WO2003070706A1 - Tricyclic pyrazole derivatives for the treatment of inflammation - Google Patents

Tricyclic pyrazole derivatives for the treatment of inflammation Download PDF

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WO2003070706A1
WO2003070706A1 PCT/US2003/004844 US0304844W WO03070706A1 WO 2003070706 A1 WO2003070706 A1 WO 2003070706A1 US 0304844 W US0304844 W US 0304844W WO 03070706 A1 WO03070706 A1 WO 03070706A1
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group
aryl
alkyl
heteroaryl
hydrido
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PCT/US2003/004844
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French (fr)
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Xiangdong Xu
Michael Clare
Patrick Lennon
Suzanne Metz
Michael Vazquez
Richard M. Weier
Serge G. Wolfson
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Pharmacia Corporation
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Priority to EP03742812A priority Critical patent/EP1476431A1/en
Priority to AU2003225580A priority patent/AU2003225580A1/en
Priority to JP2003569613A priority patent/JP2005526730A/en
Priority to BR0307796-9A priority patent/BR0307796A/en
Priority to CA002476665A priority patent/CA2476665A1/en
Priority to MXPA04008130A priority patent/MXPA04008130A/en
Publication of WO2003070706A1 publication Critical patent/WO2003070706A1/en

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention in general is in the field of anti-inflammatory pharmaceutical agents and specifically relates to substituted tricyclic pyrazole derivatives, compositions comprising them, and their use as therapeutic agents in the treatment of diseases linked to protein kinases, particularly for treating cancer, inflammation, and inflammation-associated disorders, such as arthritis.
  • NF- ⁇ B 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 (1998) Annu. Rev. Immunol. 16, 115-260; Zandi, E., and Karin, M. (1999) Mol. Cell. Biol. 19, 4547-4551; Karin, M. (1999) J. Biol. Chem. 274, 27339- 27342).
  • 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.
  • IKBS 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 IKBS, thereby releasing NF- ⁇ B for nuclear translocation (Ghosh S., May, M. J., and Kopp. E (1998) Annu. Rev. Immunol.
  • the catalytic subunits, 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 Rothe, M. (1997) Cell 90, 373-383; DiDonato, J.A., Hayakawa, M., Rothwarf, D.M., Zandi, E. and Karin, M.
  • a third protein, NEMO is a regulatory adapter protein necessary for 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., Karin, M. (1998) Nature 395, 297; Mercurio, F., Murray, B. W., Shevchenko, A., Bennet, B. L., Young, D. B., Li, J.
  • IKK1 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. (1997) Cell 90, 373-383; DiDonato, J.A., Hayakawa, M., Rothwarf, D.M., Zandi, E. and Karin, M.
  • This kinase complex appears to represent a critical, common denominator in the activation of NF-kB 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) 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).
  • IKK1 also termed IKK ⁇ , Regnier, C, Song, H., Gao, X., Goeddel, D.,
  • IKK1 was identified as the previously cloned serine-threonine kinase, CHUK (Connelly, M. and Marcu, K. (1995) Cell. Mol. Biol. Res. 41, 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., Manning, A. and Roa, A. (1997) Science 278, 860-866; Zandi, E. Rothwarf, D.M., Delhase, M., Hayadawa, M and Karin, M.
  • 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 N- 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.
  • IKK2 demonstrates a more potent kinase activity compared to IKKl 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 IKK2. 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- ⁇ B.
  • 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. V., Mercurio, F., Lee, K., and Verma, I. M. (1999) Science 284, 321-325; Takeda, K., Tekeuchi, O., Tsujimura, T., Itami, S., Adachi, O., Kawai, T., Sanjo, H., Yoshikawa, K., Terada, N, and Akira, S.
  • 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 JL-8, cell adhesion molecules, such as ICAM and VCAM, and inducible nitric oxide synthase (iNOS).
  • cytokines such as IL-6 and JL-8
  • cell adhesion molecules such as ICAM and VCAM
  • inducible nitric oxide synthase iNOS
  • iNOS inducible nitric oxide synthase
  • inhaled steroids are known to reduce airway hyperresponsiveness and suppress the inflammatory response in asthmatic airways.
  • glucocorticoid inhibition of NF- ⁇ B one may speculate that these effects are mediated through an inhibition of NF- ⁇ B.
  • Further evidence for a role of NF- ⁇ B in inflammatory disorders comes from studies of rheumatoid synovium. Although NF- ⁇ B is normally present as an inactive cytoplasmic complex, recent immunohistochemical studies have indicated that NF- ⁇ B is present in the nuclei, and hence active, in the cells comprising rheumatoid synovium.
  • 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 in inflammatory disorders is further strengthened by studies of airway inflammation including asthma in which NF- ⁇ B has been shown to be activated. This activation may underlie the increased cytokine production and leukocyte infiltration characteristic of these disorders.
  • inhaled steroids are known to reduce airway hyper responsiveness and suppress the inflammatory response in asthmatic airways.
  • glucocorticoid inhibition of NF- ⁇ B one may speculate that these effects are mediated through an inhibition of NF- ⁇ B.
  • Further evidence for a role of NF- ⁇ B in inflammatory disorders comes from studies of rheumatoid synovium.
  • NF- KB is normally present as an inactive cytoplasmic complex
  • recent immunohistochemical studies have indicated that NF- ⁇ B is present in the nuclei, and hence active, in the cells comprising rheumatoid synovium.
  • NF- kB 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.
  • HTLV1 human T-cell leukemia virus type 1
  • IKK ⁇ and IKK ⁇ are expressed constitutively, which normally function in a transient manner (Chu Z-L et al., J of Biological Chemistry 273:15891-15894, 1998).
  • the HTLV1 transforming and transactivating protein (Tax) has been shown to bind MEKK1 and increases the activity of IKK ⁇ to enhance phosphorylation of serine residues in I ⁇ B ⁇ that lead to its degradation.
  • U.S. Patent No. 3,940,418 to R. Hamilton describes tricyclic 4,5- dihydrobenz[g]indazoles as antiinflammatory agents.
  • R. Hamilton J. Heterocyclic Chem., 13, 545 (1976)] describes tricyclic 4,5- dihydrobenz[g]indazoles as antiinflammatory agents.
  • U.S. Patent No. 5,134,155 describes fused tricyclic pyrazoles having a saturated ring bridging the pyrazole and a phenyl radical as HMG-CoA reductase inhibitors.
  • 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 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 benzenesulfamide derivatives.
  • a class of compounds, which are useful in treating cancer, inflammation, and inflammation related disorders, is defined by Formula I:
  • each CH 2 may be independently substituted with one or more substitution selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl; m is 0 to 8; n is independently selected from 0, 1 or 2;
  • Q is a 5 or 6 membered heteroaryl, or aryl, optionally saturated, or optionally substituted with R 1 , R 2 , or R 12 ;
  • B is an aromatic heterocyclic
  • X is selected from the group consisting of: N and C;
  • Y and Z are independently selected from the group consisting of: N, C, CH,
  • 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 3 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, alkenyl, al
  • 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, CONHR 16 , NH 2 , NHCOR 6 , and CH2NHCOR 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 8' , NHR 9 , NHCOR 9 , NR 9 COR 9 , NHCO(OR 9 ), NR 9 CO(OR 9 ), NR 8 SO 2 R 10 , NHSO 2 N(R 10 )R 10' , NR 6 CON(R 10 )R 10' , COR 9 , CO 2 R 8 , CON(R 8 )R 8' , wherein R 8 and R 8' may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or
  • 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, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl;
  • R 9 is independently selected from the group consisting of: hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclic, cycloalkyl, hetero
  • 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 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 11 is selected from the group consisting of: hydrido, halogen, haloalkyl,
  • R 12 is selected from the group consisting of: hydrido, halogen, alkyl, and alkoxy;
  • 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;
  • R 14' is independently selected from the group consisting of: hydrido, and lower alkyl
  • R 15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl, and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialky
  • 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 ,
  • 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 , CON(R 6 )R 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 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 16 , 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 8' , NHR 9 , NHCOR 9 , NR 9 COR 9 , NHCO(OR 9 ), NR 9 CO(OR 9 ), NR 8 SO 2 R 10 , NHSO 2 N(R 10 )R 10' , NR 6 CON(R 10 )R 10' , COR 9 , CO 2 R 8 , CON(R 8 )R 8' , wherein R 8 and R 8' may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or
  • 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, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl;
  • R 9 is independently selected from the group consisting of: hydrido, lower alkyl, aryl, heteroaryl, arylalkyl, heterocyclic, cycloalkyl,
  • 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 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 11 is selected from the group consisting of: hydrido, halogen, haloalkyl,
  • R is selected from the group consisting of: hydrido, halogen, alkyl, and alkoxy;
  • R 13 is selected from the group consisting of: hydrido, alkyl, aryl, 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:
  • R 14 is independently selected from the group consisting of: hydrido, and lower alkyl;
  • R 14' is independently selected from the group consisting of: hydrido, and lower alkyl;
  • R 15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl, and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic; and R 16 is independently selected from the group consisting of:
  • a preferred class of compounds is defined by formula HI
  • A is (CH 2 ) m , wherein each CH may be independently substituted with one or more substitution selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl; m is O to 8; Q is a 5 or 6 membered heteroaryl, or aryl, optionally saturated, or optionally substituted with R 1 , R 2 , or R 12 ; B is an aromatic 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 6 COR 7 , NR 6 CONHR 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 and R 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 CONHR 16 ;
  • R 4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic, nitro, acylamino, ary
  • 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, 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, 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, lower alkyl, heteroaryl, heterocyclic, haloalkyl, arylalkylamino, heteroarylalkyl, aryl, and arylalkyl, wherein aryl, heteroaryl, heterocyclic, or
  • R 11 is selected from the group consisting of: hydrido, halogen, haloalkyl, CN, CO 2 R 5 , lower alkyl, lower alkenyl, lower alkynyl, alkoxy, and CONH 2 ;
  • R 12 is selected from the group consisting of: hydrido, halogen, alkyl, and alkoxy;
  • 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
  • R 14 is independently selected from the group consisting of: hydrido, and lower alkyl
  • R 15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl, and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic; and
  • R 16 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, and alkoxyalkyl;
  • 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 release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
  • Compounds containing a chiral center may be used as a racemic mixture, an enantiornerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • 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 Formula I or Formula U in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
  • Compounds containing a chiral center may be used as a racemic mixture, an enantiornerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • 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.
  • radicals examples 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 for one example, 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.
  • halo atoms such as fluoro, chloro, or bromo
  • 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.
  • heteroaryl radicals examples 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.
  • alkylsulfonyl 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.
  • amido when used by itself or with other terms such as “amidoalkyl”, “N-monoalkylamido”, “N-monoarylamido”, “N,N-dialkylamido”, “N-alkyl-N-arylamido", “N-alkyl-N-hydroxyamido” and “N-alkyl-N- hydroxyamidoalkyl”, embraces a carbonyl radical substituted with an amino radical.
  • N-alkylamido and “N,N-dialkylamido” denote amido groups which have been substituted with one alkyl radical and with two alkyl radicals, respectively.
  • 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 -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 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.
  • Another aspect of the present invention is chemical intermediates in the synthesis of the claimed compounds.
  • Another aspect of the present invention is methods of syntheses of the claimed compounds.
  • Compounds of Formula I or Formula JJ 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 or Formula U 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 or Formula JJ 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 or Formula JJ 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 or Formula U 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 or JJ are useful as agents for treating cancer or anticancer agents.
  • the compounds of formula I or TI 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-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 fibro
  • protein kinases Due to the key role of protein kinases 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 or U 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 IKK/.
  • 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 (cdk), Met, PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Aurora 1, Aurora 2, Bub-1, PLK, Chkl, Chk2, HER2, rafl, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, IGF-R, VEGF-R, PI3K, weel kinase, Src, Abl, Akt, ILK, MK-2, 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 other kinases.
  • the compounds Preferably have a selectivity ratio of IKK2 inhibition over other kinase inhibition of at least 50, and more preferably of at least 100.
  • the present invention preferably includes compounds, which selectively inhibit IKK2 over IKKl .
  • the compounds Preferably, 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 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 (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, ⁇ -hydroxybutyric, sal
  • 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 subject, 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 body weight, 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.
  • Synthetic Scheme U illustrates the procedure for the preparation of substituted diketones 1.
  • An appropriately substituted ketone including but not limited to; indanones, 3-coumaranones, 3-thiocourmaranones, 3-azacourmaranones, 1-tetralones, chromanones, thiochromanones, azachromanones, isochromanones, isothiochromanones, isoazachromanones
  • 4 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 anti-inflammatory pyrazoles as illustrated in Scheme 1.
  • base such as sodium methoxide, lithium bis
  • Synthetic Scheme IJJ illustrates the three step procedure for the preparation of substituted isothiochromanones.
  • step one an appropriately substituted benzyl alcohol 5 is converted into the corresponding benzyl chloride by stirring with concentrated hydrochloric acid and then immediately converted into a thiouronium salt 6 upon treatment with thiourea at reflux.
  • step two the thiouronium salt is converted to the free mercaptide, according to the procedure of Lumma and Berchtold (J. Org. Chem., 34, 1566 (1969), and then trapped with chloroacetic acid or a related salt to provide the acetic acid derivatives 7.
  • step three the acids 7 are reacted with trifluoroacetic anhydride (TFAA) in trifluoroacetic acid (TFA) to give the isothiochromanone products 8.
  • TFAA trifluoroacetic anhydride
  • TFA trifluoroacetic acid
  • the thiouronium salts 6 can also be prepared from appropriate commercially available benzyl halides.
  • Synthetic Scheme TV illustrates a three step procedure used for the preparation of substituted thiochromanones.
  • step one an appropriate substituted thiophenol 9 is converted into the corresponding propionic acid derivatives 10 upon treatment with acrylic acid at a temperature in a range of room temperature to about 50°C.
  • step two the propionic acids 10 are subjected to treatment with a mixture of trifluoroacetic anhydride and trifluoroacetic acid to effect intramolecular Friedel- Crafts acylation, thus providing thiochromanones 11.
  • the Friedel- Crafts acylation can be affected with H 2 SO 4 .
  • Dicarbonyl compounds 1 can also be directly prepared from commercially available thiochromanones 11.
  • Synthetic Scheme V illustrates a three step procedure used for the preparation of substituted azachromanones.
  • step one an appropriate substituted aniline 12 is converted into the corresponding propionic acid derivatives 13 upon treatment with acrylic acid at a temperature in a range of room temperature to about 50°C.
  • step two the propionic acids 13 are subjected to treatment with a mixture of H 2 SO 4 to effect intramolecular Friedel-Crafts acylation, thus providing azachromanones 14.
  • Dicarbonyl compounds 1 can also be directly prepared from commercially available azachromanones 14.
  • Suitable protection of the aza nitrogen is effected when necessary using protecting groups such as benzyl, benzoyl, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc) or sulfonamido groups (mesyl, Ms or tosyl, Ts).
  • protecting groups such as benzyl, benzoyl, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc) or sulfonamido groups (mesyl, Ms or tosyl, Ts).
  • Synthetic Scheme VI details the three step procedure used to prepare substituted chromanone derivatives 17.
  • substituted phenols 15 are condensed with acrylic acid to afford 3-phenoxypropionic acids 16.
  • the acids 16 are treated with a mixture of trifluoroacetic anhydride, and trifluoroacetic acid to affect intramolecular Friedel-Crafts acylation affording selected chromanones 17.
  • the Friedel-Crafts acylation can be affected with H 2 SO 4 .
  • the dicarbonyl compounds 1 can be directly formed from commercially available chromanones 17.
  • Synthetic Scheme VTJ illustrates a procedure used to prepare isochromanone derivatives 19.
  • selected benzyl alcohol derivatives 5 are treated with sodium hydride or other suitable base and subsequently treated with ethyl bromoacetate to provide the desired ethers 18.
  • the ester group of 18 is hydrolyzed with aqueous sodium hydroxide and then treated with a mixture of trifluoroacetic acid and trifluoroacetic anhydride to promote intramolecular Friedel- Crafts acylation affording isochromanone 19 derivatives.
  • Synthetic Scheme VII illustrates a procedure used to prepare isoazachromanone derivatives 22.
  • selected benzyl amine derivatives 20 are treated with ethyl bromoacetate and a suitable acid scavenger, such as triethylamine, to provide the desired amines 21.
  • a suitable acid scavenger such as triethylamine
  • step two the ester group of 21 is hydrolyzed with aqueous sodium hydroxide and then treated with a mixture of trifluoroacetic acid and trifluoroacetic anhydride to promote intramolecular Friedel- Crafts acylation affording isochromanone 22 derivatives.
  • Suitable protection of the aza nitrogen is effected when necessary using protecting groups such as benzyl, benzoyl, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc) or sulfonamido groups (mesyl, Ms or tosyl, Ts).
  • protecting groups such as benzyl, benzoyl, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc) or sulfonamido groups (mesyl, Ms or tosyl, Ts).
  • Synthetic Scheme TX illustrates a procedure used to prepare substituted 3-coumaranones 24.
  • Phenols 15 are first treated with a base, such as NaOH, lithium diisopropyl amide (LDA) or sodium methoxide followed by condensation with ethyl bromoacetate in an appropriate solvent such as diethyl ether, ethanol, or tetrahydrofuran to provide the phenoxyacetate 23.
  • a base such as NaOH, lithium diisopropyl amide (LDA) or sodium methoxide
  • LDA lithium diisopropyl amide
  • ethyl bromoacetate in an appropriate solvent such as diethyl ether, ethanol, or tetrahydrofuran
  • step two the ester group of 23 is hydrolyzed with aqueous sodium hydroxide and then treated with a mixture of trifluoroacetic acid and trifluoroacetic anhydride to promote intramolecular Friedel- Crafts acy
  • Synthetic Scheme X illustrates a procedure used to prepare substituted 3- azacoumaranones 26.
  • Anilines 12 are treated with a acid scavenger, such as triethylamine followed by alkylation with ethyl bromoacetate in an appropriate solvent such as diethyl ether, ethanol, or tetrahydrofuran to provide the phenoxyacetate 25.
  • a acid scavenger such as triethylamine
  • ethyl bromoacetate in an appropriate solvent such as diethyl ether, ethanol, or tetrahydrofuran to provide the phenoxyacetate 25.
  • the ester group of 25 is hydrolyzed with aqueous sodium hydroxide and then treated with a mixture of trifluoroacetic acid and trifluoroacetic anhydride to promote intramolecular Friedel-Crafts acylation affording 3-azacoumaranones derivatives 24.
  • Suitable protection of the aza nitrogen is effected when necessary using protecting groups such as benzyl, benzoyl, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc) or sulfonamido groups (mesyl, Ms or tosyl, Ts).
  • protecting groups such as benzyl, benzoyl, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc) or sulfonamido groups (mesyl, Ms or tosyl, Ts).
  • Synthetic Scheme XI illustrates a procedure used to prepare substituted 3-thiocoumaranones 28.
  • Thiophenols 9 are first treated with a base, such as NaOH, lithium diisopropyl amide (LDA) or sodium methoxide followed by condensation with ethyl bromoacetate in an appropriate solvent such as diethyl ether, ethanol, or tetrahydrofuran to provide the phenoxyacetate 27.
  • a base such as NaOH, lithium diisopropyl amide (LDA) or sodium methoxide
  • LDA lithium diisopropyl amide
  • ethyl bromoacetate in an appropriate solvent such as diethyl ether, ethanol, or tetrahydrofuran
  • step two the ester group of 27 is hydrolyzed with aqueous sodium hydroxide and then treated with a mixture of trifluoroacetic acid and trifluoroacetic anhydride to promote intramolecular Friedel- Crafts
  • Synthetic Scheme XII illustrates a two step procedure used for the preparation of substituted benzyl alcohols 5.
  • step one a mixture of potassium tert-butoxide and anhydrous tetrahydrofuran, cooled to -78°C and treated with a 1.6 M solution of n-butyl lithium in hexanes, is added to an appropriate substituted benzene 29 the anion thereby generated is reacted with carbon dioxide to yield the benzoic acid 30.
  • the benzoic acid 30 is dissolved in a solvent, such as tetrahydrofuran, and treated with a reducing agent, such as borane dimethyl sulfide complex, to form the desired benzyl alcohol 5.
  • Scheme XJJJ describes the synthesis of the pyrazoles with fused heterocycles such as substituted pyrimdine and pyrazole.
  • 1,2- cyclohexanedione (31) was refluxed with alcohols such as methanol or ethanol in benzene to provide the desired enone (32).
  • enone 32 was treated with a base such as lithium bistrimethylsilylamide, followed by condensation with diethyl oxylate to afford 1,3-diketone (33).
  • 1,3-diketone was allowed to react with a suitably substituted phenylhydrazine to form pyrazole 34.
  • substituents could be; but are not limited to, methyl sulfone or sulfonamide, which may be protected.
  • a suitable protecting group for the sulfonamide is 2,5- dimethylpyrrole.
  • step four pyrazole was treated with dimethylformamide di-tert- butyl acetal to give enaminone 35.
  • step five enaminone was condensed with cyclizing agents such as hydrazine, guanidine, or thiourea to afford fused pyrazoles and pyrimidines 36. Jn the final step, the ester was converted to amide 37 by treating with ammonium hydroxide in methanol.
  • deprotection is achieved by treatment with refluxing trofluoroacetic acid and water.
  • Synthetic Scheme XTV illustrates a procedure used for the preparation of the anti-inflammatory oxidized thio-containing fused tricyclic pyrazoles 3.
  • MCPBA m-chloroperbenzoic acid
  • Compounds having differing amounts of oxidation can be prepared by controlling the stoichiometry of oxidant to sulfide or separated by chromatography.
  • Scheme XV illustrates a method for the preparation of substituted arylhydrazines 2.
  • Anilines 12 can be treated with hydroxylamine-O-sulfonic acid to generate arylhydrazines 2 (JOC, 14, 813, 1949).
  • Anilines 12 can also be diazotized used sodium nitrite, or an alkyl nitrite, followed by catalytic reduction to generate arylhydrazines 2.
  • EWG electron withdrawing group; such as nitro or methylsulfone
  • a condensing agent such as dicyclohexylcarbodiimide (DCC) or carbonyl diimidazole (CDI).
  • DCC dicyclohexylcarbodiimide
  • CDI carbonyl diimidazole
  • the compounds of the present invention may also be synthesized according to the methods of United States Patent 5,547,975.
  • 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. Cone HCl (2 mL) was added to the thick slurry and the contents were heated on a steam bath for 1 hour. Contents were allowed to cool and filtered to give an off-white solid, 6.9 g. NMR and LC/MS analysis show the solid to contain two components, the desired, and the hydrated pyrazole. TFA (60 mL) and TFAA (20 mL) were added to the solid and heated on a steam bath for 1 hour.
  • Example 1 The final product of Example 1 (2.0 g) and 10% Pd/C (350 mg) in DMF (20 mL) were shaken at 55 PSI hydrogen for 3 hours. Contents were filtered and the filtrate was concentrated in vacuo leaving an amber wax. The wax was triturated with methanol and filtered to give the product as a light amber solid, 1.6 g (86% yield). FABHRMS m/z 413.1293 (M+H, C 20 H 2I N 4 O 4 S requires 413.1284).
  • Example 4 was prepared similarly to Example 2 in 70 % yield. FABHRMS m/z 384.1136 (M+H, C 18 H 18 N 5 O 3 S requires 384.1130). ⁇ NMR (DMSO-d 6 / 300 MHz) 7.95 (d, 2H); 7.75 (d, 2H); 7.53 (br s, IH); 7.43 (br s, IH); 7.32 (br s, IH); 7.01 (d, IH); 6.44 (d of d, IH); 6.03 (s, IH); 4.81 (s, 2H); 2.93-2.65 (m, 4H).
  • step 2 The product of step 2 was prepared similarly to Example 5 starting with the material of step 1 in 67% yield.
  • FABHRMS m/z 326.1393 (M+H, C 19 H 20 NO 4 requires 326.1392).
  • ⁇ NMR (CDC1 3 / 300 MHz) 7.40-7.26 (m, 3H); 7.10-7.00 (m, 2H); 6.70-6.60 (m, 2H); 5.06 (s, 2H); 4.33 (q, 2H); 3.20-3.08 (m, 2H); 2.75-2.60 (m, 2H); 1.40 (t, 3H).
  • Example 7 The final product of Example 7 was prepared similarly to Example 6 starting with the product of step 2 in 37% yield. FABHRMS m/z 477.1609 (M+H, C 25 H 25 N 4 O 4 S requires 477.1596). ⁇ NMR (DMSO-d 6 / 300 MHz) 8.00 (d, 2H); 7.80 (d, 2H); 7.50 (s, IH); 7.40-7.20 (m, 3H); 7.20-7.05 (m, 2H); 6.80 (s, IH); 5.62 (s, IH); 5.13 (s, 2H); 4.25 (q, 2H); 3.10-2.92 (m, 2H); 2.89-2.70 (m, 2H); 1.30 (t, 3H).
  • Example 8 was prepared similarly to Example 2 starting with the compound of Example 7 in 75% yield.
  • FABHRMS m/z 448.1477 (M+H, C 23 H 22 N 5 O 3 S requires 448.1443).
  • step 1 The product of step 1 was prepared similarly to Example 5 starting with l,5,6,7-tetrahydro-l-(phenylmethyl)indazol-4-one [Heterocycles, 32 (1) 41-72 (1991)] in 89% yield.
  • ⁇ NMR (CDC1 3 / 300 MHz) 8.00 (s, IH); 7.40-7.30 (m, 3H); 7.13 (d, 2H); 5.30 (s, 2H); 4.31 (q, 2H); 3.19-3.03 (m, 2H); 2.80-2.68 (m, 2H); 1.38 (t, 3H).
  • Example 9 The final product of Example 9 was prepared similarly to Example 6 starting with the compound of step 1 in 64% yield. FABHRMS m/z 478.1549 (M+H, C 24 H 24 N 5 O 4 S requires 478.1551). ⁇ NMR (DMSO-d 6 / 300 MHz) 8.02 (d, 2H); 7.82 (d, 2H); 7.51 (s, IH); 7.40-7.22 (m, 3H); 7.21-7.13 (m, 2H); 7.10 (s, IH); 5.40 (s, 2H); 4.30 (q, 2H); 3.20-2.90 (m, 4H); 1.30 (t, 3H).
  • DMSO-d 6 / 300 MHz 8.02 (d, 2H); 7.82 (d, 2H); 7.51 (s, IH); 7.40-7.22 (m, 3H); 7.21-7.13 (m, 2H); 7.10 (s, IH); 5.40 (s, 2H); 4.30 (q, 2H); 3.20-2.90 (m,
  • Example 10 was prepared similarly to Example 2 starting with the product of Example 9 in 79% yield.
  • FABHRMS m/z 449.1399 (M+H, C 22 H 21 N 6 O 3 S requires 449.1396).
  • ⁇ NMR (DMSO-rf 6 / 300 MHz) 8.00 (d, 2H); 7.84 (d, 2H); 7.60-7.40 (m, 2H); 7.40-7.22 (m, 3H); 7.25-7.10 (m, 2H); 5.37 (s, 2H); 3.20-2.90 (m, 4H).
  • Example 9 The material of Example 9 (4.2 g, 0.009 mol), DMF (40 mL), glacial acetic acid (20 mL), and Pearlman's catalyst (1.5 g) were shaken at 55 psi hydrogen for 96 hours. Contents were filtered through celite and the filtrate was concentrated in vacuo leaving the product as a gray solid, 2.4 g (70% yield). FABHRMS m/z 388.1124 (M+H, C 17 H 18 N 5 O 4 S requires 388.1080).
  • Example 12 was prepared similarly to Example 2 starting with the material of llin 86% yield. FABHRMS m/z 359.0939 (M+H, C 15 H 13 N 6 O 3 S requires 359.0926). ⁇ NMR (DMSO-d 6 / 300 MHz) 8.02 (d, 2H); 7.87 (d, 2H); 7.56 9s, IH); 7.50 (br s, 2H); 7.35 (s, 2H); 3.20-3.00 (m, 2H); 2.95-2.80 (m, 2H).
  • step 2 The product of step 2 was prepared similarly to step 1 of Example 1 using the material of step 1 in 77% yield.
  • Step 3 The final product of Example 13 was prepared similarly to Example 6 starting with the material of step 2 in 86% yield.
  • FABHRMS m/z 404.0702 (M+H, C 18 H 18 N 3 O 4 S 2 requires 404.0739).
  • ⁇ NMR (DMSO-d 6 / 300 MHz) 8.05 (d, 2H); 7.70 (d, 2H); 7.59 (s, IH); 7.39 (d, IH); 6.40 (d, IH); 4.35 (q, 2H); 3.10 (s, 4H); 1.35 (t, 3H).
  • Example 14 was prepared similarly to Example 2 staring with the compound of Example 13 in 85% yield.
  • FABHRMS m/z 375.0601 (M+H, C 16 H 15 N 4 O 3 S 2 requires 375.0586).
  • step 1 The enolate from step 1 (717 mg, 3 mmol) was combined with 4- sulfonamidophenyl-hydrazine hydrochloride ( 669 mg, 2 mmol) in methanol (10 mL) and stirred at ambient temperature for 72 hours, then the resulting precipitate was collected by suction filtration and washed with methanol.
  • the resulting hydrated pyrazole (502 mg) was re-suspended in methanol and concentrated HCl (0.5 mL) was added. The reaction was stirred at ambient temperature for two hours, then concentrated to a yellow solid in-vacuo. The solid was triturated with methanol and collected by suction filtration. Yield 250 mg (22 %).
  • step 4 The product from step 4 (0.35 g, 0.00075 mol) was treated with a mixture of TFA (15 mL) and water (5 mL) and the dark brown solution was refluxed under nitrogen for 2 h. Cooled and basified with cone, ammonium hydroxide to precipitate out 0.18 g of crude product as a pale yellow solid. A suspension of this solid in a mixture of cone, ammonium hydroxide (15 mL) and methanol (5 mL) was stirred at RT for 3 days. Solvent was removed to half volume and the solid was filtered to afford 0.1 g of product was white powder (50% yield for two steps); mp: 347°C (decomp); Anal. Calcd. for C 15 H 14 N 6 O 3 S: C, 50.27; H, 3.94; N, 23.45; S, 8.95. Found: C, 49.65; H, 3.81; N, 22.78; S, 8.77.
  • Examples 18, and 19 were prepared according to Scheme XVm. Related compounds such as A, B and C shown in Scheme XVUI can be prepared in a similar manner using the appropriate R 4 group. SCHEME XVIfl
  • Table 1 shows the bioactivity for the exemplified compounds as measured in the IKK heterodimer Resin Enzyme Assay expressed as LC50.
  • SAM ⁇ 2 T 1 M 1V1 96 Biotin capture plates were from Promega.
  • Anti-FLAG affinity resin, FLAG-peptide, NP-40 (Nonidet P-40), BSA, ATP, ADP, AMP, LPS (E. coli serotype 0111:B4), and dithiothreitol were obtained from Sigma Chemicals.
  • Antibodies specific for NEMO (IKK ⁇ ) (FL-419), IKKl(H-744), IKK2(H-470) and I B (C-21) were purchased from Santa Cruz Biotechnology.
  • Ni-NTA resin was purchased from Qiagen.
  • Peptides were purchased from American Peptide Company.
  • Protease inhibitor cocktail tablets were from Boehringer Mannheim.
  • Sephacryl S-300 column was from Pharmacia LKB Biotechnology. Centriprep-10 concentrators with a molecular weight cutoff of 10 kDa and membranes with molecular weight cut-off of 30 kDa were obtained from Amicon. [Y- 33 P] ATP (2500 Ci/mmol) and [Y- 32 P] ATP (6000 Ci/mmol) were purchased from Amersham. The other reagents used were of the highest grade commercially available.
  • cDNAs of human IKKl and IKK2 were amplified by reverse transcriptase-polymerase chain reaction from human placental RNA (Clonetech).
  • hIKKl was subcloned into pFasfBac HTa (Life Technologies) and expressed as N- terminal His 6 -tagged fusion protein.
  • the hTKK2 cDNA was amplified using a reverse oligonucleotide primer which incorporated the peptide sequence for a FLAG-epitope tag at the C-terminus of the IKK2 coding region (DYKDDDDKD).
  • the hIKK2:FLAG cDNA was subcloned into the baculovirus vector pFastBac.
  • the rhIKK2 (S177S, E177E) mutant was constructed in the same vector used for wild type rhIKK2 using a QuikChangeTM mutagenesis kit (Stratagene). Viral stocks of each construct were used to infect insect cells grown in 40L suspension culture. The cells were lysed at a time that maximal expression and rhTKK activity were demonstrated. Cell lysates were stored at -80 °C until purification of the recombinant proteins was undertaken as described below.
  • Buffers used are: buffer A: 20 mM Tris-HCl, pH 7.6, containing 50 mM NaCl, 20 mM NaF, 20 mM ⁇ -Glycerophosphate, 500 uM sodiumortho-vanadate, 2.5 mM metabisulfite, 5 mM benzamidine, 1 mM EDTA, 0.5 mM EGTA, 10% glycerol, 1 mM DTT, IX CompleteTM protease inhibitors; buffer B: same as buffer A, except 150 mM NaCl, and buffer C: same as buffer A, except 500 mM NaCl.
  • rhIKKl homodimer was eluted using 300 mM imidazole in buffer C. BSA and NP-40 were added to the enzyme fractions to the final concentration of 0.1 %. The enzyme was dialyzed against buffer B, aliquoted and stored at -80 °C.
  • the protein-resin slurry was poured into a 25 ml column and washed with 250 ml of buffer A containing 10 mM imidazole followed by 125 ml of buffer A containing 50 mM imidazole. Buffer A, containing 300 mM imidazole, was then used to elute the protein. A 75 ml pool was collected and NP-40 was added to a final T U 03/04844 concentration of 0.1%. The protein solution was then dialyzed against buffer B. The dialyzed heterodimer enzyme was then allowed to bind to 25 ml of anti-FLAG M2 agarose affinity gel overnight with constant mixing.
  • the protein-resin slurry was then centrifuged for 5 min at 2,000 rpm. The supernatant was collected and the resin re-suspended in 100 ml of buffer C containing 0.1% NP-40. The resin was washed with 375 ml of buffer C containing 0.1 % NP-40. The protein-resin was poured into a 25 ml column and the enzyme eluted using buffer B containing FLAG peptide. Enzyme fractions (100 ml) were collected and concentrated to 20 ml using an Amicon membrane with molecular weight put-off of 30 kDa. Bovine serum albumin was added to the concentrated enzyme to final concentration of 0.1 %. The enzyme was then aliquoted and stored at -80 °C.
  • Wt 70Z/3 and 1.3E2 cells were grown in RPMI 1640 (Gibco) supplemented with 7 % defined bovine serum (Hyclone) and 50 ⁇ M 2-mercaptoethanol.
  • Human monocytic leukemia THP-1 cells obtained from ATCC, were cultured in RPMI 1640 supplemented with 10% defined bovine serum, 10 mM HEPES, 1.0 mM sodium pyruvate and 50 ⁇ M 2- mercaptoethanol.
  • cells were plated in 6 well plates at 1x10 cells/ml in fresh media.
  • Pre-B cells were stimulated by the addition of 10 ⁇ g/ml LPS for varying lengths of time ranging from 0-4 hr.
  • THP-1 cells were stimulated by the addition of 1 ⁇ g/ml LPS for 45 minutes.
  • Cells were pelleted, washed with cold 50 mM sodium phosphate buffer, pH 7.4 containing 0.15 M NaCl and lysed at 4 °C in 20 mM Hepes buffer, pH 7.6 containing 50 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM sodium orthovanadate, 10 mM ⁇ -glycerophosphate, 1 mM NaF, 1 mM PMSF, 1 mM DTT and 0.5 % NP40 (lysis buffer).
  • the cytosolic fractions obtained following centrifugation at 10,000 X g were stored at -80° C until used. Immunoprecipitation and Western Blotting
  • SF9 cells paste containing rhIKKs were centrifuged (100,000 X g, 10 min) to remove debris.
  • rhIKKs were immunoprecipitated (100 ⁇ g of cell paste) from the cell supernatant using 3 ⁇ g of anti-NEMO antibody ( FL-419), followed by coupling to protein A sepharose beads.
  • rhIKKs were also immunoprecipitated from affinity chromatography purified protein preparations (1 ⁇ g) using anti-FLAG, anti- His or anti-NEMO antibodies (1-4 ⁇ g) followed by protein A sepharose coupling.
  • the native, human IKK complex was immunoprecipitated from THP-1 cell homogenates (300 ⁇ g/condition) using the anti-NEMO antibody.
  • Immune complexes were pelleted and washed 3 times with 1 ml cold lysis buffer. Immunoprecipitated rhIKKs were chromatographed by SDS-PAGE (8% Tris- glycine) and transferred to nitrocellulose membranes (Novex) and detected by chemiluminescense (SuperSignal) using specific anti-IKK antibodies (IKK2 H-470, IKKl H-744). Native IKK2, I ⁇ B ⁇ and NEMO proteins from cytosolic lysates (20- 80 ⁇ g) were separated by SDS-PAGE and visualized by chemiluminescense using specific antibodies.
  • IKK ⁇ kinase activity was measured using a biotinylated I ⁇ B ⁇ peptide (Gly-Leu-Lys-Lys-Glu-Arg-Leu-Leu-Asp-Asp-Arg-His-Asp-Ser 32 -Gly-Leu-Asp-
  • the standard reaction mixture contained 5 ⁇ M biotinylated I ⁇ B ⁇ peptide, 1 ⁇ M [ ⁇ - 33 P] ATP (about 1 X 10 5 cpm), 1 mM DTT, 50 mM KC1, 2 mM MgCl 2 , 2 mM MnCl 2 , 10 mM NaF, 25 mM Hepes buffer, pH. 7.6 and enzyme solution (1-10 ⁇ l) in a final volume of 50 ⁇ l.
  • One unit of enzyme activity was defined as the amount required to catalyze the transfer of 1 nmole of phosphate from ATP to I ⁇ B ⁇ peptide per min. Specific activity was expressed as units per mg of protein.
  • various concentrations of ATP or I ⁇ B ⁇ peptide were used in the assay at either a fixed I ⁇ B ⁇ or ATP concentration.
  • I ⁇ B ⁇ peptide K m assays were carried out with 0.1 ⁇ g of enzyme, 5 ⁇ M ATP and I ⁇ B ⁇ peptide from 0.5 to 20 ⁇ M.
  • IKK ⁇ kinase activity was measured using a biotinylated IkB ⁇ peptide (Gly-Leu-Lys-Lys-Glu-Arg-Leu-Leu-Asp-Asp-Arg-His-Asp-Ser 2 -Gly-Leu-Asp- Ser 36 -Met-Lys-Asp-Glu-Glu) (American Peptide Co.).
  • 20 ul of the standard reaction mixture contained 5 ⁇ M biotinylated I ⁇ B ⁇ peptide, 0.1 ⁇ Ci/reaction [ ⁇ - 33 P] ATP (Amersham) (about 1 X 10 5 cpm), 1 ⁇ M ATP (Sigma), 1 mM DTT (Sigma), 2 mM MgCl 2 (Sigma), 2 mM MnCl 2 (Sigma), 10 mM NaF (Sigma), 25 mM Hepes (Sigma) buffer, pH 7.6 and 20 ⁇ l enzyme solution and 10 ul inhibitor in a final volume of 50 ⁇ l.
  • IKK heterodimer kinase activity was measured using a biotinylated IkB ⁇ peptide (Gly-Leu-Lys-Lys-Glu-Arg-Leu-Leu-Asp-Asp-Arg-His-Asp-Ser 32 -Gly-Leu- Asp-Ser 36 -Met-Lys-Asp-Glu-Glu) (American Peptide Co.).
  • 20 ul of the standard reaction mixture contained 5 ⁇ M biotinylated IkB ⁇ peptide, 0.1 ⁇ Ci/reaction [ ⁇ - 33 P] ATP (Amersham) (about 1 X 10 5 cpm), 1 ⁇ M ATP (Sigma), 1 mM DTT (Sigma), 2 mM MgCl 2 (Sigma), 2 mM MnCl 2 (Sigma), 10 mM NaF (Sigma), 25 mM Hepes (Sigma) buffer, pH 7.6 and 20 ⁇ l enzyme solution and 10 ⁇ l inhibitor in a final volume of 50 ⁇ l.

Abstract

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

Description

TRICYCLIC PYRAZOLE DERIVATIVES FOR THE TREATMENT OF
INFLAMMATION
FIELD OF THE INVENTION
[001] The present invention in general is in the field of anti-inflammatory pharmaceutical agents and specifically relates to substituted tricyclic pyrazole derivatives, compositions comprising them, and their use as therapeutic agents in the treatment of diseases linked to protein kinases, particularly for treating cancer, inflammation, and inflammation-associated disorders, such as arthritis.
BACKGROUND OF THE INVENTION
[002] The following description of the background of the invention is provided to aid in the understanding the invention, but is not admitted to be or describe prior art to the invention.
[003] NF-κB 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 (1998) Annu. Rev. Immunol. 16, 115-260; Zandi, E., and Karin, M. (1999) Mol. Cell. Biol. 19, 4547-4551; Karin, M. (1999) J. Biol. Chem. 274, 27339- 27342). 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-α (TNFα) and interleukin-β (ILlβ). Through the synergistic interaction with other transcription factors, further specificity can be achieved while maintaining enormous potential to coordinately induce a large number of functionally related genes. NF-κB 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 IκB 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. 274, 27339-27342). IKBS mask the nuclear localization signal on NF-κB, preventing nuclear translocation and hence DNA binding to the promoter regions of responsive genes. Stimulation of cells with an agonist that activates NF-κB leads to a series of biochemical signals, ultimately resulting in the phosphorylation, ubiquitinylation, and degradation of IKBS, thereby releasing NF-κB for nuclear translocation (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. 274, 27339-27342). Recently, two IκB kinases (IKK1 or IKKα and IKK2 or IKKβ), which phosphorylate IKBS and thereby initiate their degradation, have been cloned and characterized by a number of laboratories (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) /. Biol Chem. 274, 27339- 27342). The catalytic subunits, IKK1 and IKK2, are similar structurally as well as enzymatically and exist as a heterodimer in a large protein complex referred to as the IKK signalsome (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. (1997) Nature 388, 548-554; Mercurio, F., Zhu, H., Murray, B.W., Shevchenko, A., Bennett, B.L., Li, J.W., Young, D.B., Barbosa, M., Mann, M., Manning, A. and Roa, A. (1997) Science 278, 860-866; Zandi, E. Rothwarf, D.M., Delhase, M., Hayadawa, M and Karin, M. (1997) Cell 91, 243- 252; Woronicz, J.D., Gao, X., Cao, Z., Rothe, M. And Goeddel, D.V. (1997) Science 278, 866-869). A third protein, NEMO (IKKγ, IKKAP1), is a regulatory adapter protein necessary for 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., Karin, M. (1998) Nature 395, 297; Mercurio, F., Murray, B. W., Shevchenko, A., Bennet, B. L., Young, D. B., Li, J. W., Pascual, G., Motiwala, A., Zhu, H., Mann, M and Manning, A. M. (1999) Mol. Cell. Biol. 2, 1526-1538). IKK1 and IKK2 are 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. (1997) Cell 90, 373-383; DiDonato, J.A., Hayakawa, M., Rothwarf, D.M., Zandi, E. and Karin, M. (1997) Nature 388, 548-554; Mercurio, F., Zhu, H., Murray, B.W., Shevchenko, A., Bennett, B.L., Li, J.W., Young, D.B., Barbosa, M., Mann, M., Manning, A. and Roa, A. (1997) Science 278, 860-866; Zandi, E. Rothwarf, D.M., Delhase, M., Hayadawa, M and Karin, M. (1997) Cell 91, 243- 252; Woronicz, J.D., Gao, X., Cao, Z., Rothe, M. and Goeddel, D.V. (1997) Science 278, 866-869; Hu, M. C. T., and Wang, Y. (1998) Gene 111, 31-40). This kinase complex appears to represent a critical, common denominator in the activation of NF-kB in a number of signal transduction pathways stimulated by a variety of agonists including cytokines, such as TNFα and ILlβ, 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) 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).
[004] IKK1 (also termed IKKα, 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. (1997) Nαtwre 388, 548-554; Mercurio, F., Zhu, H., Murray, B.W., Shevchenko, A., Bennett, B.L., Li, J.W., Young, D.B., Barbosa, M., Mann, M., Manning, A. And Roa, A. (1997) Science 278, 860-866) was cloned simultaneously by standard biochemical purification of the IκB kinase activity from TΝFα stimulated HeLa S3 cells and by its interaction with the MAP3K, ΝF-κB 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. 41, 537-549). IKK1 (also termed IKKα) 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 IKKβ) was also cloned by standard biochemical purification, copurifying with IKK1 from TNFα 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., Manning, A. and Roa, A. (1997) Science 278, 860-866; Zandi, E. Rothwarf, D.M., Delhase, M., Hayadawa, M and Karin, M. (1997) Cell 91, 243-252; Woronicz, J.D., Gao, X., Cao, Z., Rothe, M. And Goeddel, D.V. (1997) Science 278, 866-869). 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. Data obtained using transient mammalian expression analysis, by in vitro translation experiments and by coexpression in a baculoviral system reveals that IKK1 and IKK2 associate preferentially as a heterodimer through their leucine zipper motifs. Although homodimers have also been described in these systems, the heterodimer is thought to be the physiologic form of the kinase in mammalian cells (Zandi, E. Rothwarf, D.M., Delhase, M., Hayadawa, M and Karin, M. (1997) Cell 91, 243-252; Li, J., Peet, G.W., Pullen, S.S., Schembri-King, J., Warren, T.C., Marcu, K.B., Kehry, M.R., Barton, R. and Jakes, S. (1998) J. Biol. Chem. 273, 30736-30741). Finally, NEMO (also termed IKKγ) contains three α-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 (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., Karin, M. (1998) Nature 395, 297; Mercurio, F., Murray, B. W., Shevchenko, A., Bennet, B. L., Young, D. B., Li, J. W., Pascual, G., Motiwala, A., Zhu, H., Mann, M and Manning, A. M. (1999) Mol. Cell. Biol. 2, 1526-1538).
[005] 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. (1997) Nature 388, 548-554; Mercurio,F., Zhu, H., Murray, B.W., Shevchenko, A., Bennett, B.L., Li, J.W., Young, D.B., Barbosa, M., Mann, M., Manning, A. and Roa, A. (1997) Science 278, 860-866; Zandi, E. Rothwarf, D.M., Delhase, M., Hayadawa, M and Karin, M. (1997) Cell 91, 243-252; Woronicz, J.D., Gao, X., Cao, Z., Rothe, M. and Goeddel, D.V. (1997) Science 278, 866-869; Dehase, M., Hayakawa, M., Chen, Y., and Karin, M. (1999) Science 284, 309-313). Both IKK subunits contain a canonical MAPKK activation loop motif near the N- 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. 274, 27339- 27342; Karin, M., and Delhase, M. (1998) Proc. Natl. Acad. Sci. USA 95, 9067- 9069). Finally, phosphorylation of serines in the C-terminus of IKK2 results in a decrease in IKK activity and it is postulated to be responsible for the transient kinase activity seen after stimulation of cells with an agonist (Dehase, M., Hayakawa, M., Chen, Y., and Karin, M. (1999) Science 284, 309-313).
[006] IKK2 demonstrates a more potent kinase activity compared to IKKl using IκBα or IκBβ as a substrate (Mercurio, F., Zhu, H., Murray, B.W., Shevchenko, A., Bennett, B.L., Li, J.W., Young, D.B., Barbosa, M., Mann, M., Manning, A. and Roa, A. (1997) Science 278, 860-866; Zandi, E. Rothwarf, D.M., Delhase, M., Hayadawa, M and Karin, M. (1997) Cell 91, 243-252; Woronicz, J.D., Gao, X., Cao, Z., Rothe, M. and Goeddel, D.V. (1997) Science 278, 866-869; Dehase, M., Hayakawa, M., Chen, Y., and Karin, M. (1999) Science 284, 309-313). Mutations of the phospho-acceptor serine residues within the MAPKK activation loop alters IKK2 kinase activity; the serine to alanine substitutions result in decreased kinase activity whereas the serine to glutamic acid substitutions result in a constitutively active kinase. Similar alanine mutations in IKKl do not result in a decreased stimulation of total IKK activity in response to TNFα or JLlβ (Dehase, M., Hayakawa, M., Chen, Y., and Karin, M. (1999) Science 284, 309-313). IKK2 being the dominant kinase activity within the IKK complex is further supported by the analysis of fibroblasts from mice deficient in IKKl or IKK2. Fibroblasts lacking IKKl retain full IKK activity in response to cytokines and could activate NF-κB. In contrast, fibroblasts lacking IKK2 do not exhibit IKK activity when stimulated with cytokines nor do they activate NF-κB. 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. V., Mercurio, F., Lee, K., and Verma, I. M. (1999) Science 284, 321-325; Takeda, K., Tekeuchi, O., Tsujimura, T., Itami, S., Adachi, O., Kawai, T., Sanjo, H., Yoshikawa, K., Terada, N, and Akira, S. (1999) Science 284, 313-316; Hu, Y., Baud, V., Delhase, M., Zhang, P., Deerinck, T., Ellisman, M., Johnson, R., and Karin, M. (1999) Science 284, 315-320; Li, Q., Lu, Q., Hwang, J. Y., Buscher, D., Lee, K., Izpisua-Belmonte, J. C, and Verma, I. M. (1999) Gene and Development 13, 1322-1328; Tanaka, M., Fuentes, M. E., Yamaguchi, K., Durnin, M. H., Dalrymple, S. A., Hardy, K. L, and Goeddel, D. V. (1999) Immunity 10, 421-429).
[007] It is well-known that 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 JL-8, cell adhesion molecules, such as ICAM and VCAM, and inducible nitric oxide synthase (iNOS). Such 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. The importance of NF-κB in inflammatory disorders is further strengthened by studies of airway inflammation including asthma in which NF-κB has been shown to be activated. This activation may underlie the increased cytokine production and leukocyte infiltration characteristic of these disorders. In addition, inhaled steroids are known to reduce airway hyperresponsiveness and suppress the inflammatory response in asthmatic airways. L light of the recent findings with regard to glucocorticoid inhibition of NF-κB, one may speculate that these effects are mediated through an inhibition of NF-κB. Further evidence for a role of NF-κB in inflammatory disorders comes from studies of rheumatoid synovium. Although NF-κB is normally present as an inactive cytoplasmic complex, recent immunohistochemical studies have indicated that NF-κB is present in the nuclei, and hence active, in the cells comprising rheumatoid synovium. Furthermore, NF-κB 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).
[008] NF-κB in inflammatory disorders is further strengthened by studies of airway inflammation including asthma in which NF-κB has been shown to be activated. This activation may underlie the increased cytokine production and leukocyte infiltration characteristic of these disorders. In addition, inhaled steroids are known to reduce airway hyper responsiveness and suppress the inflammatory response in asthmatic airways. In light of the recent findings with regard to glucocorticoid inhibition of NF-κB, one may speculate that these effects are mediated through an inhibition of NF-κB. Further evidence for a role of NF-κB in inflammatory disorders comes from studies of rheumatoid synovium. Although NF- KB is normally present as an inactive cytoplasmic complex, recent immunohistochemical studies have indicated that NF-κB is present in the nuclei, and hence active, in the cells comprising rheumatoid synovium. Furthermore, NF- kB has been shown to be activated in human synovial cells in response to stimulation with TNF-α. 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).
[009] The NF-κB/Rel and IκB 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). In addition, rearrangement and/or amplification of the genes encoding these proteins are seen in 20-25% of certain human lymphoid tumors. In addition, a role for NF-κB in the regulation of apoptosis, cell cycle progression, invasion, and metastasis has been reported (Bours V. et al., Biochemical Pharmacology 60:1085- 1090, 2000) strengthening the role of this transcription factor in the control of cell proliferation. The inhibition of NF-κB has been shown to potentiate TNF- and cancer therapy through increased apoptosis (Wang C-Y et al., Science 274:784-787, 1996; Wang C-Y et al., Nat Med 5:412-417, 1999). It has also been shown that human T-cell leukemia virus type 1 (HTLV1) infected cells (the etiological agent of an aggressive malignancy of activated CD4+ T lymphocytes), IKKα and IKKβ are expressed constitutively, which normally function in a transient manner (Chu Z-L et al., J of Biological Chemistry 273:15891-15894, 1998). The HTLV1 transforming and transactivating protein (Tax) has been shown to bind MEKK1 and increases the activity of IKKβ to enhance phosphorylation of serine residues in IκBα that lead to its degradation.
[0010] Pyrazoles have been described for use in the treatment of inflammation. 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.
[0011] U.S. Patent No. 3,940,418 to R. Hamilton describes tricyclic 4,5- dihydrobenz[g]indazoles as antiinflammatory agents. In addition, R. Hamilton [J. Heterocyclic Chem., 13, 545 (1976)] describes tricyclic 4,5- dihydrobenz[g]indazoles as antiinflammatory agents. U.S. Patent No. 5,134,155 describes fused tricyclic pyrazoles having a saturated ring bridging the pyrazole and a phenyl radical as HMG-CoA reductase inhibitors. European publication EP 477,049, published Mar. 25, 1992, describes [4,5-dihydro-l -phenyl- 1H- benz[g]indazol-3-yl]amides as having antipsychotic activity. European publication EP 347,773, published Dec. 27, 1989, describes [4,5-dihydro-l -phenyl- 1H- benz[g]indazol-3-yl]propanamides as immunostimulants. M. Hashem et al [/. Med. Chem., 19, 229 (1976)] describes fused tricyclic pyrazoles, having a saturated ring bridging the pyrazole and a phenyl radical, as antibiotics.
[0012] Certain substituted pyrazolyl-benzenesulfonamides have been described in the literature as synthetic intermediates. Specifically, 4-[5-(4-chlorophenyl)-3- phenyl-lH-pyrazol-l-yl]benzenesulfonamide has been prepared from a pyrazoline compound as an intermediate for compounds having hypoglycemic activity [R. Soliman et al, J. Pharm. Sci., 76, 626 (1987)]. 4-[5-[2-(4-Bromophenyl)-2H- 1,2,3- triazol-4-yl]-3-methyl-lH-pyrazol-l-yl]benzenesulfonamide has been prepared from a pyrazoline compound and described as potentially having hypoglycemic activity [Η. Mokhtar, Pat J. Sci. Ind. Res., 31, 762 (1988)]. Similarly, 4-[4-bromo-5-[2-(4- chlorophenyl)-2H-l,2,3-triazol-4-yl]-3-methyl-lH-pyrazol-l- yl]benzenesulfonamide has been prepared [Η. Mokhtar et al, Pak. J. Sci. Ind. Res., 34, 9 (1991)].
[0013] The phytotoxicity of pyrazole derivatives is described [M. Cocco et al, //. Farmaco-Ed. Sci., 40, 272 (1985)], specifically for l-[4-(aminosulfonyl)phenyl]- 5-phenyl- 1 Η-pyrazole-3 ,4-dicarboxylic acid.
[0014] The use of styryl pyrazole esters for antidiabetes drugs is described [H. Mokhtar et al, Pharmazie, 33, 649-651 (1978)]. The use of styryl pyrazole carboxylic acids for antidiabetes drugs is described [R. Soliman et al, Pharmazie, 33, 184-5 (1978)]. The use of 4-[3,4,5-trisubstituted-pyrazol-l- yl]benzenesulfonamides as intermediates for sulfonylurea anti-diabetes agents is described, and specifically, l-[4-(aminosulfonyl)phenyl]-3-methyl-5-phenyl-lH- pyrazole-4-carboxylic acid [R. Soliman et al, J. Pharm. Sci, 72, 1004 (1983)]. 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 [Η. Feid-Allah, Pharmazie, 36, 754 (1981)]. In addition, l-(4-[aminosulfonyl]phenyl)-5- phenylpyrazole-3-carboxylic acid has been prepared from the above described 4-[3- methyl-5-phenyl-lH-pyrazol-l-yl]benzenesulfonamide compound [R. Soliman et al, J. Pharm. Sci, 70, 602 (1981)].
[0015] WO 00/27822 discloses tricyclic pyrazole derivatives, WO 00/59901 discloses dihydroindeno pyrazoles, WO 95/15315 discloses diphenyl pyrazole compounds, WO 95/15317 discloses triphenyl pyrazole compounds, WO 95/15318 discloses tri-substituted pyrazole compounds, and WO 96/09293 discloses benz[g]indazolyl derivatives. [0016] WO 95/15316 discloses substituted pyrazolyl benzenesulfamide derivatives.
DETAILED DESCRIPTION OF THE INVENTION
[0017] A class of compounds, which are useful in treating cancer, inflammation, and inflammation related disorders, is defined by Formula I:
Figure imgf000011_0001
wherein
A is selected from the group consisting of: (CH2)m and (CH2)n-CH=CH-
(CH2)n; wherein each CH2 may be independently substituted with one or more substitution selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl; m is 0 to 8; n is independently selected from 0, 1 or 2;
Q is a 5 or 6 membered heteroaryl, or aryl, optionally saturated, or optionally substituted with R1 , R2, or R12;
B is an aromatic heterocyclic;
X is selected from the group consisting of: N and C;
Y and Z are independently selected from the group consisting of: N, C, CH,
CR3, S, and O; R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6 3 SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 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, SO2, 0, and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optional substituted with, hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 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, SO2, O, and NR6;
R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, NO2, SR6, NHR6, CON(R6)R7, NHCONHR6, CO2H, and haloalkyl;
R1 and R2 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 R1; R3 is selected from the group consisting of: substituted or unsubstituted amidine, alkylamino, aminoalkyl, CONHR16, NH2, NHCOR6, and CH2NHCOR6;
R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, SO2N(R8)R8', NHR9, NHCOR9, NR9COR9, NHCO(OR9), NR9CO(OR9), NR8SO2R10, NHSO2N(R10)R10', NR6CON(R10)R10', COR9, CO2R8, CON(R8)R8', wherein R8 and R8'may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6, and wherein R10 and R10'may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR wherein said aryl, heterocyclic, heteroaryl, or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, 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: OR14, N(R14)R14', and glycols;
R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic;
R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic;
R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl; R9 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, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanate, isothiocyanate, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyl'oxy, and heterocyclic optionally substituted with alkyl, alkylamino, aminoalkyl, hydroxyalkyl, and alkylaminoalkyl;
R10 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,
R10' 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, R11 is selected from the group consisting of: hydrido, halogen, haloalkyl,
CN, CO2R5, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, and CONH2;
R12 is selected from the group consisting of: hydrido, halogen, alkyl, and alkoxy;
R13 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, 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: OR14, N(R14)R14', and glycols; R14 is independently selected from the group consisting of: hydrido, and lower alkyl;
R14' is independently selected from the group consisting of: hydrido, and lower alkyl; R15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl, and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic; and R16 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, and alkoxyalkyl;
or isomers, tautomers, carriers, esters, prodrugs, pharmaceutically acceptable salts thereof.
Another class of compounds is defined by formula II
Figure imgf000015_0001
wherein
A is selected from the group consisting of: (CH2)m and (CH2)n-CH=CH- (CH2)n; wherein each CH2 may be independently substituted with one or more substitution selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl; m is 0 to 8; n is independently selected from 0, 1, or 2; Q is a 5 or 6 membered heteroaryl, or aryl, optionally saturated, or optionally substituted with R1, R2, or R12; B is an aromatic heterocyclic;
R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO2, OR5, OCOOR5, CO2R7,
CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 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, SO2, O, and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optional substituted with, hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 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, SO2, O, and NR6;
R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, NO2, SR6, NHR6, CON(R6)R7, NHCONHR6, CO2H, and haloalkyl;
R1 and R2 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 R1; R3 is selected from the group consisting of: substituted or unsubstituted amidine, alkylamino, aminoalkyl, CONHR16, NH2, NHCOR6, and CH2NHCOR6;
R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, SO2N(R8)R8', NHR9, NHCOR9, NR9COR9, NHCO(OR9), NR9CO(OR9), NR8SO2R10, NHSO2N(R10)R10', NR6CON(R10)R10', COR9, CO2R8, CON(R8)R8', wherein R8 and R8'may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6, and wherein R10 and R10 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6 wherein said aryl, heterocyclic, heteroaryl, or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, 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: OR14, N(R14)R14', and glycols;
R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic;
R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic;
R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl; R8' is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl; R9 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, 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, alkylamino, aminoalkyl, hydroxyalkyl, and alkylaminoalkyl;
R10 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,
R10' 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, R11 is selected from the group consisting of: hydrido, halogen, haloalkyl,
CN, CO2R5, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, and CONH2;
R is selected from the group consisting of: hydrido, halogen, alkyl, and alkoxy;
R13 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:
OR14, N(R14)R14', and glycols;
R14 is independently selected from the group consisting of: hydrido, and lower alkyl; R14' is independently selected from the group consisting of: hydrido, and lower alkyl;
R15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl, and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic; and R16 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, and alkoxyalkyl;
or isomers, tautomers, carriers, esters, prodrugs, pharmaceutically acceptable salts thereof.
A preferred class of compounds is defined by formula HI
Figure imgf000019_0001
wherein A is (CH2)m, wherein each CH may be independently substituted with one or more substitution selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl; m is O to 8; Q is a 5 or 6 membered heteroaryl, or aryl, optionally saturated, or optionally substituted with R1, R2, or R12; B is an aromatic heterocyclic;
R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7,
NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 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, SO2, O, and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optional substituted with, hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 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, SO2, O, and NR6;
R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, NO2, SR6, NHR6, CON(R6)R7, NHCONHR6, CO2H, and haloalkyl; R and R 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 R1; R3 is CONHR16; R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, SO2N(R8)R8', NHR9, NHCOR9, NR9COR9, NHCO(OR9), NR9CO(OR9), NR8SO2R10, NHSO2N(R10)R10', NR6CON(R10)R10', COR9, CO2R8, CON(R8)R8', wherein R8 and R8'may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6, and wherein R10 and R10 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6 wherein said aryl, heterocyclic, heteroaryl, or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, 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: OR14, N(R14)R14', and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic; R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic;
R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl;
R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl;
R9 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, 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, alkylamino, aminoalkyl, hydroxyalkyl, and alkylaminoalkyl ;
R10 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, R10 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,
R11 is selected from the group consisting of: hydrido, halogen, haloalkyl, CN, CO2R5, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, and CONH2; R12 is selected from the group consisting of: hydrido, halogen, alkyl, and alkoxy;
R13 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, 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: OR14, N(R14)R14', and glycols;
R14 is independently selected from the group consisting of: hydrido, and lower alkyl;
R14 is independently selected from the group consisting of: hydrido, and lower alkyl;
R15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl, and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic; and
R16 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, and alkoxyalkyl;
or isomers, tautomers, carriers, esters, prodrugs, pharmaceutically acceptable salts thereof.
Definitions
[0020] 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 release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Compounds containing a chiral center may be used as a racemic mixture, an enantiornerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
[0021] The meaning of any substituent at any one occurrence in Formula I or any sub-formula thereof is independent of its meaning, or any other substituents meaning, at any other occurrence, unless specified otherwise.
[0022] 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 Formula I or Formula U in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Compounds containing a chiral center may be used as a racemic mixture, an enantiornerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
[0023] The meaning of any substituent at any one occurrence in Formula I or Formula JJ or any sub-formula thereof is independent of its meaning, or any other substituents meaning, at any other occurrence, unless specified otherwise.
[0024] The term "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 (-CH2-) radical. The term "halo" means halogens such as fluorine, chlorine, and bromine or iodine atoms. The term "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, for one example, 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. The term "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. The terms "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. The term "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. Examples of "alkoxy" radicals include methoxy, butoxy, and trifluoromethoxy. The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two, or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronapthyl, indane, and biphenyl. The term "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. The term "heteroaryl" embraces unsaturated heterocyclic radicals. Examples of 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. The term "heterocyclic alkyl" embraces alkyl attached to the heterocyclic. The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO2- "Alkylsulfonyl", embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. The term "arylsulfonyl" embraces sulfonyl radicals substituted with an aryl radical. The terms "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 (-SO2-NH2). The terms "N-alkylsulfamyl" and "N,N- dialkylsulfamyl" denote sulfamyl radicals substituted, respectively, with one alkyl radical, a cycloalkyl ring, or two alkyl radicals. The terms "N-arylsulfamyl" and "N- alkyl-N-arylsulfamyl" denote sulfamyl radicals substituted, respectively, with one aryl radical, and one alkyl and one aryl radical. The terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", denotes -CO2H. The term "carboxyalkyl" embraces radicals having a carboxyradical as defined above, attached to an alkyl radical. The term "carbonyl", whether used alone or with other terms, such as "alkylcarbonyl", denotes -(C=O)-. The term "alkylcarbonyl" embraces radicals having a carbonyl radical substituted with an alkyl radical. An example of an "alkylcarbonyl" radical is CH3-(C=O)-. The term "alkylcarbonylalkyl" denotes an alkyl radical substituted with an "alkylcarbonyl" radical. The term "alkoxycarbonyl" means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl (C=O) radical. Examples of such "alkoxycarbonyl" radicals include (CH3)3CO-C=O)- and -(O=)C-OCH3. The term "alkoxycarbonylalkyl" embraces radicals having "alkoxycarbonyl", as defined above substituted to an alkyl radical. Examples of such "alkoxycarbonylalkyl" radicals include (CH3)3COC(=O) (CH2)2- and - (CH2)2(O=)COCH . The term "amido" when used by itself or with other terms such as "amidoalkyl", "N-monoalkylamido", "N-monoarylamido", "N,N-dialkylamido", "N-alkyl-N-arylamido", "N-alkyl-N-hydroxyamido" and "N-alkyl-N- hydroxyamidoalkyl", embraces a carbonyl radical substituted with an amino radical. The terms "N-alkylamido" and "N,N-dialkylamido" denote amido groups which have been substituted with one alkyl radical and with two alkyl radicals, respectively. The terms "N-monoarylamido" and "N-alkyl-N-arylamido" denote amido radicals substituted, respectively, with one aryl radical, and one alkyl and one aryl radical. The term "N-alkyl-N-hydroxyamido" embraces amido radicals substituted with a hydroxyl radical and with an alkyl radical. The term "N-alkyl-N- hydroxyamidoalkyl" embraces alkyl radicals substituted with an N-alkyl-N- hydroxyamido radical. The term "amidoalkyl" embraces alkyl radicals substituted with amido radicals. The term "aminoalkyl" embraces alkyl radicals substituted with amino radicals. The term "alkylaminoalkyl" embraces aminoalkyl radicals having the nitrogen atom substituted with an alkyl radical. The term "amidino" denotes an -C(=NH)-NH2 radical. The term "cyanoamidino" denotes an -C(=N- CN)-NH2 radical. The term "heterocycloalkyl" embraces heterocyclic-substituted alkyl radicals such as pyridylmethyl and thienylmethyl. The term "aralkyl" embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenethyl, and diphenethyl. The terms benzyl and phenylmethyl are interchangeable. The term "cycloalkyl" embraces radicals having three to ten carbon atoms, such as cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkenyl" embraces unsaturated radicals having three to ten carbon atoms, such as cylopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. The term "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 -S-). The term "alkylsulfinyl" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent -S(=O)- atom. The terms "N-alkylamino" and "N, N- dialkylamino" denote amino groups which have been substituted with one alkyl radical and with two alkyl radicals, respectively. The term "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. The term "acylamino" embraces an amino radical substituted with an acyl group. An example of an "acylamino" radical is acetylamino (CH3C(=O)-NH-).
[0025] Another aspect of the present invention is chemical intermediates in the synthesis of the claimed compounds.
[0026] Another aspect of the present invention is methods of syntheses of the claimed compounds.
[0027] Compounds of Formula I or Formula JJ 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. For example, compounds of Formula I or Formula U 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 or Formula JJ 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 or Formula JJ 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 or Formula U 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 or JJ are useful as agents for treating cancer or anticancer agents. The compounds of formula I or TI 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. More specifically, the compounds of this invention are useful in the treatment of a variety of cancers including, but not limited to: carcinoma such as 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-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. Due to the key role of protein kinases 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 or U 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, IKKα/IKKβ heterodimer, TBK or IKK/. 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 (cdk), Met, PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Aurora 1, Aurora 2, Bub-1, PLK, Chkl, Chk2, HER2, rafl, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, IGF-R, VEGF-R, PI3K, weel kinase, Src, Abl, Akt, ILK, MK-2, 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 other kinases. Preferably the compounds have a selectivity ratio of IKK2 inhibition over other kinase inhibition of at least 50, and more preferably of at least 100. The present invention preferably includes compounds, which selectively inhibit IKK2 over IKKl . Preferably, the compounds have an IKK2 IC50 of less than 1 μM, 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 μM, and more preferably of greater than 100 μM. The compounds of formula 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.
[0028] While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. 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. Also included in the family of compounds of the present invention are the pharmaceutically acceptable salts thereof. The term "pharmaceutically acceptable salts" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds of the present invention may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Appropriate 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 (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, β-hydroxybutyric, salicyclic, galactaric and galacturonic acid. 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.
[0029] Also embraced within this invention are pharmaceutical 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. Accordingly, 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. For oral administration, 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. 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 subject, 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 body weight, 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. For therapeutic purposes, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered orally, 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. 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. For rectal administration, 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. By 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. By systemic administration is meant oral, intravenous, intraperitoneal, and intramuscular administration. The amount of a compound of the present invention (hereinafter referred to as the active ingredient) required 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.
[0030] The topical formulations of the present invention, both for veterinary and for human medical use, 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.
[0031] 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. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of 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.
[0032] 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. They may be made by mixing the active ingredient in finely divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis. 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. Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations. GENERALSYNTHETIC PROCEDURES
[0033] The starting materials used herein are commercially available or are prepared by routine methods well known to those of ordinary skill in the art and can be found in standard reference books, such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I- VI (published by Wiley-Jnterscience).
[0034] The compounds of the invention can be synthesized according to the following procedures of Schemes I-XVI, wherein the R1-R7 substituents, linker A, are as defined for Formula I and Formula TJ, above, except where further noted.
SCHEME I
Figure imgf000036_0001
[0035] 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.
SCHEME II
Figure imgf000036_0002
[0036] Synthetic Scheme U illustrates the procedure for the preparation of substituted diketones 1. An appropriately substituted ketone, including but not limited to; indanones, 3-coumaranones, 3-thiocourmaranones, 3-azacourmaranones, 1-tetralones, chromanones, thiochromanones, azachromanones, isochromanones, isothiochromanones, isoazachromanones, 4 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 anti-inflammatory pyrazoles as illustrated in Scheme 1. Alternatively, the dicarbonyl compounds 1 can be directly prepared from commercially available cyclic ketones 4.
SCHEME III
Figure imgf000037_0001
NaOH/ EtOH ClCH2Cθ2H
Figure imgf000037_0002
[0037] Synthetic Scheme IJJ illustrates the three step procedure for the preparation of substituted isothiochromanones. In step one, an appropriately substituted benzyl alcohol 5 is converted into the corresponding benzyl chloride by stirring with concentrated hydrochloric acid and then immediately converted into a thiouronium salt 6 upon treatment with thiourea at reflux. In step two, the thiouronium salt is converted to the free mercaptide, according to the procedure of Lumma and Berchtold (J. Org. Chem., 34, 1566 (1969), and then trapped with chloroacetic acid or a related salt to provide the acetic acid derivatives 7. In step three, the acids 7 are reacted with trifluoroacetic anhydride (TFAA) in trifluoroacetic acid (TFA) to give the isothiochromanone products 8. The thiouronium salts 6 can also be prepared from appropriate commercially available benzyl halides. SCHEME IV
Figure imgf000038_0001
10 11
[0038] Synthetic Scheme TV illustrates a three step procedure used for the preparation of substituted thiochromanones. In step one, an appropriate substituted thiophenol 9 is converted into the corresponding propionic acid derivatives 10 upon treatment with acrylic acid at a temperature in a range of room temperature to about 50°C. In step two, the propionic acids 10 are subjected to treatment with a mixture of trifluoroacetic anhydride and trifluoroacetic acid to effect intramolecular Friedel- Crafts acylation, thus providing thiochromanones 11. Alternatively, the Friedel- Crafts acylation can be affected with H2SO4. Dicarbonyl compounds 1 can also be directly prepared from commercially available thiochromanones 11.
SCHEME V
Figure imgf000038_0002
[0039] Synthetic Scheme V illustrates a three step procedure used for the preparation of substituted azachromanones. In step one, an appropriate substituted aniline 12 is converted into the corresponding propionic acid derivatives 13 upon treatment with acrylic acid at a temperature in a range of room temperature to about 50°C. In step two, the propionic acids 13 are subjected to treatment with a mixture of H2SO4 to effect intramolecular Friedel-Crafts acylation, thus providing azachromanones 14. Dicarbonyl compounds 1 can also be directly prepared from commercially available azachromanones 14. Suitable protection of the aza nitrogen is effected when necessary using protecting groups such as benzyl, benzoyl, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc) or sulfonamido groups (mesyl, Ms or tosyl, Ts). SCHEME VI
Figure imgf000039_0001
15 16 17
[0040] Synthetic Scheme VI details the three step procedure used to prepare substituted chromanone derivatives 17. In step one, substituted phenols 15 are condensed with acrylic acid to afford 3-phenoxypropionic acids 16. In step two, the acids 16 are treated with a mixture of trifluoroacetic anhydride, and trifluoroacetic acid to affect intramolecular Friedel-Crafts acylation affording selected chromanones 17. Alternatively, the Friedel-Crafts acylation can be affected with H2SO4. The dicarbonyl compounds 1 can be directly formed from commercially available chromanones 17.
SCHEME vπ
Figure imgf000039_0002
18 19
[0041] Synthetic Scheme VTJ illustrates a procedure used to prepare isochromanone derivatives 19. In step one, selected benzyl alcohol derivatives 5 are treated with sodium hydride or other suitable base and subsequently treated with ethyl bromoacetate to provide the desired ethers 18. In step two, the ester group of 18 is hydrolyzed with aqueous sodium hydroxide and then treated with a mixture of trifluoroacetic acid and trifluoroacetic anhydride to promote intramolecular Friedel- Crafts acylation affording isochromanone 19 derivatives. SCHEME VIII
Figure imgf000040_0001
20 21 22
[0042] Synthetic Scheme VII illustrates a procedure used to prepare isoazachromanone derivatives 22. In step one, selected benzyl amine derivatives 20 are treated with ethyl bromoacetate and a suitable acid scavenger, such as triethylamine, to provide the desired amines 21. In step two, the ester group of 21 is hydrolyzed with aqueous sodium hydroxide and then treated with a mixture of trifluoroacetic acid and trifluoroacetic anhydride to promote intramolecular Friedel- Crafts acylation affording isochromanone 22 derivatives. Suitable protection of the aza nitrogen is effected when necessary using protecting groups such as benzyl, benzoyl, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc) or sulfonamido groups (mesyl, Ms or tosyl, Ts).
SCHEME IX
Figure imgf000040_0002
15 23 24
[0043] Synthetic Scheme TX illustrates a procedure used to prepare substituted 3-coumaranones 24. Phenols 15 are first treated with a base, such as NaOH, lithium diisopropyl amide (LDA) or sodium methoxide followed by condensation with ethyl bromoacetate in an appropriate solvent such as diethyl ether, ethanol, or tetrahydrofuran to provide the phenoxyacetate 23. In step two, the ester group of 23 is hydrolyzed with aqueous sodium hydroxide and then treated with a mixture of trifluoroacetic acid and trifluoroacetic anhydride to promote intramolecular Friedel- Crafts acylation affording 3-coumaranones derivatives 24. SCHEME X
Figure imgf000041_0001
12 25 26
[0044] Synthetic Scheme X illustrates a procedure used to prepare substituted 3- azacoumaranones 26. Anilines 12 are treated with a acid scavenger, such as triethylamine followed by alkylation with ethyl bromoacetate in an appropriate solvent such as diethyl ether, ethanol, or tetrahydrofuran to provide the phenoxyacetate 25. In step two, the ester group of 25 is hydrolyzed with aqueous sodium hydroxide and then treated with a mixture of trifluoroacetic acid and trifluoroacetic anhydride to promote intramolecular Friedel-Crafts acylation affording 3-azacoumaranones derivatives 24. Suitable protection of the aza nitrogen is effected when necessary using protecting groups such as benzyl, benzoyl, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc) or sulfonamido groups (mesyl, Ms or tosyl, Ts).
SCHEME XI
Figure imgf000041_0002
27 28
[0045] Synthetic Scheme XI illustrates a procedure used to prepare substituted 3-thiocoumaranones 28. Thiophenols 9 are first treated with a base, such as NaOH, lithium diisopropyl amide (LDA) or sodium methoxide followed by condensation with ethyl bromoacetate in an appropriate solvent such as diethyl ether, ethanol, or tetrahydrofuran to provide the phenoxyacetate 27. In step two, the ester group of 27 is hydrolyzed with aqueous sodium hydroxide and then treated with a mixture of trifluoroacetic acid and trifluoroacetic anhydride to promote intramolecular Friedel- Crafts acylation affording 3-coumaranones derivatives 28.
SCHEME XII
Figure imgf000042_0001
2. C02 (or) LiAlH4
29 30
[0046] Synthetic Scheme XII illustrates a two step procedure used for the preparation of substituted benzyl alcohols 5. In step one, a mixture of potassium tert-butoxide and anhydrous tetrahydrofuran, cooled to -78°C and treated with a 1.6 M solution of n-butyl lithium in hexanes, is added to an appropriate substituted benzene 29 the anion thereby generated is reacted with carbon dioxide to yield the benzoic acid 30. In step two, the benzoic acid 30 is dissolved in a solvent, such as tetrahydrofuran, and treated with a reducing agent, such as borane dimethyl sulfide complex, to form the desired benzyl alcohol 5.
SCHEME XJJJ
Figure imgf000042_0002
31 32 33
Figure imgf000042_0003
35
34
cyclizing agents
Figure imgf000042_0004
36 37 [0047] Scheme XJJJ describes the synthesis of the pyrazoles with fused heterocycles such as substituted pyrimdine and pyrazole. In step one, 1,2- cyclohexanedione (31) was refluxed with alcohols such as methanol or ethanol in benzene to provide the desired enone (32). In step two, enone 32 was treated with a base such as lithium bistrimethylsilylamide, followed by condensation with diethyl oxylate to afford 1,3-diketone (33). In step three, 1,3-diketone was allowed to react with a suitably substituted phenylhydrazine to form pyrazole 34. Appropriate substituents could be; but are not limited to, methyl sulfone or sulfonamide, which may be protected. A suitable protecting group for the sulfonamide is 2,5- dimethylpyrrole. In step four, pyrazole was treated with dimethylformamide di-tert- butyl acetal to give enaminone 35. In step five, enaminone was condensed with cyclizing agents such as hydrazine, guanidine, or thiourea to afford fused pyrazoles and pyrimidines 36. Jn the final step, the ester was converted to amide 37 by treating with ammonium hydroxide in methanol. For compounds where the sulfonamide is protected with the 2,5-dimethylpyrrole, deprotection is achieved by treatment with refluxing trofluoroacetic acid and water.
SCHEME XIV
Figure imgf000043_0001
[0048] Synthetic Scheme XTV illustrates a procedure used for the preparation of the anti-inflammatory oxidized thio-containing fused tricyclic pyrazoles 3. The appropriate pyrazole 3 from Scheme 1, where A is S or -(CH2)mS(CH2)n-, is treated with an oxidizing agent such as m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, peracids, or potassium peroxymonosulfate. Compounds having differing amounts of oxidation (sulfinyls and sulfones) can be prepared by controlling the stoichiometry of oxidant to sulfide or separated by chromatography. SCHEME XV
Figure imgf000044_0001
[0049] Scheme XV illustrates a method for the preparation of substituted arylhydrazines 2. Anilines 12 can be treated with hydroxylamine-O-sulfonic acid to generate arylhydrazines 2 (JOC, 14, 813, 1949). Anilines 12 can also be diazotized used sodium nitrite, or an alkyl nitrite, followed by catalytic reduction to generate arylhydrazines 2. In selected cases, suitably activated aryl rings, such as; 4- fluoronitrobenzene or 4-fluorophenylmethylsulfone (EWG = electron withdrawing group; such as nitro or methylsulfone), can be converted to arylhydrazines via displacement of the fluorine with hydrazine or a carbazate, followed by hydrolysis of the protecting group.
03 04844
SCHEME XVI
Figure imgf000045_0001
direct aminolysis amine ( HNR4R5)
DCC orCDI
Figure imgf000045_0002
[0050] Synthetic Scheme XVI shows procedures for preparing antiinflammatory agents 3 of Formula 1, wherein R3 = OCH3 is converted to OH or NHR7. The esters 1 R3 = OCH3, which can be prepared as shown in Scheme I, is dissolved in aqueous methanol and a base such as 10% NaOH is added. The reaction is stirred at room temperature or heated to reflux to give the acids 3, R3 = OH. The acids 3, R3 = OH, can be converted to the appropriate amides 3, R3 = NHR7, by dissolving in methanol and treating with an appropriate amine in the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC) or carbonyl diimidazole (CDI). The amides 3, R3 = NHR7 can also be prepared by direct aminolysis of 3, R3 = OCH3.
[0051] The following examples contain detailed descriptions of the methods of preparation of compounds of Formula I. These detailed descriptions fall within the scope, and serve to exemplify, the above-described General Synthetic Procedures that form part of the invention. These detailed descriptions are presented for T U 03/04844 illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are in degrees centigrade unless otherwise indicated.
[0052] The compounds of the present invention may also be synthesized according to the methods of United States Patent 5,547,975.
[0053] The complete content of all publications, patents, and patent applications cited in this disclosure are herein incorporated by reference as if each individual publication, patent, or patent application were specifically and individually indicated to incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for the purposes of clarity of understanding, it will be readily apparent to one skilled in the art in light of the teachings of this invention that changes and modifications can be made without departing from the spirit and scope of the present invention. The following examples are provided for exemplification purposes only and are not intended to limit the scope of the invention, which has been described in broad terms above.
EXAMPLES
Example 1
Ethyl l-{4-[(aminothio)peroxy]phenyl}-8-nitro-4,5-dihydro-lH-benzo[g]indazole-
3-carboxylate
Figure imgf000046_0001
Step 1
Figure imgf000047_0001
[0054] To 7-nitro-l-tetralone (4.6 g, 0.024 mol) and ethyl oxalate (3.5 mL, 0.026 mol) in ether (100 mL) was added dropwise lithium bis(trimethylsilyl)amide (IM in THF, 26 mL). The slurry was stirred overnight and filtered to give the product as an olive green solid, 6.2 g (87% yield). Η NMR (DMSO-d6/ 300 MHz) 8.45 (d, IH); 8.05 (d of d, IH); 7.42 (d, IH); 4.08 (q, 2H); 2.82-2.72 (m, 2H); 2.51- 2.43 (m, 2H); 1.21 (t, 3H).
Step 2
[0055] 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. Cone HCl (2 mL) was added to the thick slurry and the contents were heated on a steam bath for 1 hour. Contents were allowed to cool and filtered to give an off-white solid, 6.9 g. NMR and LC/MS analysis show the solid to contain two components, the desired, and the hydrated pyrazole. TFA (60 mL) and TFAA (20 mL) were added to the solid and heated on a steam bath for 1 hour. Contents were concentrated in vacuo leaving the product as a solid, 6.4 g (69% yield). FABHRMS m/z 443.1020 (M+H, C20HI9N4O6S requires 443.1025). Η NMR (DMSO-d6/ 300 MHz) 8.10 (d of d, IH); 8.03 (d, 2H); 7.82 (d, 2H); 7.70 (d, IH); 7.62 (s, IH); 7.50 (d, IH); 4.33 (q, 2H); 3.20-2.95 (m, 4H); 1.33 (t, 3H).
Anal. Calcd for C20H18N4O6S: C, 54.29; H, 4.10; N, 12.66. Found: C, 54.49; H, 4.00; N, 12.52.
Example 2 l-{4-[(aminothio)peroxy]phenyl}-8-nitro-4,5-dihydro-lH-benzo[g]indazole-3- carboxamide
Figure imgf000048_0001
[0056] The final product of Example 1 (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, C18H16N5O5S requires 414.0872). Η NMR (DMSO-dJ 300 MHz) 8.15 - 7.95 (m, 3H); 7.83 (d, 2H); 7.80-7.40 (m, 6H); 3.20-2.95 (m, 4H).
Anal. Calcd for C18H15N5O5S: C, 52.30; H, 3.66; N, 16.94. Found: C, 52.04; H, 3.64; N, 16.61.
Example 3 ethyl 8-amino-l-[4-(aminosulfonyl)phenyl]-4,5-dihydro-lH-benzo[g]indazole-3- carboxylate
Figure imgf000048_0002
[0057] The final product of Example 1 (2.0 g) and 10% Pd/C (350 mg) in DMF (20 mL) were shaken at 55 PSI hydrogen for 3 hours. Contents were filtered and the filtrate was concentrated in vacuo leaving an amber wax. The wax was triturated with methanol and filtered to give the product as a light amber solid, 1.6 g (86% yield). FABHRMS m/z 413.1293 (M+H, C20H2IN4O4S requires 413.1284). Η NMR (DMSO-d6/ 300 MHz) 8.00 (d, 2H); 7.73 (d, 2H); 7.50 (s, 2H); 7.01 (d, IH); 6.43 (d of d, IH); 6.00 (d, IH); 4.83 (br s, 2H); 4.30 (q, 2H); 2.85-2.70 (m, 4H); 1.31 (t, 3H). Anal. Calcd for C20H20N4O4S (0.25 H2O): C, 57.61; H, 4.96; N, 13.44. Found: C, 57.62; H, 5.11; N, 13.15.
Example 4 8-amino- 1 - {4-[(aminothio)peroxy]phenyl } -4,5-dihydro- lH-benzo[g]indazole-3- carboxamide
Figure imgf000049_0001
[0058] Example 4 was prepared similarly to Example 2 in 70 % yield. FABHRMS m/z 384.1136 (M+H, C18H18N5O3S requires 384.1130). Η NMR (DMSO-d6/ 300 MHz) 7.95 (d, 2H); 7.75 (d, 2H); 7.53 (br s, IH); 7.43 (br s, IH); 7.32 (br s, IH); 7.01 (d, IH); 6.44 (d of d, IH); 6.03 (s, IH); 4.81 (s, 2H); 2.93-2.65 (m, 4H).
[0059] Anal. Calcd for C18H17N5O3S: C, 56.38; H, 4.47; N, 18.27. Found: C, 56.31; H, 4.42; N, 18.31.
Example 5
Figure imgf000049_0002
[0060] To 6-hydroxy-l-tetralone (10.4 g, 0.064 mol) and ethyl oxalate (17.4 mL, 0.128 mol) in THF (100 mL) was added dropwise lithium bis(trimethylsilyl)amide (IM in THF, 130 mL). The slurry was stirred overnight and a solid was filtered. The solid was dissolved in water and made acidic to pH 2.5 with 3 N HCl, precipitating a waxy solid. The waxy solid was extracted into EtOAc, dried (MgSO4) and concentrated in vacuo leaving a dark solid (15.7 g). The solid was purified by chromatography on silica gel, eluting with 15% EtOAc/hexanes to give a yellow solid (5.9 g). The solid was recrystallized from EtOAc/hexanes to give the product as a yellow solid, 3.7 g (22% yield). FABHRMS m/z 263.0925 (M+H, C14H15O5 requires 263.0919). Η NMR (CDC13 / 300 MHz) 7.93 (d, IH); 6.80 (d of d, IH); 6.68 (s, IH); 5.72 (s, IH); 4.39 (q, 2H); 3.00-2.75 (m, 4H); 1.40 (t, 3H).
Anal. Calcd for C14H14O5: C, 64.12; H, 5.38. Found: C, 63.79; H, 5.35.
Example 6 ethyl l-[4-(aminosulfonyl)phenyl]-7-hydroxy-4,5-dihydro-lH-benzo[g]indazole-3- carboxylate
Figure imgf000050_0001
[0061] The material prepared in Example 5 (2.0 g, 0.0076 mol) and 4- sulfonamidophenylhydrazine hydrochloride (1.9 g, 0.0085) were stirred in glacial acetic acid (25 mL) for 96 hours. Contents were heated at 55°C for 5 hours, allowed to cool, diluted with water (75 mL), and filtered to give the product as a white solid, 3.1 g (90% yield). FABHRMS m/z 414.1146 (M+H, C20H20N3O5S requires 414.1124). Η NMR (DMSO-d6 / 300 MHz) 9.72 (s, IH); 8.00 (d, 2H); 7.73 (d, 2H); 7.53 (s, IH); 6.80 (s, IH); 6.60-6.40 (m, 2H); 4.30 (q, 2H); 2.90 (s, 4H); 1.30 (t, 3H).
Anal. Calcd for C20H19N3O5S (0.2 H2O): C, 57.60; H, 4.69; N, 10.08. Found: C, 57.72; H, 4.91; N, 9.68.
Example 7 ethyl l-[4-(aminosulfonyl)phenyl]-6-benzyl-l,4,5,6-tetrahydropyrrolo[2,3- g]indazole-3-carboxylate
Figure imgf000051_0001
Step l
Figure imgf000051_0002
[0062] To l,5,6,7-tetrahydro-4H-indol-4-one (5.0 g, 0.037 mol) in DMF (20 mL) was added benzyl chloride (4.4 mL, 0.038 mol) and potassium carbonate (5.3 g, 0.038 mol). Contents were heated at 70°C overnight. Contents were allowed to cool and partitioned between EtOAc and water. The EtOAc layer was dried (MgSO4) and concentrated in vacuo leaving an amber oil, 7.9g. The oil was purified by chromatography on silica gel eluting with 25% EtOAc/hexanes to give the desired as a white solid, 7.1 g (85% yield). FABHRMS m/z 226.1213 (M+H, C15H16NO requires 226.1232). Η NMR (CDC13 / 300 MHz) 7.40-7.28 (m, 3H); 7.10-7.00 (m, 2H); 6.63-6.53 (m, 2H); 5.02 (s, 2H); 2.70-2.60 (m, 2H); 2.50-2.40 (m, 2H); 2.10-2.06 (m, 2H).
Anal. Calcd for C15H15NO: C, 79.97; H, 6.71; N, 6.22. Found: C, 79.90; H, 6.65; N, 6.09.
Step 2
Figure imgf000051_0003
[0063] The product of step 2 was prepared similarly to Example 5 starting with the material of step 1 in 67% yield. FABHRMS m/z 326.1393 (M+H, C19H20NO4 requires 326.1392). Η NMR (CDC13/ 300 MHz) 7.40-7.26 (m, 3H); 7.10-7.00 (m, 2H); 6.70-6.60 (m, 2H); 5.06 (s, 2H); 4.33 (q, 2H); 3.20-3.08 (m, 2H); 2.75-2.60 (m, 2H); 1.40 (t, 3H).
Anal. Calcd for C19H19NO4 : C, 70.14; H, 5.89; N, 4.31. Found: C, 70.09; H, 5.75; N, 4.08.
Step 3
[0064] The final product of Example 7 was prepared similarly to Example 6 starting with the product of step 2 in 37% yield. FABHRMS m/z 477.1609 (M+H, C25H25N4O4S requires 477.1596). Η NMR (DMSO-d6 / 300 MHz) 8.00 (d, 2H); 7.80 (d, 2H); 7.50 (s, IH); 7.40-7.20 (m, 3H); 7.20-7.05 (m, 2H); 6.80 (s, IH); 5.62 (s, IH); 5.13 (s, 2H); 4.25 (q, 2H); 3.10-2.92 (m, 2H); 2.89-2.70 (m, 2H); 1.30 (t, 3H).
Anal. Calcd for C25H24N4O4S: C, 63.01; H, 5.08; N, 11.76. Found: C, 62.95; H, 5.02; N, 11.76.
Example 8 l-[4-(aminosulfonyl)phenyl]-6-benzyl-l,4,5,6-tetrahydropyrrolo[2,3-g]indazole-3- carboxamide
Figure imgf000052_0001
[0065] Example 8 was prepared similarly to Example 2 starting with the compound of Example 7 in 75% yield. FABHRMS m/z 448.1477 (M+H, C23H22N5O3S requires 448.1443). Η NMR (DMSO-^ / 300 MHz) 8.00 (d, 2H); T U 03/04844
7.80 (d, 2H); 7.60-7.15 (m, 3H); 7.10 (d, 2H); 6.79 (d, IH); 5.65 (d, IH); 5.12 (s, 2H); 3.10-2.93 (m, 2H); 2.82-2.68 (m, 2H).
Anal. Calcd for C23H21N5O3S: C, 61.73; H, 4.73; N, 15.65. Found: C, 61.33; H, 4.52; N, 15.43.
Example 9 ethyl 1 - [4-(aminosulfonyl)phenyl]-6-benzyl- 1 ,4,5 ,6-tetrahydropyrazolo[3 ,4- e]indazole-3-carboxylate
Figure imgf000053_0001
Step l
Figure imgf000053_0002
[0066] The product of step 1 was prepared similarly to Example 5 starting with l,5,6,7-tetrahydro-l-(phenylmethyl)indazol-4-one [Heterocycles, 32 (1) 41-72 (1991)] in 89% yield. FABHRMS m/z 327.1347 (M+H, C18H19N2O4 requires 327.1345). Η NMR (CDC13 / 300 MHz) 8.00 (s, IH); 7.40-7.30 (m, 3H); 7.13 (d, 2H); 5.30 (s, 2H); 4.31 (q, 2H); 3.19-3.03 (m, 2H); 2.80-2.68 (m, 2H); 1.38 (t, 3H).
Anal. Calcd for C18H18N2O4: C, 66.25; H, 5.56; N, 8.58. Found: C, 66.35; H, 5.47; N, 8.78.
Step 2 03 04844
[0067] The final product of Example 9 was prepared similarly to Example 6 starting with the compound of step 1 in 64% yield. FABHRMS m/z 478.1549 (M+H, C24H24N5O4S requires 478.1551). Η NMR (DMSO-d6/ 300 MHz) 8.02 (d, 2H); 7.82 (d, 2H); 7.51 (s, IH); 7.40-7.22 (m, 3H); 7.21-7.13 (m, 2H); 7.10 (s, IH); 5.40 (s, 2H); 4.30 (q, 2H); 3.20-2.90 (m, 4H); 1.30 (t, 3H).
Anal. Calcd for C24H23N5O4S: C, 60.36; H, 4.85; N, 14.67. Found: C, 60.60; H, 4.86; N, 14.71.
Example 10 l-[4-(aminosulfonyl)phenyl]-6-benzyl-l,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3- carboxamide
Figure imgf000054_0001
[0068] Example 10 was prepared similarly to Example 2 starting with the product of Example 9 in 79% yield. FABHRMS m/z 449.1399 (M+H, C22H21N6O3S requires 449.1396). Η NMR (DMSO-rf6 / 300 MHz) 8.00 (d, 2H); 7.84 (d, 2H); 7.60-7.40 (m, 2H); 7.40-7.22 (m, 3H); 7.25-7.10 (m, 2H); 5.37 (s, 2H); 3.20-2.90 (m, 4H).
Anal. Calcd for C22H20N6O3S (0.8 H2O): C, 57.08; H, 4.70; N, 18.15. Found: C, 57.54; H, 4.56; N, 17.77.
Example 11 ethyl l-[4-(aminosulfonyl)phenyl]-l,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3- carboxylate
Figure imgf000055_0001
[0069] The material of Example 9 (4.2 g, 0.009 mol), DMF (40 mL), glacial acetic acid (20 mL), and Pearlman's catalyst (1.5 g) were shaken at 55 psi hydrogen for 96 hours. Contents were filtered through celite and the filtrate was concentrated in vacuo leaving the product as a gray solid, 2.4 g (70% yield). FABHRMS m/z 388.1124 (M+H, C17H18N5O4S requires 388.1080). Η NMR (DMSO-^/ 300 MHz) 8.02 (d, 2H); 7.80 (d, 2H); 7.60 (br s, IH); 7.30 (s, IH); 4.35 (q, 2H); 3.15-3.00 (m, 2H); 3.00-2.80 (m, 2H); 1.32 (t, 3H).
Anal. Calcd for C17H17N5O4S: C, 52.70; H, 4.42; N, 18.08. Found: C, 52.47; H, 4.18; N, 17.89.
Example 12 l-[4-(aminosulfonyl)phenyl]-l,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3- carboxamide
Figure imgf000055_0002
[0070] Example 12 was prepared similarly to Example 2 starting with the material of llin 86% yield. FABHRMS m/z 359.0939 (M+H, C15H13N6O3S requires 359.0926). Η NMR (DMSO-d6/ 300 MHz) 8.02 (d, 2H); 7.87 (d, 2H); 7.56 9s, IH); 7.50 (br s, 2H); 7.35 (s, 2H); 3.20-3.00 (m, 2H); 2.95-2.80 (m, 2H).
[0071] Anal. Calcd for C15H14N6O3S: C, 50.27; H, 3.94; N, 23.45. Found: C, 50.07; H, 3.73; N, 23.08. 03 04844
Example 13 ethyl l-[4-(aminosulfonyl)phenyl]-4,5-dihydro-lH-thieno[2,3-g]indazole-3- carboxylate
Figure imgf000056_0001
Step l
Figure imgf000056_0002
[0072] 4-(2-Thienyl)butyric acid (9.7 g, 0.057 mol), acetic anhydride (12 mL), and phosphoric acid (85%, 0.25 mL) were refluxed for 3 hours. Contents were allowed to cool and partitioned between EtOAc and water. The EtOAc layer was dried (MgSO4) and concentrated in vacuo leaving a dark oil, 9.0 g. The oil was distilled on a kugelrohr apparatus at 50°C (0.1 mm) to give a white solid, 5.0 g (58% yield). Η NMR (CDCL 300 MHz) 7.37 (d, IH); 7.02 (d, IH); 3.08-2.95 (m, 2H); 2.60-2.50 (m, 2H); 2.30-2.10 (m, 2H).
Step 2
Figure imgf000056_0003
[0073] The product of step 2 was prepared similarly to step 1 of Example 1 using the material of step 1 in 77% yield. Η NMR (DMSO-d6/ 300 MHz) 7.32- 7.05 (m, 2H); 4.05 (q, 2H); 2.85-2.50 (m, 4H); 1.20 (t, 3H).
Step 3 [0074] The final product of Example 13 was prepared similarly to Example 6 starting with the material of step 2 in 86% yield. FABHRMS m/z 404.0702 (M+H, C18H18N3O4S2 requires 404.0739). Η NMR (DMSO-d6 / 300 MHz) 8.05 (d, 2H); 7.70 (d, 2H); 7.59 (s, IH); 7.39 (d, IH); 6.40 (d, IH); 4.35 (q, 2H); 3.10 (s, 4H); 1.35 (t, 3H).
Anal. Calcd for C18H17N3O4S2: C, 53.58; H, 4.25; N, 10.41. Found: C, 53.51; H, 4.02; N, 10.45.
Example 14 l-[4-(aminosulfonyl)phenyl]-4,5-dihydro-lH-thieno[2,3-g]indazole-3-carboxamide
[0075] Example 14 was prepared similarly to Example 2 staring with the compound of Example 13 in 85% yield. FABHRMS m/z 375.0601 (M+H, C16H15N4O3S2 requires 375.0586). Η NMR (DMSO-J, / 300 MHz) 8.05 (d, 2H); 7.70 (d, 2H); 7.59 (s, IH); 7.55 (s, 2H); 6.47 (d, IH); 3.10 (s, 4H).
Anal. Calcd for C16H14N4O3S2: C, 56.06; H, 4.70; N, 13.08. Found: C, 56.49; H, 4.74; N, 13.21.
Example 15 l-[4-(aminosulfonyl)phenyl]-4,5-dihydro-lH-pyrazolo[3,4-f]isoquinoline-3- carboxamide
Figure imgf000058_0001
Step l
Figure imgf000058_0002
[0076] To 7,8-Dihydroisoquinolin-5(6H)-one (1.17 gm, 8 mmol) in diethyl ether (50 mL) was added IM LHMDS (8 mL, 8 mmol) dropwise over several minutes (cf. Lardenois, P.; et al. Synthetic Communications 26(12), 2305-8, 1996). A precipitate slowly formed and the reaction became light yellow. After about 15 minutes, dimethyl oxalate (944 mg, 8 mmol) was added as a solid and the reaction stirred at room temperature for 72 hours. The resulting precipitate was collected by suction filtration and washed extensively with diethyl ether. A bright yellow solid was obtained. Yield; 1.7 gm (89%). Η-NMR (d6-DMSO) 2.41 (t, 2H); 2.63 (t, 2H); 3.56 (s, 3H); 7.51 (d, IH); 8.37 (s, IH); 8.40 (d, IH).
[0077] Step 2
Figure imgf000058_0003
[0078] The enolate from step 1 (717 mg, 3 mmol) was combined with 4- sulfonamidophenyl-hydrazine hydrochloride ( 669 mg, 2 mmol) in methanol (10 mL) and stirred at ambient temperature for 72 hours, then the resulting precipitate was collected by suction filtration and washed with methanol. The resulting hydrated pyrazole (502 mg) was re-suspended in methanol and concentrated HCl (0.5 mL) was added. The reaction was stirred at ambient temperature for two hours, then concentrated to a yellow solid in-vacuo. The solid was triturated with methanol and collected by suction filtration. Yield 250 mg (22 %). Η-NMR (d6- DMSO) 3.09 (s, 4H); 3.87 (s, 3H); 6.91 (d, IH); 7.60 (s, 2H); 7.84 (d, 2H); 8.03 (d, 2H); 8.50 (d, IH); 8.80 (s, IH). FABHRMS m/z 385.0987 (M+H, C18H17N4O4S requires 385.0971).
[0079] Step 3
The methyl ester from step 2 (240 mg, 0.625 mmol) was suspended in methanol (10 mL) and concentrated ammonium hydroxide (2 mL) was added. The reaction was heated to 95 C in a sealed tube for 16 hours. The reaction was cooled and concentrated to a reddish solid, which was triturated with methanol. Η-NMR suggested some carboxylic acid may be present, so the solid was dissolved in methanol (15mL) and 1 N HCl (3 mL). The homogeneous solution was then made basic with saturated NaHCO3 solution to pH = 8. After concentrating the solution under a stream of nitrogen, a brown solid was collected (100 mg). This solid was filtered through a plug of silica gel (10 gm) using 10% methanol/dichloromethane to obtain an off white solid. Yield: 90 mg (39 %). FABHRMS m/z 370.0966 (M+H, C17H16N5O3S requires 370.0974).
'H-NMR (d4-MeOH + TFA) 3.25 (s, 4H); 7.25 (d, IH); 7.83 (d, 2H); 8.14 (d, 2H); 8.49 (d, IH); 8.79 (s, IH).
Example 16 l-[4-(aminosulfonyl)phenyl]-l,4,5,8-tetrahydropyrazolo[4,3-g]indazole-3- carboxamide
Figure imgf000059_0001
T U 03/04844
Step 1
[0080] A mixture of 1,2-cyclohexanedione (26.0 g) and ethanol (100 mL) in 500 mL of benzene was heated at reflex with a Dean-Stark trap overnight. After the removal of solvent, the residue was purified by chromatography on silica gel (ethyl acetate/hexane, 2:8) to give 15.3 g of the desired 2-ethoxy-2-cyclohexen-l-one as a light yellow oil (47% yield). To 120 mL 1.0 M solution of LiHMDS in THF was added a solution of the above compound (15.3 g, 0.11 mol) in 100 mL of ether at - 78°C. After the addition, the dark brown mixture was stirred at this temperature forh h, a solution of diethyl oxylate (17.5 g, 0.12 mol) in 30 mL of ether was added in one portion. The reaction was allowed to warm up to room temperature over 18 h. Water was added and acidified to pH = 4 with 1 N HCl. The aqueous phase was extracted with ethyl acetate and the organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated to afford 21.5 g of product as a dark brown liquid that was used without further purification.
Step 2
[0081] A mixture of the crude from step 1 (20.0 g, 0.083 mol) and l-(4- hydrazinophenylsulfonyl)-2,5-dimethylpyrrole (22.0 g, 0.083 mol) in 400 mL of acetic acid was stirred at room temperature overnight. The solvent was removed and the residue was partitioned between ethyl acetate and cone, ammonium hydroxide. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by chromatography on silica gel (ethyl acetate/ hexane, 3:7) to give 16.2 g of pure product as a yellow solid,
Step 3
[0082] A mixture of the product from step 2 (3.1 g, 0.0062 mol) and N, N- dimethylformamide di-tert-butyl acetal (10.2 g, 0.062 mol) was heated at reflux overnight. After cooling, excess reagent was removed under vacuum and the residue was triturated with cold ethanol to give 2.3 g of pure product as a yellow solid (77% yield); mp: 230-231°C; Anal. Calcd. for C25H28N4O5S: C, 60.47; H, 5.68; N, 11.28; S, 6.46. Found: C, 59.98; H, 5.42; N, 10.93; S, 6.11.
Step 4
[0083] To a suspension of the product from step 3 (0.45 g, 0.0009 mol) in 10 mL of ethanol was added hydrazine (0.03 mL, 0.0009 mol) and the mixture was stirred at reflux overnight. Solvent was removed and the residue was purified by chromatography on silica gel (ethyl acetate/hexane, 2:8) to give 0.38 g of product as a yellow solid (93% yield); mp: 134-136°C; Anal. Calcd. for C23H23N5O4S: C, 59.34; H, 4.98; N, 15.04; S, 6.89. Found: C, 59.28; H, 4.95; N, 14.76; S, 6.93.
Step 5
[0084] The product from step 4 (0.35 g, 0.00075 mol) was treated with a mixture of TFA (15 mL) and water (5 mL) and the dark brown solution was refluxed under nitrogen for 2 h. Cooled and basified with cone, ammonium hydroxide to precipitate out 0.18 g of crude product as a pale yellow solid. A suspension of this solid in a mixture of cone, ammonium hydroxide (15 mL) and methanol (5 mL) was stirred at RT for 3 days. Solvent was removed to half volume and the solid was filtered to afford 0.1 g of product was white powder (50% yield for two steps); mp: 347°C (decomp); Anal. Calcd. for C15H14N6O3S: C, 50.27; H, 3.94; N, 23.45; S, 8.95. Found: C, 49.65; H, 3.81; N, 22.78; S, 8.77.
Example 17
8-amino-l-[4-(aminosulfonyl)ρhenyl]-4,5-dihydro-lH-pyrazolo[4,3-h]quinazoline-
3-carboxamide 03 04844
Figure imgf000062_0001
Ste l
[0085] To a suspension of the product from step 3 of Example 16 (8.7 g, 0.018 mol) and guanidine hydrochloride (1.7 g, 0.018 mol) in 250 mL of ethanol, was added sodium ethoxide (1.22 g, 0.018 mol) and the mixture was refluxed under nitrogen overnight. After the removal of solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 3:7) to give 5,2 g of product as brown solid (60% yield); mp: 111-112°C; Anal. Calcd. for C24H24N6O4S: C, 58.52; H, 4.91; N, 17.06; S, 6.51. Found: C, 58.24; H, 4.84; N, 16.80; S, 6.68.
Step 2
[0086] This compound was synthesized by following the same procedure as step 5 in Example 1 in 52% yield; mp: 332°C (decomp); Anal. Calcd. for C16H15N7O3S: C, 49.86; H, 3.92; N, 25.44; S, 8.32. Found: C, 49.49; H, 3.86; N, 25.52; S, 7.93.
[0087] Examples 18, and 19 were prepared according to Scheme XVm. Related compounds such as A, B and C shown in Scheme XVUI can be prepared in a similar manner using the appropriate R4 group. SCHEME XVIfl
Figure imgf000063_0001
Figure imgf000063_0002
Example 18 8-Chloro-l-(4-fluorophenyl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide
Figure imgf000063_0003
Step 1 4844
Ethyl (2-chloro-8-oxo-5,6,7,8-tetrahydroquinolin-7-yl)(oxo)acetate
Figure imgf000064_0001
[0088] To a suspension of 10.8 g of 2-chloro-6,7-dihydroquinolin-8(5H)-one 38 in 30 ml of anhydrous ethanol, cooled to about 10° C, 24.4 ml of a 21 wt% solution of sodium ethoxide (65.46 mmol) in anhydrous ethanol (24.4 ml) was added dropwise with stirring under nitrogen atmosphere for 10 minutes. After 5 minutes 8.82 g of diethyl oxalate (59.54 mmol) was added over 2 minutes. The reaction mixture was stirred at 10° C for 30 minutes, then 1 hour at room temperature. To the reaction mixture, cooled to about 0° C, 66 ml of a IM solution of HCl in ethanol was added dropwise for 10 minutes. A white precipitate was separated by filtration and washed with 30 ml of chloroform. The organic portions were combined and solvents were removed to give 16.5 g (99% yield) of the crude desired product 39, which was used in following synthesis without additional purification. 1H NMR (300 MHz, δ, DCC13): 1.45 (t, 3H, J = 7.15 Hz), 2.88-3.02 (m, 4H), 4.44 (q, 2H, J = 7.15 Hz), 7.43 (d, IH, J = 8.05 Hz), 7.62 (d, IH, J = 8.05 Hz), 13.6-14.2 (IH, broad). ESI mass spectrum for (C13H12ClNO4 + 1)+: 282.1
Step 2
Ethyl 8-chloro-l-(4-fluorophenyl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxylate
Figure imgf000064_0002
[0089] The mixture of ethyl (2-chloro-8-oxo-5,6,7,8-tetrahydroquinolin-7- yl)(oxo)acetate 39 from step 1 (13 g, 46.15 mmol) and 4-fluorophenylhydrazine hydrochloride (7.51 g, 46.15 mmol) in 500 ml of IM solution of HCl in ethanol was placed in 1 L flask with a condenser under nitrogen atmosphere and heated at reflux for 1 hour. Then, it was cooled to room temperature and placed in refrigerator overnight at -5° C. The white crystalline precipitate was filtered and washed with ether to give 12.3 g of ethyl 8-chloro-l-(4-fluorophenyl)-4,5-dihydro-lH- pyrazolo[4,3-h]quinoline-3-carboxylate 40 (71% yield). It was used in following synthesis without additional purification. 1H NMR (300 MHz, δ, DCC13): 1.48 (t, 3H, J = 7.15 Hz), 3.01-3.25 (m, 4H), 4.49 (q, 2H, J = 7.15 Hz), 7.10-7.24 (m, 3H), 7.50-7.62 (m, 3H). ESI mass spectrum for (C19H15ClFN3O2 + 1)+: 372.1
Step 3
8-Chloro-l-(4-fluorophenyl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide
Figure imgf000065_0001
[0090] A mixture of 1 g of ethyl 8-chloro-l-(4-fluorophenyl)-4,5-dihydro-lH- pyrazolo[4,3-h]quinoline-3-carboxylate 40 from step 2, 25 ml of methanol, and 25 ml of liquid ammonia were placed in an autoclave and stirred overnight at 130° C. After cooling to room temperature and removing ammonia, a suspension of gray crystalline precipitate in methanol was obtained. The solid was isolated by filtration to give 0.8 g (87% yield) of 8-chloro-l-(4-fluorophenyl)-4,5-dihydro-lH- pyrazolo[4,3-h]quinoline-3-carboxamide. 1H NMR (400 MHz, δ, DCC13): 3.01- 3.25 (m, 4H), 5.38 (s, IH), 6.81 (s, IH), 7.09 (d, IH, J = 7.9 Hz) 7.11-7.19 (m, 2H), 7.45-7.56 (m, 3H). ESI mass spectrum for (C17H12ClFN4O + 1)+: 343.1 Example 19 l-(4-Fluorophenyl)-N-(4-methoxybenzyl)-8-[(4-methoxybenzyl)amino]-4,5- dihydro-lH-pyrazolo[4,3-h]quinoline-3-carboxamide
Figure imgf000066_0001
[0091] Ethyl 8-chloro-l-(4-fluoroρhenyl)-4,5-dihydro-lH-ρyrazolo[4,3- h]quinoline-3-carboxylate 40 (3.8 g, 10.22 mmol) in 35 ml of 4- methoxybenzylamine was heated at 185° C for 26 hours. The reaction mixture contained the title compound as a major product. It was isolated by thin layer silica chromatography (ethyl acetate-hexane 60:40). 1H NMR (400 MHz, δ, DCC13): 2.86-292 (m, 2H), 3.14-3.21 (m, 2H), 3.76-3.78 (m, 6H), (3.95 (d, 2H, J = 5.9 Hz), 4.28 (t, IH, J = 5.8 Hz), 4.54 (d, 2H, J = 5.9 Hz), 6.20 (d, IH, J = 8.2 Hz), 6.78-6.86 (m, 4H), 6.93-7.02 (m, 2H), 7.01-7.06 (m, 2H), 7.20 (t, IH, J = 5.64), 7.26-7.30 (m, 3H), 7.42-7.48 (m, 2H). ESI mass spectrum for (C33H3oFN5O3 + 1)+: 564.2
[0092] Table 1 shows the bioactivity for the exemplified compounds as measured in the IKK heterodimer Resin Enzyme Assay expressed as LC50.
4844
TABLE 1
Figure imgf000067_0001
03 04844
TABLE 1 cont
Figure imgf000068_0001
[0093] In a likewise manner the following compounds of Table 2 could also be 5 prepared.
U 03/04844
TABLE 2
Ethyl l-{4-
[(methylamino)sulfonyl]phenyl } - 1 ,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
Ethyl l-[4-
(anilinosulfonyl)phenyl]-l,4,5,6- tetrahydropyrazolo [3 ,4-e] indazole- 3-carboxylate
Ethyl l-{4-
[(butylamino)sulfonyl]phenyl } - 1 ,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
ethyl l-{4-
[(dimethylamino)sulfonyl]phenyl } - 1 ,4,5,6-tetrahydropyrazolo[3,4- e] indazole-3 -carboxylate
ethyl l-(4-methoxyphenyl)-l ,4,5,6- tetrahydropyrazolo[3,4-e]indazole- 3-carboxylate
Figure imgf000069_0001
0304844
TABLE 2 cont
Figure imgf000070_0001
04844
TABLE 2 cont
Figure imgf000071_0001
3 04844
TABLE 2 cont
Figure imgf000072_0001
BIOLOGICAL EVALUATION
Materials
[0094] SAM τ2 T 1M1V1 96 Biotin capture plates were from Promega. Anti-FLAG affinity resin, FLAG-peptide, NP-40 (Nonidet P-40), BSA, ATP, ADP, AMP, LPS (E. coli serotype 0111:B4), and dithiothreitol were obtained from Sigma Chemicals. Antibodies specific for NEMO (IKKγ) (FL-419), IKKl(H-744), IKK2(H-470) and I B (C-21) were purchased from Santa Cruz Biotechnology. Ni-NTA resin was purchased from Qiagen. Peptides were purchased from American Peptide Company. Protease inhibitor cocktail tablets were from Boehringer Mannheim. Sephacryl S-300 column was from Pharmacia LKB Biotechnology. Centriprep-10 concentrators with a molecular weight cutoff of 10 kDa and membranes with molecular weight cut-off of 30 kDa were obtained from Amicon. [Y-33P] ATP (2500 Ci/mmol) and [Y-32P] ATP (6000 Ci/mmol) were purchased from Amersham. The other reagents used were of the highest grade commercially available.
Cloning and Expression
[0095] cDNAs of human IKKl and IKK2 were amplified by reverse transcriptase-polymerase chain reaction from human placental RNA (Clonetech). hIKKl was subcloned into pFasfBac HTa (Life Technologies) and expressed as N- terminal His6-tagged fusion protein. The hTKK2 cDNA was amplified using a reverse oligonucleotide primer which incorporated the peptide sequence for a FLAG-epitope tag at the C-terminus of the IKK2 coding region (DYKDDDDKD). The hIKK2:FLAG cDNA was subcloned into the baculovirus vector pFastBac. The rhIKK2 (S177S, E177E) mutant was constructed in the same vector used for wild type rhIKK2 using a QuikChange™ mutagenesis kit (Stratagene). Viral stocks of each construct were used to infect insect cells grown in 40L suspension culture. The cells were lysed at a time that maximal expression and rhTKK activity were demonstrated. Cell lysates were stored at -80 °C until purification of the recombinant proteins was undertaken as described below.
Enzyme Isolation
[0096] All purification procedures were carried out at 4 °C unless otherwise noted. Buffers used are: buffer A: 20 mM Tris-HCl, pH 7.6, containing 50 mM NaCl, 20 mM NaF, 20 mM β-Glycerophosphate, 500 uM sodiumortho-vanadate, 2.5 mM metabisulfite, 5 mM benzamidine, 1 mM EDTA, 0.5 mM EGTA, 10% glycerol, 1 mM DTT, IX Complete™ protease inhibitors; buffer B: same as buffer A, except 150 mM NaCl, and buffer C: same as buffer A, except 500 mM NaCl.
Isolation ofrhlKKl homodimer
[0097] Cells from an 8 liter fermentation of baculovirus-expressed IKKl tagged with His peptide were centrifuged and the cell pellet (MOI 0.1, 1=72 hr) was resuspended in 100 ml of buffer C. The cells were microfluidized and centrifuged at 100,000 X g for 45 min. The supernatant was collected, imidazole added to the final concentration of 10 mM and incubated with 25 ml of Ni-NTA resin for 2 hrs. The suspension was poured into a 25 ml column and washed with 250 ml of buffer C and then with 125 ml of 50 mM imidazole in buffer C. rhIKKl homodimer was eluted using 300 mM imidazole in buffer C. BSA and NP-40 were added to the enzyme fractions to the final concentration of 0.1 %. The enzyme was dialyzed against buffer B, aliquoted and stored at -80 °C.
Isolation ofrhIKK2 homodimer
[0098] A 10 liter culture of baculo virus-expressing IKK2 tagged with FLAG peptide was centrifuged and the cell pellet (MOI=0.1 and 1=72 hrs) was resuspended in buffer A. These cells were microfluidized, and centrifuged at 100,000 X g for 45 min. Supernatant was passed over a G-25 column equilibrated with Buffer A. Protein peak was collected and incubated with anti-FLAG affinity resin on a rotator overnight in buffer B. The resin was washed in batch with 10-15 bed volumes of buffer C. Washed resin was poured into a column and rhIKK2 homodimer was eluted using 5 bed volumes of buffer B containing FLAG peptide. 5 mM DTT, 0.1% NP-40 and BSA (concentrated to 0.1% in final amount) was added to the eluted enzyme before concentrating in using an Amicon membrane with a molecular weight cut-off of 30 kDa. Enzyme was aliquoted and stored at -80 °C.
Isolation of rhIKKl/IKK2 heterodimer
[0099] The heterodimer enzyme was produced by coinfection in a baculovirus system (FLAG IKK2/TKK1 His; MOI=0.1 and 1=72 hrs). Infected cells were centrifuged and the cell pellet (10.0 g) was suspended in 50 ml of buffer A. The protein suspension was microfluidized and centrifuged at 100,000 X g for 45 min. Imidazole was added to the supernatant to a final concentration of 10 mM. The protein was allowed to bind 25 ml of Ni-NTA resin by mixing for 2 hrs. The protein-resin slurry was poured into a 25 ml column and washed with 250 ml of buffer A containing 10 mM imidazole followed by 125 ml of buffer A containing 50 mM imidazole. Buffer A, containing 300 mM imidazole, was then used to elute the protein. A 75 ml pool was collected and NP-40 was added to a final T U 03/04844 concentration of 0.1%. The protein solution was then dialyzed against buffer B. The dialyzed heterodimer enzyme was then allowed to bind to 25 ml of anti-FLAG M2 agarose affinity gel overnight with constant mixing. The protein-resin slurry was then centrifuged for 5 min at 2,000 rpm. The supernatant was collected and the resin re-suspended in 100 ml of buffer C containing 0.1% NP-40. The resin was washed with 375 ml of buffer C containing 0.1 % NP-40. The protein-resin was poured into a 25 ml column and the enzyme eluted using buffer B containing FLAG peptide. Enzyme fractions (100 ml) were collected and concentrated to 20 ml using an Amicon membrane with molecular weight put-off of 30 kDa. Bovine serum albumin was added to the concentrated enzyme to final concentration of 0.1 %. The enzyme was then aliquoted and stored at -80 °C.
Cell Culture
[00100] The wild type (wt) human pre-B cell line, 70Z 3, and its mutant, 1.3E2, were generously provided by Dr. Carol Sibley. Wt 70Z/3 and 1.3E2 cells were grown in RPMI 1640 (Gibco) supplemented with 7 % defined bovine serum (Hyclone) and 50 μM 2-mercaptoethanol. Human monocytic leukemia THP-1 cells, obtained from ATCC, were cultured in RPMI 1640 supplemented with 10% defined bovine serum, 10 mM HEPES, 1.0 mM sodium pyruvate and 50 μM 2- mercaptoethanol. For experiments, cells were plated in 6 well plates at 1x10 cells/ml in fresh media. Pre-B cells were stimulated by the addition of 10 μg/ml LPS for varying lengths of time ranging from 0-4 hr. THP-1 cells were stimulated by the addition of 1 μg/ml LPS for 45 minutes. Cells were pelleted, washed with cold 50 mM sodium phosphate buffer, pH 7.4 containing 0.15 M NaCl and lysed at 4 °C in 20 mM Hepes buffer, pH 7.6 containing 50 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM sodium orthovanadate, 10 mM β-glycerophosphate, 1 mM NaF, 1 mM PMSF, 1 mM DTT and 0.5 % NP40 (lysis buffer). The cytosolic fractions obtained following centrifugation at 10,000 X g were stored at -80° C until used. Immunoprecipitation and Western Blotting
[00101] SF9 cells paste containing rhIKKs were centrifuged (100,000 X g, 10 min) to remove debris. rhIKKs were immunoprecipitated (100 μg of cell paste) from the cell supernatant using 3 μg of anti-NEMO antibody ( FL-419), followed by coupling to protein A sepharose beads. rhIKKs were also immunoprecipitated from affinity chromatography purified protein preparations (1 μg) using anti-FLAG, anti- His or anti-NEMO antibodies (1-4 μg) followed by protein A sepharose coupling. The native, human IKK complex was immunoprecipitated from THP-1 cell homogenates (300 μg/condition) using the anti-NEMO antibody. Immune complexes were pelleted and washed 3 times with 1 ml cold lysis buffer. Immunoprecipitated rhIKKs were chromatographed by SDS-PAGE (8% Tris- glycine) and transferred to nitrocellulose membranes (Novex) and detected by chemiluminescense (SuperSignal) using specific anti-IKK antibodies (IKK2 H-470, IKKl H-744). Native IKK2, IκBα and NEMO proteins from cytosolic lysates (20- 80 μg) were separated by SDS-PAGE and visualized by chemiluminescense using specific antibodies.
Phosphatase Treatment
[00102] Immunoprecipitated rhIKKs were washed 2 times in 50 mM Tris-HCl, pH 8.2 containing 0.1 mM EDTA, 1 mM DTT, 1 mM PMSF and 2 mM MnCl2 and resuspended in 50 μl. Phosphatase (λPPase, 1000 U) was pre-diluted in the same buffer and added to the IKK samples. Following an incubation at room temperature for 30 minutes with intermittent mixing, cold lysis buffer was added to the tubes to stop the reaction. After several washes, 10 % of the beads were removed for Western analysis, and the remaining material was pelleted and resuspended in 100 μl of the buffer used for the in vitro kinase assay.
IKKaSAM Enzyme Assay
[00103] IKKα kinase activity was measured using a biotinylated IκBα peptide (Gly-Leu-Lys-Lys-Glu-Arg-Leu-Leu-Asp-Asp-Arg-His-Asp-Ser32-Gly-Leu-Asp-
Ser36-Met-Lys-Asp-Glu-Glu), a SAM2 ™ 96 Biotin capture plate, and a vacuum system. The standard reaction mixture contained 5 μM biotinylated IκBα peptide, 1 μM [γ-33P] ATP (about 1 X 105 cpm), 1 mM DTT, 50 mM KC1, 2 mM MgCl2, 2 mM MnCl2, 10 mM NaF, 25 mM Hepes buffer, pH. 7.6 and enzyme solution (1-10 μl) in a final volume of 50 μl. After incubation at 25 °C for 30 min, 25 μl of the reaction mixture was withdrawn and added to a SAM2 ™ 96 Biotin capture 96-well plate. Each well was then washed successively with 800 μl 2 M NaCl, 1.2 ml of NaCl containing 1% H3PO4, 400 μl H2O, and 200 μl 95% ethanol. The plate was allowed to dry in a hood at 25 °C for 1 hr and then 25 μl of scintillation fluid (Microscint 20) was added to each well. Incorporation of [γ-33P] ATP was measured using a Top-Count NXT (Packard). Under each assay condition, the degree of phosphorylation of IκBα peptide substrate was linear with time and concentration for all purified enzymes. Results from the biotinylated peptide assay were confirmed by SDS-PAGE analysis of kinase reaction utilizing a GST-IkBα1-54 and [γ-32P] ATP. The resulting radiolabeled substrate was quantitated by Phosphoimager (Molecular Dynamics). An ion exchange resin assay was also employed using [γ-33P] ATP and GST-lKBa1-54 fusion protein as the substrates. Each assay system yielded consistent results in regard to Km and specific activities for each of the purified kinase isoforms. One unit of enzyme activity was defined as the amount required to catalyze the transfer of 1 nmole of phosphate from ATP to IκBα peptide per min. Specific activity was expressed as units per mg of protein. For experiments related to Km determination of purified enzymes, various concentrations of ATP or IκBα peptide were used in the assay at either a fixed IκBα or ATP concentration. For IκBα peptide Km, assays were carried out with 0.1 μg of enzyme, 5 μM ATP and IκBα peptide from 0.5 to 20 μM. For ATP Km, assays were carried out with 0.1 μg of enzyme, 10 μM IκBα peptide and ATP from 0.1 to 10 μM. For Km determination of rhIKKl homodimer, due to its low activity and higher Km for IκBα peptide, rhIKKl homodimer (0.3 μg) was assayed with 125 μM IκBα peptide and a 5-fold higher specific activity of ATP (from 0.1 to 10 μM) for ATP Km experiments and a 5-fold higher specific activity of 5 μM ATP and MBα peptide (from 5 to 200 μM) for IκBα peptide Km experiments. 03 04844
IKKβ Resin Enzyme Assay
[00104] IKKβ kinase activity was measured using a biotinylated IkBα peptide (Gly-Leu-Lys-Lys-Glu-Arg-Leu-Leu-Asp-Asp-Arg-His-Asp-Ser 2-Gly-Leu-Asp- Ser36-Met-Lys-Asp-Glu-Glu) (American Peptide Co.). 20 ul of the standard reaction mixture contained 5 μM biotinylated IκBα peptide, 0.1 μCi/reaction [γ-33P] ATP (Amersham) (about 1 X 105 cpm), 1 μM ATP (Sigma), 1 mM DTT (Sigma), 2 mM MgCl2 (Sigma), 2 mM MnCl2 (Sigma), 10 mM NaF (Sigma), 25 mM Hepes (Sigma) buffer, pH 7.6 and 20 μl enzyme solution and 10 ul inhibitor in a final volume of 50 μl. After incubation at 25 °C for 30 min, 150 μl resin (Dowex anion- exchange resin AG1X8 200-400 mesh) in 900 mM formate, pH 3.0 was added to each well to stop the reaction. Resin was allowed to settle for one hour and 50 ul of supernatant was removed to a Micolite-2 flat bottom plate (Dynex). 150 μl of scintillation fluid (Microscint 40) (Packard) was added to each well. Incorporation of [γ-33P] ATP was measured using a Top-Count NXT (Packard).
IKK heterodimer Resin Enzyme Assay
[00105] IKK heterodimer kinase activity was measured using a biotinylated IkBα peptide (Gly-Leu-Lys-Lys-Glu-Arg-Leu-Leu-Asp-Asp-Arg-His-Asp-Ser32-Gly-Leu- Asp-Ser36-Met-Lys-Asp-Glu-Glu) (American Peptide Co.). 20 ul of the standard reaction mixture contained 5 μM biotinylated IkBα peptide, 0.1 μCi/reaction [γ-33P] ATP (Amersham) (about 1 X 105 cpm), 1 μM ATP (Sigma), 1 mM DTT (Sigma), 2 mM MgCl2 (Sigma), 2 mM MnCl2 (Sigma), 10 mM NaF (Sigma), 25 mM Hepes (Sigma) buffer, pH 7.6 and 20 μl enzyme solution and 10 μl inhibitor in a final volume of 50 μl. After incubation at 25 °C for 30 min, 150 μl resin (Dowex anion- exchange resin AG1X8 200-400 mesh) in 900 mM formate, pH 3.0 was added to each well to stop the reaction. Resin was allowed to settle for one hour and 50 ul of supernatant was removed to a Micolite-2 flat bottom plate (Dynex). 150 μl of scintillation fluid (Microscint 40) (Packard) was added to each well. Incorporation of [γ-33P] ATP was measured using a Top-Count NXT (Packard).

Claims

What is claimed is:
1. A compound of formula I
Figure imgf000079_0001
wherein
A is (CH )m; wherein each CH2 may be independently substituted with one or more substitution selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl; m is 0 to 8;
Q is a 5 or 6 membered heteroaryl, or aryl, optionally saturated, or optionally substituted with R1, R2, or R12; B is an aromatic heterocyclic;
X is selected from the group consisting of: N and C;
Y and Z are independently selected from the group consisting of: N,
C, CH, CR3, S, and O;
R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO2, OR5,
OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7,
NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and
SO2N(R6)R7 wherein R6 and R7 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, SO2, O, and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optional substituted with, hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein 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, SO2, O, and NR6; R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, NO2, SR6, NHR6, CON(R6)R7,
NHCONHR6, CO2H, and haloalkyl;
R and R 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 R1 ;
R3 is selected from the group consisting of: substituted or unsubstituted amidine, alkylamino, aminoalkyl, CONHR16, NH2, NHCOR6, and CH2NHCOR6; R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, SO2N(R8)R8', NHR9, NHCOR9, NR9COR9, NHCO(OR9), NR9CO(OR9), NR8SO2R10, NHSO2N(R10)R10', NR6CON(R10)R10', COR9, CO2R8, CON(R8)R8', wherein R8 and R8 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6, and wherein R10 and R10 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6 wherein said aryl, heterocyclic, heteroaryl, or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, 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: OR14, N(R14)R14', and glycols;
R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic; R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl;
R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl;
R9 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, 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, alkylamino, aminoalkyl, hydroxyalkyl, and alkylaminoalkyl;
R10 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, R10' 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, R11 is selected from the group consisting of: hydrido, halogen, haloalkyl, CN, CO2R5, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, and CONH2;
R is selected from the group consisting of: hydrido, halogen, alkyl, and alkoxy; R13 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: OR14, N(R14)R14', and glycols; R is independently selected from the group consisting of: hydrido, and lower alkyl; R14' is independently selected from the group consisting of: hydrido, and lower alkyl;
R15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxy alkyl, nitro, cyano, alkylthio, alkylsulfinyl, and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic; and
R16 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, and alkoxyalkyl;
or isomers, tautomers, carriers, esters, prodrugs, pharmaceutically acceptable salts thereof.
A compound of formula π
Figure imgf000083_0001
wherein
A is (CH2)m; wherein each CH2 may be independently substituted with one or more substitution selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl; m is 0 to 8;
Q is a 5 or 6 membered heteroaryl, or aryl, optionally saturated, or optionally substituted with R1, R2, or R12;
B is an aromatic heterocyclic;
R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and
SO2N(R6)R7 wherein R6 and R7 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, SO2, O, and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optional substituted with, hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 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, SO2, O, and NR6;
R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, NO2, SR6, NHR6, CON(R6)R7, NHCONHR6, CO2H, and haloalkyl;
R and R 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 R1; R3 is selected from the group consisting of: substituted or unsubstituted amidine, alkylamino, aminoalkyl, CONHR16, NH2, NHCOR6, and CH2NHCOR6; R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, SO2N(R8)R8', NHR9, NHCOR9, NR9COR9, NHCO(OR9), NR9CO(OR9), NR8SO2R10,
NHSO2N(R10)R10', NR6CON(R10)R10', COR9, CO2R8, CON(R8)R8', wherein R8 and R8 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR , and wherein R10 and R10 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6 wherein said aryl, heterocyclic, heteroaryl, or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, heterocyclicalkyl, and heteroarylalkyl, wherein aryl, alkyl, arylalkyl, hejteroaryl, heterocyclicalkyl, or heteroarylalkyl are optionally substituted with one or more radicals selected from the group consisting of: OR14, N(R14)R14, and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic; R7 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 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl; R8' is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl; R9 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, 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, alkylamino, aminoalkyl, hydroxyalkyl, and alkylaminoalkyl;
R10 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, R10' is independently selected from the group consisting of: hydrido, Jower 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, R11 is selected from the group consisting of: hydrido, halogen, haloalkyl, CN, CO2R5, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, and CONH2;
R is selected from the group consisting of: hydrido, halogen, alkyl, and alkoxy;
R13 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: OR14, N(R14)R14 , and glycols; R14 is independently selected from the group consisting of: hydrido, and lower alkyl; R14 is independently selected from the group consisting of: hydrido, and lower alkyl;
R15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl, and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic; and
R16 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, and alkoxyalkyl;
or isomers, tautomers, carriers, esters, prodrugs, pharmaceutically acceptable salts thereof. The compound of claim 2
Figure imgf000088_0001
wherein
A is (CH2)m; wherein each CH2 may be independently substituted with one or more substitution selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl; m is 0 to 8;
Q is a 5 or 6 membered heteroaryl, or aryl, optionally saturated, or optionally substituted with R1, R2, or R12; B is an aromatic heterocyclic;
R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 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, SO2, O, and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optional substituted with, hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein 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, SO2, O, and NR6;
R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, NO2, SR6, NHR6, CON(R6)R7,
NHCONHR6, CO2H, and haloalkyl;
R1 and R2 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 R1 ;
R3 is CONHR16;
R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, SO2N(R8)R8', NHR9, NHCOR9,
NR9COR9, NHCO(OR9), NR9CO(OR9), NR8SO2R10, NHSO2N(R10)R10', NR6CON(R10)R10', COR9, CO2R8, CON(R8)R8', wherein R8 and R8 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6, and wherein
R10 and R10 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6 wherein said aryl, heterocyclic, heteroaryl, or alkenyl are optionally substituted with R9;
R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, 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: OR14, N(R14)R14', and glycols;
R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic;
R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic;
R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl;
R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl; R9 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, 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, alkylamino, aminoalkyl, hydroxyalkyl, and alkylaminoalkyl;
R10 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,
R10' 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, R11 is selected from the group consisting of: hydrido, halogen, haloalkyl, CN, CO2R5, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, and CONH2;
R12 is selected from the group consisting of: hydrido, halogen, alkyl, and alkoxy;
R13 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, 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: OR14, N(R14)R14 , and glycols; R14 is independently selected from the group consisting of: hydrido, and lower alkyl; R14 is independently selected from the group consisting of: hydrido, and lower alkyl;
R15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl, and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic; and
R16 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, and alkoxyalkyl;
or isomers, tautomers, carriers, esters, prodrugs, pharmaceutically acceptable salts thereof.
The compound of claim 3
Figure imgf000092_0001
wherein
A is (CH2)m; wherein each CH2 may be independently substituted with one or more substitution selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl; m is 0 to 8;
Q is a 5 or 6 membered heteroaryl, or aryl, optionally saturated, or optionally substituted with R1, R2, or R12;
B is an aromatic heterocyclic;
R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO2, OR5,
OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 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, SO2, O, and NR ; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR are optional substituted with, hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 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, SO2, O, and NR6; R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, NO2, SR6, NHR6, CON(R6)R7,
NHCONHR6, CO2H, and haloalkyl;
R1 and R2 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 R1 ;
R3 is CONHR16;
R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, SO2N(R8)R8', NHR9, NHCOR9,
NR9COR9, NHCO(OR9), NR9CO(OR9), NR8SO2R10, NHSO2N(R10)R10', NR6CON(R10)R10', COR9, CO2R8, CON(R8)R8', wherein R8 and R8 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6, and wherein
R10 and R10' may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6 wherein said aryl, heterocyclic, heteroaryl, or alkenyl are optionally substituted with R9;
R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, 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: OR14, N(R14)R14', and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic;
R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic;
R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl;
R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl; R9 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, 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, alkylamino, aminoalkyl, hydroxyalkyl, and alkylaminoalkyl; R10 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,
R10 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, R11 is selected from the group consisting of: hydrido, halogen, haloalkyl, CN, CO2R5, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, and CONH2;
R12 is hydrido;
R13 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: OR14, N(R14)R14', and glycols; R14 is independently selected from the group consisting of: hydrido, and lower alkyl;
R14' is independently selected from the group consisting of: hydrido, and lower alkyl; R15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl, and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic; and
R is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, and alkoxyalkyl;
or isomers, tautomers, carriers, esters, prodrugs, pharmaceutically acceptable salts thereof.
The compound of claim 3
Figure imgf000096_0001
wherein A is (CH2)m; wherein each CH2 may be independently substituted with one or more substitution selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl; m is 0 to 8; n is independently selected from 0, 1, or 2;
Q is a 5 or 6 membered heteroaryl, or aryl, optionally saturated, or optionally substituted with R1, R2, or R12;
B is an aromatic heterocyclic; R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 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, SO2, O, and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optional substituted with, hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7,
NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 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, SO2, O, and NR6;
R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, NO2, SR6, NHR6, CON(R6)R7, NHCONHR6, CO2H, and haloalkyl; R1 and R2 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 R1; 03 04844
R3 is CONHR16;
R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, SO2N(R8)R8', NHR9, NHCOR9,
NR9COR9, NHCO(OR9), NR9CO(OR9), NR8SO2R10, NHSO2N(R10)R10', NR6CON(R10)R10', COR9, CO2R8, CON(R8)R8', wherein R8 and R8 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6, and wherein
R10 and R10 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR wherein said aryl, heterocyclic, heteroaryl, or alkenyl are optionally substituted with R9;
R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, 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: OR14, N(R14)R14', and glycols;
R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic; R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl; R is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl; R9 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, 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, alkylamino, aminoalkyl, hydroxyalkyl, and alkylaminoalkyl;
R10 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, R10 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, R11 is hydrido;
R12 is selected from the group consisting of: hydrido, halogen, alkyl, and alkoxy;
R13 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, 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: OR14, N(R14)R14', and glycols;
R14 is independently selected from the group consisting of: hydrido, and lower alkyl;
R14' is independently selected from the group consisting of: hydrido, and lower alkyl; R15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl, and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic; and R16 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, and alkoxyalkyl;
or isomers, tautomers, carriers, esters, prodrugs, pharmaceutically acceptable salts thereof.
The compound of claim 3
Figure imgf000101_0001
wherein
A is (CH2)m; wherein each CH2 may be independently substituted with one or more substitution selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl; m is O to 8;
Q is a 5 or 6 membered heteroaryl, or aryl, optionally saturated, or optionally substituted with R1, R2, or R12; B is an aromatic heterocyclic;
R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 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, SO2, O, and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optional substituted with, hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 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, SO2, O, andd NR6;
R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, NO2, SR6, NHR6, CON(R6)R7, NHCONHR6, CO2H, and haloalkyl;
R1 and R2 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 R1; R3 is CONHR16;
R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, SO2N(R8)R8', NHR9, NHCOR9, NR9COR9, NHCO(OR9), NR9CO(OR9), NR8SO2R10,
NHSO2N(R10)R10', NR6CON(R10)R10', COR9, CO2R8, CON(R8)R8', wherein R8 and R8 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6, and wherein R10 and R10 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6 wherein said aryl, heterocyclic, heteroaryl, or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, 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: OR14, N(R14)R14', and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic;
R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic;
R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl;
R8' is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl; R9 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, 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, alkylamino, aminoalkyl, hydroxyalkyl, and alkylaminoalkyl;
R10 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,
R10 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, R11 is hydrido; R12 is hydrido; R 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: OR14, N(R14)R14, and glycols; R14 is independently selected from the group consisting of: hydrido, and lower alkyl;
R14' is independently selected from the group consisting of: hydrido, and lower alkyl;
1 ^
R is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl, and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic; and R16 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, and alkoxyalkyl;
or isomers, tautomers, carriers, esters, prodrugs, pharmaceutically acceptable salts thereof.
The compound of claim 4
wherein
A is (CH2)m, wherein each CH2 may be independently substituted with one or more substitution selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl; m is 1 or 2;
B is a 5 or 6 membered aromatic heterocyclic;
Q is a 5 or 6 membered heteroaryl, or aryl, optionally saturated, or optionally substituted with R1;
B is an aromatic heterocyclic; R1 is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 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, SO2, O, and NR6; wherein said alkenyl, alkynyl, alkyl, aryl, heteroaryl or OR5 are optional substituted with, hydrido, halogen, alkyl, hydroxyalkyl, aryl, heteroaryl, haloalkyl, COCF3, CN, NO2, OR5, OCOOR5, CO2R7, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6COR7,
NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)R7 wherein R6 and R7 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, SO2, O, and NR6; R2 is hydrido; R3 is CONHR16;
R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, SO2N(R8)R8', NHR9, NHCOR9, NR9COR9, NHCO(OR9), NR9CO(OR9), NR8SO2R10,
NHSO2N(R10)R10', NR6CON(R10)R10', COR9, CO2R8, CON(R8)R8', wherein R8 and R8 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6, and wherein R10 and R10 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6 wherein said aryl, heterocyclic, heteroaryl, or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, 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: OR14, N(R14)R14, and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic; R7 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 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl; R is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl; R9 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, 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, alkylamino, aminoalkyl, hydroxyalkyl, and alkylaminoalkyl; R10 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, R10' 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, R11 is selected from the group consisting of hydrido, halo, CF3, CN, CO2R5, and CONH2; R12 is hydrido;
R 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: OR14, N(R14)R14, and glycols;
R14 is independently selected from the group consisting of: hydrido, and lower alkyl;
R14 is independently selected from the group consisting of: hydrido, and lower alkyl; R is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl, and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic; and R16 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, and alkoxyalkyl; or isomers, tautomers, carriers, esters, prodrugs, pharmaceutically acceptable salts thereof.
The compound of claim 7
wherein
A is (CH2)m, wherein each CH2 may be independently substituted with one or more substitution selected from the group consisting of: hydroxy, halo, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl; m is 2;
B is a 5 or 6 membered aromatic heterocyclic; R1 is selected from the group consisting of SO NH2, SO N(R6)2, and SO2R6; R3 is CONH2;
R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, SO2N(R8)R8', NHR9, NHCOR9, NR9COR9, NHCO(OR9), NR9CO(OR9), NR8SO2R10,
NHSO2N(R10)R10', NR6CON(R10)R10', COR9, CO2R8, CON(R8)R8', wherein R8 and R8 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6, and wherein R10 and R10 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO , O, N, and NR6 wherein said aryl, heterocyclic, heteroaryl, or alkenyl are optionally substituted with R9; R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, 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: OR14, N(R14)R14, and glycols; R6 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic;
R7 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxy, alkoxyalkyl, heterocyclicalkyl, and heterocyclic;
R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl; R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl; R9 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, 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, alkylamino, aminoalkyl, hydroxyalkyl, and alkylaminoalkyl;
R10 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, R10' 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, R11 is selected from the group consisting of hydrido, halo, CF3, CN, CO2R5, and CONH2; R12 is hydrido; R13 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: OR14, N(R14)R14, and glycols; R14 is independently selected from the group consisting of: hydrido, and lower alkyl;
R14 is independently selected from the group consisting of: hydrido, and lower alkyl;
1 ^
R is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro,
no cyano, alkylthio, alkylsulfinyl, and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic; and
R16 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, and alkoxyalkyl;
or isomers, tautomers, carriers, esters, prodrugs, pharmaceutically acceptable salts thereof.
The compound of claim 6 of the formula
Figure imgf000112_0001
wherein
A is (CH2)m; m is 1 or 2;
B is a 5 or 6 membered aromatic heterocyclic;
R4 is selected from the group consisting of: halogen, alkylsulfinyl, alkylsulfonyl, cyano, alkoxycarbonyl, alkyl, haloalkyl, hydrido, hydroxyalkyl, haloalkoxy, heterocyclic, nitro, acylamino, aryl, heteroaryl, and alkenyl, OR13, SR8, SO2N(R8)R8', NHR9, NHCOR9,
NR9COR9, NHCO(OR9), NR9CO(OR9), NR8SO2R10,
NHSO2N(R10)R10', NR6CON(R10)R10', COR9, CO2R8, CON(R8)R8', wherein R8 and R8 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6, and wherein R10 and R10 may be taken together to form a 3-7 membered carbocyclic ring having 1 to 3 substituted or unsubstituted heteroatoms selected from S, SO, SO2, O, N, and NR6 wherein said aryl, heterocyclic, heteroaryl, or alkenyl are optionally substituted with R9;
R8 is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl;
R8' is independently selected from the group consisting of: hydrido, aryl, heteroaryl, arylalkyl, heterocyclic, haloalkyl, arylalkylamino, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkenyl, alkynyl, heteroarylalkyl, and heterocyclicalkyl;
R9 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, 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, alkylamino, aminoalkyl, hydroxyalkyl, and alkylaminoalkyl; R10 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, R10 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 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: OR14, N(R14)R14, and glycols; R14 is independently selected from the group consisting of: hydrido, and lower alkyl;
R14 is independently selected from the group consisting of: hydrido, and lower alkyl; R15 is selected from the group consisting of: hydrido, halogen, alkyl, cycloalkyl, aryl, haloalkyl, heteroaryl, heterocyclic, alkylalkene, alkylalkyne, hydroxy, hydroxyalkyl, alkylhydroxy, amino, aminoalkyl, alkylamino, alkylaminoalkyl, alkylhydroxyalkyl, nitro, cyano, alkylthio, alkylsulfinyl, and alkylsulfonyl; wherein aryl or arylalkyl are optionally substituted with one or more radical selected from alkyl, alkoxy, halo, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, benzyloxy, dialkylaminoalkyloxy, heterocyclic; and R16 is independently selected from the group consisting of: hydrido, aryl, arylalkyl, lower alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, aminoalkyl, alkoxy, and alkoxyalkyl;
or isomers, tautomers, carriers, esters, prodrugs, pharmaceutically acceptable salts thereof.
10. The compound of 3, 4, 5, 6, or 7 wherein R3 is CONH2.
11. The compound of claim 3, 4, 5, 6, 7, 8, or 9 wherein B is selected from the group consisting of: thiophene, pyrrole, imidazole, pyrazole, pyridazine, pyrimidine, pyridine, and pyrazine.
12. The compound of claim 10 wherein B is selected from the group consisting of: thiophene, pyrrole, imidazole, pyrazole, pyridazine, pyrimidine, pyridine, and pyrazine.
13. The compound of claim 9 selected from the group consisting of:
ethyl l-[4-(aminosulfonyl)phenyl]-6-benzyl-l,4,5,6- tetrahydropyrrolo[2,3-g]indazole-3-carboxylate, l-[4-(aminosulfonyl)phenyl]-6-benzyl-l,4,5,6-tetrahydropyrrolo[2,3- g]indazole-3-carboxamide, ethyl l-[4-(aminosulfonyl)phenyl]-6-benzyl-l,4,5,6- tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, l-[4-(aminosulfonyl)phenyl]-6-benzyl-l,4,5,6- tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, ethyl l-[4-(aminosulfonyl)phenyl]-l,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylate, 1 -[4-(aminosulfonyl)phenyl] - 1 ,4,5 ,6-tetrahydropyrazolo[3 ,4- e] indazole-3 -carboxamide, ethyl 1 -[4-(aminosulfonyl)phenyl]-4,5-dihydro-lH-thieno[2,3- g]indazole-3-carboxylate, l-[4-(aminosulfonyl)phenyl]-4,5-dihydro-lH-thieno[2,3-g]indazole-
3-carboxamide, . l-[4-(aminosulfonyl)phenyl]- ,5-dihydro-lH-ρyrazolo[3,4- f]isoquinoline-3-carboxamide,
1 -[4-(aminosulfonyl)ρhenyl]- 1 ,4,5,8-tetrahydropyrazolo[4,3- g]indazole-3-carboxamide,
8-amino-l-[4-(aminosulfonyl)phenyl]-4,5-dihydro-lH-pyrazolo[4,3- h]quinazoline-3-carboxamide,
8-Chloro- 1 -(4-fluorophenyl)-4,5-dihydro- 1 H-pyrazolo[4,3- h]quinoline-3-carboxamide, l-(4-Fluorophenyl)-N-(4-methoxybenzyl)-8-[(4- methoxybenzyl)amino]-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide,
8-[(3-chloroisonicotinoyl)amino]-l-(4-fluorophenyl)-4,5-dihydro- lH-pyrazolo[4,3-h]quinoline-3-carboxamide,
8-{[(2-ch]oropyridin-3-yl)carbonyl]amino}-l-(4-fluorophenyl)-4,5- dihydro-lH-pyrazolo[4,3-h]quinoline-3-carboxamide, and 8-{[5-chloro-2-(4-methylpiperazin-l-yl)isonicotinoyl]amino}-l-(4- fluorophenyl)-4,5-dihydro-lH-pyrazolo[4,3-h]quinoline-3- carboxamide.
14. A composition comprising the compound of claim 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 13 and at least one pharmaceutically acceptable carrier.
15. A composition comprising the compound of claim 10 and at least one pharmaceutically acceptable carrier.
16. A composition comprising the compound of claim 11 and at least one pharmaceutically acceptable carrier.
115
RECTIFIED SHEET (RULE 91) ISA/EP
17. A composition comprising the compound of claim 12 and at least one pharmaceutically acceptable carrier.
18. A method of treating cancer, inflammation or an inflammation associated disorder in a subject, said method comprising administering to the subject having or susceptible to such cancer, inflammation or inflammation associated disorder, a therapeutically-effective amount of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 13.
19. A method of treating cancer, inflammation or an inflammation associated disorder in a subject, said method comprising administering to the subject having or susceptible to such cancer, inflammation or inflammation associated disorder, a therapeutically-effective amount of a compound of claim 10.
20. A method of treating cancer, inflammation or an inflammation associated disorder in a subject, said method comprising administering to the subject having or susceptible to such cancer, inflammation or inflammation associated disorder, a therapeutically-effective amount of a compound of claim 11.
21. A method of treating cancer, inflammation or an inflammation associated disorder in a subject, said method comprising administering to the subject having or susceptible to such cancer, inflammation or inflammation associated disorder, a therapeutically-effective amount of a compound of claim 12.
22. The method of claim 21 for use in the treatment of cancer.
23. The method of claim 21 for use in the treatment of inflammation.
24. The method of claim 21 for use in the treatment of an inflammation- associated disorder.
116
RECTIFIED SHEET (RULE 91) ISA/EP
25. The method of claim 24 wherein the inflammation-associated disorder is arthritis.
26. The method of claim 24 wherein the inflammation-associated disorder is pain
27. The method of claim 24 wherein the inflammation-associated disorder is fever.
117
RECTIFIED SHEET (RULE 91) ISA/EP
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