Classifications

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  • 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
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  • 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
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  • 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
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  • 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

Definitions

• the present invention in general is in the field of anti-inflammatory pharmaceutical agents and specifically relates to substituted pyrazolyl derivatives, compositions comprising such, and methods for treating cancer, inflammation, and inflammation-associated disorders, such as arthritis.
• NF-kB is a ubiquitous transcription factor that plays a prominent role in the activation of the immune system and in stress responses by regulating the transcription of many early, inducible genes including proinflammatory cytokines, adhesion molecules, growth factors, enzymes, and receptors (Ghosh S., May, M. J., and Kopp. E (199S) 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). Specificity of gene expression is determined at a cellular level by a diverse array of external stimuli such as bacterial products including LPS, as well as cytokines, most importantly tumor necrosis factor- ⁇ (TNF ⁇ ) and interleukin- ⁇
• TNF ⁇ tumor necrosis factor- ⁇
• NF- ⁇ B is composed of homo and heterodimers of the Rel protein family and is sequestered in an inactive form in the cytoplasm by members of the I ⁇ B family of inhibitory proteins (Ghosh S., May, M. J., 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. 21 A, 27339-27342).
• I ⁇ Bs mask the nuclear localization signal on NF- ⁇ B, preventing nuclear translocation and hence DNA binding to the promoter regions of responsive genes. Stimulation of cells with an agonist that activates NF- ⁇ B leads to a series of biochemical signals, ultimately resulting in the phosphorylation, ubiquitinylation, and degradation of I ⁇ Bs, thereby releasing NF- ⁇ B for nuclear translocation (Ghosh
• IKK1 and IKK2 are similar structurally as well as enzymatically and exist as a heterodimer in a large protein complex referred to as the IKK signalsome (Regnier, C, Song, H., Gao, X., Goeddel, D., Cao, Z. and
• NEMO IKK ⁇ , IKKAP1
• IKK activation and kinase activity Yamaoka, S., Courtois, G., Bessia, C, Whiteside, S. T., Weil, R., Agou, F., Kirk, H. E., Kay, R. J., and Ireal, A. (1998) Cell 93, 1231-1240; Rothwarf, D. M., Zandi, E., Natoli, G.,
• KKl and IKK2 are co-expressed in most human adult tissues as well as in different developmental stages of mouse embryos (Regnier, C, Song, H., Gao, X., Goeddel, D., Cao, Z. and Rothe, M.
• This kinase complex appears to represent a critical, common denominator in the activation of ⁇ F- ⁇ B in a number of signal transduction pathways stimulated by a variety of agonists including cytokines, such as TNF ⁇ and ILl ⁇ , 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, M. J., and Kopp. E (1998)
• IKK1 also termed IKK ⁇ , Regnier, C, Song, H., Gao, X., Goeddel, D., Cao, Z. and Rothe, M. (1997) Cell 90, 373-383; DiDonato, J.A., Hayakawa, M.,
• IKK1 MAP3K, NF- ⁇ B inducing kinase (NIK), in a yeast two-hybrid screen.
• IKK1 was identified as the previously cloned serine-threonine kinase, CHUK (Connelly, M. and Marcu, K. (1995) Cell. Mol. Biol. Res. Al, 537-549).
• IKK1 also termed IKK ⁇ is an 85 kDa, 745 amino acid protein that contains an N-terminal serine/threonine kinase catalytic domain, a leucine zipper-like amphipathic helix, and a C-terminal helix-loop-helix domain.
• IKK2 (also termed IKK ⁇ ) was also cloned by standard biochemical purification, copurifying with IKK1 from TNF ⁇ stimulated HeLa S3 cells as well as by being identified in the public database from an EST clone with sequence homology to IKK1 (Mercurio, F., Zhu, H., Murray, B.W., Shevchenko, A., Bennett, B.L., Li, J.W., Young, D.B., Barbosa, M., Mann, M strictly Manning, A. and Roa, A. (1997) Science 278, 860-866; Zandi, E. Rothwarf, D.M., Delhase, M., Hayadawa, M and Karin, M. (1997) Cell 91, 243-252;
• IKK2 is an 87 kDa, 756 amino acid protein with the same over all topology as IKK1 except for the addition of an 11 amino acid extension at the C-terminus.
• IKK1 and IKK2 are 52% identical overall with 65% identity in the kinase domain and 44% identity in the protein interaction domains in the C- terminus.
• NEMO also termed IKK ⁇
• IKK ⁇ contains three ⁇ -helical regions including a leucine zipper, interacts preferentially with IKK2 and is required for activation of the heterodimeric kinase complex perhaps by bringing other proteins into the signalsome complex
• the kinase activities of IKK1 and IKK2 are regulated by phosphorylation and require an intact leucine zipper (LZ) for dimerization as well as an intact helix-loop-helix (HLH) domain, which can exert a positive regulatory effect on kinase activity even when it is expressed in trans with the remainder of the IKK protein (Regnier, C, Song, H., Gao, X., Goeddel, D., Cao, Z. and Rothe, M. (1997) Cell 90, 373-383; DiDonato, J.A., Hayakawa, M., Rothwarf, D.M., Zandi, E. and Karin, M.
• LZ leucine zipper
• HH helix-loop-helix
• Both IKK subunits contain a canonical MAPKK activation loop motif near the ⁇ - terminus which is the target for phosphorylation and activation of kinase activity by
• MAP3Ks such as NIK and MEKK1, although the physiologic regulation by these two upstream kinases awaits further characterization (Zandi, E., and Karin, M. (1999) Mol. Cell. Biol. 19, 4547-4551; Karin, M. (1999) J. Biol. Chem. 21 A, 27339- 27342; Karin, M., and Delhase, M. (1998) Proc. Natl. Acad. Sci. USA 95, 9067- 9069).
• IKK2 demonstrates a more potent kinase activity compared to D Kl using I ⁇ B ⁇ or I ⁇ B ⁇ as a substrate
• I ⁇ B ⁇ or I ⁇ B ⁇ as a substrate
• IKK2 being the dominant kinase activity within the IKK complex is further supported by the analysis of fibroblasts from mice deficient in IKKl or IK-K2. Fibroblasts lacking IKKl retain full IKK activity in response to cytokines and could activate NF- ⁇ B. In contrast, fibroblasts lacking IKK2 do not exhibit IKK activity when stimulated with cytokines nor do they activate NF-kB. Furthermore, the phenotypes of each IKK knock out is unique with IKKl deficiency resulting in skin and skeletal defects and IKK2 knock out being embryonic lethal due to hepatocyte apoptosis (Li, Q., Antwerp, D.
• NF-KB plays 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 (iNOS).
• cytokines such as IL-6 and IL-8
• cell adhesion molecules such as ICAM and VCAM
• inducible nitric oxide synthase iNOS
• mediators are known to play a role in the recruitment of leukocytes at sites of inflammation and in the case of iNOS, may lead to organ destruction in some inflammatory and autoimmune diseases.
• iNOS inducible nitric oxide synthase
• NF- ⁇ B has been shown to be activated in human synovial cells in response to stimulation with TNF- ⁇ . Such a distribution may be the underlying mechanism for the increased cytokine and eicosanoid production characteristic of this tissue. See Roshak, A. K., et al., J. Biol. Chem., 271, 31496-31501 (1996).
• NF- ⁇ B/Rel and I ⁇ B proteins are also likely to play a key role in neoplastic transformation.
• Family members are associated with cell transformation in vitro and in vivo because of overexpression, gene amplification, gene rearrangements, 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).
• rearrangement and/or amplification of the genes encoding these proteins are seen in 20-25% of certain human lymphoid tumors.
• HTLVl human T-cell leukemia virus type 1
• IKK ⁇ and IKK ⁇ are expressed constitutively, which normally function in a transient manner.
• the HTLVl transforming and transactivating protein (Tax) has been shown to bind MEKKl and increases the activity of IKK ⁇ to enhance phosphorylation of serine residues in I ⁇ B ⁇ that lead to its degradation.
• U.S. Patent No. 5,134,142 to Matsuo et al describes 1,5-diaryl pyrazoles, and specifically, l-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-trifluoromethyl pyrazole, as having anti-inflammatory activity.
• a series of 4-[3-substituted methyl-5-phenyl-lH-pyrazol-l-yl]benzenesulfonamides has been prepared as intermediates for anti-diabetes agents, and more specifically, 4-[3-methyl-5-phenyl-lH-pyrazol-l-yl]benzenesulfonamide [ ⁇ . Feid-Allah, Pharmazie, 36, 754 (1981)].
• WO 00/27822 discloses tricyclic pyrazole derivatives
• WO 00/59901 discloses dihydroindeno pyrazoles
• WO 99/17769 discloses indeno[l,2-c]-, naphtho[l,2-c]- and benzo[6,7]cyclohepta[l,2-c]pyrazole derivatives
• US 5,196,445 discloses heteroaryl-3-oxo-propanenitrile derivatives useful in the treatment of rheumatoid arthritis
• WO 97/10210 discloses tricyclic pyrrolidine derivatives as calcium channel antagonists
• WO 95/15315 discloses diphenyl pyrazole compounds
• WO 95/15317 discloses triphenyl pyrazole compounds
• WO 95/15318 discloses tri-substituted pyrazole compounds
• WO 96/09293 discloses benz[g]indazolyl derivatives.
• WO 95/15316 discloses substituted pyrazolyl benzenesulfonamide derivatives and WO 01/32663 discloses pyrazlecarboxylic acid tricyclic derivatives as CBi cannabinoid receptor inhibitors.
• a class of compounds, which are useful in treating cancer, inflammation, and inflammation related disorders, is defined by Formula I:
• A is (CH 2 ) m ; wherein each CH 2 may be independently substituted with one or more substitution selected from the group consisting of: aryl, heteroaryl, alkanoyl, hydroxy, halogen, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl; m is 1 to 4;
• B is a 5 or 6 membered heteroaryl, aryl, saturated or unsaturated heterocyclic wherein said aryl, heteroaryl, or heterocyclic are optionally substituted with R 1 , R 2 , and R 12 ;
• X is selected from the group consisting of: N and C;
• Y and Z are independently selected from the group consisting of: N,
• R 1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO 2 , OR 5 ,
• OCOOR 5 CO 2 R 7 , CON(R 6 )R 7 , COR 6 , SR 6 , SOR 6 , SO 2 R 6 , NR 6 R 7 ,
• R 6 and R 7 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from the group consisting of: S, SO, SO 2 , O, and NR 6 ; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR 5 are optional substituted with, hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF 3 , CN, NO 2 , OR 5 , OCOOR 5 , CO 2 R 7 , CON(R 6 )R 7 , COR 6 , SR 6 , SOR 6 , SO 2 R 6 , NR 6 R 7 , NR 6 COR 7 , NR 6 CONHR 7 , NR 6 SO 2 R 7 , NR 6 SO 2 NHR 7 , and SO 2 N(R 6 )
• R and R may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from the group consisting of: S, SO, SO 2 , O, and NR 6 ;
• R 2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR 6 , CN, NO 2 , SR 6 , NHR 6 , CON(R 6 )R 7 , NHCONHR 6 , CO 2 H, and haloalkyl;
• R 1 and R 2 may be taken together to form a 5 to 7 membered saturated or unsaturated carbocyclic ring optionally containing 0 to 3 heteroatoms selected from the group consisting of N, O, or S, and wherein said ring is optionally substituted with R 1 ;
• R 3 is selected from the group consisting of: substituted or unsubstituted amidine, alkylamino, aminoalkyl,
• R 5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclicalkyl, and heteroarylalkyl, wherein 5 aryl, alkyl, arylalkyl, heteroaryl, heterocyclicalkyl, or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of OR 14 , N(R 14 )R 14 , and glycols;
• R 6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl,
• R 7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl,
• R 8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl;
• R 8' is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl;
• R 9 is independently selected from the group consisting of: hydrido,
• alkylsulfonamide sulfamyl, alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanate, isothiocyanate, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy, and heterocyclic optionally substituted with alkyl
• R 10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic, haloalkyl, arylalkylamino, heteroarylalkyl, aryl, and arylalkyl, wherein aryl, heteroaryl, heterocyclic, or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, and heterocyclic, R 10' is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic, haloalkyl, arylalkylamino, heteroarylalkyl, aryl, and arylalkyl, wherein aryl, heteroaryl, heterocyclic, or
• R 13 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclicalkyl, and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclicalkyl, or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of OR 14 , N(R 14 )R 14 , and glycols; R 14 is independently selected from the group consisting of hydrido, and lower alkyl; and
• R 14 is independently selected from the group consisting of hydrido, and lower alkyl
• each CH 2 may be independently substituted with one or more substitution selected from the group consisting of: aryl, heteroaryl, alkanoyl, hydroxy, halogen, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl; m is 1 to 4;
• 20 B is a 5 or 6 membered heteroaryl, aryl, saturated or unsaturated heterocyclic wherein said aryl, heteroaryl, or heterocyclic are optionally substituted with R 1 , R 2 , and R 12 ;
• R 1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO 2 , OR 5 , OCOOR 5 , CO 2 R 7 , CON(R 6 )R 7 , COR 6 , SR 6 , SOR 6 , SO 2 R 6 , NR 6 R 7 , NR 6 COR 7 , NR 6 CONHR 7 , NR 6 SO 2 R 7 , NR 6 SO 2 NHR 7 , and SO 2 N(R 6 )R 7 wherein R 6 and R 7 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from the group consisting of: S, SO, SO 2 , 0, and NR 6 ; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR 5 are optional substitute
• R and R may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from the group consisting of: S, SO, SO , O, and NR 6 ;
• R is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR 6 , CN, NO 2 , SR 6 , NHR 6 , CON(R 6 )R 7 , NHCONHR 6 , CO 2 H, and haloalkyl;
• R 1 and R 2 may be taken together to form a 5 to 7 membered saturated or unsaturated carbocyclic ring optionally containing 0 to 3 heteroatoms selected from the group consisting of N, O, or S, and wherein said ring is optionally substituted with R 1 ;
• R 3 is selected from the group consisting of: substituted or unsubstituted amidine, alkylamino, aminoalkyl, CONHR 7 , NH 2 , NHCOR 6 , and CH 2 NHCOR 6 ;
• R 4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR 13 , SR 8 , SO 2 N(R 8 )
• R s is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclicalkyl, and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, heteroaryl, heterocyclicalkyl, or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of OR 14 , N(R 14 )R 14 , and glycols;
• R 6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic;
• R 7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic;
• R 8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl;
• R 8' is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylamino
• R 9 is independently selected from the group consisting of: hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclic, cycloalkyl, heterocyclicalkyl, haloalkyl, arylalkylamino, amino, aminoalkyl, aminoacyl, nitro, azido, and heteroarylalkyl, wherein alkyl, aryl, heteroaryl, aminoalkyl, or arylalkyl are optionally substituted with one or more radical selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, 5 carboxyl
• R 10 is independently selected from the group consisting of: hydrido, lower alkyl, heteroaryl, heterocyclic, haloalkyl, arylalkylamino, heteroarylalkyl, aryl, and arylalkyl, wherein aryl, heteroaryl,
• heterocyclic, or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halogen, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, and heterocyclic,
• R 10 is independently selected from the group consisting of: hydrido,
• R 11 is selected from the group consisting of: hydrido, halogen, haloalkyl, CN, CO R 5 , lower alkyl, lower alkenyl, lower alkynyl, alkoxy, and CONH 2 ;
• R 12 is selected from the group consisting of: hydrido, halogen, alkyl,
• R 13 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclicalkyl, and heteroarylalkyl, wherem aryl, alkyl, arylalkyl, heteroaryl, heterocyclicalkyl, or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of OR 14 , N(R I4 )R 14 , and glycols; R 14 is independently selected from the group consisting of hydrido, and lower alkyl; and
• R 14 is independently selected from the group consisting of hydrido, and lower alkyl
• B is a 5 or 6 membered heteroaryl, aryl, saturated or unsaturated heterocyclic wherein said aryl, heteroaryl, or heterocyclic are optionally substituted with R 1 , R 2 , and R 12 ;
• W is a 5 or 6 membered heteroaryl, aryl, saturated or unsaturated heterocyclic;
• R 1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO 2 , OR 5 , OCOOR 5 , CO 2 R 7 , CON(R 6 )R 7 , COR 6 , SR 6 , SOR 6 , SO 2 R 6 , NR 6 R 7 , NR°COR 7 , NR 6 CONHR 7 , NR 6 SO 2 R 7 , NR 6 SO 2 NHR 7 , and
• R 6 and R 7 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from the group consisting of: S, SO, SO 2 , O, and NR 6 ; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR 5 are optional substituted with, hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF 3 , CN, NO 2 , OR 5 , OCOOR 5 , 5 CO 2 R 7 , CON(R 6 )R 7 , COR 6 , SR 6 , SOR 6 , SO 2 R 6 , NR 6 R 7 , NR 6 COR 7 ,
• R 2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR 6 , CN, NO 2 , SR 6 , NHR 6 , CON(R 6 )R 7 , NHCONHR 6 , CO 2 H, and haloalkyl; R 1 and R 2 may be taken together to form a 5 to 7 membered
• R 15 saturated or unsaturated carbocyclic ring optionally containing 0 to 3 heteroatoms selected from the group consisting of N, O, or S, and wherein said ring is optionally substituted with R 1 ;
• R 5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclicalkyl, and heteroarylalkyl, wherein
• aryl, alkyl, arylalkyl, heteroaryl, heterocyclicalkyl, or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of OR 14 , N(R 14 )R 14 , and glycols;
• R 6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl,
• R 7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl,
• R 12 is selected from the group consisting of: hydrido, halogen, alkyl, and alkoxy;
• R 15 is selected from the group consisting of: alkylsulfonamide, sulfamyl, alkyl wherein said alkyl is optionally substituted with a carbocyclic or heterocyclic wherein said carbocyclic or heterocyclic is optionally substituted with one to six substituents selected from 5 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, (CH ) n C(R')R'
• n is 0 to 4 and each R' is independently selected from the group consisting of hydrido, hydroxy, amino, O, S, and alkyl, (CH 2 ) n NHCON(R')R' wherein n is 0 to 4 and each R' is independently selected from the group consisting of hydrido, hydroxy, amino, and alkyl, (CH 2 ) n NHC(O)OR' wherein n is 0 to 4
• R 15 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,
• CO2(alkyl), CON(alkyl)(alkyl'), formyl, cycloalkyl, heterocyclic, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl, and heteroarylalkyl; and R 18 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], CO2(alkyl), CON(alkyl)(alkyl'), formyl, cycloalkyl, heterocyclic, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl, and heteroary
• the present invention includes the use of all hydrates, solvates, complexes and prodrugs of the compounds of this invention.
• Prodrugs are any covalently bonded compounds, which releases the active parent drug according to
• alkyl is used, either alone or within other terms such as “haloalkyl” and “alkylsulfonyl”; it embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms.
• More preferred alkyl radicals are "lower alkyl" radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about five carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl and the, like.
• the term "hydrido" denotes a single hydrogen atom (H).
• This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (-CH 2 -) radical.
• halo means halogens such as fluorine, chlorine, and bromine or iodine atoms.
• haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals.
• a monohaloalkyl radical may have a bromo, chloro, or a fluoro atom within the radical.
• Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
• hydroxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxylradicals.
• alkoxy and “alkoxyalkyl” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical.
• alkoxyalkyl also embraces alkyl radicals having two or more alkoxy radicals attached to the alkyl radical, that is, to form 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.
• alkoxy radicals include methoxy, butoxy, and trifluoromethoxy.
• aryl alone or in combination, means a carbocyclic aromatic system containing one, two, or three rings wherein such rings may be attached together in a pendent manner or may be fused.
• aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronapthyl, indane, and biphenyl.
• heterocyclic embraces saturated, partially saturated, and unsaturated heteroatom-containing ring- shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include pyrrolidyl and morpholinyl.
• heteroaryl embraces unsaturated heterocyclic radicals.
• unsaturated heterocyclic radicals also termed “heteroaryl” radicals include thienyl, pyrrolyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, and tetrazolyl.
• the term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.
• heterocyclic alkyl embraces alkyl attached to the heterocyclic.
• sulfonyl whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO 2 - "Alkylsulfonyl”, embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above.
• arylsulfonyl embraces sulfonyl radicals substituted with an aryl radical.
• sulfamyl or “sulfonamidyl”, whether alone or used with terms such as “N- alkylsulfamyl”, “N-arylsulfamyl”, “N,N-dialkylsulfamyl” and “N-alkyl-N- arylsulfamyl”, denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-SO 2 -NH 2 ).
• N-alkylsulfamyl and “N,N- dialkylsulfamyl” denote sulfamyl radicals substituted, respectively, with one alkyl radical, a cycloalkyl ring, or two alkyl radicals.
• N-arylsulfamyl and “N- alkyl-N-arylsulfamyl” denote sulfamyl radicals substituted, respectively, with one aryl radical, and one alkyl and one aryl radical.
• carbboxy or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes -CO 2 H.
• carboxyalkyl embraces radicals having a carboxyradical as defined above, attached to an alkyl radical.
• alkylcarbonyl embraces radicals having a carbonyl radical substituted with an alkyl radical.
• alkylcarbonylalkyl denotes an alkyl radical substituted with an "alkylcarbonyl” radical.
• N-monoarylamido and “N-alkyl-N-arylamido” denote amido radicals substituted, respectively, with one aryl radical, and one alkyl and one aryl radical.
• N-alkyl-N-hydroxyamido embraces amido radicals substituted with a hydroxyl radical and with an alkyl radical.
• N-alkyl-N- hydroxyamidoalkyl embraces alkyl radicals substituted with an N-alkyl-N- hydroxyamido radical.
• amidoalkyl embraces alkyl radicals substituted with amido radicals.
• aminoalkyl embraces alkyl radicals substituted with amino radicals.
• alkylaminoalkyl embraces aminoalkyl radicals having the nitrogen atom substituted with an alkyl radical.
• heterocycloalkyl embraces heterocyclic-substituted alkyl radicals such as pyridylmethyl and thienylmethyl.
• aralkyl embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenethyl, and diphenethyl.
• benzyl and phenylmethyl are interchangeable.
• cycloalkyl embraces radicals having three to ten carbon atoms, such as cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
• cycloalkenyl embraces unsaturated radicals having three to ten carbon atoms, such as cylopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
• alkylthio embraces 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, (CH 3 -S-).
• N-alkylamino and N, N- dialkylamino denote amino groups which have been substituted with one alkyl radical and with two alkyl radicals, respectively.
• acyl whether used alone, or within a term such as “acylamino”, denotes a radical provided by the residue after removal of hydroxyl from an organic acid.
• acylamino embraces an amino radical substituted with an acyl group.
• Compounds of Formula I, Formula II or Formula Dl would be useful for, but not limited to, the treatment of inflammation in a subject, and for treatment of other inflammation-associated disorders, such as, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever.
• compounds of Formula I, Formula II or Formula IH would be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondylo arthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis.
• Such compounds of Formula I, Formula II or Formula IH would be useful in the treatment of asthma, bronchitis, menstrual cramps, tendinitis, bursitis, and skin related conditions such as psoriasis, eczema, burns, and dermatitis.
• Compounds of Formula I, Formula II or Formula Dl also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, and ulcerative colitis and for the prevention of colorectal cancer.
• Compounds of Formula I, Formula II or Formula DO- would be useful in treating inflammation in such diseases as vascular diseases such as vascularitus, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, conjunctivitis, swelling occurring after injury, myocardial ischemia, and the like.
• the compounds of the present invention may also be used for pain.
• the compounds are useful as antiinflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects.
• the compounds of Formula I, II or HI are useful as agents for treating cancer or anticancer agents.
• the compounds of Formula I, II or ID may be proapoptotic, antiapoptotic, anticell cycle progressive, antiinvasive, antiproliferative, antiangiogenic, and antimetastatic.
• the cancer may be colon, ovarian, breast, prostate, gastric, B-cell lymphoma, and multiple myeloma.
• the compounds of this invention are useful in the treatment of a variety of cancers including, but not limited to: carcinoma such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-
• carcinoma such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma
• hematopoietic tumors of lymphoid lineage including leukemia, acute lympho
• Hodgkin's lymphoma hairy cell lymphoma and Burkett's lymphoma
• hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias, 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, thyroid follicular cancer and Kaposi's sarcoma.
• PKs Due to the key role of PKs in the regulation of cellular proliferation, these compounds are also useful in the treatment of a variety of cell proliferative disorders such as, for instance, benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
• the compounds of Formula I, II, or IH may be used as an anitviral agent.
• the compounds of this invention are useful as inhibitors of protein kinases.
• the compounds of this invention are useful as inhibitors of IKKl and/or IKK2, IKK ⁇ /IKK ⁇ heterodimer, TBK or IKKL
• the compounds of the invention may also useful as inhibitors of other protein kinases such as, for instance, protein kinase C in different isoforms.
• cyclin dependent kinase Met, PAK-4, PAK-5, ZC- 1 , STLK-2, DDR-2, Aurora 1, Aurora 2, Bub-1, PLK, Chkl, Chk2, HER2, rafl, MEKl, 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 over IKKl.
• the compounds have an IKK2 IC50 of less than 1 ⁇ M, and have a selectivity ratio of IKK2 inhibition over IKKl inhibition of at least 50, and more preferably of at least 100. Even more preferably, the compounds have an IKKl IC50 of greater than 10 ⁇ M, and more preferably of greater than 100 ⁇ M.
• the compounds of Formula I, ⁇ , or Dl may also be used to treat angiogenesis associated cardiovascular, ophthalmology and osteoporosis disorders.
• the compounds of the present invention may also be used for treatment of knee injury such as sport injuries.
• the present invention comprises a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in association with at least one pharmaceutically acceptable carrier, adjuvant, or diluent.
• the present invention also comprises a method of treating inflammation or inflammation associated disorders in a subject, the method comprising administering to the subject having such inflammation or disorders a therapeutically effective amount of a compound of the present invention.
• pharmaceutically acceptable salts are also included in the family of compounds of the present invention.
• pharmaceutically acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
• Suitable pharmaceutically acceptable acid addition salts of compounds of the present invention may be prepared from an inorganic acid or from an organic acid.
• inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid.
• organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic, salicyclic, phydroxybenzoic, phenylacetic, mandelic, embonic
• Suitable pharmaceutically acceptable base addition salts of compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. All of these salts may 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.
• compositions comprising one or more compounds of the present invention in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants and/or excipient (collectively referred to herein as "carrier” materials) and, if desired, other active ingredients.
• carrier non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants and/or excipient
• the compounds of the present invention may be used in the manufacture of a medicament.
• Pharmaceutical compositions of the compounds of the present invention prepared as herein before described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
• the liquid formulation may be a buffered, isotonic aqueous solution.
• 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.
• the compounds and composition may, for example, be administered intravascularly, intraperitoneally, intravenously, subcutaneously, intramuscularly, intramedullary, orally, or topically.
• the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension, or liquid.
• the active ingredient may also be administered by injection as a composition wherein, for example, normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution may be used as a suitable carrier.
• Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride, or sodium citrate.
• excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride, or sodium citrate.
• the pharmaceutical composition is preferably made 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 condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the sub-ject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may 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 bodyweight, preferably between about 0.1 and about 50 mg/kg body weight and most preferably between about 1 to 20 mg/kg bodyweight, may be appropriate.
• the daily dose can be administered in one to four doses per day.
• the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
• the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
• Such capsules or tablets may contain a controlled release formulation as may be provided in a dispersion of active compound in a sustained release material such as glyceryl monostearate, glyceryl distearate, hydroxypropylmethyl cellulose alone or with a wax.
• Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
• the compounds may 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 made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
• a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, or an aqueous or non- aqueous suspension.
• Such a liquid formulation may be administered orally or filled into a soft gelatin capsule.
• the compounds of the present invention may also be combined with excipients such as cocoa butter, glycerin, gelatin, or polyethylene glycols and molded into a suppository.
• the methods of the present invention include topical administration of the compounds of the present invention.
• topical administration is meant non-systemic administration, including the application of a compound of the invention externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye, and nose, wherein the compound does not significantly enter the blood stream.
• systemic administration is meant oral, intravenous, intraperitoneal, and intramuscular administration.
• the amount of a compound of the present invention (hereinafter referred to as the active ingredient) required for therapeutic or prophylactic effect upon topical administration will, of course, vary with the compound chosen, the nature and severity of the condition being treated and the animal undergoing treatment, and is ultimately at the discretion of the physician.
• the topical formulations of the present invention comprise an active ingredient together with one or more acceptable carriers therefore, and optionally any other therapeutic ingredients.
• the carrier must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of where treatment is required such as: liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
• the active ingredient may comprise, for topical administration, from 0.01 to 5.0 wt%. of the formulation.
• Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may 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 surface active agent.
• the resulting solution may then be clarified by filtration, transferred to a suitable container, which is then sealed and sterilized by autoclaving, or maintaining at 90-100° C for half an hour.
• the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
• bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.00217c), benzalkonium chloride (0.0 1%) and chlorhexidine acetate (0.0 1%).
• Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol, and propylene glycol.
• Lotions according to the present invention include those suitable for application to the skin or eye.
• An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
• Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
• Creams, ointments, or pastes according to the present invention are semi-solid formulations of the active ingredient for external application.
• the basis 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, arachis, castor 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 may incorporate any suitable surface-active agent such as an anionic, cationic, or non-ionic surface-active agent such as sorbitan esters or polyoxyethylene derivatives thereof.
• Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin may also be included.
• Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
• Synthetic Scheme I illustrates the procedure used to prepare the antiinflammatory pyrazoles of the present invention.
• 1,3-Dicarbonyl compounds such as 1, or the shown enol form which is in equilibrium with the 1,3-diketone, are allowed to react with a substituted hydrazine hydrochloride 2 in warm methanol or ethanol or acetic acid to provide the pyrazoles 3 via a condensation reaction.
• A -CH 2 CH 2 -
• Synthetic Scheme II illustrates the procedure 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 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 1 which are suitable for conversion into antiinflammatory pyrazoles as illustrated in Scheme I.
• the dicarbonyl compounds 1 can be directly prepared from commercially available cyclic ketones 4.
• Synthetic Scheme Dl illustrates a three-step procedure used for the preparation of substituted 1-tetralones.
• step one an appropriate substituted benzene 5 is condensed with succinic anhydride and a catalyst such as aluminum chloride into the corresponding 4-phenyl-4-ketobutanoic acid derivatives 6.
• step two the keto group of the 4-phenyl-4-ketobutanoic acids 6 is reduced using catalytic hydrogenation or Wolff-Kishner type reductions, thus providing 4-phenylbutanoic acids 7.
• ketone reductions can be carried out using metal amalgams.
• step three the 4-phenylbutanoic acids are treated with a mixture of trifluoroacetic anhydride, and trifluoroacetic acid to effect intramolecular Friedel-Crafts acylation affording selected tetralones 8.
• the Friedel-Crafts acylation can be affected with other strong acids such as polyphosphoric acid, sulfuric acid, or aluminum chloride.
• Synthetic Scheme IV describes an alternate synthetic route to 1-tetralones 8.
• step one addition of allylmagnesium bromide in a suitable solvent such as, THF or diethyl ether, to an appropriately substituted benzoate 9 affords the l-phenylbut-3- ene-1-ones 10.
• step two the l-phenylbut-3-ene-l-ones 10 can be cyclized under Friedel-Crafts alkylation conditions, provided R4 is a ring activating substituent, using catalysts such as aluminum chloride to produce 1-tetralones 8.
• Scheme V describes the direct modification of 1 -tetralone to substituted tetralones.
• 1 -tetralone may be treated with a variety of electrophilic reagents such as bromine, ammonium nitrite or vinylsilanes, represented by E + , with or without a catalyst to generate directly a substituted tetralone 8, containing bromo, nitro or vinyl groups.
• electrophilic reagents such as bromine, ammonium nitrite or vinylsilanes, represented by E +
• Such tetralones 8 can be further embellished to provide the desired substitution patterns. Mixtures may be readily separated using chromatographic techniques.
• Scheme VI An alternate to Scheme V is Scheme VI wherein an appropriately substituted decaline is subjected to electrophilic addition to generate substituted decalins 11.
• Substituted decalins may also be prepared by Friedel-Crafts alkylation of substituted benzenes. Substituted decalins 11 can then be oxidized to the tetralones 8 using oxidants such as KMnO 4 or SeO 2 .
• Scheme VII describes the modification of existing tetralones into analogs containing differing functional groups that can also be further modified.
• Triflate 8b can the be subjected to Pd(OAc) 2 an appropriate phosphine and CO in the presence of methanol to generate tetralone 12 containing a carboxy methyl group.
• Triflates can be used in a variety of palladium coupling reactions to introduce additional functional groups.
• Synthetic Scheme VIA illustrates a three step procedure used for the preparation of substituted 1-indanones 16.
• step one an appropriate substituted benzaldehyde 13 is condensed with methyl acetate and a catalyst such as triethylamine into the corresponding methyl cinnamate derivatives 14.
• step two the olefin group of the cinnamate 14 is reduced using catalytic hydrogenation and the ester hydrolyzed with base, such as NaOH, thus providing 3-phenylpropanoic acids 15.
• step three the 3-phenylpropanoic acids are treated with a mixture of trifluoroacetic anhydride and trifluoroacetic acid to effect intramolecular Friedel- Crafts acylation affording selected 1-indanones 16.
• the Friedel-Crafts acylation can be effected with other strong acids such as sulfuric acid or aluminum chloride.
• Synthetic Scheme IX illustrates a two-step route for the preparation of substituted 1-indanones 16.
• Commercially available methyl benzoates 9, or other alkyl esters may be treated with a vinyl lithium reagent to afford phenyl vinyl ketones 17.
• dimethylamides or N-methyl-O-methylhydroxamides may be used in place of the esters.
• other vinyl metals such as; vinylmagnesium bromide may be used in place of the vinyl lithium reagent.
• the resulting phenylvinyl ketones may be cyclized using Friedel-Crafts alkylating catalysts, such as aluminum chloride.
• Synthetic Scheme X illustrates a three step procedure used for the preparation of substituted 1-benzosuberones 20.
• step one an appropriate substituted benzene 5 is condensed with glutaric anhydride and a catalyst such as aluminum chloride into the corresponding 5-phenyl-5-ketopentanoic acid derivatives 18.
• step two the keto group of the 5-phenyl-5-ketopentanoic acids 18 is reduced using catalytic hydrogenation or Wolff-Kishner type reductions, thus providing 5-phenylpentanoic acids 19.
• ketone reductions can also be carried out using metal amalgams.
• step three the 5-phenylpentanoic acids are treated with a mixture of trifluoroacetic anhydride, and trifluoroacetic acid to effect intramolecular Friedel- Crafts acylation affording selected benzosuberones 20.
• the Friedel- Crafts acylation can be affected with other strong acids such as polyphosphoric acid, H 2 SO or A1C1 3 .
• 5-phenyl-5-ketopentanoic acids 18, can be prepared from glutaric acid and a phenyllithium or a phenyl Grignard reagent appropriately substituted and compatible with reaction conditions.
• step one 3- or 4-benzyloxylphenylhydrazine was refluxed with ethyl (7-nitro- 1- oxo-1, 2,3 ,4-tetrahydronaphthalen-2-yl)(oxo)acetate 1 in acetic acid to give pyrazole. Then the nitro group was reduced to amine by using tin (D) chloride in ethanol. In the following step, the conversion of ester to amide was achieved by reacting with liquid ammonia in a pressured tube at high temperature. The resulting compound can either react with acid and HATU in DMF or acid chloride in pyridine to give the desired amide. The benzyl group was deprotected by stirring with TFA at room temperature.
• Step 1 The material of Step 1 (6.2 g, 0.021 mol) and 4-sulfonamidophenylhydrazine hydrochloride (5.1 g, 0.023 mol) were stirred in methanol (100 mL) overnight.
• Step 3 The material of Step 2 (718 mg, 0.0016 mol), cone, ammonium hydroxide (30 mL), and methanol (15 mL) were stirred in a stoppered flask for 72 hours. Contents were filtered to give 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, C 18 H 16 N 5 O 5 S requires 414.0872). 1H NMR
• Example 2 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 L). Contents were stirred overnight, diluted with water (75 mL), and filtered to give the desired as a white solid, 1.0 g (90% yield). FABHRMS m/z 426.1235 (M+H, C 20 H 20 N 5 O 4 S requires 426.1236).
• Example 4 1 - ⁇ 4- [(aminothio)peroxy]phenyl ⁇ -8- ⁇ [(methylthio)peroxy] amino ⁇ -4,5-dihydro- 1 H- benzo[g]indazole-3-carboxamide
• Example 2 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, was added dropwise methanesulfonyl chloride (0.278 mL, 0.0035 mol) in CH 2 C1 2 (2 mL). Contents were stirred overnight, slowly coming to room temperature. Contents were 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, C ⁇ 9 H 2 oN 5 O 5 S 2 requires 462.0906). 1H NMR (DMSO- 5 /
• the sulfonamides, amides, and urea were synthesized in a library format by using a Bohdan reaction block.
• the starting materials are the product of Example 2 (8- amino-l- ⁇ 4-[(aminothio)peroxy]phenyl ⁇ -4,5-dihydro-lH-benzo[g]indazole-3- carboxamide) and appropriate sulfonyl chlorides, acyl chlorides and isocyanates. Thirty-five reactions constituted this library.
• Example 42 l-[4-(aminosulfonyl)phenyl]-8-[(4-methylbenzyl)amino]-4,5-dihydro-lH- benzo[g]indazole-3-carboxamide
• Example 41 The title compound (36 mg, 71%) was synthesized by the same procedure as in Example 41 starting with the product of Example 2 (8-amino-l- ⁇ 4- [(aminothio)peroxy] ⁇ henyl ⁇ -4,5-dihydro-lH-benzo[g]indazole-3-carboxamide) (38.3 mg, 0.10 mmol) and p-anisaldehyde (38 mg, 0.30 mmol). Its structure was confirmed by 1H NMR and MS (504, M+l). C 26 H 25 N 5 O 4 S.(Et 2 O) 0 . 6 . Calc: C: 62.24, H: 5.70, N: 12.78; Found, C: 61.68, H: 5.43, N: 12.54.
• Example 41 The title compound (27 mg, 61%) was synthesized by the same procedure as in Example 41 starting with the product of Example 2 (8-amino-l- ⁇ 4- [(aminothio)peroxy]phenyl ⁇ -4,5-dihydro-lH-benzo[g]indazole-3-carboxamide) (38.3 mg, 0.10 mmol) and isopropyl aldehyde (22 mg, 0.30 mmol). Its structure was confirmed by 1H NMR and MS (440, M+l). C 22 H 25 N 5 O 3 S.H 2 O.(Et 2 O) 0 . 2. Calc: C: 57.97, H: 6.19, N: 14.83; Found, C: 57.63, H: 5.76 N: 14.04.
• the sulfonamides, amides, and ureas of Examples 51-91 were synthesized in a 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]indazole-3-carboxamide) and appropriate sulfonyl chlorides, acyl chlorides and isocyanates.
• Table 1 shows the compound identification, compound, IKK resin assay values, formula weight, and mass spectroscopy characterization for the compounds from the library.
• Examples 92-125 shown in Table 2 were synthesized using the following synthesis procedure similar to scheme I where R 9 is the appropriate aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or cycloalkyl.
• Step 2 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 then stirred overnight at 100°C. After cooling, the mixture was concentrated. The residue was taken up in dichloromethane - methanol and chromatographed over silica gel using ethyl acetate as eluent to give the title compound, as an oil which crystallized on standing.
• Example 126 was synthesized using the following scheme. Scheme XVI
• R 4-F, 4-S0 2 Me, 3,4- DO, etc.
• Examples 127-158 shown in Table 3 were synthesized by the following synthesis scheme were R 9 is the appropriate aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or cycloalkyl.
• Example 127 l-[4-(methylsulfonyl)phenyl]-8-nitro-4,5-dihydro-lH-benzo[g]indazole-3- carboxylic acid
• Example 92 ethyl l-[4-(methylsulfonyl) ⁇ henyl]-8-nitro- 4,5-dihydro-lH-benzo[g]indazole-3-carboxylate
• THF 115 mL
• the solution was acidified with 2N HCl and extracted three times with ethyl acetate.
• Rink amide resin (10 g, NovaBiochem #01-64-0013, 100- 200 mesh, 0.61 mmol/g) was washed sequentially with dichloromethane (DCM) and dimethylformamide (DMF). The resin was filtered, treated twice with 50% piperidine in DMF for 15 min, and subsequently washed three times each with
• Example 127 DMF, DCM, and anhydrous DMF. To the resin was added 4.65 g of Example 127,
• resin 2 (6.0 mmol) was added 50 mL of 2M SnCl 2 -2H 2 O in wet DMF. After agitation of the mixture overnight, the reagents were removed by filtration and the resin washed three times each with DMF, THF, and DCM. The resin was filtered and dried to give 10.96 g of resin 2. A 92.1 mg portion of the resin was treated twice with 20% TFA in CH 2 C1 2 and washed three times with CH 2 C1 2 .
• Resin 2 (0.45 mmol/g, 0.200g, 90 ⁇ mol) was washed three times with anhydrous
• Examples 132-158 were prepared as previously described for Example 130 using the appropriate aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or cycloalkyl and are listed in Table 3.
• Amino resin 3 (0.402 mmols/g, 0.0804 mmols, 0.200g) was pre-treated in DCM for one hour followed by washing using anhydrous NMP. To this resin added 5.0 equiv. of Fmoc-His-OH (0.402 mmols, 152 mg) followed by addition of PyBroP
• Examples 161-206 Examples 161-206 shown in Table 4 were synthesized using the following synthesis procedure similar to Scheme I where R 9 is the appropriate aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or cycloalkyl.
• R 9 is the appropriate aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or cycloalkyl.
• the detailed synthesis of l-(l,3-benzodioxol-5-yl)-8- ⁇ [(2- chloropyridin-3-yl)carbonyl]ami ⁇ io ⁇ -4,5-dihydro-lH-benzo[g]indazole-3- carboxamide (Example 161) is described below and is illustrative for the compounds of Table 4.
• step 1 The title compound of step 1 was prepared by the method disclosed by T. Komatsu et sl, Ameim.-Forsch. (1972) 22(12), 2099-104.
• Step 4 A solution 4.79g of the title product of Step 2 in acetic acid was treated at room temperature with 5% palladium on carbon under an atmosphere of hydrogen gas at 5 psi. The reaction was followed by LC-MS. When the conversion was complete, the mixture was filtered and concentrated to give the title compound as a brownish oil that was used directly for the next step. [0085] Step 4
• Step 3 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 over silica gel using ethyl acetate as eluent to give the title compound, 890mg, as an oil which crystallized on standing. Anal, for
• Example 208 l-(l,3-benzodioxol-5-yl)-8-[( ⁇ 2-[(2-hydroxyethyl)amino]pyridm-3- yl ⁇ carbonyl)amino]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide
• Example 207 The title compound was synthesized by the same procedure as in Example 207 starting with product of Example 161 (lg, 0.0020 mol) and ethanolamine (0.626g, 0.010 mol) in 4 mL of EtOH to afford 0.475 g of title compound (yield: 46 %). Mp: 250-253 °C. 1H NMR (300 MHz, ⁇ .
• Example 209 The title compound of Example 209 (1.96 g, 0.0033 mol) was dissolved in 6 mL CH 2 C1 2 and reacted with 5 mL TFA at room temperature for 36 h. The crude reaction mixture was diluted with CH 2 C1 and basified with a saturated aqueous solution of Na 2 CO 3 . The layers were separated and the organic layer was dried over
• Step 2 l-(l,3-benzodioxol-5-yl)-8-[(5-chloro-2-morpholin-4-ylisonicotinoyl)amino]-4,5- dihydro-lH-benzo[g]indazole-3-carboxamide
• the title compound was synthesized by the same procedure as in Example 211 starting with the title material from 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 Et 3 N (0.39 mL, 0.00279 mol) in DMF (8 mL) to yield 0.487 g of the title compound (yield: 88%). Mp: 269-271°C.
• the title compound was synthesized by the same procedure as in Example 211 starting with 5-chloro-2-(methyl-thio)pyrimidine-4 carboxylic acid (1.76 g, 0.00861 mol), the title compound of step 4 of Example 161 (2 g, 0.00574 mol), HATU (3.27 g, 0.00857mol), and Et 3 N (2.32 mL, 0.0166 mol) in DMF (29 mL) to yield 1.3 g of the title compound (yield: 42%).
• the title compound was synthesized from 1.653 g of 3,6-dichloro-2-pyridine carboxylic acid (CP92740, prepared by the method of E. Marzi, A. Bigi, M. Schlosser, EMr. 7. 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 211.
• the title compound is a brown solid (2.4 g, 80%), m.p. 263-265 °C.
• Step 2 l-(l,3-benzodioxol-5-yl)-8-( ⁇ [3-chloro-6-(4-methylpiperazin-l-yl)pyridin-2- yl]carbonyl ⁇ amino)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide
• the title compound was synthesized from 0.30 g of 3-chloro-6-(4-methylpiperazin- l-yl)-2-pyridine carboxylic acid, obtained by acidification of its K-salt from 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%), m.p. 264-266° C (decomposition).
• the title compound was synthesized from 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,
• Example 216 The title compound was synthesized from 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 EtOH was replaced by 0.5 ml of DMA. The reaction was carried out at
• Example 220 l-(l,3-benzodioxol-5-yl)-8-( ⁇ [3-chloro-6-(methylamino)pyridin-2- yl]carbonyl ⁇ amino)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide
• Example 216 The title compound was synthesized from N-methylamine (6 mL of 33 w% solution in EtOH) and the compound of Example 216 (1.04 g) by the same procedure used for Example 207 except that 1 mL of DMA was added. 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
• R 4-F, 4-S0 2 Me, 3,4-MDO, etc.
• Step 1 A solution of 2-chloro-5-bromobenzoic acid (23.6 g, 0.1 mol), cone, sulfiiric acid (5 mL) and condensed isobutene (400 mL) was prepared in a pressure vessel and stirred at room temperamre under 12 psi for 2 days. The vessel was opened and the excess isobutene was released. The remaining liquid was treated with sat. NaHCO 3 solution and extracted with methylene chloride. The organic layer was washed with brine, dried over MgSO 4> and filtered. The filtrate was concentrated in vacuum to give 20.5 g of the crude product as brown oil, which was used without further purification (70%).
• Step 2 A mixture of tert-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), Pd 2 (dba) 3 (0.18 g, 0.0002 mol) and BINAP (0.2 g, 0.0003 mol) in toluene was heated at 100°C under nitrogen for 16 h. 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 layer was washed with brine, dried over MgSO ; and filtered. The filtrate was concentrated in vacuum 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 tert-butyl 2-chloro-5-(4-methylpiperazin-l- yl)benzoate (7.3 g, 0.023 mol) in methylene chloride (150 mL) was added trifluoroacetic acid (62 mL, 0.8 mol) dropwise at 0-5°C. The reaction mixture was stirred overnight while allowing to warm up to room temperature. 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; ⁇ NMR (DMSO, 400 MHz) ⁇ : 10.11 (s, IH), 7.39 (d, J
• Step 4 To a mixture of 2-chloro-5-(4-methylpiperazin-l-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 h.
• 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 the appropriate aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or cycloalkyl.
• This material was prepared from 4-fluorophenyl hydrazine by the method described for Example 92.
• Example 207 The title compound was synthesized by the same procedure as in Example 207 starting with the title compound of Example 225 (0.81 g, 0.017 mol) and piperazine (3 g, 0.0348 mol) in 4 mL Et OH to afford 0.523 g of title compound (yield: 58 %). Mp: 156-157 °C.
• the product mixture was dissolved in water (560 mL) and added to 132 mL of 6 N HCl with vigorous stirring over about 20 min.
• the precipitate was recovered by vacuum filtration, washed with water (3 x 35 mL), and dried in vacuo at 100 °C to afford 7.11 g of a tan powder.
• Example 246 The title compound of Example 246 (1.47 mmoles) and morpholine (23.1 mmoles) were dissolved in 10 mL of N,N-dimethylacetamide. The reaction mixture was then placed under nitrogen and stirred in an oil bath at 100°C for 27 h. The mixture was partially stripped of solvent then added to water, filtered, and washed with water. The solid was recrystallized from acetonitrile, then dissolved in acetonitrile and dried over anhydrous MgSO 4 . The solvent was then stripped down to a solid.
• Example 244 The title compound of Example 244 (0.757 mmoles), 5-chloro-2-morpholin-4- ylisonicotinic acid, (1.38 mmoles), and HATU (1.57 mmoles) were dissolved in 5 mL DMF followed by the addition of 0.4 mL of triethylamine. The mixture was stirred at room temperature for 3 hrs and partially stripped of DMF. The reaction mixture was then added to water, filtered, and washed with water. The solid was dissolved in THF, decolorized with decolorizing carbon, and dried over anhydrous MgSO .
• N-methylpiperazine (30.7g, 0.30 mol) in 10 mL of N,N-dimethylacetamide.
• the title compound was synthesized by the same procedure as in Example 211 starting with 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 (0.755g, 0.00198mol) and Et 3 N (1.09 mL, 0.0078 mol) in DMF (8 mL) to yield 0.305 g of the title compound (yield: 40%).
• Example 244 8-amino-l-(4-fluorophenyl)-4,5-dihydro- lH-benzo[g]indazole-3-carboxamide) and 2-chloroisonicotinic acid by the method described for Example 246 step 3.
• step 1 The material from step 1 (2.17 mmoles) and N-methyl piperazine (32.9 mmoles) were dissolved in 5.0 mL N,N-dimefhylacetamide. The reaction mixture was then placed under nitrogen and stirred in an oil bath at 100°C for 88 h. The mixture was partially stripped of solvent then added to water, filtered, and washed with water. The solid was then dissolved in acetonitrile, decolorized with decolorizing carbon, and dried over anhydrous MgSO 4 . The solvent was stripped, then the solid residue was recrystallized from acetonitrile. Mp: 277-279°C.
• Example 248 The title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 248 (lg, 0.0020 mol) and piperazine (3.44g, 0.040 mol) in 5 mL of EtOH. The reaction was ran at 100°C for 24 h. The off-white precipitate that formed in the crude reaction mixture was filtered and washed with EtOH to afford 0.579 g of title compound (yield: 53%).
• the title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 248 (0.8 g, 0.0016 mol) and N,N,N'-trimethylethylene diamine (3.3 g, 0.032 mol). The reaction was run at 100°C for 24 h. After removal of the volatiles under vacuum, the residue was partitioned between water and CH 2 C1 2 . The organic layer was washed an additional time with water and dried over MgSO . The crude product mixture was purified by preparative HPLC to give 0.424 g of the title product, yield: 47%.
• the title compound was synthesized from 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 (BF 4 ).
• the title compound is a brown solid (0.37 g, 84%), m.p. 252-254 °C.
• the title compound was synthesized from 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 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%), m.p. 218-220°C.
• Examples 259-263 were synthesized with the corresponding starting compounds using the following synthesis procedures similar to scheme I where R 9 is the appropriate aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or cycloalkyl.
• Step 1 A mixture of 4-benzyloxylphenylhydrazine hydrochloride
• Step 2 A mixture of the product from step 1 (15.0 g, 0.032 mol) and tin chloride (21.6 g, 0.096 mol) in 400 mL of ethanol was heated at reflux overnight. Another two equivalent of tin chloride was added and stirred for 6 h. 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 a light yellow solid (96% yield); 1 HNMR (DMSO, 400 MHz) ⁇ : 8.07 (dd, IH), 7.66 (d, IH), 7.35-7.53
• Step 3 A sealed reaction vessel containing the product from step 2 (6.2 g, 0.014 mol) and 40.mL of liquid ammonia in 200 mL of absolute alcohol was heated at 120°C and 600 psi for 24 h.
• Step 4 To a solution of the product from 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 reaction mixture was stirred at room temperature overnight. Solvent was removed and the residue was stirred with water. The precipitate was collected by filtration and air-dried to give 7.5 g of product as a white solid (80% yield); X HNMR (DMSO, 400 MHz) ⁇ : 10.29 (s, IH), 7.15-7.51 (m, 18 H), 5.16 (s, 2H), 2.90 (m, 4H); Anal. Calcd. for C 32 H 25 ClN 4 O 3 : C, 70.01 ; H, 4.59; N, 10.20. Found: C, 69.62; H, 4.44; N, 10.24.
• Example 260 l-[4-(benzyloxy)phenyl]-8- ⁇ [(2-chloropyridin-3-yl)carbonyl]amino ⁇ -4,5-dihydro- lH-benzo[g]indazole-3-carboxamide
• Example 263 8- ⁇ [(2-chloropyridin-3-yl)carbonyl] amino ⁇ - 1 -(4-hydroxyphenyl)-4,5-dihydro- 1H- benzo [g]indazole-3-carboxamide
• Example 266 8-[(2-chlorobenzoyl)amino]-l-[4-(2,3-dihydroxypropoxy)phenyl]-4,5-dihydro-lH- benzo[g]indazole-3-carboxamide
• Examples 267-275 were synthesized as described in Example 264 using the appropriate aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or cycloalkyl.
• Stepl The product (45.0 g, 0.096 mol) from step 1 of Example
• Step 2 A sealed reaction vessel containing the product from step 1
• Step 3 To a solution of the product form 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, 0.04 mol) in one portion. The reaction mixture was stirred at room temperature for 36 h. Solvent was removed and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. This crude 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 from step 3 ( 1.05 g, 0.0024 mol) and 2-chloro-4,5-methylenedioxanylbenzoic cid (0.73 g, 0.0036 mol) in 25 mL of DMF was added 1 mL of diisopropylethylamine, followed by the addition of HATU (1.37 g, 0.0036 mol). The reaction was stirred at room temperature for 16 h and concentrated. The residue was partitioned between water and ethyl acetate and the organic phase was concentrated. This crude was then dissolved in 20 mL of THF and treated with 10 eq of TBAF for lh at RT.
• Example 278 8-[(2-chloro-5-nitrobenzoyl)amino]-l-(4-hydroxyphenyl)-4,5-dihydro-lH- benzo[g]indazole-3-carboxamide
• Example 290-308 listed in the Table 11 were prepared according to the procedure of Example 289 using the appropriate alkene.
• PS-MB- CHO Arnaut Technologies, 1.46 mmol/g loading
• the resin was washed with N,N-dimethylformamide.
• 2- Methoxyethylamine (1.11 g, 14.8 mmol) was added to the mixture. The mixture was allowed to shake on an orbital shaker for 16 hrs.
• the solution was drained from the resin and washed with a solution of 8 parts N,N-dimethylfromamide to 1 part trimethylorthoformate to 1 part acetic acid.
• the resin was then washed with N,N-dimethylformamide, 1 part N,N-dimethylformamide to 1 part triethylamine, N,N-dimethylformamide, dichloromethane, and diethyl ether.
• the resin was dried under vacuum.
• Example 317 8-[(2-chlorobenzoyl)amino]-l-[4-(3-furyl)phenyl]-4,5-dihydro-lH- benzo [g]indazole-3 -carboxamide
• 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 an overhead stirrer. The mixture was stirred for 15 min, filtered, and treated a second time with 30 % piperidine/DMF for 15 min. The solvent was removed by filtration and the resin washed with DMF ( 3x), MeOH (3x), and DCM (4x).
• Step 3 In a solid phase reactor equipped with an overhead stirrer to a suspension of resin from step 2 (7.8 g, 4.43 mmol) in NMP (15 mL) was added 2M SnCl 2 in NMP (15 mL). The mixture was stirred for 1 h, filtered, and retreated with 2M SnCl 2 in NMP (15 mL). After stirring overnight the resin was filtered, washed with DMF (3x), MeOH (3x), DCM (4x), filtered, and air dried to afford the intermediate amine resin. Determined resin loading by direct cleavage H NMR: 0.414 mmol/g. In a solid phase reactor equipped with an overhead stirrer was prepared a suspension of 0.4 g of the amine resin in NMP.
• Step 4 The resin was allowed to stir for 5 min and 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 lh. The resultant resin was filtered, subjected to a second treatment of 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 air dried to afford resin. Determined resin loading by direct cleavage ⁇
• Step 5 To a reaction vessel was added resin from step 4 (0.20g,
• Step 3 A mixture of the product from step 1 (8.0 g, 0.034 mol) and hydrazine (2.3 g, 0.068 mol) in 100 mL of ethanol was heated at reflux for 2 h. cooled to room temperature, and the solid was collected by filtration, washed with sat. NaHCO 3 , water, air-dried to give 4.0 g of crude as a pale white solid (63% yield); NMR spectrum was consistent with the proposed structure. [00190] Step 3
• step 3 The product from step 3 (1.6 g, 0.0036 mol) was hydrogenated in a Parr shaker with 20% Pd(OH) 2 /C in acetic acid for 2 h at 5 psi. After the removal of 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 HNMR (DMSO, 400 MHz) ⁇ : 9.01 (dd, IH), 8.62 (dd, IH), 8.07 (dd, IH), 7.01 (d, IH), 6.46 (dd, IH), 6.12 (d, IH), 4.90 (brs, 2H), 4.33 (q, 2H), 3.42 (s, 3H), 2.87 (m, 2H), 2.78 (m, 2H), 1.33 (t, 3H); Anal.
• Example 368 8-[(2-chlorobenzoyl)amino]-l-[6-(methylsulfonyl)pyridin-3-yl]-4,5-dihydro-lH- benzo[g]indazole-3-carboxamide
• Example 325 using standard conditions.
• the bioactivity in the IKK2 Resin assay for the compounds of Examples 370-380 is shown in Table 15.
• Step 1 A 100 mL 3-neck flask was charged with (in order) Cul (300 mg, 1.6 mmol), 1,10-phenanthroline (350 mg, 1.94 mmol) and 25 mL DMF. A dark cherry red solution resulted. 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 DMF and Cs 2 CO 3 (4.75 g, 14.6 mmol). To the flask was attached a reflux condenser with a nitrogen inlet, a thermometer and a glass stopper.
• Step 2 To a mixture of the product from step 1 (6.35 g, 0.023mol) and ethyl (7-nitro- 1 -oxo-1, 2,3, 4-tetrahydronaphthalen-2-yl)(oxo)acetate (6.6 g, 0.023 mol) in 200 mL of ethanol was added 10 mL of IN HCl and the reaction mixture was heated at reflux under nitrogen for 6 h.
• Step 3 The product from step 2 (7.5 g, 0.019 mol) was hydrogenated in a Parr shaker with 5% Pt/C in acetic acid for 2 h at 5 psi. After the removal of 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 HNMR (DMSO,
• Step 4 To a mixture of the product from step 3 (0.96 g, 0.0026 mol) and 3-chloroisonicotinic cid (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 h and concentrated.
• Step 5 A sealed reaction vessel containing the product from step 4
• Step 1 To a mixture of tert-butyl l-thien-2-ylhydrazinecarboxylate
• Step 2 A sealed reaction vessel containing the crude product from step (1.3 g, 0.004 mol) and 10 mL of liquid ammonia in 50 mL of absolute alcohol was heated at 120°C and 600 psi for 24 h. After cooling, 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.
• Example 384 l-(4-amino-3,5-difluorophenyl)-8-[(3-chloroisonicotinoyl)amino]-4,5-dihydro-lH- benzo [g] indazole-3-carboxamide
• Step 1 1 -Bromo- 3,4,5 trifluorobenzene (5 g, 24 mmol) was added to a slurry of Pd(OAc) 2 (0.269 g , 5 mol %), bisdiphenylphosphino-ferrocene (1.0 g,
• Step 2 The product from step 1 (1.9 g) and ethyl (7-nitro- 1-oxo- l,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate (1.66 g) were dispersed in IM HCl in ethanol (125 mL), heated to reflux, and stirred until the starting material disappeared (overnight). The solution was cooled down to 4 °C and stirred for 2 hrs.
• Step 3 The product from step 2 (1.17 g, 0.0028mol) was hydrogenated in a Parr shaker with 5% Pt/C in acetic acid for 4 h at 5 psi. After the removal of 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 absolute alcohol was heated at 120°C and 600 psi for 24 h.
• Step 4 To a mixture of the product from step 3 (0.75 g, 0.0021 mol) and 3-chloroisonicotinic cid (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.
• Example 384 mp: 289-290°C; ! HNMR (DMSO, 400 MHz) ⁇ : 10.55 (s, IH), 8.75 (s, IH), 8.63 (d, IH), 7.57 (d, IH), 7.55 (s, IH), 7.39 (m, 4H), 7.29 (s, IH), 6.70 (m, IH), 5.90 (brs, 2H), 2.89(s, 4H); Anal. Calcd. for C 24 H 17 FClN 6 O 2 : C, 58.25; H, 3.46; N, 16.98. Found: C, 57.65; H, 3.73; N, 16.82.
• Tetrabutylammonium fluoride 25 mL of IM THF solution, 25 mmol was added at
• step 2 The crude product of 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 then left at room temperature overnight. The ethanol was concentrated down to a smaller volume then water was added. A white precipitate formed and was collected (12.87 g, 68%).
• the desired compound (l-[4-
• Example 393 8-[(2-chlorobenzoyl)amino]- l-[4-(iso ⁇ ropylsulfonyl)phenyl]-4,5-dihydro- 1H- benzo[g]indazole-3-carboxamide
• step 1 The product of step 1 (640 mg, 3.15 mmol) was dissolved in absolute ethanol (12 mL), the system was flushed with N 2 and hydrazine ( 404 mg, 12.6 mmol) was added and the reaction refluxed overnight. HPLC showed 78% product and 21% starting material. To drive the reaction to completion 2 equivalents of additional hydrazine was added and reaction was refluxed for additional 5 hours, at this time
• the reaction mixture was concentrated and the residue was stirred with water. A white solid, 390 mg (58%) was isolated. 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 MgSO 4 , and concentrated to yield 258 mg (38%) of l-[4-(isopropylsulfonyl)phenyl]hydrazine with 99% purity.
• MH+ 215.
• the 390 mg was re-dissolved in 10 mL ethanol and treated once more with additional hydrazine to obtain additional product with the desired purity.

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