtered and washed with acetonitrile. Mp: 251-254 ° C. Mass Spectrum: M + 1 = 574. EXAMPLE 477 8- [5-Chloro-2- (4-isopropylpiperazin-1-yl) isonicotinoyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide The title compound of Example 248 (8 - [(2,5-dichloroisonicotinoyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide) (1, 81 mmol) and (1-isopropyl) piperazine (18.1 mmol) were combined with 4.5 ml of DMA. The reaction mixture was introduced under a nitrogen atmosphere and stirred in an oil bath at 100 ° C for 21 hours. The mixture was added to water, forming a precipitate, which was filtered and washed with water. The solid was dissolved in acetonitrile, dried over MgSO4 and the solvent was distilled. The product was subsequently filtered and washed with acetonitrile. Mp: 220-226 ° C. Mass Spectrum: M + I = 588. EXAMPLE 478 8 ^ [5-Chloro-2- (4-methylpiperazin-1-yl) isonicotinoyl] amino} -1-pyridin-4-yl-4,5-dihydro-1H-benzo [g] indazole-3-carboxamide Step 1 8 - [(2,5-Dichloro-sonicotinoyl) amino] -1-pyridin-4-yl -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The compound of Step 1 was synthesized by the same procedure as in Example 211, starting from 8-amino-1-pyridin-4-yl-4,5-dihydro-1 H -benzo [g] indazol-3. -carboxamide (1.56 g, 5.1 mmol), 2,5-dichloroisonicotinic acid (1.47 g, 7.6 mmol), HATU (2.91 g, 7.3 mmol) and? ¾? (2.85 g, 2.07 mL, 28 mmol) in DMF (25 mL). The crude reaction mixture was concentrated and the product precipitated after the addition of water and filtered. Trituration in 250 mL of hot CH3CN afforded the title compound as a yellow solid, 40% yield. 1 H NMR (400 Hz, or DMSO): d 2.92 (s, 4H), 7.33-7.4 (m, 3H), 7.52 (dd, 1H, J = 8.15 Hz, 2 Hz ), 7.62-7.64 (m, 3H), 7.8 (s, 1H), 8.61 (s, 1H), 8.74 (dd, 2H, J = 4.6 Hz, 1, 5 Hz), 10.61 (s, 1H). Mass Spectrum, M + 1 = 480. Stage 2 8-. { [5-Chloro-2- (4-methyl-piperazin-1-yl) isonicotinoyl] amino} -1-pyridin-4-yl-4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 214 starting from the compound of Step 1 (0.8 g, 1.66 mmol) and N-methylpiperazine (3 g, 3.34 mL, 30 mmol) in 1 , 5 ml of EtOH. The reaction was carried out at 100 ° C for 2 days. The white precipitate that formed in the crude reaction mixture was filtered and washed with EtOH yielding the title product, yield: 73%. H NMR (400 MHz, cfe-DMSO): d 2.16 (s, 3H), 2.32 (t, 4H, J = 4.8 Hz), 2.9 (s, 4H), 3.47 ( t, 4H, J = 4.8 Hz), 6.89 (s, 1 H), 7.34-7.38 (m, 3H), 7.54 (dd, 1 H, J = 8.3 Hz , 2 Hz), 7.60-7.61 (m, 3H), 8.12 (s, 1 H), 8.72 (dd, 2H, J = 4.5 Hz, 1.6 Hz), 10 , 4 (s, 1 H). Mass Spectrum, M + 1 = 544. Example 479 1- (1,3-Benzodioxol-5-yl) -8- ( { [5-chloro-2- (4-methyl-piperazin-1-yl) pyrimidine- 4-yl] carbonyl.} Amino) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide Step 1: 5-Chloro-2- (methylsulfonyl) -4-pyrimidinecarboxylic acid 5-Chloro-2- (methylsulfonyl) -4-pyrimidinecarboxylic acid was prepared by the procedure of Liang Yong-min, Luo Sheng ^ un, Zhang Zhao-xin and Ma Yong-xiang, Synthetic Commun., 32 (1), 153-157, 2002. Step 2 1- (1,3-Benzodioxol-5-yl) -8- ( { [5-chloro-2- (methylsulfonyl) pyrimidin-4-yl] carbonyl} amino) -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide The title compound of Step 2 was synthesized by the same procedure as in Example 211 starting from 5-chloro-2- (methylsulfonyl) -4-pyrimidinecarboxylic acid (step 1) (0.987 g, 4.17 mmol) , Example 161, step 3 (8-amino-1- (1, 3-benzodioxol-5-yl) -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide) (0.968 g, 2.78 mmol), HATU (1.58 g, 4, 15 mmol) and Et3N (1.54 g, 1.12 ml, 15 mmol) in DMF (8 ml). Trituration with CH2Cl2 yielded the title compound in 38% yield. 1 H NMR (400 MHz, cfe-DMSO): d 2.86-2.91 (m, 4H), 3.42 (s, 1 H), 6.05 (s, 2H), 6.94 (dd, 1 H, J = 8.2 Hz, 2 Hz), 7 (d, 1 H, J = 2.2 Hz), 7.1 (d, 1 H, J = 2 Hz), 7.23-7, 26 (m, 2H), 7.31-7.37 (m, 2H), 7.48 (s, 1 H), 9.35 (s, 1H), 10.73 (s, 1 H). Mass Spectrum, M + 1 = 567. Step 3 1- (1,3-Benzodioxol-5-yl) -8- ( { [5-Chloro-2- (4-methyl-piperazin-1-yl) pyrimidine- 4-yl] carbonyl.] Amino) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 214 starting from the compound of Step 2 (0.625 g, 1.1 mmol) and N-methylpiperazine (1.98 g, 2.2 ml, 20 mmol) in 3 ml EtOH. The reaction was carried out at 95 ° C for 2.5 hours. The volatile components were removed and the residue was partitioned between H20 and CH2Cl2. The organic extracts were dried over MgSO4. Purification by preparative reverse phase HPLC yielded the title product in 16% yield. 1 H NMR (400 MHz, oVDMSO): d 2.18 (s, 3 H), 2.33 (t, 4 H, J = 4.7 Hz), 2.86-2.92 (m, 4 H), 3, 67 (t, 4H, J = 4.7 Hz), 6.08 (s, 2H), 6.94 (dd, 1H, J = 8.2 Hz, 2.1 Hz), 7 (d, 1 H) , J = 8.2 Hz), 7.1 (d, 1 H, J = 2 Hz), 7.27-7.31 (m, 2H), 7.4 (dd, 1 H, J = 8, 2 Hz, 2 Hz), 7.49 (s, 1 H), 8.5 (s, 1 H), 10.34 (s, 1 H). Mass Spectrum, M + 1 = 567. EXAMPLE 480 8- ( { [5-Chloro-2- (4-methyl-piperazin-1-yl) -pyrimidin-4-yl] -carbonyl} -amino) -1- ( 4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide Step 1 8- ( { [5-Chloro-2- (4-methyl-piperazin-1-yl) -pyrimidine-4- il] carbonyl.} amino) -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The compound of Step 1 was synthesized by the same procedure as in Example 211 starting from the compound of Step 1 of Example 479 (2.7 g, 11.4 mmol), 8-amino-1- (1,3- benzodioxol-5-yl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide (2.45 g, 7.6 mmol), HATU (4.32 g, 11.3 mmol) and EI3N (2.17 g, 3 mL, 21 mmol) in DMF (8 mL). Purification by preparative reverse phase HPLC afforded the title compound in 62% yield. 1 H NMR (400 MHz, oVDMSO): d 2.88-2.92 (m, 4H), 3.41 (s, 3H), 7.22 (s, broad, 1H), 7.25 (s, broad). , 1H), 7.34-7.37 (m, 4H), 7.52-7.58 (m, 3H), 9.34 (s, 1 H), 10.72 (s, 1 H). Mass Spectrum, M + 1 = 541. Step 2 8- ( { [5-Chloro-2- (4-methyl-piperazin-1-yl) -pyrimidin-4-yl] -carbonyl} -amino) -1- ( 4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide The title compound was synthesized by the same procedure as in Example 214 starting from the material of step 1 (0.9 g, 1.66 mmol) and N-methylpiperazine (1.66 g, 1.84 mi, 16%). 5 mmol) in 3 ml of EtOH. The reaction was carried out at 45 ° C for 7 hours. The yellow precipitate that formed in the crude reaction mixture was filtered and purified by reverse phase preparative HPLC yielding the title product in 15% yield. 1 H NMR (400 MHz, cfe-D SO): d 2.18 (s, 3 H), 2.32 (t, 4 H, J = 4.9 Hz), 2.88-2.93 (m, 4 H) , 3.68 (t, 4H, J = 4.9 Hz), 7.18 (t, 1H, J = 2.4 Hz), 7.27 (s, 1H), 7.31-7.39 ( m, 3H), 7.42 (dd, 1 H, J = 8.2 Hz, 2 Hz), 7.53-7.59 (m, 3H), 8.49 (s, 1 H), 10.412 ( s, 1 H). Mass Spectrum, M + 1 = 562. The bioactivity in the IKK2 resin assay of the compounds of Examples 452-480 is shown in Table 24 Table 24 BIOLOGICAL EVALUATION Materials The Biotin SAM2 ™ 96 capture plates were from Promega. The affinity resin Anti-FLAG, the FLAG peptide, NP-40 (Nonidet P-40), BSA, ATP, ADP, AMP, LPS fserotype 0111: B4 from E. coli) and dithiothreitol were obtained from Sigma Chemicals. Antibodies specific for NEMO (????) (FL-419), IKK1 (H-744), I K2 (H-470) and ??? a (C-21) were purchased from Santa CBiotechnology. The Ni-NTA resin was purchased from Qiagen. The peptides were purchased from the American Peptide Company. The tablets of the protease inhibitor cocktail were from Boehringer Mannheim. The Sephacril S-300 column was from Pharmacia LKB Biotechnology. Concentrators Centriprep-10 with a molecular weight cut-off of 10 kDa and membranes with a molecular weight cut-off of 30 kDa were obtained from Amicon. The [? -33?] ATP (2500 Ci / mmol) and [? -32?] ??? (6000 Ci / mmol) were purchased in Amersham. The other reagents were of the highest quality available in the market. Cloning and Expression The human IKK1 and IKK2 cDNAs were amplified by polymerase-reverse transcriptase chain reaction from human placental RNA (Clonetech). HlKK1 was subcloned into pFastBac HTa (Life Technologies) and expressed as N-terminal fusion protein labeled with HiS6. The hl 2 cDNA was amplified using an inverse oligonucleotide primer incorporating the peptide sequence for a FLAG-epitope tag at the C-terminus of the IKK2 coding region (DYKDDDDKD). The hlKK2: FLAG cDNA was subcloned into the baculovirus vector pFastBac. The mutant rhlKK2 (S 177S, E177E) was constructed in the same vector used for the wild-type rhlKK2 using a QuikChange ™ mutagenesis kit (Stratagene). The viral stock solutions of each construct were used to infect insect cells cultured in 40 I suspension culture. The cells were lysed at the time of maximum expression and the rhIKK activity was demonstrated. The cell lysates were stored at -80 ° C until the purification of the recombinant proteins was performed as described below. Enzyme Isolation All purification procedures were performed at 4 ° C unless otherwise indicated. The buffers used were: buffer A: 20 mM Tris-HCl, pH 7.6, containing 50 mM NaCl, 20 mM NaF, 20 mM β-glycerophosphate, 500 μM sodium orthovanadate, 2.5 mM metabisulfite, 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 150 mM NaCl and buffer C: same as buffer A, except 500 mM NaCl. Isolation of the homodimer rhIKKI Cells were centrifuged from an 8 I fermentation of IKK1 expressed in baculovirus labeled with the His peptide and the cell pellets (MOI 0.1, I = 72 hours) were resuspended in 100 ml of buffer C. The cells were microfluidized and centrifuged at 100,000 X g for 45 minutes. The supernatant was collected, 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 homodimer rhIKKI was eluted using 300 mM imidazole in buffer C. BSA was added and NP-40 to the enzymatic fractions up to a final concentration of 0.1%. The enzyme was dialyzed against buffer B, was divided into aliquots and stored at -80 ° C. Isolation of the homodimer rhlKK2 A culture of 10 liters of IKK2 expressed in baculovirus labeled with the FLAG peptide was centrifuged and the cell pellet (MOI = 0, 1 and I = 72 hours) was resuspended in buffer A. These cells were microfluidized and centrifuged to 100,000 X g for 45 minutes. The supernatant was passed through a G-25 column equilibrated with Buffer A. The protein peak was collected and incubated with anti-FLAG affinity resin on rotating equipment overnight in buffer B. The resin was washed in batches with 10- 15 bed volumes of buffer C. The washed resin was poured into a column and the rhlKK2 homodimer was eluted using 5 bed volumes of buffer B containing the FLAG peptide. 5mM DTT, 0.1% NP-40 and BSA (concentrated to 0.1% in final amount) were added to the eluted enzyme before concentrating using an Amicon membrane with a molecular weight cut-off of 30 kDa. The enzyme was aliquoted and stored at -80 ° C. Isolation of the heterodimer rhlKKI / IKK2 The heterodimeric enzyme was produced by coinfection in a baculovirus system (FLAG IKK2 / IKK1His, MOI = 0.1 and I = 72 hours). 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 X g for 45 minutes. Imidazole was added to the supernatant at a final concentration of 10 mM. The protein is bound 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, which contained 300 mM imidazole, was subsequently used to elute the protein. A combination of 75 ml was collected and NP-40 was added to a final concentration of 0.1%. The protein solution was subsequently dialyzed against buffer B. The dialyzed heterodimeric enzyme was then linked to 25 ml of anti-FLAG M2 agarose affinity gel overnight with constant mixing. The protein-resin suspension was then centrifuged for 5 minutes 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 resin was washed with 375 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. Enzyme fractions (100 ml) were collected and concentrated to 20 ml using an Amicon membrane with molecular weight cut-off of 30 kDa. Bovine serum albumin was added to the concentrated enzyme at a final concentration of 0.1%. Then, the enzyme was aliquoted and stored at -80 ° C. Cell Culture The pre-B wild type (wt), 70Z / 3 human cell line and its mutant, 1.3E2, were generously provided by Dr. Carol Sibley. The 70Z / 3 wt and 1.3E2 cells were cultured in RPMI 1640 (Gibco) supplemented with bovine serum defined at 7% (Hyclone) and 2-mercaptoethanol 50 μ ?. THP-1 cells of human monocytic leukemia, obtained in 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 placed in 6-well plates with 1x106 cells / ml in fresh medium. The pre-B cells were stimulated with the addition of 10 μ9 / ??? of LPS for different periods of time in the range of 0-4 hours. THP-1 cells were stimulated by the addition of 1 μ9 ??? of LPS for 45 minutes. The cells were agglomerated, washed with cold 50 mM sodium phosphate buffer, pH 7.4 containing 0.15 M NaCl and lysed at 4 ° C in 20 mM l-lepes buffer, pH 7.6 containing 50 mM NaCl. , 1 mM EDTA, 1 mM EGTA, 1 mM sodium orthovanadate, 10 mM β-glycerophosphate, 1 mM NaF, 1 mM PMSF, 1 mM DTT and 0.5% NP40 (lysis buffer). The cytosolic fractions obtained after centrifugation at 10,000 g were stored at -80 ° C until use. Immunoprecipitation and Western Blotting A paste of SF9 cells containing rhIKK (100,000 X g, 10 min) was centrifuged to remove the debris. The rhIKK were immunoprecipitated (100 μg of cell paste) from the cell supernatant using 3 μg of anti-NEMO antibody (FL-419), followed by coupling to protein A sepharose beads. The rhIKK was also immunoprecipitated from purified protein preparations by affinity chromatography (1 μg) using anti-FLAG, anti-His or anti-NEMO antibodies (1-4 μg) followed by coupling to protein A sepharose beads. The native human IKK complex was immunoprecipitated to Starting from homogenates of THP-1 cells (300 μg / condition) using the anti-NEMO antibody. The immune complexes were pelleted and washed 3 times with 1 ml of cold lysis buffer. The immunoprecipitated rhIKKs were chromatographed by SDS-PAGE (Tris-glycine 8%) and transferred to nitrocellulose membranes (Novex) and detected by chemiluminescence (SuperSignal) using specific anti-IKK antibodies (IKK2 H-470, IKK1 H-744 ). The native IKK2, IkBa and NEMO proteins of the cytosolic lysates (20-80 μg) were separated by SDS-PAGE and visualized by chemiluminescence using specific antibodies. Treatment with Phosphatase The immunoprecipitated rhIKK were washed 2 times in 50 mM Tris-HCl, pH 8.2 containing 0.1 mM EDTA, 1 mM DTT, 1 mM PMSF and 2 mM MnCl2 and resuspended in 50 μM. The phosphatase (APPase, 1000 U) was pre-diluted in the same buffer and added to the IKK samples. After incubating at room temperature for 30 minutes with intermittent mixing, cold lysis buffer was added to the tubes to interrupt the reaction. After several washes, 10% of the beads were removed for Western analysis and the remaining material was pelleted and resuspended in 100 μ? of the buffer used for the in vitro kinase assay. IKKa SAM Enzyme Assay IKKa kinase activity was measured using a biotinylated peptide (Gly-Leu-Lys-Lys-Glu-Arg-Leu-Leu-Asp-Asp-Arg-His-Asp-Ser32-Gly) -Leu-Asp-Ser36-Met-Lys-Asp-Glu-Glu), a capture plate Biotin SAM2 ™ 96 and a vacuum system. The standard reaction mixture contained biotinylated peptide ??? at 5 μ ?, [? - ^?] ATP 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 incubation at 25 ° C for 30 minutes, 25 μ? of the reaction mixture and were added to a 96-well capture plate SAM2 ™ 96. Then, each well was washed successively with 800 μ? of NaCI 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 bell at 25 ° C for 1 hour and then 25 μ? of scintillation fluid (Microscint 20) to each well. Incorporation of [? -33?] ATP was measured using a Top-Count NXT (Packard). In each of the assay conditions, the degree of phosphorylation of the peptide substrate αα was linear over time and the concentration of all purified enzymes. The results of the biotinylated peptide assay were confirmed by SDS-PAGE analysis of the kinase reaction using a GST-lkBon-54 and [? -32?] ATP. The resulting radiolabeled substrate was quantified with Phosphoimager (Molecular Dynamics). An ion exchange resin assay was also employed using [y-33P] ATP and GST-lkBai-M fusion protein as substrates. Each test system provided consistent results in relation to Km and the specific activities of each of the purified kinase isoforms. One unit of enzymatic activity was defined as the amount required to catalyze the transfer of 1 nmole of ATP phosphate to the peptide ??? a per minute. The specific activity was expressed as units per mg of protein. For experiments related to the determination of Km of purified enzymes, various concentrations of ATP or peptide were used in the assay in a fixed concentration of αα or ATP concentration. For the Km of the peptide? A, assays were performed with 0.1 μg of enzyme, 5 μP ATP? and peptide ??? a from 0.5 to 20 μ. For the Km of the ATP, tests were carried out with 0.1 μg of enzyme, peptide ??? to 10 μ? and ATP from 0.1 to 10 μ ?. For the determination of the Km of the rhIKKI homodimer, due to its low activity and greater Km for the peptide Δα, the homodimer rhIKKI (0.3 μ9) was analyzed with peptide 1α to 125μ? and a 5-fold higher specific activity of ATP (from 0.1 to 10 μm) for the ATP Km experiments and a 5-fold higher specific activity of 5 μP ATP and α-peptide (from 5 to 200 μ? ) for experiments of the Km of the peptide ??? a. Enzyme Assay? ß in Resin The kinase activity? Β was measured using a biotinylated peptide ??? a (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). 20 μ? of the standard reaction mixture contained biotinylated peptide IkBa 5 μ ?, 0, 1 ?? / p38? a ?? [? -33?] ATP (Amersham) (approximately 1 X 105 cpm), ATP 1 μ? (Sigma), 1 mM DTT (Sigma), 2 mM gCI2 (Sigma), 2 mM MnCl2 (Sigma), 10 mM NaF (Sigma), 25 mM Hepes buffer (Sigma), pH 7.6 and 20 μM? of enzymatic solution and 10 μ? of inhibitor in a final volume of 50 μ ?. After incubation at 25 ° C for 30 minutes, 50 μ? of resin (Dowex AG1X8 anion exchange resin 200-400 mesh) in 900 mM formate, pH 3.0 was added to each well to interrupt the reaction. The resin was allowed to stand for one hour and 50 μ? of supernatant to a plain bottom plate Micolite-2 (Dynex). 150 μ? of scintillation fluid (Microscint 40) (Packard) to each well. Incorporation of [? -33?] ATP was measured using a Top-Count NXT (Packard). Enzyme Assay with IKK Heterodimer in Resin The kinase activity of the IKK heterodimer 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.). 20 μ? of the standard reaction mixture contained biotinylated peptide? ? a 5 μ ?, 0.1 μ ?? / Gßß? a ?? [? -?] ATP (Amersham) (approximately 1 X 105 cpm), ATP 1 μ? (Sigma), 1 mM DTT (Sigma), 2 mM MgCl 2 (Sigma), 2 mM MnCl 2 (Sigma), 10 mM NaF (Sigma), 25 mM Hepes buffer (Sigma), pH 7.6 and 20 μM? of enzymatic solution and 10 μ? of inhibitor in a final volume of 50 μ ?. After incubation at 25 ° C for 30 minutes, 150 μ? of resin (Dowex AG1X8 anion exchange resin 200-400 mesh) in 900 mM formate, pH 3.0 was added to each well to interrupt the reaction. The resin was allowed to stand for one hour and 50 μ? of supernatant to a plain bottom plate Micolite-2 (Dynex). 150 μ? of scintillation fluid (Microscint 40) (Packard) to each well. Incorporation of [? -33?] ATP was measured using a Top-Count NXT (Packard).

Claims (35)

  1. The compound of Formula wherein B is a 5 or 6 membered saturated or saturated heteroaryl, aryl, heterocyclyl ether wherein said aryl, heteroaryl, or heterocyclyl are optionally substituted with R1, R2 and R12; W is a 5 or 6 membered heteroaryl, aryl, saturated or unsaturated heterocyclyl; 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 where R6 and R7 can be taken together to form a 3- to 7-membered carbocyclic ring having from 1 to 3 substituted or unsubstituted heteroatoms selected from the group consisting of: 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 where R6 and R7 can be taken together to form a 3- to 7-membered carbocyclic ring having from 1 to 3 heteroatoms substituted or not substituted ones 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, SR5, NHR6, CON (R6) R7, NHCONHR6, CO2H and haloalkyl; R1 and R2 may be taken together to form a 5-7 membered saturated or unsaturated carbocyclic ring optionally containing 0 to 3 heteroatoms selected from the group consisting of N, 0 or S and wherein said ring is optionally substituted with R1; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclylalkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclylalkyl, or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of OR14, N (R1) R1 and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclylalkyl, and heterocyclyl; R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclylalkyl, and heterocyclyl; R 12 is selected from the group consisting of: hydrido, halogen, alkyl and alkoxy; R15 is selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl wherein said alkyl is optionally substituted with a carbocyclyl or heterocyclyl where said carbocyclyl or heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogen, (CH2) nC ( R ') R' wherein n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R') R 'where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR' where n is 0 to 4 and R 'is selected from the group compue This is by hydride, hydroxy, amino and alkyl; alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanato, isothiocyanato, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy and heterocyclyl where said heterocyclyl is optionally substituted with one to six selected substituents among the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogen, (CH2) nC (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl or, (CH2) nNHC (0) OR 'where n is 0 to 4 and R "is selected from the group consisting of hydrido, hydroxy, amino and alkyl, R is selected from the group consisting of. alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4], C02 (alkyl), CON ( alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; and R18 is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4], C02 (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; or isomers, tautomers, vehicles, esters, prodrugs and pharmaceutically acceptable salts thereof.
  2. 2. The compound of claim 1, wherein R16 is selected from the group consisting of: hydrido, halogen and lower alkyl.
  3. 3. The compound of claim 2 of Formula wherein B is a 5 or 6 membered saturated or unsaturated heteroaryl, aryl, heterocyclyl ether wherein said aryl, heteroaryl, or heterocyclyl are optionally substituted with R1, R2 and R12; 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 NR6SOzR7, NR6S02NHR7, and S02N (R6) R7 where R6 and R7 can be taken together to form a 3- to 7-membered carbocyclic ring having from 1 to 3 substituted or unsubstituted heteroatoms selected from the group consisting of: 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 where R6 and R7 can be taken together to form a 3- to 7-membered carbocyclic ring having 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; R1 and R2 can be taken together to form a 5-7 membered saturated or unsaturated carbocyclic ring 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; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclylalkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclylalkyl, or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of OR14, N (R1) R14 and glycols; Rs is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclylalkyl, and heterocyclyl; R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclylalkyl, and heterocyclyl; R 2 is selected from the group consisting of: hydrido, halogen, alkyl and alkoxy; R 5 is selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl wherein said alkyl is optionally substituted with a carbocyclyl or heterocyclyl wherein said carbocyclyl or heterocyclyl are optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R') R ' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR' where n is 0 to 4 and R 'is selected from the group consisting by hydride, hydroxy, amino and alkyl; alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanato, isothiocyanato, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy and heterocyclyl wherein said heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC ( R ') R' where n is 0 to 4 and each R 'is it is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy , amine and alkyl, (CH2) nNHC (0) OR 'where n is 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino and alkyl, R is selected from the group consisting of: alkyl, hydroxyalkyo, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4 ], C02 (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; and R18 is selected from the group consisting of: alkyl, hydroxyalkio, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4], C02 (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; or isomers, tautomers, vehicles, esters, prodrugs and pharmaceutically acceptable salts thereof.
  4. 4. The compound of claim 3 of Formula wherein B is a 5 or 6 membered saturated or unsaturated heteroaryl, aryl, heterocyclyl wherein said aryl, heteroaryl, or heterocyclyl are optionally substituted with R1, R2 and R12; R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, N02, OR5, OCOOR5, C02R7, CON (R6 /? 7, COR6, SR6, SOR6, S02R6, NR6R7, NR6COR7, NR6CONHR7, NR6S02R7, NR6S02NHR7, and S02N (R6) R7 where R6 and R7 may be taken together to form a 3- to 7-membered carbocyclic ring having from 1 to 3 substituted or unsubstituted heteroatoms selected from the group consisting of : 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, C0N (R6) R7, COR6, SR6, SOR6, S02R6, NR6R7, NR6COR7, NR6CONHR7, NR6S02R7, NR6S02NHR7 and S02N (R6) R7 where R6 and R7 can be taken together to form a carbocyclic ring of 3 to 7 members having from 1 to 3 substituted or unsubstituted heteroatoms selected from the group consisting of or: 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 may be taken 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; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclylalkyl and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclylalkyl, or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of OR14, N (R1) R1 and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclylalkyl, and heterocyclyl; R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclylalkyl, and heterocyclyl; R 12 is selected from the group consisting of: hydrido, halogen, alkyl and alkoxy; wherein the piperazine is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen , cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR 'where n is 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino and alkyl; or isomers, tautomers, vehicles, esters, prodrugs and pharmaceutically acceptable salts thereof.
  5. 5. The compound of claim 1 of the Formula wherein W is a 5 or 6 membered heteroaryl, aryl, saturated or unsaturated heterocyclyl; R15 is selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl wherein said alkyl is optionally substituted with a carbocyclyl or heterocyclyl wherein said carbocyclyl or heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC ( R ') R' wherein n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R') R 'where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR' where n is 0 to 4 and R 'is selected from the group consisting of or by hydrido, hydroxy, amino and alkyl; alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanato, isothiocyanato, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy and heterocyclyl wherein said heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (a! quil) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R' where n is 0 to 4 and each R 'is s independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R ') R' where n is from 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR 'where n is 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino and alkyl, R is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4 ], C02 (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; and R 8 is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH 2) nOH [n = 0 a 4], C02 (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; or isomers, tautomers, vehicles, esters, prodrugs and pharmaceutically acceptable salts thereof.
  6. 6. The compound of claim 5, wherein R16 is selected from the group consisting of: hydrido, halogen and lower alkyl.
  7. 7. The compound of claim 6 of Formula, wherein R15 is selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl wherein said alkyl is optionally substituted with a carbocyclyl or heterocyclyl wherein said carbocyclyl or heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino , aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R') R 'where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR' where n is 0 to 4 and R 'is selected from the group consisting of hydrido, hydroxy , amino and alkyl; alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, 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, alkynylamm, alkenyl, alkynyl, dialkylaminoalkyloxy and heterocyclyl wherein said heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkylamino), alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R' where n is 0 to 4 and each R 'is s independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy , amino and alkyl, (CH2) nNHC (0) OR 'where n is 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino and alkyl, R is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4 ], C02 (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; and R18 is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4], C02 (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; or isomers, tautomers, vehicles, esters, prodrugs and pharmaceutically acceptable salts thereof.
  8. 8. The compound of claim 7 wherein R15 is piperazine attached to the 1-position of the piperazine and said piperazine is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R') R 'where n is 0 to 4 and each R' is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR 'where n is 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino and alkyl.
  9. 9. The compound of claims 7 or 8 selected from the group consisting of 8-. { [5-Chloro-2- (4-methyl-piperazin-1-yl) isonicotinoyl] amino} -1- [4- (Methylsulfonyl) phenyl] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide, and 8 - [(2,5-Dichloroisonicotinoyl) amino] -1- [4- (methylsulfonyl) phenyl] -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide.
  10. 10. The compound of claim 1 of Formula wherein W is a 5 or 6 membered heteroaryl, aryl, saturated or unsaturated heterocyclyl; R15 is selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl wherein said alkyl is optionally substituted with a carbocyclyl or heterocyclyl wherein said carbocyclyl or heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC ( R ') R' wherein n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R') R 'where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR' where n is 0 to 4 and R 'is selected from the group consisting by hydrido, hydroxy, amino and alkyl; alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanato, isothiocyanato, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy and heterocyclyl wherein said heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R') R ' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR' where n is 0 to 4 and R 'is selected from the group consisting by hydride, hydroxy, amino and alkyl, and R is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4 ], (^ (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkylalkyl, arylalkyl and heteroarylalkyl, and R 8 is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4], C02 (alkyl), CON (alkyl) (alkyl) , formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, anlalkyl and heteroarylalkyl, or isomers, tautomers, vehicles, esters, prodrugs and pharmaceutically acceptable salts thereof.
  11. 11. The compound of claim 10, wherein R16 is selected from the group consisting of: hydrido, halogen, and lower alkyl.
  12. 12. The compound of claim 11 of Formula wherein R15 is selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl wherein said alkyl is optionally substituted with a carbocyclyl or heterocyclyl wherein said carbocyclyl or heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino , aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2 ) nC (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R') R 'where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR' where n is 0 to 4 and R 'is selected from the group or composed of hydrido, hydroxy, amino and alkyl; alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanato, isothiocyanato, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy and heterocyclyl wherein said heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC ( R,) R 'where n is 0 to 4 and each R "is sel independently of the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy , amino and alkyl, (CH2) n NHC (0) OR 'where n is 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino and alkyl, R is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4 ], C02 (alkyl), CON (alk) (alkyl), formyl, cycloalkyl, heterocyclyl, hydroxylalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; and R18 is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4], C02 (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxylalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; or isomers, tautomers, vehicles, esters, prodrugs and pharmaceutically acceptable salts thereof.
  13. 13. The compound of claim 10, 11 or 12 selected from the group consisting of: 1- (1,3-Benzodioxol-5-yl) -8-. { [(6-chloro-4-methylpyridin-3-yl) carbonyl] amino} ) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide, 8- ( { [6- (Aminomethyl) -3-chloropyridin-2-yl] carbonyl} amino) -1 - (1,3-benzodioxol-5-yl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, 8- [2- (Aminomethyl) -5-chloroisonicotinoyl] amino} -1- (1,3-benzodioxol-5-yl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, 1- (1,3-Benzodioxol-5-yl) -8- ( { [3-Chloro-6- (morpholin-4-ylmethyl) pyridin-2-yl] carbonyl}. Amino) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, 1- (1,3-Benzodioxol-5-yl) -8 ^ [5-chloro-2- (2-morpholin-4-ylethyl) isonicotinoyl] arrino} -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, 1- (1,3-Benzodioxol-5-yl) -8-. { [(3-chloro-6-cyanopyridin-2-yl) carbonyl] amino} -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide 1- (1,3-Benzodioxol-5-yl) -8 - [(5-chloro-2-cyanoisonicotinoyl) amino] -4.5 -dihydro-1H-benzo [g] indazole-3-carboxamide, and 1- (1,3-benzodioxol-5-yl) -8- ( { [5-chlorch2- (methylsulfonyl) pyrimidin-4-yl] carbonyl, amino) -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide.
  14. 14. The compound of claim 12 wherein R15 is piperazine attached at the 1-position of the piperazine and said piperazine is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino , alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R') R 'where n is 0 to 4 and each R' is selected independently between the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR 'where n is 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino and alkyl.
  15. 15. The compound of claim 14 selected from the group consisting of: 1- (1,3-Benzodioxol-5-yl) -8- ( { [5-chloro-2- (4-methylpiperazin-1-yl) pyrimidine -4-yl] carbonyl.} Amino) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide.
  16. 16. The compound of claim 1 of Formula wherein W is a 5 or 6 membered heteroaryl, aryl, saturated or unsaturated heterocyclyl; R1 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, SR6, NHR6, CON (R6) R7, NHCONHR6 and haloalkyl; R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, SR6, NHR6, CON (R6) R7, NHCONHR6 and haloalkyl; R15 is selected from the group consisting of. alkylsulfonamide, sulfamyl, alkyl wherein said alkyl is optionally substituted with a carbocyclyl or heterocyclyl wherein said carbocyclyl or heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R') R 'where n is 0 to 4 and each R "is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR 'where n is 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino and alkyl; thio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanato, isothiocyanato, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy and heterocyclyl where said heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of a group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) ) nNHC (0) OR 'where n is 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino and alkyl, R17 is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4 ], C02 (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl. Arylalkyl and heteroarylalkyl; and R18 is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4], C02 (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; or isomers, tautomers, vehicles, esters, prodrugs and pharmaceutically acceptable salts thereof.
  17. 17. The compound of claim 16, wherein R2 is selected from the group consisting of: hydrido and halogen; R16 is selected from the group consisting of: hydrido, halogen and lower alkyl.
  18. The compound of claim 17 of Formula wherein R1 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, SR6, NHR6, CON (R6) R7, NHCONHR6 and haloalkyl; R2 is selected from hydrido and halogen; and R15 is selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl wherein said alkyl is optionally substituted with a carbocyclyl or heterocyclyl wherein said carbocyclyl or heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl , hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R') R 'where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR' where n is 0 to 4 and R 'is selected from the group consisting of by hydride, hydroxy, amino and alkyl; alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, bloxy, dialkylaminoacyl, thioalkyo, aminoacyloxy, thiocyanato, isothiocyanato, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy and heterocyclyl wherein said heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R' where n is 0 to 4 and each R 'is s independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy , amino and alkyl, (CH2) nNHC (0) OR 'where n is 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino and alkyl, R17 is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4 ], C02 (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; and R18 is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4], C02 (alkyl), CON (alkyl) (alkyl), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; or isomers, tautomers, vehicles, esters, prodrugs and pharmaceutically acceptable salts thereof.
  19. 19. The compound of claim 18 wherein R15 is piperazine attached at the 1-position of the piperazine wherein said piperazine is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoacylamino, dialkylaminoalkylamino , alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R') R 'where n is 0 to 4 and each R' is selected independently between the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR 'where n is 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino and alkyl.
  20. 20. The compound of claim 18 or 19 selected from the group consisting of: 8-. { [5-Chloro-2- (4-methyl-piperazin-1-yl) isonicotinoyl] amino} -1-pyridyl-4-yl-4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, and 8 - [(2,5-dichloroisonicotinoyl) ami no] -1-pyridin-4-yl-4,5-dihydro-1 H-benzo [g] ndazole-3-carboxamide.
  21. 21. The compound of claim 1 of Formula wherein W is a 5 or 6 membered heteroaryl, aryl, saturated or unsaturated heterocyclyl; R15 is selected from the group consisting of. alkylsulfonamide, sulfamyl, alkyl wherein said alkyl is optionally substituted with a carbocyclyl or heterocyclyl wherein said carbocyclyl or heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) n NHCON (R') R 'where n is 0 to 4 and each R' is independently selected between the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR 'where n is 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino and alkyl; alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, 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 heterocyclyl wherein said heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC ( R ') R' where n is 0 to 4 and each R '. is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R ') R' where n is 0 to 4 and each R "is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR 'where n is 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino and alkyl, R17 is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4 ], C02 (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; and R18 is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4], C02 (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; or isomers, tautomers, vehicles, esters, prodrugs and pharmaceutically acceptable salts thereof.
  22. 22. The compound of claim 21, wherein R16 is selected from the group consisting of: hydrido, halogen and lower alkyl.
  23. 23. The compound of claim 22 selected from the group consisting of: 1- (4-Fluorophenyl) -8 - [(2-morpholin-4-ylisonicotinoyl) amino] -4,5-dihydro-1H-benzo [g] indazole- 3-carboxamide.
  24. 24. The compound of claim 22 of Formula wherein R15 is selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl wherein said alkyl is optionally substituted with a carbocyclyl or heterocyclyl wherein said carbocyclyl or heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino , aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2 ) nC (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R') R 'where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR' where n is 0 to 4 and R 'is selected from the group composed of hydrido, hydroxy, amino and alkyl; alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanato, isothiocyanato, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy and heterocyclyl wherein said heterocyclyl is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl; alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R 'where n is 0 to 4 and each R' is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R ') R' where n is 0 to 4 and each R is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR 'where n is 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino and alkyl, R is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4 ], C02 (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; and R18 is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO (alkyl), CO (aryl), CO (CH2) nOH [n = 0 to 4], C02 (alkyl), CON (alkyl) (alkyl '), formyl, cycloalkyl, heterocyclyl, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl and heteroarylalkyl; or isomers, tautomers, vehicles, esters, prodrugs and pharmaceutically acceptable salts thereof.
  25. 25. The compound of claim 24 selected from the group consisting of: 8-. { [2- (Aminomethyl) -5-chloroisonicotinoyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, 8- ( { [3-Chloro-6- (morpholin-4-methyl) pyridin-2- il] carbonyl.} amino) -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, 8-. { [5-Chloro-2- (2-morpholin-4-ylethyl) isonicotinoyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, 8- (. {5-Chloro-2- [2- (d-methylamino) ethyl] isonicotinoyl .}. amino) -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide, 8-. { [(5-Chloro-2,4'-bipyridin-4-yl) carbonyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, 8-. { [(5-chloro-r-methyl-1 ', 2', 3 ', 6'-tetrahydro-2,4'-bipyridin-4-yl) carbonyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide, and 8-. { [5-chloro-2- (1,4-diazepan-1-yl) isonicotinoyl] amino} -1- (4-fluorophenyl) -4l5-dihydro-1 H -benzo [g] indazole-3-carboxamide.
  26. 26. The compound of claim 24 wherein R, s is piperazine attached at the 1-position of the piperazine wherein said piperazine is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino , dialkylaminoalkylamino, alkylamino (alkyl) amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogens, (CH2) nC (R ') R' where n is 0 to 4 and each R 'is independently selected from the group consisting of hydrido, hydroxy, amino, O, S and alkyl, (CH2) nNHCON (R') R 'where n is 0 to 4 and each R " it is independently selected from the group consisting of hydrido, hydroxy, amino and alkyl, (CH2) nNHC (0) OR 'where n is 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino and alkyl.
  27. 27. The compound of claim 26 selected from the group consisting of: 8- (. {5-Chloro-2- [4- (2-hydroxyethyl) piperazin-1-yl] isonicotynoyl}. 1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, 8- (. {5-Chloro-2- [4- (2-methoxyethyl) piperazin-1- il] -sonicotinoyl.}. amino) -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, 8 - [(5-chloro-2- { [2- (dimethylamino) ethyl] amino.}. Isonicotinoyl) amino] -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, 8- (. { 5-Chloro-2 - [(3R) -3-methyl-piperazin-1-yl] -isonicotinoyl] amino] -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole -3-carboxamide, 8- (. {5-Chloro-2 - [(3S) -3-methyl-piperazin-1-yl] -sonicotinoyl] -amino) -1- (4-fluorophenyl) -4.5 -dihydro-1 H-benzo [g] indazole-3-carboxamide, 8- (. {5-Chloro-2 - [(3R, 5S) -3,5-dimethyl-piperazin-1-yl] - sonicotinoyl} amino) -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, 8- (. {5-Chloro-2 - [(3R, 5S) - 3,4,5-trimethylpiperazin-1-yl] isonicotinoyl. amino) -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, 8- (. { 5-Chloro-2 - [(3R) -3,4-dimethylpiperazin-1-yl] isonicotinoyl} amino) -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, 8- (. {5-Chloro-2 - [(3S) -3,4- dimethylpiperazin-1-yl] isonicotinoyl.} amino) -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, 8-. { [5-Chloro-2- (4-ethylpiperazin-1-yl) isonicotinoyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide, 8-. { [5-Chloro-2- (4-isopropylpiperazin-1-yl) isonicotinoyl] amino} -1- (4-fluorophenyl) -4,5-dihydro-1H-benzo [g] indazole-3-carboxamide, and 8- ( { [5-Chloro-2- (4-methyl-piperazin-1 -yl) pyridin-4-yl] carbonyl, arnino) -1- (4-fluorophenyl) -4,5-dihydro-1 H -benzo [g] indazole-3-carboxamide.
  28. 28. A composition comprising the compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26 or 27 and at least one pharmaceutically acceptable carrier.
  29. 29. A method for treating cancer, inflammation or a disorder related to inflammation in a subject, said method comprising administering to the subject suffering from or susceptible to suffering from such cancer, inflammation or disorder related to inflammation, a therapeutically effective amount of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 , 25, 26 or 27.
  30. 30. The method of claim 29 for use in the treatment of cancer.
  31. 31. The method of claim 29 for use in the treatment of inflammation.
  32. 32. The method of claim 29 for use in the treatment of a disorder related to inflammation.
  33. 33. The method of claim 32 wherein the disorder related to inflammation is arthritis.
  34. 34. The method of claim 32 wherein the disorder related to inflammation is pain.
  35. 35. The method of claim 32 wherein the disorder related to inflammation is fever. The present invention relates to substituted pyrazolyl derivatives of Formula III, to compositions comprising them, to intermediates, to processes for preparing substituted pyrazolyl derivatives and to methods for treating cancer, inflammation and disorders associated with inflammation such as arthritis.
MXPA04010952A 2002-05-09 2003-03-19 Substituted pyrazolyl compounds for the treatment of inflammation. MXPA04010952A (en)

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US9079919B2 (en) 2011-05-27 2015-07-14 Hoffmann-La Roche Inc. Spiro-[1,3]-oxazines and spiro-[1,4]-oxazepines as BACE1 and/or BACE2 inhibitors
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