CA2485298C - Substituted pyrazolyl compounds for the treatment of inflammation - Google Patents

Abstract

The present invention relates to substituted pyrazolyl derivatives of Formul a III, compositions comprising such, intermediates, methods of making substituted pyrazolyl derivatives, and methods for treating cancer, inflammation, and inflammation-associated disorders, such as arthritis.</SDO AB>

Description

SUBSTITUTED PYRAZOLYL COMPOUNDS FOR THE TREATMENT OF
INFLAMMATION
FIELD OF TBE INVENTION

[001) The present invention in general is in the field of anti-inflammatory pharmaceutical agents and specifically relates to substituted pyrazolyl derivatives, compositions comprising such, and methods for treating cancer, inflammation, and inflammation-associated disorders, such as arthritis.

BACKGROUND OF THE INVENT]ON

[002] The following description of the bacl:ground 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.

[003J NF-xB 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 proinflarrvmatory 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, 4547-455 1; Karin, M. (1999) J. Biot. Chent.
274,.27339-27342). Specificity of gene expression is deterrnined 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-a (TNFa) and interleukin-[i (It.1R). 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-xB 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 IxB family of inhibitory proteins (Ghosh S., May, M. J., and Kopp. E (1998) Annu. Rev. Imrnunol. 16, 115-260; Zandi, E., and Karin, M. (1999) Mol. Cell. Biol. 19, 4547-455 1; Karin, M. (1999) J. Biol. C12em.
274, 27339-27342). IxBs mask the nuclear localization signal on NF-xB, preventing nuclear translocation and hence DNA binding to the promoter regions of responsive genes. Stimulation of cells with an agonist that activates NF-xB leads to a series of biochemical signals, ultimately resulting in the phosphorylation, ubiquitinylation, and degradation of IKBs, thereby releasing NF-xB for nuclear translocation (Ghosh S., May, M. J., and Kopp. E (1998) Annu. Rev. bnmunol. 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 IxB kinases (IKK1 or IKKa and IKK2 or IKK(3), which phosphorylate IxBs 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) J. Biol. Clzem. 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 (IKKy, IKKAP1), is a regtilatory 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 222, 31-40). This kinase complex appears to represent a critical, common denominator in the activation of NF-xB in a number of signal transduction pathways stimulated by a variety of agonists including cytokines, such as TNFa and IL1(3, 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, 21339-27342).

[004] IKKl (also termed IKKa, 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) was cloned simultaneously by standard biochemical purification of the IxB
kinase activity from TNFa stimulated HeLa S3 cells and by its interaction with the MAP3K, NF-xB inducing kinase (NIK), in a yeast two-hybrid screen. IKKI 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 IKKa) 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(3) was also cloned by standard biochemical purification, copurifying with IKKI from TNFa 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 IKKy) contains three a-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, 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, 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 IKK1 using IxBa or IicB(3 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 TNFa or IL1 J3 (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 IKK1 or IKK2. Fibroblasts lacking IKKl retain full IKK activity in response to cytokines and could activate NF-xB. In contrast, fibroblasts lacking IKK2 do not exhibit IKK activity when stimulated with cytokines nor do they activate NF-xB. Furthermore, the phenotypes of each IKK knock out is unique with IKK1 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, 0., Tsujimura, T., Itami, S., Adachi, 0., 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 Developnaent 13, 1322-1328; Tanaka, M., Fuentes, M. E., Yamaguchi, K., Durnin, M. H., Dalrymple, S. A., Hardy, K. L., and Goeddel, D. V. (1999) Ifnmunity 10, 421-429).

[0071 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-and IL-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-xB in inflammatory disorders is further strengthened by studies of airway inflammation including asthma in which NF-icB 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. In light of the recent findings with regard to glucocorticoid inhibition of NF-xB, one may speculate that these effects are mediated through an inhibition of NF-xB. Further evidence for a role of NF-xB in inflammatory disorders comes from studies of rheumatoid synovium. Although NF-icB is normally present as an inactive cytoplasmic complex, recent immunohistochemical studies have indicated that NF-xB is present in the nuclei, and hence active, in the cells comprising rheumatoid synovium. Furthermore, NF-xB has been shown to be activated in human synovial cells in response to stimulation with TNF-a. 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] The NF-xB/Rel and IxB 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-xB in the regulation of apoptosis, cell cycle progression, invasion, and metastasis has been reported (Bours V. et al., Biochemical Phaf-macology 60:1085-1090, 2000) strengthening the role of this transcription factor in the control of cell proliferation. The inhibition of NF-xB 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), IKKa and IKK(3 are expressed constitutively, which normally function in a transient manner (Chu Z-L et al., J of Biological Cl2emistry 273:15891-15894, 1998). The HTLV1 transforming and transactivating protein (Tax) has been shown to bind MEKK1 and increases the activity of IKK(3 to enhance phosphorylation of serine residues in IxBa that lead to its degradation.

[009] 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, 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-trifluoromethyl pyrazole, as having anti-inflammatory activity.

[0010] 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-lH-benz[g]indazol-3-yl]amides as having antipsychotic activity. European publication EP 347,773, published Dec. 27, 1989, describes [4,5-dihydro-1-phenyl-lH-benz[g]indazol-3-y1]propanamides as immunostimulants. M. Hashem et al [J. Med.
Chem., 19, 229 (1976)] describes fused tricyclic pyrazoles, having a saturated ring bridging the pyrazole and a phenyl radical, as antibiotics.

[0011] 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-IH-pyrazol-1-yl]benzenesulfonamide has been prepared from a pyrazoline compound and described as potentially having hypoglycemic activity [H. Mokhtar, Pak. J. Sci. Ind. Res., 31, 762 (1988)]. Similarly, 4-[4-bromo-5-[2-(4-chlorophenyl)-2H-1,2,3-triazol-4-yl]-3-methyl-lH-pyrazol-1-y1]benzenesulfonamide has been prepared [H. Mokhtar et al, Pak. J. Sci. Ind.
Res., 34, 9 (1991)].

[0012] The phytotoxicity of pyrazole derivatives is described [M. Cocco et al, Il. Farinaco-Ed. Sci., 40, 272 (1985)], specifically for 1-[4-(aminosulfonyl)phenyl]-5-phenyl-lH-pyrazole-3,4-dicarboxylic acid.

[0013] The use of styryl pyrazole esters for antidiabetes drugs is described [H.
Mokhtar et al, PhaYrnazie, 33, 649-651 (1978)]. The use of styryl pyrazole carboxylic acids for antidiabetes drugs is described [R. Soliman et al, Phannazie, 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, 1-[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-1-yl]benzenesulfonamide [H. Feid-Allah, PhaYmazie, 36, 754 (1981)]. In addition, 1-(4-[aminosulfonyl]phenyl)-5-phenylpyrazole-3-carboxylic acid has been prepared from the above described 4-[3-methyl-5-phenyl-lH-pyrazol-1-yl]benzenesulfonamide compound [R. Soliman et al, J. Pharm. Sci., 70, 602 (1981)].

[0014] WO 00/27822 discloses tricyclic pyrazole derivatives, WO 00/59901 discloses dihydroindeno pyrazoles, WO 99/17769 discloses indeno[1,2-c]-, naphtho[1,2-c]- and benzo[6,7]cyclohepta[1,2-c]pyrazole derivatives, US
5,196,445 discloses heteroaryl-3-oxo-propanenitrile derivatives useful in the treatment of rheumatoid arthritis, WO 97/10210 discloses tricyclic pyrrolidine derivatives as calcium channel antagonists, WO 95/15315 discloses diphenyl pyrazole compounds, WO 95/15317 discloses triphenyl pyrazole compounds, WO 95/15318 discloses tri-substituted pyrazole compounds, and WO 96/09293 discloses benz[g]indazolyl derivatives.

[0015] WO 95/15316 discloses substituted pyrazolyl benzenesulfonamide derivatives and WO 01/32663 discloses pyrazlecarboxylic acid tricyclic derivatives as CB 1 cannabinoid receptor inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

[0016] A class of compounds, which are useful in treating cancer, inflammation, and inflammation related disorders, is defined by Formula I:

B
R1 --( X R
Z
R
A

wherein A is (CH2),,,; wherein each CH2 may be independently substituted with one or more substitution selected from the group consisting of:
aryl, heteroaryl, alkanoyl, hydroxy, halogen, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl;
m is 1 to 4;

B is a 5 or 6 membered heteroaryl, aryl, saturated or unsaturated heterocyclic wherein said aryl, heteroaryl, or heterocyclic are optionally substituted with R1, R2, and R12;

X is selected from the group consisting of: N and C;

Y and Z are independently selected from the group consisting of: N, CH, CR3, S, and 0; , R' is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO2, OR5, OCOOR5, CO2R~, CON(R6)R7, COR6, SR6, SOR6, SO2R6, NR6R7, NR6CORI, NR6CONHR7, NR6SO2R7, NR6SO2NHR7, and SO2N(R6)W 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, ORS, OCOORS, COZR7, CON(R6)R7, COR6, SR6, SOR6, S02R6, NR6R7, NR6COR7, NR6CONHR7, NR6SO2W, NR6SO2NHR7, and SO2N(R)R' 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;

R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, NO2, SR6, NHR6, CON(R)R7, NHCONHR6, CO2H, and haloalkyl;

Rr 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, 0, or S, and wherein said ring is optionally substituted with Rl;

R3 is selected from the group consisting of: substituted or unsubstituted amidine, alkylamino, aminoalkyl, CONHW, 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, SR$, SO2N(R8)R", NHR9, NHCOR9, NR9COR9, NHCO(OR9), NR9CO(OR9), NRgS02R10, NHSOZN(R10)R10', NR6CON(Rl0)Rl0', COR9, C02Rg, CON(R)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, 0, 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, 0, 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;

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, dialkylam.inoacyl, 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, RiO' 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, halogen, haloalkyl, CN, C02R5, lower alkyl, lower alkenyl, lower alkynyl, alkoxy, and CONH2;

R12 is selected from the group consisting of: hydrido, halogen, alkyl, and alkoxy;

Ri3 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)R1, and glycols;

R14 is independently selected from the group consisting of hydrido, and lower alkyl; and R14' is independently selected from the group consisting of hydrido, and lower alkyl;

or isomers, tautomers, carriers, esters, prodrugs, pharmaceutically acceptable salts thereof.

[0017] Another class of compounds is defined by Formula .II

B

-N
\\,Rs R4 ~
A
Rt1 wherein A is (CH2)m; wherein each CH2 may be independently substituted with one or more substitution selected from the group consisting of:
aryl, heteroaryl, alkanoyl, hydroxy, halogen, alkoxy, lower alkyl, amino, aminoalkyl, alkylamino, alkenyl, and alkynyl;

m is 1 to 4;

B is a 5 or 6 membered heteroaryl, aryl, saturated or unsaturated heterocyclic wherein said aryl, heteroaryl, or heterocyclic are optionally substituted with R1, R2, and R12;

RI is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO2, ORS, OCOORS, COZR7, CON(R6)R7, COR6, SR6, SOR6, S02R6, NR6R7, NR6COR', NR6CONHR~, 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, S02, 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, NOa, ORS, OCOORS, C02R7, CON(R6)R7, COR6, SR6, SOR6, S02R6, NR6R7, NRgCOR7, 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;

R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, NO2, SR6, NHR6, CON(R6)R7 , NHCONHR6, CO2H, and haloalkyl;

Ri' 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, 0, 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, CONHR7 , 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, SRB, SO2N(R8)R", NHR9, NHCOR9, NR9COR9, NHCO(OR9), NR9CO(OR9), NR8SO2R10, NHSOZN(R10)R"", NR6CON(R10)R"", COR9, CO2R8, CON(R)R", 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, S02, 0, N, and NR6, and wherein Rl0 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, S02, O, N, and NR6 wherein said aryl, heterocyclic, heteroaryl, or alkenyl are optionally substituted with R9;

RS 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, Rli is selected from the group consisting of: hydrido, halogen, haloalkyl, CN, C02R5, 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(RI4)R14', and glycols;

R14 is independently selected from the group consisting of hydrido, and lower alkyl; and , R14' is independently selected from the group consisting of hydrido, and lower alkyl;

or isomers, tautomers, carriers, esters, prodrugs, pharmaceutically acceptable salts thereof.

Another class of compounds is defined by Formula III

\

NN
N

W

wherein B is a 5 or 6 membered heteroaryl, aryl, saturated or unsaturated heterocyclic wherein said aryl, heteroaryl, or heterocyclic are optionally substituted with R1, R2, and R12;

W is a 5 or 6 membered heteroaryl, aryl, saturated or unsaturated heterocyclic;

Rl is selected from the group consisting of: hydrido, halogen, alkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, CN, NO2, OR$, OCOORS, COZR~, CON(R6)R7, COR6, SR6, SOR6, SOZR6, NR6R7, NR6COR', NR6CONHR~, NR6SO2R7, NR6SO2NHR7, and SOZN(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, S02, 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, ORS, OCOORS, C02R7, CON(R6)R7, COR6, SR6, SOR6, S02R6, NR6R7, NR6COW, NR6CONHR7 , NR6SO2R7, NR6SO2NHR~, 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;

R2 is selected from the group consisting of: halogen, hydrido, hydroxyalkyl, alkyl, OR6, CN, NO2, SR6, NHR6, CON(R6)R7, NHCONHR6, CO2H, and haloalkyl;

Rl 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, 0, or S, and wherein said ring is optionally substituted with R1;
R5 is selected from the group consisting of: hydrido, alkyl, aryl, arylalkyl, heteroaryl, 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 12 is selected from the group consisting of: hydrido, halogen, alkyl, and alkoxy;

R15 is selected 'from the group consisting of: alkylsulfonamide, sulfamyl, alkyl wherein said alkyl is optionally substituted with a carbocyclic or heterocyclic wherein said carbocyclic or heterocyclic is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino(alkyl)amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogen, (CH2)r,C(R')R' wherein n is 0 to 4 and each R' is independently selected from the group consisting of hydrido, hydroxy, amino, 0, S, and alkyl, (CH2)õNHCON(R')R' wherein n is 0 to 4 and each R' is independently selected from the group consisting of hydrido, hydroxy, amino, and alkyl, (CH2)õNHC(O)OR' wherein n is 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino, and alkyl; alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxy, halogen, acyloxy, oxy, formyl, haloalkyl, cyano, haloalkoxy, acyl, carboxyl, hydroxy, hydroxyalkyloxy, phenoxy, nitro, azido, benzyloxy, dialkylaminoacyl, thioalkyl, aminoacyloxy, thiocyanate, isothiocyanate, alkyldioxy, hydroxyalkyl, alkylamino, alkyloxycarbonyl, alkoxyalkyl, alkenylamino, alkynylamino, alkenyl, alkynyl, dialkylaminoalkyloxy, and heterocyclic wherein said heterocyclic is optionally substituted with one to six substituents selected from the group consisting of alkyl, alkylamino, aminoalkyl, hydroxyalkyl, alkylaminoalkyl, alkylaminoalkylamino, dialkylaminoalkylamino, alkylamino(alkyl)amino, alkoxy, alkoxyalkyl, oxo, hydroxy, amino, halogen, cyano, nitro, acyl, heteroaryl wherein said heteroaryl is optionally substituted with one or more halogen, (CH2)nC(R')R' wherein n is 0 to 4 and each R' is independently selected from the group consisting of hydrido, hydroxy, amino, 0, S, and alkyl, (CH2)nNHCON(R')R' wherein n is 0 to 4, and each R' is independently selected from the group consisting of hydrido, hydroxy, amino, and alkyl, (CH2)nNHC(O)OR' wherein n is 0 to 4 and R' is selected from the group consisting of hydrido, hydroxy, amino, and alkyl, '~ R17 5'~N / .~S N R17 N
S" =

N~
N
\R18 R17 ~R18 N
and R18 R17 is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO(alkyl), CO(aryl), CO(CH2)nOH [n =
0 to 4], C02(alkyl), CON(alkyl)(alkyl'), formyl, cycloalkyl, heterocyclic, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl, and heteroarylalkyl; and R18 is selected from the group consisting of: alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, haloalkyl, acyl, thioalkyl, dialkylaminoacyl, alkylsulfonyl, arylsulfonyl, CO(alkyl), CO(aryl), CO(CH2)nOH [n =
0 to 4], C02(alkyl), CON(alkyl)(alkyl'), formyl, cycloalkyl, heterocyclic, hydroxyalkoxyalkyl, alkenylalkyl, alkynylalkyl, arylalkyl, and heteroarylalkyl;

or isomers, tautomers, carriers, esters, prodrugs, pharmaceutically acceptable salts thereof.

Definitions [0018] 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, Formula II, or Formula IH 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.

[0019] The meaning of any substituent at any one occurrence in Formula I, Formula II or Formula III or any sub-Formula thereof is independent of its meaning, or any other substituents meaning, at any other occurrence, unless specified otherwise.

[0020] 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 -SOZ-. "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 (-S02-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) (CHZ)2- and -(CH2)2(O=)COCH3. 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 ,24 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, (CH3-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 examples of an "acylamino" radical is acetylamino (CH3C(=O)-NH-).

[0021] Compounds of Formula I, Formula II or Formula III 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, Formula II or Formula III would be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondylo arthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, and juvenile arthritis.
Such compounds of Formula I, Formula II or Formula III would be useful in the treatment of asthma, bronchitis, menstrual cramps, tendinitis, bursitis, and skin related conditions such as psoriasis, eczema, burns, and dermatitis. Compounds of Formula I, Formula II or Formula III also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, and ulcerative colitis and for the prevention of colorectal cancer.
Compounds of Formula I, Formula II or Formula III would be useful in treating inflammation in such diseases as vascular diseases such as vascularitus, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, conjunctivitis, swelling occurring after injury, myocardial ischemia, and the like.
The compounds of the present invention may also be used for pain. The compounds are useful as antiinflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects. The compounds of Formula I, II or III are useful as agents for treating cancer or anticancer agents.
The compounds of Formula 1, 11 or III 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 PKs in the regulation of cellular proliferation, these compounds are also useful in the treatment of a variety of cell proliferative disorders such as, for instance, benign prostate hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis. The compounds of Formula I, II, or III 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 IKK1 and/or IKK2, IKKucIIKK(3 heterodimer, TBK or IKKi. 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, MEKl, MAPK, EGF-R, PDGF-R, FGF-R, IGF-R, VEGF-R, P13K, weel kinase, Src, Abl, Akt, ILK, MK-2, IKK-2, Cdc7, Nek, and thus be effective in the treatment of diseases associated with other protein kinases. The present invention preferably includes compounds, which selectively inhibit IKK2 over IKK1. Preferably, the compounds have an IKK2 of less than 1 M, and have a selectivity ratio of IKK2 inhibition over IKK1 inhibition of at least 50, and more preferably of at least 100. Even more preferably, the compounds have an IKKl IC50 of greater than 10 M, and more preferably of greater than 100 M. The compounds of Formula I, II, or III 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.

[0022] 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 coniinonly 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, 0-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.

[0023] 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 sub-ject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely. The pharmaceutical compositions may contain active ingredient in the range of about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mg and most preferably between about 1 and 100 mg. A
daily dose of about 0.01 to 100 mg/kg bodyweight, preferably between about 0.1 and about 50 mg/kg body weight and most preferably between about 1 to 20 mg/kg bodyweight, may be appropriate. The daily dose can be administered in one to four doses per day. 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.
[0024] 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.
[0025] 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 (0.0196) and chlorhexidine acetate (0.0 1%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol, and propylene glycol.

[0026] 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 sldn may also include an agent to basten 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 sucb 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 linzitations.

Pharmaceutical compositions/formulations of the invention may be contained in a commercial package, which may optionally further comprise instructions for the therapeutic use thereof as herein described.

GENERAL SYNTHTIC PROCEDURES
[0027] 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-Interscience).

[0028] The compounds of the invention can be synthesized according to the following procedures of Schemes I-XI, wherein the R1-R14 substituents are as defined for Formula I, Formula II or Formula III, above, except where further noted.
[0029] SCHEME I

HN~NH2 HCI R~~I_ O OH
R3 + I ~ EtOH or MeOH
R4%' ~ A O Ri 1~R2 orHOAc N; R3 R4'~ / A 0 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. When A = -CH2CH2-, the central ring may be aromatized to provide A = -CH=CH-, by using an oxidant such as DDQ, Pd or Pt on carbon with cyclooctadiene or other H2 acceptor, or sulfur in an appropriate solvent or without solvent.
[0030] SCHEME II
O O OH
R4 O T,HIVIDS R4 R3 ~~ + O O/
~~ A (or) NaOMe / MeOH A 0 O

Synthetic Scheme II illustrates the procedure for the preparation of substituted diketones 1. An appropriately substituted ketone 4, including, but not limited to; 1-indanones, 1-tetralones, and 1-benzosuberones, is first treated with base, such as sodium methoxide, lithium bistrimethylsilylamide or lithium diisopropylamide (LDA), followed by condensation with a suitable acylating agent, such as, dimethyl or diethyl oxalate, in an appropriate solvent, such as methanol, diethyl ether or tetrahydrofuran, to provide 1,3-dicarbonyl compounds 1 which are suitable for conversion into antiinflammatory pyrazoles as illustrated in Scheme I.

Alternatively, the dicarbonyl compounds 1 can be directly prepared from commercially available cyclic ketones 4.

[0031] SCHEME III

O
R4 + O A1C13 R4 I~ 00 I
/ ~ H
O O

HZ / Pd/C
O
O
~ TFAA / TFA R4 R4 ~ / OH
/

Synthetic Scheme III illustrates a three-step procedure used for the preparation of substituted 1-tetralones. In step one, an appropriate substituted benzene 5 is condensed with succinic anhydride and a catalyst such as aluminum chloride into the corresponding 4-phenyl-4-ketobutanoic acid derivatives 6. In step two, the keto group of the 4-phenyl-4-ketobutanoic acids 6 is reduced using catalytic hydrogenation or Wolff-Kishner type reductions, thus providing 4-phenylbutanoic acids 7. In addition, ketone reductions can be carried out using metal amalgams. In step three, the 4-phenylbutanoic acids are treated with a mixture of trifluoroacetic anhydride, and trifluoroacetic acid to effect intramolecular Friedel-Crafts acylation affording selected tetralones 8. Alternatively, the Friedel-Crafts acylation can be affected with other strong acids such as polyphosphoric acid, sulfuric acid, or aluminum chloride.

[0032] SCHEME IV

O BrMg , R4 f11Clg R4 i~
Rd i + / I /
O

Synthetic Scheme IV describes an alternate synthetic route to 1-tetralones S.
In step one, addition of allylmagnesium bromide in a suitable solvent such as, THF or diethyl ether, to an appropriately substituted benzoate 9 affords the 1-phenylbut-3-ene-l-ones 10. In step two, the 1-phenylbut-3-ene-l-ones 10 can be cyclized under Friedel-Crafts alkylation conditions, provided R4 is a ring activating substituent, using catalysts such as aluminum chloride to produce 1-tetralones 8.

[0033] SCHEME V

O O
E+

g Scheme V describes the direct modification of 1-tetralone to substituted tetralones.
Commercially available 1-tetralone may be treated with a variety of electrophilic reagents such as bromine, ammonium nitrite or vinylsilanes, represented by E, with or without a catalyst to generate directly a substituted tetralone 8, containing bromo, nitro or vinyl groups. Such tetralones 8 can be further embellished to provide the desired substitution patterns. Mixtures may be readily separated using chromatographic techniques.

[0034] SCHEME VI

E+ Ra I KMnO4 Ra if An alternate to Scheme V is Scheme VI wherein an appropriately substituted decaline is subjected to electrophilic addition to generate substituted decalins 11.
Substituted decalins may also be prepared by Friedel-Crafts alkylation of substituted benzenes. Substituted decalins 11 can then be oxidized to the tetralones 8 using oxidants such as KMnO4 or Se02.

[0035] SCHEME VII

\ /%Q \ Pd(OAc)z, R3P, CO O\~ 1 HO j O Tf0 ~
/ ~ MeOH
8a 8b 12 Scheme VII describes the modification of existing tetralones into analogs containing differing functional groups that can also be further modified. By example, hydroxy tetralone (8a where R4 = OH) can be converted to the triflate 8b by treatment with trifluoromethane sulfonic anhydride. Triflate 8b can the be subjected to Pd(OAc)2 an appropriate phosphine and CO in the presence of methanol to generate tetralone 12 containing a carboxy methyl group. Triflates can be used in a variety of palladium coupling reactions to introduce additional functional groups.

[0036] SCHEME VIII

R4 H + R4 i o-I

1) H2 / Pd/C
2) NaOH

O
R4 i TFAA/TFA R4 O

Synthetic Scheme VIII illustrates a three step procedure used for the preparation of substituted 1 -indanones 16. In step one, an appropriate substituted benzaldehyde 13 is condensed with methyl acetate and a catalyst such as triethylamine into the corresponding methyl cinnamate derivatives 14. Additionally, commercially available cinnamates may be used in the following steps. In step two the olefin group of the cinnamate 14 is reduced using catalytic hydrogenation and the ester hydrolyzed with base, such as NaOH, thus providing 3-phenylpropanoic acids 15.
In step three, the 3-phenylprapanoic acids are treated with a mixture of trifluoroacetic anhydride and trifluoroacetic acid to effect intramolecular Friedel-Crafts acylation affording selected 1-indanones 16. Alternatively, the Friedel-Crafts acylation can be effected with other strong acids such as sulfuric acid or aluminum chloride.

[0037] SCHEME IX

4 i~ A1C13 Rq R4 + R 1 Synthetic Scheme IX illustrates a two-step route for the preparation of substituted 1-indanones 16. Commercially available methyl benzoates 9, or other alkyl esters, may be treated with a vinyl lithium reagent to afford phenylvinyl ketones 17.

Alternatively, dimethylamides or N-methyl-O-methylhydroxamides may be used in place of the esters. Also, other vinyl metals, such as; vinylmagnesium bromide may be used in place of the vinyl lithium reagent. The resulting phenylvinyl ketones may be cyclized using Friedel-Crafts alkylating catalysts, such as aluminum chloride.
[0038] SCHEME X

~ A1C13 a I \
R4 i/ +
C O OH

HZ / Pd/C

R4 ~ / OH

15 Synthetic Scheme X illustrates a three step procedure used for the preparation of substituted 1-benzosuberones 20. In step one, an appropriate substituted benzene 5 is condensed with glutaric anhydride and a catalyst such as aluminum chloride into the corresponding 5-phenyl-5-ketopentanoic acid derivatives 18. In step two, the keto group of the 5-phenyl-5-ketopentanoic acids 18 is reduced using catalytic 20 hydrogenation or Wolff-Kishner type reductions, thus providing 5-phenylpentanoic acids 19. In addition, ketone reductions can also be carried out using metal amalgams. In step three, the 5-phenylpentanoic acids are treated with a mixture of trifluoroacetic anhydride, and trifluoroacetic acid to effect intramolecular Friedel-Crafts acylation affording selected benzosuberones 20. Alternatively, the Friedel-Crafts acylation can be affected with other strong acids such as polyphosphoric acid, H2SO4 or A1C13. Alternatively, 5-phenyl-5-ketopentanoic acids 18, can be prepared from glutaric acid and a phenyllithium or a phenyl Grignard reagent appropriately substituted and compatible with reaction conditions.
[0039] Scheme XI

\
0 0 Nz~ NHNH2'HCI N-N
O2N OEt R;/ 02N OEt CO O - r ! \ O
AcOH, reflux ethyl(7-nitro-l-oxo-1,2,3, 4-tetrahydronaphthalen-2-yl) (oxo)acetate 1 R \

SnC12 N-N OEt NH3, MeOH N-N NH2 EtOH H2N 700 psi H2N / I~ O
~
R~ l R9CO2H, HATU or \ H O N N-N NH2 TFA

Y RT
R9COCI, Pyridine R9 O

HO' /
\

Y
O

R = 3- or 4-benzyloxyl Scheme XI describes the synthesis of the pyrazoles with phenols at N-position.
In step one; 3- or 4-benzyloxylphenylhydrazine was refluxed with ethyl (7-nitro-l-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate 1 in acetic acid to give pyrazole.

Then the nitro group was reduced to amine by using tin (II) chloride in ethanol. In the following step, the conversion of ester to arnide was achieved by reacting with liquid ammonia in a pressured tube at high temperature. The resulting compound can either react with acid and HATU in DMF or acid chloride in pyridine to give the desired amide. The benzyl group was deprotected by stirring with TFA at room temperature.

[0040] 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
[0041] Example 1 1-{ 4-[(aminothio)peroxy]phenyl }-8-nitro-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide HZNSO2~aN-N
0N ~ ' NHp [0042] Step 1 0 ou OpN O\--, ~I O

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 (1M 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). 1H NMR (DMSO-d6l 300 MHz) 8.45 (d, 1H); 8.05 (d of d, 1H); 7.42 (d, 1H); 4.08 (q, 2H); 2.82-2.72 (m, 2H); 2.51-2.43 (m, 2H); 1.21 (t, 3H).

[0043] Step 2 Ethyl 1- { 4-[(aminothio)peroxy]phenyl }-8-nitro-4, 5-dihydro-1 H-benzo [g]
indazole-3-carboxylate H2NS021a N-N
02N \ I O\11-O

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.
Conc. 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, C20H19N406S requires 443.1025). 1H NMR (DMSO-d6/ 300 MHz) 8.10 (d of d, 1H); 8.03 (d, 2H); 7.82 (d, 2H); 7.70 (d, 1H); 7.62 (s, 1H); 7.50 (d, 1H); 4.33 (q, 2H); 3.20-2.95 (m, 4H); 1.33 (t, 3H).
Anal. Calcd for C20H18N406S: C, 54.29; H, 4.10; N, 12.66. Found: C, 54.49; H, 4.00; N, 12.52.

[0044] Step 3 The material of Step 2 (718 mg, 0.0016 mol), conc. ammonium hydroxide (30 mL), and methanol (15 mL) were stirred in a stoppered flask for 72 hours. Contents were filtered to give a light amber solid (606 mg). The solid was recrystallized from acetonitrile to give the product as a light arnber solid, 450 mg (68% yield).
FABHRMS m/z 414.0902 (M+H, Cl$H16N505S requires 414.0872). 'H NMR
(DMSO-d6/ 300 MHz) 8.15 - 7.95 (m, 3H); 7.83 (d, 2H); 7.80-7.40 (m, 6H); 3.20-2.95 (m, 4H).

Anal. Calcd for Cz8Hi5N505S: C, 52.30; H, 3.66; N, 16.94. Found: C, 52.04; H, 3.64; N, 16.61.

[0045] Example 2 8-amino-l-{ 4-[(aminothio)peroxy]phenyl }-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide H2NSO2 <IN-N

HZN / ~ ~ NH2 ~ I O

The compound was prepared similarly to Example 1 in 70 % yield. FABHRMS m/z 384.1136 (M+H, C18H18N503S requires 384.1130). 'H NMR (DMSO-d6/ 300 MHz) 7.95 (d, 2H); 7.75 (d, 2H); 7.53 (br s, 1H); 7.43 (br s, 1H); 7.32 (br s, 1H);
7.01 (d, IH); 6.44 (d of d, 1H); 6.03 (s, 1H); 4.81 (s, 2H); 2.93-2.65 (m, 4H).
Anal. Calcd for C18H17N503S: C, 56.38; H, 4.47; N, 18.27. Found: C, 56.31; H, 4.42; N, 18.31.
[0046] Example 3 8-(acetylamino)-1-{ 4-[(aminothio)peroxy]phenyl } -4,5-dihydro-lH-benzo [g]indazole-3-carboxamide H2NS0z N-N
AcHN / ' NH2 ~ O

To the material of Example 2 (1.0 g, 0.0026 mol) in DMF (15 mL) was added dropwise a mixture of acetic anhydride (0.283 mL, 0.003 mol) and pyridine (0.243 mL, 0.003 mol) in DMF (5 mL). Contents were stirred overnight, diluted with water (75 mL), and filtered to give the desired as a white solid, 1.0 g (90%
yield).
FABHRMS m/z 426.1235 (M+H, C20H20N504S requires 426.1236). 1H NMR
(DMSO-d6 / 300 MHz) 9.80 (s, 1H); 8.00 (d, 2H); 7.75 (d, 2H); 7.60 (s, 1H);
7.48 (s, 2H); 7.39 (s, 1H); 7.30 (d, 1H); 7.15 (s, 1H); 2.90 (s, 4H); 1.92 (s, 3H).

Anal. Calcd for C20H19N504S (1H20): C, 54.17; H, 4.77; N, 15.79. Found: C, 54.20; H, 4.97; N, 15.77.

[0047] Example 4 1- { 4-[(aminothio)peroxy]phenyl } -8-{ [(methylthio)peroxy] amino }-4,5-dihydro-lH-benzo [g] indazole-3-carboxamide N-N
MeSO2HN / ~ ~ NH2 \I O

To the material of Example 2 (1.2 g, 0.003 mol) and triethylamine (0.278 mL, 0.0035 mol) in DMF (10 mL) at 0 C, was added dropwise methanesulfonyl chloride (0.278 mL, 0.0035 mol) in CH2C12 (2 mL). Contents were stirred overnight, slowly coming to room temperature. Contents were diluted with water (50 mL) and filtered to give the product as an off-white solid, 524 mg (37% yield).
FABHRMS

m/z 462.0917 (M+H, C19H2ON505S2 requires 462.0906). 1H NMR (DMSO-d6 /
300 MHz) 9.60 (s, 1H); 7.98 (d, 2H); 7.80 (d, 2H); 7.60 (s, 1H); 7.50 (s, 2H);
7.40 (s, 1H); 7.37 (d, 1H); 7.02 (s, 1H); 6.75 (s, 1H); 2.93 (s, 4H); 2.75 (s, 3H).

Anal. Calcd for C19Hz9N505S2: C, 49.45; H, 4.15; N, 15.17. Found: C, 49.19; H, 3.77; N, 15.53.

[0048] Examples 5-40 Synthesis of the sulfonamide/amide/urea library Scheme XII

Q,O
H2N- S ~ 0 N-N 1. RSO2CI or RCOCI, Pyridine NH2 N_N
H2N 2.MP-trisamine resin NH2 O 3. MP-TsOH resin in DMF R-HN
O
The sulfonamides, amides, and urea were synthesized in a library format by using a Bohdan reaction block. The starting materials are the product of Example 2(8-amino-l- { 4-[(aminothio)peroxy]phenyl }-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide) and appropriate sulfonyl chlorides, acyl chlorides and isocyanates.

Thirty-five reactions constituted this library.

The general procedure is as follows: 48 mg of the product of Example 2(8-amino-1-{ 4-[(aminothio)peroxy]phenyl } -4,5-dihydro- lh-benzo[g]indazole-3-carboxamide) in 1 mL pyridine was placed in each reaction vessel, then 1.2 eq. of a sulfonyl chloride was added, and the mixture was shaken overnight. Then 3 mL methylene chloride and 300 mg of resin PS-trisamine were added, and then shaken over night.
After filtration and washing with 2 mL methanol twice, the filtrates were combined and solvents evaporated. The residue was dissolved in 2 mL dimethylformamide, and MS-TsOH resin (450 mg) was added and shaken for 48 hours. After filtration and washing with 2 mL DMF, the combined filtrate was analyzed by LC-MS and LC. Then the filtrate was evaporated on a SpeedVac and the residue were suspended in 2 mL of H20/tBuOH, and lyophilized for 2 days. All compounds were obtained in solid form, and the majority of the compounds have about 90% purity. Table shows the substitutions, compound identification, and IKK heterodimer assay values for the compounds from the sulfonamide library. The structures of the compounds of Examples 5-40 were confirmed Mass Spectroscopy and/or NMR
analysis.
[0049] Synthesis of Compounds of Examples 41-45 Scheme XIII

11 H N /\ O HZN 0 X= -H 70%a Example 41 z 0 I X H~ N N O -CH3 65% Example 42 N-N O H_ ~ ~ -OCH3 71% Example 43 HZN NaB(OAc)3H ~ NHZ Cl 74% Example 44 NHZ DMF-HOAc Example 2 x HzN
R--e O R=-iBu 61% Example 45 --~
NaB(OAc)3H N
DMF-HOAc R NHz [0050] Example 41 1-[4-(aminosulfonyl)phenyl]-8-(benzylamino)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide O, ,O

H2N S~ lal N~N O
H
N I NHz ~
1~, To a mixture of the product of example 2(8-amino-l-{4-[(aminothio)peroxy]phenyl }-4,5-dihydro-lh-benzo[g]indazole-3-carboxamide) (76 mg, 0.20 mmol), acetic acid (0.3 mL) and sodium triacetoxyborohydride (213 mg, 1.00 mmol) in DMF (3 mL) was added benzaldehyde (64 mg, 0.60 mmol). The resulted mixture was stirred at RT for 18 h, added water (10 mL), extracted with EtOAc (3x10 mL). The combined organic layers was washed with water (3x10 mL), dried over MgSO4, filtered through a silica gel pad with EtOAc, and concentrated. The crude product was triturated with diethyl ether to give 1-[4-(aminosulfonyl)phenyl]-8-(benzylamino)-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide as a yellow solid (66 mg, 70%). Its structure was confirmed by 1H
NMR and MS (474, M+1). C25H23N503S, Calc.: C: 63.41, H: 4.90, N: 14.79;

Found, C: 63.11, H: 4.70, N: 13.54.
[0051] Example 42 1-[4-(aminosulfonyl)phenyl]-8-[(4-methylbenzyl)amino]-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide 0,, 010 H2N"S

N-N

O

1-[4-(aminosulfonyl)phenyl]-8-[(4-methylbenzyl)amino]-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide (32 mg, 65%) was synthesized by the same procedure as in Example 41, starting with the product of Example 2(8-amino-l-{4-[(aminothio)peroxy]phenyl }-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide) (38.3 mg, 0.10 mmol) and p-Tolualdehyde (36 mg, 0.30 mmol). Its structure was confirmed by 1H NMR and MS (488, M+1). C26H25N503S, Calc.: C: 64.05, H:
5.17, N: 14.36; Found, C: 63.78, H: 4.99, N: 14.12.

[0052] Example 43 1-[4-(aminosulfonyl)phenyl]-8-[(4-methoxybenzyl)amino]-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide O , ,O

H2N/S <:IN-N

o The title compound (36 mg, 71 %) was synthesized by the same procedure as in Example 41 starting with the product of Example 2(8-amino-1-{4-[(aminothio)peroxy]phenyl }-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide) (38.3 mg, 0.10 mmol) and p-anisaldehyde (38 mg, 0.30 mmol). Its structure was confirmed by IH NMR and MS (504, M+1). C26H25N504S.(Et2O) 0.6, Calc.: C:
62.24, H: 5.70, N: 12.78; Found, C: 61.68, H: 5.43, N: 12.54.

[0053] Example 44 1-[4-(aminosulfonyl)phenyl]-8-[(4-chlorobenzyl)amino]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide O,, O
H2N"S~

N-N

O
CI

The title compound (37 mg, 74%) was synthesized by the same procedure as in Example 41 starting with the product of Example 2(8-amino-1-{4-[(aminothio)peroxy]phenyl } -4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide) (38.3 mg, 0.10 mmol) and p-chlorobenzaldehyde (42 mg, 0.30 mmol). Its structure was confirmed by'H NMR and MS (508, M+1). C25H22N503SC1, Calc.: C: 59.11, H: 4.37, N: 13.79; Found, C: 58.78, H: 4.25 N: 13.18.

[0054] Example 45 1-[4-(aminosulfonyl)phenyl]-8-(isobutylamino)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide o,,o H2N r ~
\ N,.N O
N
"C I NH2 The title compound (27 mg, 61%) was synthesized by the same procedure as in Example 41 starting with the product of Example 2(8-amino-1-{4-[(aminothio)peroxy]phenyl }-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide) (38.3 mg, 0.10 mmol) and isopropyl aldehyde (22 mg, 0.30 mmol). Its structure was confirmed by 'H NMR and MS (440, M+1). C22H25N503S.H20.(Et20) 0.2, Calc.: C: 57.97, H: 6.19, N: 14.83; Found, C: 57.63, H: 5.76 N: 14.04.

[0055] Procedures for the synthesis of Compounds of Example 46 and 47 Scheme XIV
o R o H2N-S R.N-~S /
0 ~ N_N o 1) 2eq. NaH / DMF ~ ~ N,N 0 ~ H N , ~
H2N NHZ 2) 2eq. MeI or 2 ~ ~ NH2 "~~ Br Example 2 R= CH3 Example 46 R = CH,CH=CH2 Example 47 [0056] Example 46 8-amino-l-{4-[(dimethylamino)sulfonyl]phenyl )-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide O~' "O
-~NI S
~ \ I N-O
To a stirred solution of the product of Example 2(8-amino-1-{4-[(aminothio)peroxy]phenyl}-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide) (38 mg, 0.10 mmol) in DMF (1 mL) at RT under Ar was added sodium hydride in mineral oil (60%, 8 mg, 0.20 mmol). After 2 h, iodomethane (28.4 mg, 0.20 mmol) in DMF (1 mL) was added and the resulted mixture was stirred at RT for 18 h, added water (10 mL), extracted with EtOAc (3x10 mL). The combined organic layers was washed with water (3x 10 mL), dried over MgSO4, filtered through a silica gel pad with EtOAc, and concentrated. The crude product was triturated with diethyl ether to give 8-amino-l-{4-[(dimethylamino)sulfonyl]phenyl}-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide as a yellow solid (29 mg, 70%). Its structure was confirmed,by IH NMR and MS (412, M+1). C20H21N503S.(H20) 0.3.(Et2O)o.3, Calc.: C: 57.99, H: 5.65, N: 15.95; Found, C: 57.31, H: 5.18, N: 15.26.

[0057] Example 47 8-amino-l- { 4-[(diallylamino)sulfonyl]phenyl } -4,5-dihydro-1 H-benzo [g]indazole-3-carboxamide ~N ~ S
n 1 o The title compound was synthesized by the same procedure used as for Example except iodomethane was replaced by allyl bromide (24.2 mg, 0.20 mmol). The title compound is a yellow solid (28 mg, 61%). Its structure was confirmed by 'H NMR

and MS (464, M+1). C24H25N503S, Calc.: C: 62.18, H: 5.44, N: 15.11; Found, C:
61.76, H: 5.10, N: 14.77.

[0058] Synthesis of Examples 48 and 49 Scheme XV

OH
HN
s ~ Boc 0 ~ ~ \ ~
H
H2N \ / EDC, HOB 't, TEA H2N Q HCI 2N

NH2 DMF N-N NH2 30 min N~ ~ NH2 \ ct, overnight N

\ HNN HCl.H2N
6oo IOI 0 1 Example 2 Example 48 HN,~OCH3 Boc 0 ~OH

OH
~ f HBoc 0 ~ e \ ~

H2 EDC, HOBt, TEA HZN H HCI
H2Oldioxane rt, -N DMF = -N 30 min = N-N NH
/~ ~N 2 NH2 tt, ovemight : H NH2 H2N I \ \ HN~N + \ \ HCi .H2N I \ \
/ Boc 0 0 Example 2 Example 49 [0059] Example 48 8-(L-alanylamino)-1-[4-(aminosulfonyl)phenyl]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide o~ so HZN Q N N

N
HzN O
O

To a stirring solution of 8-amino-l-{4-[(aminothio)peroxy]phenyl}-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (Example 2) (153 mg, 0.40 mmol) in DMF (6 mL) were added N-Boc-L-alanine (90 mg, 0.48 mmol), EDC (88 mg, 0.46 mmol), HOBt (60 mg, 0.44 mmol), and triethylamine (0.06 mL, 0.44 mmol). The reaction mixture was allowed to stir overnight at room temperature. The DMF was then removed under reduced pressure and the resulting residue was purified by reverse phase preparative HPLC to give a beige powder (83 mg, 38 %). The powder was then dissolved in dioxane/water (2 mL, 1:1) and 5 M HCl (1 mL) was added at room temperature. After stirring for 3 hours, the solvent was removed under reduced pressure to give an oily residue. The residue was dissolved in a minimum amount of methanol and ether was added. The resulting precipitate was filtered to give the title compound as a pale yellow solid (66 mg, 90 %). 1H NMR (400 MHz, d6-DMSO): 1.33 (d, 3H, J= 6 Hz), 2.88-2.97 (m, 4H), 3.92 (m, 1H), 7.24-8.15 (7H, m); M+1=456, Anal. Calcd for C21H23N604SC1 containing MeOH (1) and CH2C12 (1): C, 45.44; H, 4.83; N, 13.82. Found C, 45.37; H, 4.83; N, 13.60.

[0060] Example 49 8-(D-alanylamino)-1-[4-(aminosulfonyl)phenyl]-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide 0 o N-N
H2N ~ 'N / 6~ NH2 ~I{ ~ ~ O
I

To a stirring solution of 8-amino-1-{4-[(aminothio)peroxy]phenyl}-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (Example 2) (156 mg, 0.40 mmol) in DMF (6 mL) were added N-Boc-D-alanine (81 mg, 0.43 mmol), EDC (85 mg, 0.44 mmol), HOBt (58 mg, 0.43 mmol), and triethylamine (0.06 mL, 0.44 mmol). The reaction mixture was allowed to stir overnight at room temperature. The DMF was then removed under reduced pressure and the resulting residue was purified by reverse phase preparative HPLC to give a beige powder (122 mg, 56 %). The powder was then dissolved in dioxane/water (2 mL, 1:1) and 5 M HCl (1 mL) was added at room temperature. After stirring for 3 hours, the solvent was removed under reduced pressure to give the title compound as a light orange solid (92 mg, 87 %).
'H NMR (400 MHz, d6-DMSO): 1.35 (d, 3H, J= 6 Hz), 2.80-2.94 (m, 4H), 3.91 (m, 1H), 7.13-8.14 (7H, m); M+1=456.

[0061] Example 50 8-[(2-chlorobenzoyl)amino]-1-{4-[(dimethylamino)sulfonyl]phenyl } -4,5-dihydro-1 H-benzo [g] indazole-3 -carboxamide p 0 \ ~ N
H
/ ~ \ ( N- p N-N Q CI O N, ~
H2N Pyridine CI NH2 ~ ~ NH2 / I

Example 46 Example 50 To a stirred solution of 8-amino-1-{4-[(dimethylamino)sulfonyl]phenyl}-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (Example 46) (1.52 g, 3.70 mmol) in pyridine (25 mL) at RT was added 2-chlorobenzoic chloride (970 mg, 5.55 mmol).
After 14 h, trisamine (1 g) was added and the mixture was stirred for 2 h. The mixture was filtered through a silica gel pad with EtOAc and concentrated.
Column chromatography (silica gel, EtOAc) gave the title compound as a yellow solid (900 mg, 1.63 mmol, 44%). Its structure was confirmed by 1H NMR and MS (551, M+1). C27H24C1N504S, Calc.: C: 58.96, H: 4.40, N: 12.73; Found, C: 58.66, H:
4.65, N: 12.58.

[0062] Examples 51-91 Synthesis of the sulfonamide/arnide/urea library The sulfonamides, amides, and ureas of Examples 51-91 were synthesized in a library format as described in Examples 5-40. The starting materials are the product of Example 4 (8-amino-l-{4-[(aminothio)peroxy]phenyl}-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide) and appropriate sulfonyl chlorides, acyl chlorides and isocyanates. Table I shows the compound identification, compound, IKK
resin assay values, formula weight, and mass spectroscopy characterization for the compounds from the library.

Table 1 COMPOUND STRUCTURE EXAMPLE IKK2 Formula Mass -resin Weight Spec 1-[4 Example 1 > 100 413.41 414 (aminosulfonyl)phenyl]-8- HZN,S o M
nitro-4,5-dihydro-1H-benzo[g]indazole-3-~ N-N

carboxamide o=,N NH2 8-amino-l-[4- Example 2 <1 383.43 384 (aminosulfonyl)phenyl]- HzN-so 0 M
4,5-dihydro-lH- o'' C~N-N
benzo[g]indazole-3-carboxamide HNNH
z 8-(acetylamino)- 1-[4- Example 3 10 < 425.47 426 (aminosulfonyl)phenyl]- H N-s o 100 4,5-dihydro-lH- 2 0' benzo[g]indazole-3- M>
carboxamide ILN \ \ N NHZ
/
1-[4- Example 4 <1 461.52 462 (aminosulfonyl)phenyl]-8- HZN_s M
[(methylsulfonyl)amino]- .
4,5-dihydro-lH- N_N
benzo[g]indazole-3- -s N NH2 carboxamide 0 o 1-[4- Example 5 10 < 515.49 516 (aminosulfonyl)phenyl]-8- H2N;s 100 { [(trifluoromethyl)sulfony o ~
1]amino}-4,5-dihydro-1H- F o N-N NHZ M
benzo[g]indazole 3 F* s_N carboxamide F o o 1-[4- Example 6 <1 475.55 478 (aminosulfonyl)phenyl]-8- H2N.S:o M
[(ethylsulfonyl)amino]-4,5-dihydro-1 H-NHZ
benzo[g]indazole-3- s N-N
carboxamide o COMPOUND STRUCTURE EXAMPLE IKK2 Formula Mass -resin Weight Spec 1-[4- Example 7 1< 529.52 530 (aminosulfonyl)phenyl]-8- HZN,s 10 1[(2,2,2 trifluoroethyl)sulfonyl]am F F
( o H N-N NN2 M
ino}-4,5-dihydro-lH- F~-s-"

benzo[g]indazole-3- o carboxamide 1-[4- Example 8 1< 489.58 490 (aminosulfonyl)phenyl]-8- HZ".S 10 [(propylsulfonyl)amino]- 0' 4,5-dihydro-lH- o N N pM

benzo[g]indazole-3- ",."-s _N NH2 carboxamide 0 1-[4- Example 9 1< 489.58 490 (aminosulfonyl)phenyl]-8- HZN,s 10 [(isopropylsulfonyl)amino o ]-4,5-dihydro-lH- o H N-N NHZ ItM
benzo[g]indazole-3- s'"
carboxamide 1~ ~

1-[4- Example 1< 503.60 531 (aminosulfonyl)phenyl]-8- HZN,s 10 10 [(butylsulfonyl)amino]- o 4,5-dihydro-lH- o u N-N NH M>
benzo[g]indazole-3- s-" carboxamide 0 1-[4- Example 1< 537.62 538 (aminosulfonyl)phenyl]-8- H2N,s 11 10 [(benzylsulfonyl)amino]- o 4,5-dihydro-lH- 0 N-N NHz M>
benzo[g]indazole-3-carboxamide 60 1-[4- HN.S Example 10 < 573.65 574 (aminosulfonyl)phenyl]-8- ~ o [(1- O HN-N NH 12 100 naphthylsulfonyl)amino]- / s-" z M
4,5-dihydro-lH-benzo[g]indazole-3-carboxamide 1-[4- Example 1< 616.72 617 (aminosulfonyl)phenyl]-8- ~=S 13 10 ({[5-(dimethylamino)-1- \ so aphthyl]sulfonyl}amino) " "-N "~ M
n -4,5-dihydro-lH- " \ ~
benzo[g]indazole-3-carboxamide COMPOUND STRUCTURE EXAMPLE IKK2 Formula Mass -resin Weight Spec 1-[4- Example 1< 574.64 575 (aminosulfonyl)phenyl]-8- HzN.sP

[(isoquinolin-5- N 6' ~
ylsulfonyl)amino]-4,5- - o H N-N NH M
dihydro-1H- o N~ ~ o Z
benzo[g]indazole-3-carboxamide 1-[4- Example > 100 574.64 575 (aminosulfonyl)phenyl]-8- H2N. S 15 M
[(quinolin-7-ylsulfonyl)amino]-4,5- o N-N
dihydro-lH- s_N ~ NHZ
benzo[g]indazole-3- 0 C o carboxamide 1-[4- Example 1< 565.59 575 (aminosulfonyl)phenyl]-8- HzN.s 16 10 [(2,1,3-benzoxadiazol-4- o, 6 ' ~
ylsulfonyl)amino]-4,5- N~ /N o H / N-N NH M
dihydro-1 H- o 0 2 benzo[g]indazole-3-carboxamide 1-[4- Example 1< 599.69 600 (aminosulfonyl)phenyl]-8- ~".S
[(1,1'-biphenyl-4- o 1 17 10 ylsulfonyl)amino]-4,5- S-N N-N "~ M
dihydro-lH- ~o o benzo[g]indazole-3-carboxamide 1-[4- Example 10 < 606.71 607 (aminosulfonyl)phenyl]-8- Hz". So { [(5-pyridin-2-ylthien-2- o I ~ 18 100 yl)sulfonyl]amino}-4,5- CN S H~\/N-N "F~ pM
dihydro-1 H- o " o benzo[g]indazole-3-carboxamide 1-[4- Example 10 < 527.58 528 (aminosulfonyl)phenyl]-8- HZN esP 19 100 { [(1-methyl-lH-imidazol- o ~
4-yl)sulfonyl]amino}-4,5- ~ 0 H ~ N-N NH2 PM
dihydro-lH- N s'N benzo[g]indazole-3- N O
carboxamide 1-[4- Example 10 < 541.61 542 (aminosulfonyl)phenyl]-8- HZN.s 20 100 {[(1,2-dimethyl-1H- o 1 imidazol-4- \ o H N-N NH M
yl)sulfonyl]amino}-4,5- N ~ S-N ~ Z

dihydro-lH-benzo[g]indazole-3-carboxamide COMPOUND STRUCTURE EXAMPLE IKK2 Formula Mass -resin Weight Spec 8-({ [2-(acetylamino)-4- Example 1< 601.69 602 methyl-l,3-thiazol-5- H2N=s 21 10 yl]sulfonyl}amino)-1-[4- o (aminosulfonyl)phenyl]- N~o H N-N Nl~ M
4,5-dihydro-lH- "-~',s o "
benzo[g]indazole-3-carboxamide 1-[4- Example 10 < 537.62 538 (aminosulfonyl)phenyl]-8- HzN,s~ 22 100 {[(4- 6 1 methylphenyl)sulfonyl]am 0- H N-N NHZ M 3>
ino}-4,5-dihydro-lH- s"
benzo[g]indazole-3-carboxamide 1-[4- Example 10 < 553.62 554 (aminosulfonyl)phenyl]-8- HzNs= 23 100 M
methoxyphenyl)sulfonyl]a o H N-N NH, mino}-4,5-dihydro-lH- o"
benzo[g]indazole-3-carboxamide 1-[4- Example 1< 541.58 542 (aminosulfonyl)phenyl]-8- HZN.s 24 10 { [(4- (3 fluorophenyl)sulfonyl]ami o H N-N Ny2 M
no)-4,5-dihydro-lH- F / S-"
benzo[g]indazole-3- 0 carboxamide 1-[4- Example 1< 558.04 559 (aminosulfonyl)phenyl]-8- HZN=sP 25 10 {[(4- o chlorophenyl)sulfonyl]am o H N-N NHz M
ino}-4,5-dihydro-lH- s'"
benzo[g]indazole-3- o carboxamide 1-[4- Example 1< 602.49 603 (aminosulfonyl)phenyl]-8- HN.s 26 10 { [(4- o bromophenyl)sulfonyl]am o H N-N NHZ M
ino}-4,5-dihydro-lH- er / o" o benzo[g]indazole-3-carboxamide 1-[4- Example 10 < 591.59 592 (aminosulfonyl)phenyl]-8- HzN.s= 27 100 \{ [3- F F
M
(trifluoromethyl)phenyl]s o H N-N NH, ulfonyl}amino)-4,5- F s"
dihydro-lH- + o benzo[g]indazole-3-carboxamide COMPOUND STRUCTURE EXAMPLE IKK2 Formula Mass -resin Weight Spec 1-[4- Example 1< 592.48 593 (aminosulfonyl)phenyl]-8- HZN.s 28 10 {[(3,4-dichlorophenyl)sulfonyl]a }~ o H ~ N-N NH2 M
mino}-4,5-dihydro-lH- 01- o N
benzo[g]indazole-3-carboxamide 1-[4- Example 1< 592.48 593 (aminosulfonyl)phenyl]-8- HZN.s 29 10 ([(2,5- o dichlorophenyl)sulfonyl]a ci o H N-N NHZ M
mino}-4,5-dihydro-1H- S-N
benzo[g]indazole-3- C1 ~
carboxamide 1-[4- Example 1 < '592.48 593 (aminosulfonyl)phenyl]-8- H2N.s 30 10 { [(2,4- ~ I ~
dichlorophenyl)sulfonyl]a ~~ o H ~ N-N NH2 M
mino}-4,5-dihydro-lH- ci ~ I ~ N~ o benzo[g]indazole-3-carboxamide 1-[4- Example 10 < 559.57 560 (aminosulfonyl)phenyl]-8- HZN.sP 31 100 ([(2,4- o 1 difluorophenyl)sulfonyl]a ~ o N-N NHz M
mino}-4,5-dihydro-lH- F / sN
benzo[g]indazole-3- \ F o carboxamide 1-[4- Example 10 < 559.57 560 (aminosulfonyl)phenyl]-8- H2N.s 32 100 { [(3,4- 6 difluorophenyl)sulfonyl]a }~ o H ~ N-N NHZ M
mino}-4,5-dihydro-lH- F-\/ S-N i ~
benzo[g]indazole-3- ~ I
carboxamide 1-[4- Example 1< 620.48 621 (aminosulfonyl)phenyl]-8- HZN.s 33 10 { [(4-bromo-2- o fluorophenyl)sulfonyllami F o H N N NH2 M
no}-4,5-dihydro-lH- BI s benzo[g]indazole-3- \ /
carboxamide 1-[4- Example 10 < 583.64 584 (aminosulfonyl)phenyl]-8- H2N-s 34 100 dimethoxyphenyl)sulfonyl -o o N N-N N~ M
91 ]amino}-4,5-dihydro-lH- 0 oN \ ~ o benzo[g]indazole-3-carboxamide COMPOUND STRUCTURE EXAMPLE IKK2 Formula Mass -resin Weight Spec 1-[4- Example 1< 659.59 660 (aminosulfonyl)phenyl]-8- r-4N.s 35 10 ({[3,5- F F d [tM
bis(trifluoromethyl)phenyl F o" N-N NH2 ]sulfonyl}amino)-4,5- s-N
dihydro-1H- o benzo[g]indazole-3- F pF
carboxamide 1-[4- Example 1< 626.93 627 (aminosulfonyl)phenyl]-8- HZN.S 36 10 {[(2,4,5- o trichlorophenyl)sulfonyl]a ci H N-N N"2 M
mino}-4,5-dihydro-1H o benzo[g]indazole-3- ci o carboxamide 1-[4- Example 1< 439.49 440 (aminosulfonyl)phenyl]-8- HZN o 37 10 (propionylamino)-4,5-dihydro-lH- o N-N pM
NH
benzo[g]indazole-3- v ~J1--r" 2 carboxamide I o 1-[4- Example 1< 487.54 489 (aminosulfonyl)phenyl]-8- "ZN,so 38 10 (benzoylamino)-4,5- o dihydro-lH- o N-N M
benzo[g]indazole-3- "i N"2 carboxamide o 1-[4- Example 1< 454.51 455 (aminosulfonyl)phenyl]-8- HZN, 0 39 10 { [(ethylamino)carbonyl]a os mino}-4,5-dihydro-lH- o N-N M
benzo[g]indazole-3- r"i-~-rHi ~ ' N"Z
carboxamide 1-[4- Example 1< 502.55 503 (aminosulfonyl)phenyl]-8- ,%N :o 40 10 [(anilinocarbonyl)amino]- CS
4,5-dihydro-lH- o N-N M

benzo[g]indazole-3 N_1Lr", , carboxamide 1-[4- Example 1 473.56 474 (aminosulfonyl)phenyl]-8- 0; ,0 41 10 (benzylamino)-4,5- HZNS , dihydro-lH- " N-N o M
benzo[g]indazole-3- N NHZ
ca rboxamide 6-6 COMPOUND STRUCTURE EXAMPLE IKK2 Formula Mass -resin Weight Spec 1-[4- Example 10 < 487.58 488 (aminosulfonyl)phenyl]-8- 0. .0 42 100 [(4-methylbenzyl)amino]- H2N"S
4,5-dihydro-lH- H N-N NH M
benzo[g]indazole-3- N~ \ o z carboxamide 1-[4- Example 1 < 503.58 (aminosulfonyl)phenyl]-8- 0, .0 43 10 [(4- HzN"S
methoxybenzyl)amino]- H N-N NH !tM
4,5-dihydro-lH- N~ \ Z
o benzo[g]indazole-3-carboxamide o-1-[4- Example 10 <- 508.00 509 (aminosulfonyl)phenyl]-8- 0 0 44 100 [(4-chlorobenzyl)amino]- HZN"S
4,5-dihydro-lH- N-N M
benzo[g]indazole-3- NHZ
~ \ o carboxamide ci 1-[4- Example 10 < 439.54 440 (aminosulfonyl)phenyl]-8- o, 45 100 (isobutylamino)-4,5- H2N"s /
M
dihydro-lH- H~ I N-N 0 benzo[g]indazole-3- N Nrl2 carboxamide 8-amino-1-{4- Example 1< 411.48 412 [(dimethylamino)sulfonyl] o. ;0 46 10 phenyl}-4,5-dihydro-lH- _N"S abenzo[g]indazole-3- N"N NH2 M

carboxamide HZN &-po 8-amino-l-{4- Example 1< 463.56 464 [(diallylamino)sulfonyl]ph (? , 47 10 enyl)-4,5-dihydro-lH-benzo[g]indazole-3- M
carboxamide H N ~N NHZ

COMPOUND STRUCTURE EXAMPLE IKK2 Formula Mass -resin Weight Spec 8-(L-alanylamino)-1-[4- Example 1< 490.97 492 (aminosulfonyl)phenyl]- p 48 10 4,5-dihydro-lH- HZNOS
benzo[g]indazole-3- N-N NHZ M
carboxamide HCI
H
hydrochloride ~" v i o HZN o 8-(D-alanylamino)-1-[4- Example 1< 490.97 492 (aminosulfonyl)phenyl]- o. ..0 49 10 4,5-dihydro-lH- "~"'S ~
benzo[g]indazole-3- /~ M
carboxamide "-"
hydrochloride H01 " \ o "~

8-[(2- Example <1 550.04 551 chlorobenzoyl)amino]-1- 50 M
14- -"= .o [(dimethylamino)sulfonyl] -s phenyl }-4,5-dihydro-lH-benzo[g]indazole-3- o N-N
NHZ
carboxamide ci 6 -(o 1-[4- H2N\ Example 1< 467.55 467 (aminosulfonyl)phenyl]-8- I 51 10 (pentanoylamino)-4,5-dihydro-lH- M
benzo[g]indazole-3- ~ L Acarboxamide ~/

1-[4- Example 1< 493.59 494 (aminosulfonyl)phenyl]-8- 52 10 [(cyclohexylcarbonyl)ami no]-4,5-dihydro-lH- e; F~M
benzo[g]indazole-3- $ o carboxamide 1-[4- HZN\f Example 1< 470.56 480 (aminosulfonyl)phenyl]-8- 53 10 [(cyclopentylcarbonyl)ami no]-4,5-dihydro-lH- x2 M
benzo[g]indazole-3- 8 carboxamide COMPOUND STRUCTURE EXAMPLE IKK2 Formula Mass -resin Weight Spec 1-[4- H N Example 1< 465.53 466 (aminosulfonyl)phenyl]-8- 2 \~ \ 54 10 [(cyclobutylcarbonyl)ami no]-4,5-dihydro-lH- M
benzo[g]indazole-3- $
carboxamide 1-[4- õZN\~ Example 1< 451.51 452 (aminosulfonyl)phenyl]-8- 55 10 [(cyclopropylcarbonyl)am ino]-4,5-dihydro-lH- ~ -\ H2 M
benzo[g]indazole-3- H
carboxamide 1-[4- HZN\~ Example 1< 453.52 454 (aminosulfonyl)phenyl]-8- so 56 10 (butyrylamino)-4,5-dihydro-lH- M
benzo[g]indazole-3- $ e \
carboxamide 1-[4- Example 1< 501.57 502 (aminosulfonyl)phenyl]-8- 57 10 [(phenylacetyl)amino]-4,5-dihydro-lH- benzo[g]indazole-3- 0J-11 carboxamide 1-[4- 112N 4 Example 1< 455.49 456 (aminosulfonyl)phenyl]-8- 58 10 [(methoxyacetyl)amino]-4,5-dihydro-lH- M
benzo[g]indazole-3- J-H I \
carboxamide i 1-[4- H2N\g Example 1< 453.52 454 (aminosulfonyl)phenyl]-8- 59 10 (isobutyrylamino)-4,5-dihydro-lH- M
benzo[g]indazole-3-R \
carboxamide COMPOUND STRUCTURE EXAMPLE IKK2 Formula Mass -resin Weight Spec Example 1< 555.54 556 (aminosulfonyl)phenyl]-8- 60 10 {[4-(trifluoromethyl)benzoyl]a M
mino}-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide !3 1-[4- g,N~ Example <1 517.56 518 (aminosulfonyl)phenyl]-8- 61 M
[(4-methoxybenzoyl)amino]- \ pa:
4,5-dihydro-lH-benzo[g]indazole-3-carboxamide ~

1-[4- $ZN~~ Example <1 521.98 522 (aminosulfonyl)phenyl]-8- e 62 M
[(4-chlorobenzoyl)amino]-4,5-dihydro-lH- benzo[g]indazole-3- $ \
carboxamide 1-[4- $ZN~ Example <1 505.53 506 (aminosulfonyl)phenyl]-8-[(4-fluorobenzoyl)amino]- 63 M
4,5-dihydro-lH-H:
benzo[g]indazole-3-carboxamide 1-[4- Example 1< 547.59 548 (aminosulfonyl)phenyl]-8-[(3,4- 64 10 dimethoxybenzoyl)amino] e \ ~ H: M
-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide 1-[4 ~ Example 10 < 477.5 478 (aminosulfonyl)phenyl]-8- Z i ~ 65 100 (2-furoylamino)-4,5-dihydro-lH- M
benzo[g]indazole-3-carboxamide COMPOLTND STRUCTURE EXAMPLE IKK2 Formula Mass -resin Weight Spec 1-[4- AzN Example 10 < 493.57 494 (aminosulfonyl)phenyl]-8- \

[(thien-2-ylcarbonyl)amino]-4,5- M
dihydro-lH- H
benzo[g]indazole-3-carboxamide 1-[4- AzN Example <1 488.53 489 (aminosulfonyl)phenyl]-8- 67 M
(isonicotinoylamino)-4,5-dihydro-lH- benzo[g]indazole-3-carboxarxride 8-[(1- Example 1< 545.66 546 adamantylcarbonyl)amino ]-1-[4- 68 10 (aminosulfonyl)phenyl]- I N M
4,5-dihydro-lH-benzo[g]indazole-3-carboxamide 1-[4- ,,,N Example 1< 523.59 526 (aminosulfonyl)phenyl]-8-[(phenylsulfonyl)amino]-4,5-dihydro-lH- H; M
benzo[g]indazole-3-carboxamide 1-[4- H2N Example 1< 555.54 556 (aminosulfonyl)phenyl]-8- ~/
{[3- 0 70 10 (trifluoromethyl)benzoyl]a õ, M
mino}-4,5-dihydro-lH-benzo[g]indazole-3- kt, carboxamide 1-[4- H2N Example <1 501.57 502 (aminosulfonyl)phenyl]-8- ~J~, [(3- ~\/I\ 71 M
methylbenzoyl)amino]-H, 4,5-dihydro-lH-benzo[g]indazole-3-carboxamide COMPOUND STRUCTURE EXAMPLE IKK2 Formula Mass --resin Weight Spec 1-[4- xzN,, Example <1 566.43 567 (aminosulfonyl)phenyl]-8- I 72 M
[(3-bromobenzoyl)amino]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide 1-[4= $2N ~ Example 1< 531.59 532 (aminosulfonyl)phenyl]-8- 73 10 {[(3-methoxyphenyl)acetyl]ami B , M
no }-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide 1-[4- Example <1 488.53 489 (aminosulfonyl)phenyl]-8- a2N- ~ 74 M
[(pyridin-3-ylcarbonyl)amino]-4,5-dihydro-lH- g2 benzo[g]indazole-3-carboxamide 1-[4- Example <1 521.98 522 (aminosulfonyl)phenyl]-8- aZN-~~ 75 M
[(2-chlorobenzoyl)amino]-4,5-dihydro-1 H- 8 benzo[g]indazole-3- Z
carboxamide 1-[4- Example 1< 602.49 603 (aminosulfonyl)phenyl]-8-{ [(3- 76 10 bromophenyl)sulfonyl]ami gZ M
no}-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide 1-[4- Example 1 558.04 559 (aminosulfonyl)phenyl]-8- ezN-{ [(3 77 10 chlorophenyl)sulfonyl]ami g, M
no}-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide COMPOUND STRUCTURE EXAMPLE IKK2 Formula Mass -resin Weight Spec 1-[4- ~ Example <1 512.55 513 (aminosulfonyl)phenyl]-8- ~ 78 M
[(3-cyanobenzoyl)amino]- $ZN
4,5-dihydro-lH-gZ
benzo[g]indazole-3-carboxamide -N

1-[4- Example 10 < 537.62 538 (aminosulfonyl)phenyl]-8- azNi 79 100 {[(3-methylphenyl)sulfonyl]am 132 M
ino}-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide 1-[4- Example <1 517.56 518 (aminosulfonyl)phenyl]-8- 80 M
[(3-methoxybenzoyl)amino]- \ Q2 4,5-dihydro-lH- ~ -benzo [g]indazole-3-carboxamide 1-[4- L' Example <1 521.98 522 (anunosulfonyl)phenyl]-8- $'Ni [(3-chlorobenzoyl)amino]- 81 M
4,5-dihydro-lH-$ / ~ \ Naa benzo[g]indazole-3-carboxamide cx 1-[4- Example 10 < 517.56 518 (aminosulfonyl)phenyl]-8-N'N~ 82 100 [(2-methoxybenzoyl)amino]- M
4,5-dihydro-lH- H, benzo[g]indazole-3-carboxamide 1-[4- Example <1 555.54 556 (aminosulfonyl)phenyl]-8- H1H~ 83 M
{ [2-(trifluoromethyl)benzoyl]a mino}-4,5-dihydro-lH- $ \ N1 benzo[g]indazole-3- C
carboxamide 3 COMPOUND STRUCTURE EXAMPLE IKK2 Formula Mass -resin Weight Spec 1-[4- Example <1 501.57 502 (aminosulfonyl)phenyl]-8- H=N-[(2-methylbenzoyl)amino]-4,5-dihydro-lH- ~ N \ NN=
benzo[g]indazole-3-carboxamide 1-[4- Example <1 556.43 557 (aminosulfonyl)phenyl]-8- H=N~ ~110 85 M
[(2,6- r dichlorobenzoyl)amino]- I ) 1 4,5-dihydro-lH- ~ \ \ NH=
benzo[g]indazole-3-c7 o carboxamide 0 1-[4- Example <1 571.53 572 $,N
(aminosulfonyl)phenyl]-8-{ [2(trifluoromethoxy)benzoyl ]amino}-4,5-dihydro-lH- $ ~ \ $2 benzo[g]indazole-3-carboxamide 1-[4- Example <1 556.43 557 (aminosulfonyl)phenyl]-8- $=N- ~ 87 M
[(2>3-dichlorobenzoyl)amino]-4,5-dihydro-lH- ~ 8 \ ~ Na=
benzo a1 J
[g]indazole-3-cl o carboxamide 1-[4- " Example <1 505.53 506 (aminosulfonyl)phenyl]-8- H=N- ~
[(2-fluorobenzoyl)amino]- 88 M
4,5-dihydro-lH-[g]
indazole-3- carboxamide benzo ?Y.

1-[4- Exarnple <1 522.97 523 (aminosulfonyl)phenyl]-8-"=N- 89 M
{[(2-chloropyridin-3-yl)carbonyl]amino }-4,5-dihydro-lH- I H g=
benzo[g]indazole-3- ~
carboxamide 1 0 COMPOUND STRUCTURE EXAMPLE IKK2 Formula Mass -resin Weight Spec 1[4 Example 10 < 558.04 558 (aminosulfonyl)phenyl]-8- x2N-{ c [(2hlorophenyl)sulfonyl]ami C1 M
no}-4,5-dihydro-lH- Hz benzo[g]indazole-3-carboxamide 1-[4- Example <1 566.43 567 (aminosulfonyl)phenyl]-8- A2N-[(2-bromobenzoyl)amino]- 91 M
4,5-dihydro-lH-benzo[g]indazole-3- er R, carboxamide [0063] Examples 92-125 [0064] Examples 92-125 shown in Table 2 were synthesized using the following synthesis procedure similar to scheme I where R9 is the appropriate aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or cycloalkyl.

Scheme XV

%S o O O 4-(Methylsulfonyl)-phenylhydrazine N-N OEt OzN OEt AcOH, A OZN
~ 0 1 0 ethyl (7-nitro-l-oxo-1,2,3, ethyli-[4-(methylsulfonyl)phenyl)-8-nftro-4,5-4-tetrahydronaphthalen-2-yl) dihydro-1 H-benzo[glindazole-3-carboxylate (oxo)acetate 1 ~ S'O O~S IO
/
Pd(OH)2 ~ / NH3, MeOH Q-HzN \ N OEt 700 psl NH2 H
~ O zN
O
Example 92 OSO
/

N-N
N\~\JJ NHZ
R9CO2H, HATU or Ry~~
O ~~ O
R9COCI, Pyridine [0065] Example 92 8-amino-l-[4-(methylsulfonyl)phenyl]-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide hydrochloride O\\ S 0 N-N

[0066] Step 1 O\\ S O

h N-N
02N r \ \ COOEt I

A mixture of (17.2 mmoles) of diketo ester and (17.2 mmoles) 4-(Methylsulfonyl)-phenylhydrazine in 100m1 of acetic acid was refluxed with stirring for 3h, and then cooled. The mixture was concentrated, and the residue triturated with ethyl acetate 'affording a brown solid, which was filtered, washed with ethyl acetate, and dried to give the title compound. The structure was supported by 1H NMR.
[0067] Step 2 N-N
H2N COOEt ( A solution of the title product of Step 1 in acetic acid was treated at room temperature with 5% palladium on carbon under an atmosphere of hydrogen gas at 5 psi. The reaction was followed by LC-MS. When the conversion was complete, the mixture was filtered and concentrated to give the title compound as a brownish oil that was used directly for the next step.

[0068] Step 3 8-amino-l-[4-(methylsulfonyl)phenyl]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide hydrochloride O\\ S 0 /

N-N
H2N CONHz I

The title product of Step 2 was dissolved in anhydrous ethanol and then an approximately equal volume of liquid ammonia was added. The resulting mixture was sealed in a pressure vessel and then stirred overnight at 100 C. After cooling, the mixture was concentrated. The residue was taken up in dichloromethane -methanol and chromatographed over silica gel using ethyl acetate as eluent to give the title compound, as an oil which crystallized on standing.

Table 2.

Structure Formula Name IKK Example Weight Resin IC50 0 418.91 8-amino-l-[4- 1< 92 ~S%o (methylsulfonyl)phen 10 / yl]-4,5-dihydro-lH-~ N_N benzo[g]indazole-3- M
H2N NH2 carboxamide /
\ ~ o hydrochloride HCI

0 554.55 1-[4- <1 93 -S-o (methylsulfonyl)phen yl]-8-{ [2- M
_ (trifluoromethyl)benz ~/ N N NH2 oyl]amino}-4,5-,~ dihydro-lH-~ F o benzo[g]indazole-3-F carboxamide _S o 500.58 8-[(2- <1 94 n/\ methylbenzoyl)amino M
]-1-[4-\ _ (methylsulfonyl)phen N N NHZ yl]-4,5-dihydro-IH-/ benzo[g]indazole-3-\ o carboxamide s,o 521.00 8-[(2- <1 95 a,,-- chlorobenzoyl)amino M
]-1-[4- [t N-N (methylsulfonyl)phen N NH 2 yl]-4,5-dihydro-lH-benzo[g]indazole-3-~
CI 0 carboxamide _ 555.44 8-[(2,3- <1 96 ~Q o S- dichlorobenzoyl)ami / ~ no]-1-[4- M
(methylsulfonyl)phen c~ N ~\ NH2 yl]-4,5-dihydro-lH-benzo[g]indazole-3-ci o \ ~ o carboxamide Structure Formula Name IKK Example Weight Resin IC50 ( %S,O 504.54 8-[(2- <1 97 \ fluorobenzoyl)amino] PM
/ -1-[4-~ (methylsulfonyl)phen ~' H N_\ NH2 yl]-4,5-dihydro-lH-F N benzo[g]indazole-3-o 0 carboxamide 0S,o 521.99 8-{ [(2-chloropyridin- <1 98 yl)carbonyl]amino}- p I _ 1-[4-N-~ N H N\ NH2 (methylsulfonyl)phen c~ o \ o yl]-4,5-dihydro-lH-\ benzo[g]indazole-3-carboxamide seo 476.52 1-[4- 1< 99 -~ a"-- (methylsulfonyl)phen 10 yl]-8-[(1H-pyrazol-4-NI H N" N NH2 ylcarbonyl)amino]- M
H~N 0 4,5-dihydro IH-o benzo[g]indazole-3-carboxamide ~ 0 501.57 8-{[(2-methylpyridin- <1, 100 -s, 3-~ yl)carbonyl]amino) - M
1-[4-~ N- N
H NH 2 (methylsulfonyl)phen N N yl]-4,5-dihydro-lH-0 0 benzo[g]indazole-3-carboxamide 0 522.53 8-[(2,3- <1 101 ~S o difluorobenzoyl)amin M
~ N-N (methylsulfonyl)phen ~ , N ~ ~ NH2 yl]-4,5-dihydro-lH-F ( o benzo[g]indazole-3-F o \ carboxamide 0 531.55 1-[4- <1 102 -S"O (methylsulfonyl)phen yl]-8-[(2- M
nitrobenzoyl)amino]-I~ N \ N NH2 4,5-dihydro-lH-O benzo[g]indazole-3-No o carboxamide Structure Formula Name IKK Example Weight Resin ICso ( 0 558.61 3-[({3- 1< 103 (aminocarbonyl)-1-[4-(methylsulfonyl)phen M
N- ~ NH2 yl]-4,5-dihydro-lH-0 ~o o benzo[g]indazol-8-yl}amino)carbonyl]-2-methylphenyl acetate _ 538.99 8-[(3-chloro-2- <1 104 ~S-o fluorobenzoyl)amino]
-1-[4- pM
N-N NH (methylsulfonyl)phen 2 yl]-4,5-dihydro-lH-N
ei o benzo[g]indazole-3-F 0 carboxamide 11 521.99 8-{ [(4-chloropyridin- 1 < 105 ~s=~ 3-yl)carbonyl]amino}-N 1-[4- M
N~ H N- i NHZ (methylsulfonyl)phen I N yl]-4,5-dihydro-lH-o benzo[g]indazole-3-carboxamide 11 0 514.61 8-[(2,3- 1 < 106 dimethylbenzoyl)ami ~ 10 no]-1-[4-~ N \ NH2 (methylsulfonyl)phen M
yl]-4,5-dihydro-lH-~ o benzo[g]indazole-3-0 carboxamide s~o 516.58 8-[(3-hydroxy-2- <1 107 methylbenzoyl)amino M
]-1-[4-H N-N NH (methylsulfonyl)phen N, ~ 2 yl]-4,5-dihydro-lH-Ho o \ o benzo[g]indazole-3-carboxamide "10 555.44 8-[(2,5- <1 108 ''S, d ichlorobenzoyl)ami no]-1-[4- M
H N- N NH (methylsulfonyl)phen N 2 yl]-4,5-dihydro-lH-0- o benzo[g]indazole-3-carboxamide Structure Formula Name IKK Example Weight Resin ( 0 501.57 8-[(2- 1 < 109 aminobenzoyl)amino 10 H N-N NH (methylsulfonyl)phen M
(2 yl]-4,5-dihydro-lH-o benzo[g]indazole-3-carboxamide 0 487.54 8- <1 110 is (isonicotinoylamino) M
1-[4-NH N \ NH2 (methylsulfonyl)phen ~ N, yl]-4,5-dihydro-lH-0 o benzo[g]indazole-3 carboxamide s 566.00 8-[(2-chloro-5- <1 111 nitrobenzoyl)amino]- M
No2 1-[4-H \ NH (methylsulfonyl)phen N 2 yl]-4,5-dihydro-lH-0 o benzo[g]indazole-3-ci carboxamide o ~0 572.47 8-[(5-amino-2- <1 112 HCI -~S~ chlorobenzoyl)amino NH2 ]-1 [4 M
(methylsulfonyl)phen ~ \ NHz yl]-4,5-dihydro-lH-~ benzo[g]indazole-3-I o o carboxamide hydrochloride ,~0 536.01 8-[(3-amino-4- <1 113 Q,-- chlorobenzoyl)amino M
]-1-[4-cl N- N (methylsulfonyl)phen NH
~ 2 yl]-4,5-dihydro-lH-HZN o benzo[g]indazole-3-carboxamide S~o 536.01 8-[(4-amino-2- <1 114 ~ chlorobenzoyl)amino pM
i H2N H N-N NH2 (methylsulfonyl)phen N yl]-4,5-dihydro-lH-O o benzo[g]indazole-3-ci carboxamide ",p 536.01 8-[(2-amino-5- 1 < 115 chlorobenzoyl)amino N-N (methylsulfonyl)phen M
N/ NH2 yl] 4,5 dihydro 1H
benzo[g]indazole-3-NHZ 0- carboxamide Structure Formula Name IKK Example Weight Resin ( 536.01 8-[(3-amino-2- <1 116 chlorobenzoyl)aniino M
H NH2 (methylsulfonyl)phen " \
HZN yl]-4,5-dihydro-lH-ci o \ ~ benzo[g]indazole-3-carboxamide s~o 536.01 8-[(2-amino-4- <1 117 chlorobenzoyl)amino pM
ci N- N NH (methylsulfonyl)phen Z ylj-4,5-dihydro-lH-o benzo[g]indazole-3-NHZ
carboxamide %\,O 536.01 8-[(2-amino-3- <1 118 ~ chlorobenzoyl)amino M
\ N'"N (methylsulfonyl)phen ~ ~ N "HZ yl]-4,5-dihydro-lH-C, N \ I benzo[g]indazole-3-H2 carboxamide 0 i~o 657.58 8-({2-chloro-5- <1 119 -NH [(N,N M
dimethylglycyl)amin '\ ~~ NHZ o]benzoyl}amino}-1-[4-Z~l (methylsulfonyl)phen yl]-4,5-dihydro-1H-HcI benzo[g]indazole-3-carboxamide hydrochloride o 564.07 8-{ [2-chloro-5- <1 120 's' (dimethylamino)benz M
~ oyljamino}-1-[4-ci 0 H N-N NHz (methylsulfonyl)phen N: o yl]-4,5-dihydro-lH-~ benzo[g]indazole-3-,~N carboxamide O 572.56 8-[(5-azido-2- <1 121 N3 -S--~-ro -N NH2 nitrobenzoyl)amino]- M
/ V1-[4- u (methylsulfonyl)phen yl]-4,5-dihydro-lH-NO2 O benzo[g]indazole-3-carboxamide Structure Formula Name IKK Example Weight Resin ( 0 527.57 8-[(4- <1 122 /Si azidobenzoyl)amino]
N3 ~ o -1-[4 M
\ ~ N \N NH 2 (methylsulfonyl)phen yl]-4,5-dihydro-lH-o benzo[g]indazole-3-carboxamide 11 ~O 556.43 8-1[(2,5- <1 123 ~S~ O1N..N dichloropyridin-3-CI ) yl)carbonyl]amino}- M
1-[4-~ ~ NH2 (methylsulfonyl)phen N ~ N y1]-4,5-dihydro-lH-O O benzo[g]indazole-3-CI
carboxamide O, O 583.09 8-{ [2-chloro-5- <1 124 g%O S~ (methylsulfinyl)benz M
oyl]amino}-1-[4-N-N (methylsulfonyl)phen N NH2 yl]-4,5-dihydro-lH-CI o I.~ O benzo[g]indazole-3-carboxamide 0 565.01 8-{ [(6-chloro-1,3- <1 125 o benzodioxol-5- M
ro QV\' yl)carbonyl] amino}-o o 1-[4-N-N NHz (methylsulfonyl)phen HN
~
c yl]-4,5-dihydro-lH-~ o benzo[g]indazole-3-carboxamide Meo2s a~,- 619.13 8-{[2-chloro-5-(4- <1 126 methylpiperazin-l- M
N N yl)benzoyl]amino}-1-O CONH2 [4 ci ~ (methylsulfonyl)phen ~ ~ yl]-4,5-dihydro-lH-N- benzo[g]indazole-3-~ N~ carboxamide [0069] Example 126 8- { [2-chloro-5-(4-methylpiperazin-l-yl)benzoyl]amino }-1-[4-(methylsulfonyl)phenyl]-4,5-dihydro-1 H-benzo[g] indazole-3-carboxamide Example 126 was synthesized using the following scheme.
Scheme XVI

CI ~ CI O~ rNH CI O
C02H -' I\ O

conc. H2SO4 Pd2(dba)3 Br 70% Br BINAP / N
Na'BuO
(' Jl 95%
N
R
R

C1'NN
N H TFA OH HN j, ~ CONHZ O N I CONH
a CH-= N CI

88% N-~) N ~,N
NI
R 4-F, 4-SO2Me, 3,4-MDO, etc.
Me02S~_aN-N

O N I ~ \ CONHZ
CI /
N~
~N~
To a mixture of 2-chloro-5-(4-methylpiperazin-1-yl)benzoic acid (0.9 g, 0.0035 mol), the title compound of Example 92 (0.0024 mol) and 1 mL of diisopropylethylamine in 25 mL of DMF was added HATU (1.3 g, 0.0035 mol) in one portion. The reaction mixture was stirred at room temperature for 16 h.
Solvent was removed and the residue was purified on preparative HPLC to give the product as a pale white solid (89% yield); mp: 194-195 C; 'HNMR (DMSO + TFA-d, 400 MHz) 8: 10.29 (s, 1H), 8.10 (d, J = 8.7 Hz, 2H), 7.86 (d, J = 8.7 Hz, 2H), 7.64 (s, 1H), 7.43 (dd, J = 2.1, 8.2 Hz, 1H), 7.41 (s, 1H), 7.37 (dd, J = 2.0, 8.2 Hz, 1H), 7.35 (d, J 8.2Hz, 1H), 7.08 (dd, J = 3.0, 8.9 Hz, 1H), 7.04 (d, J= 3.0 Hz, 1H), 3.89 (d, J 12.8 Hz, 2H), 3.51 (d, J= 12.8 Hz, 2H), 3.23(s, 3H), 3.11 (m, 2H), 2.95 (m, 4H), 2.86 (m, 2H). The bioactivity in the IKK 2 Resin assay for the compound of Example 126 is shown in Table 2.

[0070] Examples 127-158 shown in Table 3 were synthesized by the following synthesis scheme were R9 is the appropriate aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or cycloalkyl.

Scheme XVII

OOS CH3 O S CH3 O~S,CH3 ~ ~ ~

N-N OEt hydrolysis N-N Rink resin N-N
02N \ \ \ OH 02N NH
O2N I~ \ O HOBt, DIC, 0 DMF /
Exam le 92 Resin 1 p Example 127 SnC12, DMF
TFA
~ S CH3 O S CH3 O S CH3 O ~\ p ~ p' ~
[\\~~ - \ / \ ~
N TFA

H2N H2N \ ~\ O 02N ~ O
o ~/

Example 129 RiCOOH, Resin 2 Example 128 PyBrop, DIEA, NMP

O' S CH3 0 N-N NH
s H TFA Rs N \ ~\ 0 2 N NH
R~N 0 I
O
Examples 130-158.
Resin 3 [0071] Example 127 1-[4-(methylsulfonyl)phenyl]-8-nitro-4,5-dihydro-1 H-benzo [g] indazole-3-carboxylic acid To 5.0 g (11.3 mmol) of Example 92 (ethyl 1-[4-(methylsulfonyl)phenyl]-8-nitro-4,5-dihydro-lH-benzo[g]indazole-3-carboxylate) in 115 mL of THF was added 115 mL of 1N NaOH and the mixture allowed to stir overnight at RT. The solution was acidified with 2N HC1 and extracted three times with ethyl acetate. Combined extracts were washed with 10% aq. HCI, brine, dried with Na2SO4 and concentrated to afford 4.97 g (100%) of a yellow solid: IH NMR (d6-DMSO) 3.00 (m, 2H), 3.11 (m, 2H), 3.31 (s, 3H), 7.39 (d, 1H), 7.67 (d, 1H), 7.90 (d, 2H), 8.07 (dd, 1H), 8.16 (d, 1H); MS (ESI+) 414 (M+1).

[0072] Example 128 Resin 1 and 1-[4-(methylsulfonyl)phenyl]-8-nitro-4,5-dihydro-lH-benzo [g] indazole-3-carboxamide Commercially available Rink amide resin (10 g, NovaBiochem #01-64-0013, 100-200 mesh, 0.61 mmol/g) was washed sequentially with dichloromethane (DCM) and dimethylformamide (DMF). The resin was filtered, treated twice with 50%
piperidine in DMF for 15 min, and subsequently washed three times each with DMF, DCM, and anhydrous DMF. To the resin was added 4.65 g of Example 127, 1.52 g of HOBt and 1.75 mL of DIC in 35 mL anhydrous DMF. After 3 h at RT, the reagents were removed by filtration and the resin washed three times each with DMF, methanol, and DCM. The resin was used directly in the next step. A small portion (approx. 100 mgs) of resin was cleaved by treatment with 20% TFA in CH2C12 for 30 min. The resin washed twice with CH2C12 and the collected filtrates concentrated in vacuo. The product was purified by silica chromatography to give the title compound as a light yellow solid: 'H NMR(CDC13) 9.03 (s, 2H), 8.20(d, J=8.4Hz, 2H), 8.10(dd, J=2Hz, 8.4Hz, 1H), 7.79(d, J=8.4Hz, 2H), 7.53(d, J=8.4Hz, 1H), 7.51(d, J=2Hz, 1H), 3.25(s, 3H), 3.16(m, 4H); MS(ESI+) 413 (M+1, 100).

[0073] Example 129 Resin 2 and 8-amino-l-[4-(methylsulfonyl)phenyl]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide, trifluoroacetic acid salt To resin 2 (6.0 mmol) was added 50 mL of 2M SnC12-2H20 in wet DMF. After agitation of the mixture overnight, the reagents were removed by filtration and the resin washed three times each with DMF, THF, and DCM. The resin was filtered and dried to give 10.96 g of resin 2. A 92.1 mg portion of the resin was treated twice with 20% TFA in CH2C12 and washed three times with CHaC12. The combined filtrates were concentrated in vacuo and resin loading determined by direct cleavage NMR of the title compound: resin loading of 0.46 meq/g; 1H NMR
(CDC13/TFA) 3.14 (brs, 4H), 3.31 (s, 3H), 6.78 (d, 1H, 2.0 Hz), 7.33 (dd, 1H), 7.54 (d, 1H, 8.0 Hz), 7.83 (d, 2H), 8.16 (d, 2H); MS(ESI+) 383 (M+1, 100).

[0074] Resin 3 Resin 2 (0.45 mmol/g, 0.200g, 90 mol) was washed three times with anhydrous NMP and subsequently treated with 0.45 mmol of carboxylic acid R9COOH in 0.5 mL of anhydrous NMP, 0.45 mmol of PyBrop in 0.5 niL of anhydrous NMP and 0.9 mmol of DIEA. The resin was shaken at RT under N2 for 2h. Subsequently, the reagents were removed by filtration, the resins retreated with the appropriate carboxylic acid, PyBrop, and DIEA in the same manner as described above. After agitation of the reaction vessels overnight at RT, the reagents were removed by filtration and the resins washed three times each with NMP, DMF, methanol, and DCM. The products were cleaved from the resins by adding 0.5 mL of 20%
TFA/DCM and agitating the mixture for 15 min. The filtrate was collected and the resin retreated with additional TFA/DCM for 15 min. The resin was washed twice with DCM and the filtrates combined and concentrated in vacuo to afford the final products.

[0075] Example 130 8-[(cyclobutylcarbonyl)amino]-1-[4-(methylsulfonyl)phenyl]-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide Using the method described from resin 3, the product was obtained in 57% yield as a light yellow solid: 1H NMR(CDC13/CD3OD). 8.13 (d, J=8.4 Hz, 2H), 7.76(d, J=8.4 Hz, 2H), 7.38(d, J=1.6 Hz, 1H), 7.24(d, J=8 Hz, 1H), 6.97(dd, J=2 Hz, 8 Hz, 1H), 6.88 (s, 1H), 3.23(s, 3H), 3.10(m, 2H), 3.02(m, 1H), 2.95(m, 2H), 2.16(m, 4H), 1.95(m, 1H), 1.82(m, 1H). 13C NMR(CDC13/CD30D): 165.0, 144.2, 142.9, 140.4, 137.1, 133.0, 129.3, 129.2, 126.4, 126.0, 123.3, 119.4, 114.8, 114.7, 60.7, 44.8, 40.6, 31.7, 29.6, 25.3, 22.8, 20.1, 18.1, 14.3. High resolution Mass:
M+H+
=465.1591 (observed), 465.1608 (theoretical).

[0076] Example 131 8-[(2-chloro-4,5-dimethoxybenzoyl)amino]-1-[4-(methylsulfonyl)phenyl]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide Using the method described from resin 3, the product was obtained in 62% yield as a light yellow solid: 1H NMR(CDC13). 8.14(d, J=8.8Hz, 2H), 8.03(s, 1H), 7.79(d, J=8.8Hz, 2H), 7.40(d, 1H), 7.29(m, 1H), 7.21(s, 1H), 7.16(m, 1H), 6.81(s, 1H), 3.89(s, 3H), 3.88(s, 3H), 3.14(m, 2H), 3.13(s, 3H), 2.99(m, 2H). 13C
NMR(CDC13):
171.4, 164.4, 163.7, 151.7, 148.4, 144.3, 143.1, 140.8, 140.2, 136.4, 134.0, 129.6, 129.4, 126.7, 126.4, 126.1, 123.3, 122.4, 119.7, 115.3, 113.2, 113.0, 60.6, 45.0, 29.8, 21.3, 20.2. High resolution Mass: M+H+ = 581.1277 (observed), 5 81.1256(theoretical).

[0077] Examples 132-158 The compounds of Examples 132-158 were prepared as previously described for Example 130 using the appropriate aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or cycloalkyl and are listed in Table 3.

[0078] Example 159 8- { [2-chloro-5-(methylsulfonyl)benzoyl]amino }-1-[4-(methylsulfonyl)phenyl]-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide Scheme XVIII

R CH3 0 0i ,CH3 O;8 CH3 ,S
~S \ O
O I OH SCH3 ~/ Q S02CH3 / N
_N ~ / CI N_N 1) MCPBA H \ N
N
NH NH -~ NHz HzN I\ PyBrop, DIFJ1, N O 2) TFA/CH2CI2 N \ ~
\~\/%O NMP CI O I i CI O I O

Resin 2 Example 159 To 0.30 g of amino resin 2 (pretreated in DCM for two hrs and washed with dry NMP) was added PyBrop (0.42g, 0.90 mmol), 2-chloro-5-methylthiobenzoic acid (182mg, 0.9 mmol), DIEA(314 uL, 1.8 mmol) and dry NMP (2 mL). The resin was shaken for two hrs. The excess reagents were drained, and the resin was washed with DMF(x3), methanol (x3), and DCM (x3), and treated with 20% TFA/DCM
mixture containing 1% triisopropylsilane (2 x 12 min x 3 mL). The resin was washed with DMC (2 x 4 mL). The combined filtrate and washings were evaporated to a solid, which was further dissolved in 10 mL of DCM. To the resulting solution was added MCPBA (440 mg, 77% pure, 1.96 mmol ). After 3h, the reaction was quenched with 30 mL ethylacetate. The organic phase was washed with sat. sodium bicarbonate (x3) and brine (x2), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica chromatography with 8:2 EtOAc/hexane. The product was isolated as light yellow solid, 37 mg (34%): 1H NMR(CDC13/CD3OD) 8.00(d, J=8.8Hz, 2H), 7.83(s, 1H), 7.81(dd, 1H), 7.68(d, J=8.4Hz, 2H), 7.51(d, J=8.4 iHz, 1H), 7.34(s, 1H), 7.25-7.17(m, 2H), 3.02(s, 3H), 2.98(s, 3H), 2.96(m, 2H), 2.88(m, 2H). LC-MS: 599.0 (M+H+). High resolution Mass: M+NH4+=616.1077 (observed), 616.1086(theoretical).

[0079] Example 160 8-(L-histidylamino)-1-[4-(methylsulfonyl)phenyl]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide SCHEME XIX

O' ,CH3 R, sCH3 Rl,CH3 O~ HN O~ ,S
HN ~
N-N (? Fmoc-Hls-OH 'N I H N-N 1)p(peridine/DMF ~~ ~ H NHZ
NH NH -'' N N-N
H N PyBrop, DIEA, Fmoc~N N 2) TFA/CHzC12 N ~ ~
z I o NMP H o ~ O HzN ~ ~ O
2 Example 143 Amino resin 3 (0.402 mmols/g, 0.0804 mmols, 0.200g) was pre-treated in DCM for one hour followed by washing using anhydrous NMP. To this resin added 5.0 equiv. of Fmoc-His-OH (0.402 mmols, 152 mg) followed by addition of PyBroP

(NovaBiochem, 0.402 mmols, 187 mg). To this mixture was added 10.0 equiv. of DIEA (0.804 mmols, 140 l) followed by addition of anhydrous NMP (1 ml).
Reaction vessel was capped and agitated under nitrogen for two hours. Reagents were removed by filtration and the resin washed as follows: NMP (x3), DMF
(x3), DCM (x3), and anhydrous NMP (xl). Retreated resin as described above and let agitate under nitrogen overnight. Drained vessel and washed as follows: NMP
(x3), DMF (x3), MeOH (x3), DCM (x3), and DMF (xl). Deprotected Fmoc group using 50:50 piperidine/DMF (x2, 2ml) 40 minutes each. Washed resin as follows:
DMF (x3), MeOH (x3), and DCM (x3). Let resin air dry for approximately one hour. Resin was then treated with 20:80 TFA/DCM containing 1%
triisopropylsilane (x2, 1 ml, 45 minutes). Collected filtrates and washed resin with DCM (x3, lml). Collected all washings and remove volatiles under nitrogen to afford 17.2 mg of an orange solid. MS+ +1 (C25H25N704S): 520 (measured).

Table 3.

Structure Formula Name IKK Example Weight Resin s~ 464.55 8- 1< 10 130 C [(cyclobutylcarbonyl)a M
N-N o mino]-1-[4- p N NHZ (methylsulfonyl)pheny 0 11-4,5-dihydro-lH-~ O benzo[g]indazole-3-carboxamide Structure Formula Name IKK Example Weight Resin ICso 581.05 8-[(2-chloro-4,5- <1 M 131 dimethoxybenzoyl)ami N'N o no]-1-[4-o N NH2 (methylsulfonyl)pheny oi 1]-4,5-dihydro-lH-benzo[g]indazole-3-~ o- carboxamide ~o 0 566.00 8-[(4-chloro-2- <1 M 132 's' ~ nitrobenzoyl)amino]-~ 1-[4-cl ~ N_N (methylsulfonyl)pheny NH2 1]-4,5-dihydro-lH-~ benzo[g]indazole-3-~ o No2 0 carboxamide %S 545.58 8-[(2-methyl-3- 1< 10 133 nitrobenzoyl)amino]- M
1-[4-N-N (methylsulfonyl)pheny N NHz 1]-4,5-dihydro-lH-benzo[g]indazole-3-0 o 0 carboxamide "~0 538.99 8-[(2-chloro-6- <1 M 134 iS fluorobenzoyl)amino]-~ ~ 1-[4-/ N-N (methylsulfonyl)pheny H NH2 1]-4,5-dihydro-lH-N benzo[g]indazole-3-carboxamide o,0 566.00 8-[(2-chloro-3- <1 M 135 --S' ~ nitrobenzoyl)amino]-~ 1-[4-'~ N-N (methylsulfonyl)pheny ~ H NH
~ N 2 1] 4,5 dihydro-1H
No2 o benzo[g]indazole-3-ci o carboxanude QS,o 599.89 8-[(5-bromo-2- <1 M 136 chlorobenzoyl)amino]-Br 1-[4-(methylsulfonyl)pheny ( N N O NHz 1]-4,5-dihydro-lH-~ benzo[g]indazole-3-cl 0 carboxamide Structure Formula Name IKK Example Weight Resin S~o 567.09 8-{ [2-chloro-5- <1 M 137 ~ (methylthio)benzoyl]a s ~ N nnino}-1-[4-_\ (methylsulfonyl)pheny H NH2 1]-4,5-dihydro-lH-4N benzo[g]indazole-3-cl o o carboxamide %S~o 536.01 8-{[(2-chloro-6- <1 pM 138 methylpyridin-3-/ yl)carbonyljamino}-1-N CI N-N NH [4-\ 2 (methylsulfonyl)pheny 1]-4,5-dihydro-lH-o benzo[g]indazole-3-carboxamide 0 0 566.00 8-[(5-chloro-2- <1 pM 139 nitrobenzoyl)amino]-ci 1-[4-N-N (methylsulfonyl)pheny N \ NHZ 1]-4,5-dihydro-lH-0 \ ~ o benzo[g]indazole-3-carboxamide o, s ,0 486.55 8-(benzoylamino)-l- <1 M 140 [4-~ / (methylsulfonyl)pheny N-N NH2 11-4,5-dihydro-lH-\ ! N ~ benzo[g]indazole-3-o o carboxamide 0= 0 532.64 1-[4- 1< 10 142 (methylsulfonyl)pheny M
~ / 11-8-{[2-N-N NH (methylthio)benzoyl]a Hi Z
r mino}-4,5-dihydro-"Is o o 1H-benzo[g]indazole-3-carboxamide o. 516.58 8-[(3- 1< 10 142 methoxybenzoyl)amin M
/ o]-1-[4-/ N-N H2 (methylsulfonyl)pheny ~ ~ N l1-4,5-dihydro-lH-~ benzo[g]indazole-3-o I carboxamide Structure Formula Name IKK Example Weight Resin 01,90 516.58 8-[(4- <1 M 143 methoxybenzoyl)amin o / o]-1-[4-/ N-N NHz (methylsulfonyl)pheny N 1]-4,5-dihydro-lH-o benzo[g]indazole-3-carboxamide o0 511.56 8-[(4- <1 M 144 ~s cyanobenzoyl)amino]-N 1-[4-N_N (methylsulfonyl)pheny N ~ NHz 1]-4,5-dihydro-lH-~ benzo[g]indazole-3-0 o carboxamide 0 ; 0 554.63 8-1[(3,7- 1 < 10 145 S dimethylimidazo[1,2-pM
a]pyridin-2-~ N-N NH yl)carbonyl]amino}-1-N ~ [4-o (methylsulfonyl)pheny 1]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide 0 566.00 8-[(2-chloro-4- <1 M 146 %S'o nitrobenzoyl)amino]-1-[4-~ \
No2 N-N (methylsulfonyl)pheny NMZ 1]-4,5-dihydro-lH-o o benzo[g]indazole-3-oi carboxaniide QS ~ 561.58 8-[(5-methoxy-2- <1 M 147 ' _ nitrobenzoyl)amino]-o~ / 1-[4-(methylsulfonyl)pheny N \N NH2 1]-4,5-dihydro-lH-benzo[g]indazole-3-0-N .0 o carboxamide QS o 588.63 3-[({3- <1 M 148 N
(aminocarbonyl)-1-[4-g (methylsulfonyl)pheny _ 1]-4,5-dihydro-lH-~ N NH2 benzo[g]indazol-8-N yl}amino)carbonyl]-4-o'N o 0 nitrophenyl thiocyanate Structure Fonnula Name IKK Example Weight Resin o, S~ 567.53 8-[(4,5-difluoro-2- <1 M 149 ~" _ nitrobenzoyl)amino]-F ~ ~ 1-[4-F N-N (methylsulfonyl)pheny H NH2 1]-4,5-dihydro-lH-N benzo[g]indazole-3--N o carboxamide o,,,Q 591.60 8-[(4,5-dimethoxy-2- <1 M 150 nitrobenzoyl)amino]-~ o 1-[4-o N_N (methylsulfonyl)pheny N ~ NHZ 1]-4,5-dihydro-lH-~ benzo[g]indazole-3-oao o I/ o carboxamide o; ,~ 549.54 8-[(5-fluoro-2- <1 M 151 ~-S nitrobenzoyl)amino]-F ' ~ 1-[4-~ (methylsulfonyl)pheny N \N NH2 1]-4,5-dihydro-lH-~ benzo[g]indazole-3-O 0 I ~ carboxamide o,P, 599.55 1-[4- <1 [tM 152 ~S _ (methylsulfonyl)pheny F F \ ~ I]-8-{[2-nitro-4-(trifluoromethyl)benzo F H NNH2 yl]amino}-4,5-N dihydro-1 H-oo I)CY o benzo[g]indazole-3-carboxamide o,,,,0 545.58 8-[(5-methyl-2- <1 M 153 ~ S nitrobenzoyl)amino]-' ~ 1-[4-~ (methylsulfonyl)pheny / = N-N
H NHz 1]-4,5-dihydro-lH-N o benzo[g]indazole-3-o-.N,o o I/ carboxamide ,~ 545.58 8-[(3-methyl-2- 1< 10 154 ''S nitrobenzoyl)amino}-1-[4- M
(methylsulfonyl)pheny ~H,,6-/N~ NH2 1]-4,5-dihydro-lH-N benzo[g]indazole-3-'o o o carboxamide Structure Formula Name IKK Example Weight Resin 00 576.55 8-[(2,4- <1 M 155 's dinitrobenzoyl)amino]
~* / 1 [4 o N_N NH (methylsulfonyl)pheny N 2 1]-4,5-dihydro-lH-; o 0 benzo[g]indazole-3 0 o carboxamide S o,,,0 500.58 8-[(3- 1< 10 156 '"S methylbenzoyl)amino]
-1-[4- M
(methylsulfonyl)pheny ~ ~ M N-N NHZ 1]-4,5-dihydro-lH-benzo[g]indazole-3-o carboxamide o,,~ 530.61 8-{[(3- <1 M 157 S methoxyphenyl)acetyl]
amino}-1-[4-H N NH2 (methylsulfonyl)pheny \ o N 1]-4,5-dihydro-lH-o benzo[g]indazole-3-I~
carboxamide 0 0 500.58 1-[4- 1< 10 158 's (methylsulfonyl)pheny A 1]-8- M
H N-N NH [(phenylacetyl)amino]-Z
N 4,5-dihydro-lH-I o benzo[g]indazole-3-o carboxamide Qs~o 599.09 8-{ [2-chloro-5- <1 M 159 o (methylsulfonyl)benzo o:s ~ yl]amino}-1-[4-_ (methylsulfonyl)pheny H N\ NH2 1]-4,5-dihydro-lH-N
benzo[g]indazole-3-clill 0 carboxamide s 519.59 8-(L-histidylamino)-1- 1< 10 160 [4 M
M
(methylsulfonyl)pheny O N-N 1]-4,5-dihydro-IH-HZN,, rHi NHZ benzo[g]indazole-3-~ o carboxamide NH

[0080] Examples 161-206 Examples 161-206 shown in Table 4 were synthesized using the following synthesis procedure similar to Scheme I where R9 is the appropriate aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or cycloalkyl. The detailed synthesis of 1-(1,3-benzodioxol-5-yl)-8-{[(2-chloropyridin-3-yl)carbonyl]amirio }-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide (Example 161) is described below and is illustrative for the compounds of Table 4.

SCHEME XX

o O 0 3,4-(Methylenedioxy)-~
phenylhydrazine N-N OEt OzN 1-1 ~OE2 ACOH, 4 I O2N

ethyl (7-nitro-l-oxo-1,2,3, 4-tetrahydronaphthalen-2-yl) (oxo)acetate i ~O
/'-_ O
Pd(OH)2 \ I N-N \ ~
NH3, MeOH ~
H2 Et N-H2N 700 psi N-N

O/'- ~
\ ~
R9CO2H, HATU or Ry N N-N NH2 R9COCI, Pyridine [0081] Example 161 1-(1,3-benzodioxol-5-yl)-8-{ [(2-chloropyridin-3-yl)carbonyl]amino }-4,5-dihydro-1 H-benzo [g]indazole-3-carboxamide N-N
N \ HN r ~ \ CONH2 ~ / \ I

[0082] Step 1 /'-0 \ ~ ~ HCI
H-.NH2 The title compound of step 1 was prepared by the method disclosed by T.
Komatsu et al, Azneim.-Forsch. (1972) 22(12), 2099-104.

[0083] Step 2 N-N
02N COOEt I

A mixture of 5.OOg (17.2 mmoles) of diketo ester and 3.24g (17.2 mmoles) of the title product of Step 1 in 100ml of acetic acid was refluxed with stirring for 3h, and then cooled. The mixture was concentrated, and the residue triturated with ethyl acetate affording a brown solid which was filtered, washed with ethyl acetate, and dried to give the title compound, 4.79g. The structure was supported by 1H
NMR.
[0084] Step 3 N-N
H2N C00Et I

A solution 4.79g of the title product of Step 2 in acetic acid was treated at room temperature with 5% palladium on carbon under an atmosphere of hydrogen gas at 5 psi. The reaction was followed by LC-MS. When the conversion was complete, the mixture was filtered and concentrated to give the title compound as a brownish oil that was used directly for the next step.

[0085] Step 4 8-amino-l-(1,3-benzodioxol-5-yl)-4,5 -dihydro-1 H-benzo [g] indazole-3-carboxamide /'-0 N-N
H2N CONHz The title product of Step 3 was dissolved in anhydrous ethanol and then an approximately equal volume of liquid ammonia was added. The resulting mixture was sealed in a pressure vessel and then stirred overnight at 100 C. After cooling, the mixture was concentrated. The residue was taken up in dichloromethane -methanol and chromatographed over silica gel using ethyl acetate as eluent to give the title compound, 890mg, as an oil which crystallized on standing. Anal. for C19H16N403=0.75 H20 (MW 361.87): Calc'd.: C, 63.06;, H, 4.46, N, 15.48.
Found: C, 63.24; H, 4.70, N, 14.58.

[0086] Step 5 N-N
N \ HN / \ \ CONH2 A mixture of the title product of Example 4 (3.6 g, 0.01 mol) and 2-chloronicotinyl chloride (1.8 g, 0.01 mol) in 50 ml of pyridine was stirred at room temperature overnight. Solvent was removed and the residue was triturated with a mixture of acetonitrile and methanol (20:1) to give 2.6 g of the title compound as a light brown solid. The mother liquor was concentrated and purified the same way to give another 0.69 g of product (68% yield); mp: 165-166C. Anal. Calcd. for C25H18C1N504= 0.5 H20: C, 60.43; H, 3.85; 14.09. Found: C, 60.27; H, 3.59; N, 14.14.

Table 4 Structure Mol. Compound Name(s) IKK2 Resin Example Wt. IC50 o O 487.90 1-(1,3-benzodioxol-5-yl)-8- <1 M 161 {[(2-chloropyridin-3-yl)carbonyl]amino }-4,5-ci O N-N NH2 N/ 2 benzo[g]indazole-3-I o carboxamide /- 522.35 1-(1,3-benzodioxol-5-yl)-8- <1 M 162 ci 0 {[(2,5-dichloropyridin-3-~ yl)carbonyl]amino}-4,5-I H N' ; dihydro-lH-N - N NHa benzo[g]indazole-3-ci 0 i o carboxamide 0 o 565.01 1-(1,3-benzodioxol-5-yl)-8- <1 M 163 {[2-chloro-4-~s ~ (methylsulfonyl)benzoyl]amin N N-N o}-4,5-dihydro-lH-benzo[g]indazole-3-ci o 0 carboxamide o 504.91 1-(1,3-benzodioxol-5-yl)-8- <1 M 164 [(2-chloro-4-F/ c~ o \/ N_N fluorobenzoyl)amino]-4,5-~ r"~ CONH2 dihydro-lH-o benzo[g]indazole-3-carboxamide 0 0 486.92 1-(1,3-benzodioxol-5-yl)-8- <1 M 165 [(2-chlorobenzoyl)amino]-4,5-dihydro-lH-ca 0 N-N benzo[g]indazole-3-H NHZ
carboxamide Nz~ N o o_ 522.90 1-(1,3-benzodioxol-5-yl)-8- <1 M 166 F o / [(2-chloro-4,5-F N-N difluorobenzoyl)amino]-4,5-~ cONHz dihydro-lH-ci 0 benzo[g]indazole-3-carboxamide Structure Mol. Compound Name(s) IKK2 Resin Example Wt. IC50 0 0 501.93 1-(1,3-benzodioxol-5-yl)-8- <1 M 167 { [(2-chloro-6-methylpyridin-3-yl)carbonyl]amino }-4,5-cl O N-N NH dihydro-lH-~ 2 benzo[g]indazole-3-ry o carboxamide 0 /~ 530.93 1-(1,3-benzodioxol-5-yl)-8- <1 M 168 ro { [(6-chloro-1,3-benzodioxol-0 5-yl)carbonyl]amino }-4,5-~ \ O N-N NH dihydro-lH-~I HN 2 benzo[g]indazole-3-~ o carboxaniide 0 0 501.93 8-[(2-amino-6- <1 M 169 chlorobenzoyl)amino]-1-(1,3-NHz ~ benzodioxol-5-yl)-4,5-~ o N-N dihydro-lH-~ ~ NH2 benzo[g]indazole-3-c1 HN + ~ o carboxamide /--0 487.91 1-(1,3-benzodioxol-5-yl)-8- <1 M 170 o [(3-~ chloroisonicotinoyl)amino]-N ~ 4,5-dihydro-lH-N-N
~ i N coNH2 benzo[g]indazole-3-carboxannide CI o 0 0 538.39 8-[(3-amino-2- <1 M 171 chlorobenzoyl)amino]-1-(1,3-~ ~ benzodioxol-5-yl)-4,5-~ N-N dihydro-lH-H2N CI cIa,NH2 benzo[g]indazole-3-o carboxamide hydrochloride HCI

0 0 501.93 8-[(5-amino-2- <1 M 172 HZN chlorobenzoyl)amino]-1-(1,3-~ benzodioxol-5-yl)-4,5-~ o N_N dihydro-lH-~ NHZ benzo[g]indazole-3-CI HN /
o carboxamide Structure Mol. Compound Name(s) IKK2 Resin Example Wt. IC50 ~--0 531.92 1-(1,3-benzodioxol-5-yl)-8- <1 M 173 [(2-chloro-5-NOz nitrobenzoyl)amino]-4,5-H N NH2 dihydro-lH-~ N/ benzo[g]indazole-3-carboxamide cl o 546.97 1-(1,3-benzodioxol-5-yl)-8- <1 M 174 [(2-chloro-4,5-~ dimethoxybenzoyl)amino]-\ p / \ N Nrl~ 4,5-dihydro-lH-benzo[g]indazole-3-~ I Y \ carboxamide 1~

0 o 546.97 1-(1,3-benzodioxol-5-yl)-8- <1 M 175 [(2-chloro-3,4-dimethoxybenzoyl)amino]-cl o N-N NHZ 4,5-dihydro-lH-~0~ benzo[g]indazole-3-1 &100 carboxamide /-0 549.01 1-(1,3-benzodioxol-5-yl)-8- <1 M 176 {[2-chloro-5-S (methylsulfinyl)benzoyl]amin H N- \ o}-4,5-dihydro-lH-N NH2 benzo[g]indazole-3-ci o o carboxamide .~
o 531.37 1-(1,3-benzodioxol-5-yl)-8- <1 M 177 [(2-bromobenzoyl)amino]-/ ~ 4,5-dihydro-lH-sr benzo[g]indazole-3-N \ N CONH carboxamide 0 /~0 516.95 1-(1,3-benzodioxol-5-yl)-8- <1 M 178 [(2-chloro-5-methoxybenzoyl)amino]-4,5-cl 0 H N-N NH2 dihydro-lH-N benzo[g]indazole-3-~ r \ carboxamide ~

494.51 8-[(4-acetylbenzoyl)amino]-1- 1< 10 pM 179 o (1,3-benzodioxol-5-yl)-4,5-N-N dihydro-lH-I r"J CONHZ benzo[g]indazole-3-0 carboxamide Structure Mol. Compound Name(s) IKK2 Resin Example Wt. IC50 0 0 501.93 8-[(4-anuno-2- <1 M 180 chlorobenzoyl)amino]-1-(1,3-~ benzodioxol-5-yl)-4,5-' N--N NHZ dihydro-lH-ci HN benzo[g]indazole-3-~ o carboxanlide 0 555.90 1-(1,3-benzodioxol-5-yl)-8- <1 M 181 ({[2-chloro-6-~ (trifluoromethyl)pyridin-3-~
o NHZ yl]carbonyl}amino)-4,5-N dihydro-lH-cF3 o benzo[g]indazole-3-carboxamide 516.95 1-(1,3-benzodioxol-5-yl)-8- <1 M 182 [(2-chloro-4-~o _ methoxybenzoyl)amino]-4,5-~ I p N~ NHz dihydro-lH-ci o o benzo[g]indazole-3-carboxamide 0 0 529.99 1-(1,3-benzodioxol-5-yl)-8- <1 M 183 {[2-chloro-5-(dimethylamino)benzoyl]amin cl 0 N- N NHZ o}-4,5-dihydro-lH-N benzo[g]indazole-3-~ carboxamide ,N\

0 0 531.92 1-(1,3-benzodioxol-5-yl)-8- <1 M 184 [(2-chloro-4-~ nitrobenzoyl)amino]-4,5-Noa '' 0 N_N NH dihydro-lH-ci HN 2 benzo[g]indazole-3-~ o carboxamide /~o 565.01 1-(1,3-benzodioxol-5-yl)-8- <1 M 185 0 Si 0 {[2-chloro-5-~ (methylsulfonyl)benzoyl]amin H N-N NH o}-4,5-dihydro-lH-N Z benzo[g]indazole 3-a carboxamide 0 469.46 1-(1,3-benzodioxol-5-yl)-8- <1 M 186 [(6-hydroxypyridin-3-Ho / N-N yl)carbonyl]amino}-4,5 N~ ~ coNH dihydro-1 H-o [g]indazole-3-~ 2 benzo carboxamide l Structure Mol. Compound Name(s), IKK2 Resin Example Wt. IC50 Co 467.49 1-(1,3-benzodioxol-5-yl)-8- <1 [IM 187 o ~/j { [(4-methylpyridin-3-yl)carbonyl] amino }-4,5-Cj~ N -N CONH dihydro-lH-~ 2 benzo[g]indazole-3-0 I carboxamide o O 466.50 1-(1,3-benzodioxol-5-yl)-8- 1< 10 M 188 [(2-methylbenzoyl)amino]-~ ~ 4,5-dihydro-lH-~ N-N benzo[g]indazole-3-H NNHz carboxamide N O

Co 521.36 1-(1,3-benzodioxol-5-yl)-8- <1 M 189 [(2,5-/ N_N dichlorobenzoyl)amino]-4,5-ci CONH dihydro-lH-2 benzo[g]indazole-3-0 carboxamide 0 0 533.01 1-(1,3-benzodioxol-5-yl)-8- <1 M 190 ~S {[2-chloro-5-~ (methylthio)benzoyl]amino }-~ H N-N 4,5-dihydro-lH-N NHZ benzo[g]indazole-3 c~ o ,4- o carboxamide o O 574.04 1-(1,3-benzodioxol-5-yl)-8- 1< 10 M 191 ({2-chloro-5-[2-(dimethylamino)ethoxy]benzo ci 0 N-N NH2 yl}amino)-4,5-dihydro-lH-N benzo[g]indazole-3-~ o carboxamide N

0 0 497.47 1-(1,3-benzodioxol-5-yl)-8- <1 M 192 [(2-nitrobenzoyl)amino]-4,5-/ dihydro-lH-benzo[g]indazole-3-H N carboxamide N CONHZ

NOz O I /

Structure Mol. Compound Name(s) IKK2 Resin Example Wt. IC50 Co 474.50 1-(1,3-benzodioxol-5-yl)-8- 1< 10 M 193 o { [(4-methyl-1,2,3-thiadiazol-N 5-yl)carbonyl]amino }-4,5-N S ~ nHi N CONHZ dihydro-lH-benzo[g]indazole-3-o ~ carboxamide /~0 521.36 1-(1,3-benzodioxol-5-yl)-8- <1 M 194 [(2,3-dichlorobenzoyl)amino]-4,5-ci N-N dihydro-lH-cl I ~ N NHZ benzo[g]indazole-3-~ ~ carboxamide Co 521.36 1-(1,3-benzodioxol-5-yl)-8- <1 M 195 [(2,4-ci N_N dichlorobenzoyl)amino]-4,5-~ N CONH dihydro-lH-~ 2 benzo[g]indazole-3-0 carboxamide 0 0 453.46 1-(1,3-benzodioxol-5-yl)-8- <1 M 196 (isonicotinoylaniino)-4,5-~ ~ dihydro-lH-o ~ N_N benzo[g]indazole-3-H NHz carboxamide I ~ N /
N / ~ ~ O

o _ 527.50 1-(1,3-benzodioxol-5-yl)-8- 1< 10 M 197 oMe o ~ ~ [(5-methoxy-2-OMe N N-N o dihydro-lH-~ benzo[g]indazole-3-NOZ 0 ~ / NH2 carboxamide 0 0 482.50 1-(1,3-benzodioxol-5-yl)-8- <1 M 198 [(3-hydroxy-2-~ methylbenzoyl)amino]-4,5-H N-N NH dihydro-lH-o N 2 benzo[g]indazole-3-~ carboxamide i I
HO

o_ 469.46 1-(1,3-benzodioxol-5-yl)-8- 1< 10 M 199 o / [(1-l N'H N-N oxidoisonicotinoyl)alnlno]-~ N cONH2 4,5-dihydro-lH-0 benzo[g]indazole-3-carboxamide Structure Mol. Compound Name(s) IKK2 Resin Example Wt. IC50 0 442.44 1-(1,3-benzodioxol-5-yl)-8- 1< 10 M 200 (3-furoylamino)-4,5-dihydro-1H-benzo[g]indazole-3-N \ \ ~ CONHZ carboxamide O

501.93 8-[(3-amino-4- 1< 10 M 201 / chlorobenzoyl)amino]-1-(1,3-ci benzodioxol-5-yl)-4,5-N-N NH dihydro-lH-HZN HN r-I benzo[g]indazole-3-\ carboxamide 467.49 1-(1,3-benzodioxol-5-yl)-8- 1 < 10 M 202 { [(2-methylpyridin-3-I \ H N_N yl)carbonyl]amino}-4,5-N / N CONH dihydro-lH-\ \ z benzo[g]indazole-3-carboxamide 'N o O 587.04 1-(1,3-benzodioxol-5-yl)-8- 1 < 10 M 203 0 ~ ({ 2-chloro-4-[(N,N-~ ~ \ o ~ ~ dimethylglycyl)amino]benzoy ' N-N NHz 1}amino)-4,5-dihydro-lH-i H benzo[g]indazole-3-\ carboxamide o O 536.46 1-(1,3-benzodioxol-5-yl)-8- 1< 10 pM 204 {[2-Ft F (trifluoromethoxy)benzoyl]am 0 0 ~ N-N ino}-4,5-dihydro-lH-H NH2 benzo[g]indazole-3-~ j \ carboxamide 0 469.46 1-(1,3-benzodioxol-5-yl)-8- 1< 10 M 205 0 ' / {[(6-hydroxypyridin-2-~ N-N yl)carbonyl] amino } -4,5-\
~ ~ N CONH2 dihydro-lH-Ho N \ benzo[g]indazole-3-O carboxamide o -N 477.48 1-(1,3-benzodioxol-5-yl)-8- 1< 10 M 206 [(4-cyanobenzoyl)amino]-4,5-/ ~ dihydro-lH-Nc benzo[g]indazole 3-/ I
\ N CONH2 carboxan--ide O

[0087] SCHEME XXI

Ar-, N_N RiR2NH (5 equiv.), EtOH, H Ar-, N-N
O N i~ CONH2 100 C O N CONH2 CI R2RiN
N~ I N, [0088] Example 207 1-(1,3-benzodioxol-5-yl)-8-( { [2-(methylamino)pyridin-3-yl]carbonyl } amino)-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide [--O
O llz:~
1, N-N
H
O N I ~ \ N CONH2 HN /

N~

A mixture of the title product of Example 161 (1.4 g, 0.0028 mol) and methylamine (0.014 mol) in 6 mL EtOH was heated in a sealed tube to 100 C for 48 h. The off-white precipitate that formed in the crude reaction mixture was filtered and washed with EtOH and Et20 to afford 1.05 g of title compound (yield: 75%). Mp: 273-275 C. 1H NMR (300 MHz, d6-DMSO): S 2.88-2.95 (m, 4H + 3H), 6.12 (s, 2H), 6.57-6.61 (dd, 1H, J = 7.6 Hz, 4.7 Hz), 6.95-6.98 (dd, 1H, J =, 8 Hz, 2 Hz), 7.07 (d, 1H, J = 8 Hz), 7.13 (d, 1H, J = 2 Hz), 7.25-7.34 (m, 3H), 7.45-7.50 (m, 2H), 7.82-7.83 (m, 1H), 7.91-7.95 (dd, 1H, J= 7.6 Hz, 1.7 Hz), 8.18-8.20(dd, 1H, J= 4.8 Hz, 1.8 Hz), 10.02 (s, 1H). M + 1 = 483.

[0089] Example 208 1-(1,3-benzodioxol-5-yl)-8-[( { 2-[(2-hydroxyethyl)amino]pyridin-3-yl } carbonyl)amino]-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide ~O
O 1-1:

OH H ~1!5:~: N-N
' O N I ~ ~ CONH2 N~ I

The title compound was synthesized by the same procedure as in Example 207 starting with product of Example 161 (lg, 0.0020 mol) and ethanolamine (0.626g, 0.010 mol) in 4 mL of EtOH to afford 0.475 g of title compound (yield: 46 %).
Mp:

250-253 C. iH NMR (300 MHz, d6-DMSO): S 2.86-2.93 (m, 4H), 3.43-3.47 (m, 2H), 3.53-3.54 (m, 2H), 4.76 (s, IH), 6.12 (s, 2H), 6.56-6.59 (dd, 1H, J = 7.5 Hz, 4.8 Hz), 6.95-6.97 (dd, 111, J = 8 Hz, 2 Hz), 7.05 (d, 1H, J = 8 Hz), 7.11 (d, IH, J =
2 Hz), 7.26-7.37 (m, 4H), 7.51 (s, 1H), 7.89-7.91 (dd, 1H, J = 7.6 Hz, 1.5 Hz), 7.97-7.99 (t, 1H, J= 5 Hz), 8.14-8.15 (dd, 1H, J= 4.7 Hz, 1.6 Hz), 10.02 (s, 1H).
Anal.
Calcd. for C27H24N605: C, 63.27; H, 4.72; N, 16.40. Found: C, 63.38; H, 4.7;
N, 16.34. M+1=513.

[0090] Example 209 1-(1,3-benzodioxol-5-yl)-8-[({ 2-[(4-methoxybenzyl)amino]pyridin-3-yl}carbonyl)amino]-4,5-dihydro-IH-benzo[g]indazole-3-carboxamide r-- O

I /
- H N-N

N

N~
The title compound was synthesized by the same procedure as in Example 207 starting with product of Example 161 (2 g, 0.0040 mol) and p-methoxybenzylamine (2.8 g, 0.020 mol) in 10 mL EtOH to yield 1.96 g of the title compound (yield:

60%). Mp: 181-182 C. 1H NMR (300 MHz, d6-DMSO): S 2.88-2.94 (m, 4H), 3.71 (s, 3H), 4.56 (d, 2 H, J = 5.6 Hz), 5.98 (s, 2H), 6.60-6.64 (dd, 1H, J = 7.5 Hz, 4.7 Hz), 6.88 (d, 2H, J = 8.4 Hz), 6.96 (s, 2H), 7.11 (s, 1H), 7.23-7.35 (m, 5 H), 7.39 (s, 1H), 7.49 (s, 1H), 7.95 (d, 1H, J= 7.45 Hz), 8.17 (d, 1H, J= 4.7 Hz), 8.23 (t, 1H, J
= 5.6 Hz), 10.06 (s, 1H). Anal. Calc. for C33H28N605: C, 67.34; H, 4.79; N, 14.28.
Found C, 67.08; H, 4.78; N, 14.19. M + 1 = 589.

[0091] Example 210 8- { [(2-aminopyridin-3-yl)carbonyl]amino } -1-(1,3-benzodioxol-5-yl)-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide o N-N
O N I ~CONH2 H2N 10 N' The title compound of Example 209 (1.96 g, 0.0033 mol) was dissolved in 6 mL
CH2Cl2 and reacted with 5 mL TFA at room temperature for 36 h. The crude reaction mixture was diluted with CH2C12 and basified with a saturated aqueous solution of Na2CO3. The layers were separated and the organic layer was dried over MgSO4. The residue obtained after removal of the solvent under vacuum was triturated with EtOH to afford 0.503 g of title compound (yield: 32%). Mp: 265-267 C. 1H NMR (300 MHz, d6-DMSO): S 2.88-2.95 (m, 4H), 6.12 (s, 2H), 5.58-6.62 (dd, 1H, J= 7.6 Hz, 4.7 Hz), 6.97-7.08 (m, 4H), 7.17 (d, 1H, J= 1.9 Hz), 7.28 (s, IH), 7.32 (s, 2H), 7.55 (s, 2H), 7.95-7.98 (dd, 1H, J= 7.7 Hz, 1.7 Hz), 8.11-8.13 (dd, 1H, J= 4.7 Hz, 1.7 Hz), 9.99 (s, 1H). M + 1= 469.

SCHEME XXII

Ar,, RCOOH, HATU, Et3N, Ar~N-N
N-N DMF, rt 0 N

HzN ~ \ \ CONH2 y CO

[0092] Example 211 1-(1,3-benzodioxol-5-yl)-8-[(2,5-dichloroisonicotinoyl)amino]-4,5-dihydro-lH-benzo [g] indazole-3-carboxamide /~'- O
O

N-N

CI

N CI
2,5-Dichloroisonicotinic acid (1.65g, 0.0086 mol), HATU (3.27g, 0.0086 mol) and finally Et3N (2.32 mL, 0.0166 mol) were added to a solution of the title compound of step 4 of Example 161 (2g, 0.00574 mol) in 29 mL of DMF. The reaction mixture was stirred at room temperature for 3 h. The completion of the reaction was confirmed by monitoring the disappearance of the title compound of step 4 of Example 161 in LC/MS. The crude reaction mixture was concentrated to about 10 mL of DMF. Upon addition of water to this DMF residue, a white solid was formed. This white solid was triturated in water for 20 min and filtered. The solid was collected, dissolved in THF, and dried with MgSO4. Removal of the solvent afforded a brown solid that was triturated in warm CH3CN (80 C) to give 2.2g of the title compound (yield 73%). Mp: 292-293 C. 'H NMR (300 MHz, d6-DMSO):
S 2.90-2.92 (m, 4H), 6.09 (s, 2H), 6.94-7.04 (m, 2H), 7.12 (d, 1H, J = 2 Hz), 7.26-7.38 (m, 4H), 7.51 (s, 1 H), 7.81 (s, 1 H), 8.61 (s, 1 H), 10.54 (s, 1 H). M +
1= 523.
[0093] Example 212 1-(1,3-benzodioxol-5-yl)-8-[(5-chloro-2-morpholin-4-ylisonicotinoyl)amino]-4,5-dihydro-1 H-benzo [g] indazole-3 -carboxamide r--O
O ~
H f~
N-N

CI

N
~O -[0094] Step 1 5-chloro-2-morpholin-4-ylisonicotinic acid CI

N
2,5-Dichloroisonicotinic acid, prepared by the method of E. Marzi, A. Bigi, M.
Schlosser, Eur. J. Org. Chem. 2001, 1371 - 1376, (1.6g, 0.0083 mol) and morpholine (10.9g, 0.125 mol) in 4 mL of N,N-dimethylacetamide were heated at 80 C for 4 days. The volatiles were removed under vacuum and the resulting yellow solid partitioned between water and Et20. The aqueous layer was acidified to pH =
1.5 using an aqueous solution of HC1 and extracted once with Et20 (25 mL) and three times with CH2C12 (25 mL). The organic extracts were combined and the solvents removed under vacuum. The resulting yellow solid was crystallized from MeOH to afford the title compound 1.07 g (yield: 34 %). 1H NMR (300 MHz, d6-DMSO): 8 3.45 (t, 4H, J = 4.8 Hz), 3.67 (t, 4H, J= 4.8 Hz), 7.06 (s, 1H), 8.21 (s, 1H), 13.79 (s (broad), 1H). 13C HMR (100 MHz, d6-DMSO): S 45.6, 66.4, 107.3, 116.1, 141.3, 148.3, 158.5, 166.8. M+ 1= 243.

[0095] Step 2 1-(1,3-benzodioxol-5-yl)-8-[(5-chloro-2-morpholin-4-ylisonicotinoyl)amino]-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide r--O
O

H N-N

CI
II
N
The title compound was synthesized by the same procedure as in Example 211 starting with the title material from step 1 (0.35 g, 0.00144 mol), the title compound of step 4 of Example 161 (0.333 g, 0.00096 mol), HATU (0.54 g, 0.00142 mol) and Et3N (0.39 mL, 0.00279 mol) in DMF (8 mL) to yield 0.487 g of the title compound (yield: 88%). Mp: 269-271 C. 1H NMR (300 MHz, d6-DMSO): 6 2.88-2.93 (m, 4H), 3.46 (t, 4H, J = 4.6 Hz), 3.66 (t, 4H, J= 4.6 Hz), 6.09 (s, 2H), 6.94 (s, IH), 6.97 (d, IH, J = 2 Hz), 7.02 (d, 1H, J = 8.2 Hz), 7.11 (d, 1H, J = 1.9 Hz), 7.25 (s, 1H), 7.29-7.32 (m, 2 H), 7.39-7.42 (dd, 1H, J= 8.2 Hz, 2 Hz), 7.5 (s, 1H), 8.19 (s, 1H), 10.36 (s, 1H). M + 1 = 574.

[0096] Example 213 1-(1,3-benzodioxol-5-yl)-8-( { [5-chloro-2-(methylthio)pyrimidin-4-yl]carbonyl } amino)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide r--O
O I-lLN-N ~ , O N \ \ \

N
~ I
N S-~

The title compound was synthesized by the same procedure as in Example 211 starting with 5-chloro-2-(methyl-thio)pyrimidine-4 carboxylic acid (1.76 g, 0.00861 mol), the title compound of step 4 of Example 161 (2 g, 0.00574 mol), HATU
(3.27 g, 0.00857mo1), and Et3N (2.32 mL, 0.0166 mol) in DMF (29 mL) to yield 1.3 g of the title compound (yield: 42%). 'H NMR (300 MHz, d6-DMSO): S 2.52 (s, 3H), 2.88-2.93 (m, 4H), 6.08 (s, 2H), 6.94-6.97 (dd, 1H, J= 8.2 Hz, 1.9 Hz), 7.01 (d, 1H, J= 8.2 Hz), 7.11 (d, 1H, J= 1.9 Hz), 7.25-7.33 (m, 3H), 7.38-7.41 (dd, 1H, J=
8.2 Hz, 1.9 Hz), 7.5 (s, 1H), 8.88 (s, 1H), 10.59 (s, 1H). M + 1= 536.
SCHEME XXIII

H Ar-, N-N H Ar-, N-N
O N I~ CONHZ RiR2NH (20 equiv.), neat O N CONH2 CI or EtOH, 100 C CI

N CI N NRyR2 [0097] Example 214 1-(1,3-benzodioxol-5-yl)-8-{ [5-chloro-2-(4-methylpiperazin-l-yl)isonicotinoyl] amino } -4,5-dihydro- 1 H-benzo[g]indazole-3-carboxamide r--O
O ~

N
-N
O N )::Io~

CI ID~
IJ
N N-~
A mixture of the title compound of Example 211 (1.2g, 0.0023 mol) and N-methylpiperazine (4.6 mL, 0.046 mol) was heated at 100 C in a sealed tube for 24 h.
The completion of the reaction was checked by HPLC. After removal of the volatiles under vacuum, the residue was partitioned between water and CH2Cl2.
The organic layer was washed an additional time with water and dried over MgSO4.
The crude product mixture was purified by chromatography on silica gel using CH2C12/MeOH: 12/1 to 10/2 to give 0.62g of the title product, yield: 46%. Mp:
305-307 C. 'H NMR (400 MHz, d6-DMSO): S 2.18 (s, 3H), 2.34-2.35 (d, 2H, J= 5 Hz), 2.89-2.91 (m, 4H), 3.49 (d, 2H, J = 5 Hz), 6.08 (s, 2H), 6.91-7.03 (m, 3H), 7.1 (d, 1H, J = 2 Hz), 7.24-7.3 (m, 3H), 7.38-7.41 (dd, 1H, J = 8.3 Hz, 2 Hz), 7.49 (s, 1H), 8.13 (s, 1H), 10.33 (s, 1H). M + 1 = 587.

[0098] Example 215 1-(1,3-benzodioxol-5-yl)-8-[(5-chloro-2-piperazin-1-ylisonicotinoyl)amino]-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide O t~N-N

CI

N QH

The title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 211 (1 g, 0.0018 mol) and piperazine (3 g, 0.036 mol) in EtOH (4 mL). The reaction was run at 95 C for 24h. After allowing the reaction nlixture to cool down, the volatiles were removed under vacuum. The residue was triturated with H20 and finally with EtOH to yield 0.572 g of the title compound (yield: 55%). 1H NMR (300 MHz, d6-DMSO): 6 2.71 (s, broad, 4H), 2.86-3.30 (m, 4H), 3.39 (s, broad, 4H), 6.07 (s, 2H), 6.85 (s, 1H), 6.93-6.95 (dd, 1 H, J= 8.2 Hz, 1.9 Hz), 7.00 (d, 1 H, J= 8.2 Hz), 7.09 (d, 1 H, J=
1.9 Hz), 7.24-7.30 (m, 3H), 7.38-7.41 (dd, 1H, J = 8.2 Hz, 1.74 Hz), 7.49 (s, 1H), 8.12 (s, 1H), 10.32 (s, 1H). M + 1= 573.

[0099] Example 216 1-(1,3-benzodioxol-5-yl)-8-{ [(3,6-dichloropyridin-2-yl)carbonyl]amino } -4,5-dihydro-lH-benzo[g]indazole-3-carboxamide /--O
O
CI
H N_\ O
CI N N \ \

The title compound was synthesized from 1.653 g of 3,6-dichloro-2-pyridine carboxylic acid (CP92740, prepared by the method of E. Marzi, A. Bigi, M.
Schlosser, Eur. J. Org. Chem. 2001, 1371 - 1376) and the title compound of step 4 of Example 161 (2.0 g) by the same procedure used for Example 211. The title compound is a brown solid (2.4 g, 80%), m.p. 263-265 C. Its structure was confirmed by 'H NMR and LClMS: 1H NMR (d6-DMSO): S 2.82-3.01 (m, 4H)), 6.11 (s, 2H), 6.97-7.07 (m, 2H), 7.38 d, 1H, J = 1 Hz), 7.81 (s, 1H), 7.33-7.42 (m, 3H), 7.52 (s, 1H), 7.51 (d, 1H, J= 9 Hz), 8.15 (d, 1H, J= 9 Hz), 10.57 (s, 1H). ESI
mass spectrum for C25H18C12N5O4+: 522 (M + 1).

[00100] Example 217 1-(1,3-benzodioxol-5-yl)-8-( { [3-chloro-6-(4-methylpiperazin-1-yl)pyridin-2-yl]carbonyl}amino)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide /'O

cl I ~ H N-N

~N N N I \ \ CONH2 /NJ O

[00101] Step 1 Potassium 3-chloro-6-(4-methylpiperazin-1-yl)pyridine-2-carboxylate 0 OK+

cl / N

N--) ~\,N\
Potassium 3-chloro-6-(4-methylpiperazin-1-yl)pyridine-2-carboxylate was synthesized by the reaction used in Example 250 step 1 starting with 3,6-dichloro-2-pyridine carboxylic acid (0.60 g, 3.125 mmol) N-methylpiperazine (7.2 g, 72 mmol). The reaction was carried out at 95 C for 3 days. The volatiles were removed under vacuum. The resulting residue was washed with a saturated solution of K2C03 and with CH2Cla. Three layers were formed. The middle was separated, dried, and the solvent was removed under reduced pressure giving 0.89 g of Potassium 3-chloro-6-(4-methylpiperazin-1-yl)pyridine-2-carboxylate (96%). Its structure was confirmed by 1H NMR and LC/MS: 1H NMR (D20): S 2.18 (s, 3H), 2.43 (s, broad, 4H), 3.37 (s, broad, 411), 6.77 (d, 1H, J = 9 Hz), 7.58 (d, 1H, J = 9 Hz). ESI mass spectrum for C11H15C1N302+: 256 (M + 1) in the presence of TFA.
[00102] Step 2 1-(1,3-benzodioxol-5-yl)-8-({ [3-chloro-6-(4-methylpiperazin-1-yl)pyridin-2-y1]carbonyl } amino)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide /'o ci I ~ H N-N

N N N I \ \ CONH2 NJ O

The title compound was synthesized from 0.30 g of 3-chloro-6-(4-methylpiperazin-1-yl)-2-pyridine carboxylic acid, obtained by acidification of its K-salt from step 1, and the title compound of step 4 of Example 161 (0.217 g) by the same procedure used for Example 260. The title compound is a brown solid (0.23 g, 61%), m.p.

264-266 C(decomposition). Its structure was confirmed by 'H NMR and LC/MS:
1H NMR (d6-DMSO): S 2.70 (s, 3H), 2.72-4.30 (m, 12H), 6.02 (s, 2H), 6.92-7.12 (m, 4H), 7.22-7.36 (m, 3H), 7.42-7.53 (m, 2H), 7.77 (d, 1H, J = 9 Hz), 10.32 (s, 1H). ESI mass spectrum for C30H29C1N7O4+: 586 (M + 1).

[00103] Example 218 1-(1,3-benzodioxol-5-yl)-8- { [(3-chloro-6-{ [2-(dimethylamino)ethyl]thio }
pyridin-2-yl)carbonyl] amino }-4, 5-dihydro-1 H-benzo [g] indazole-3-carboxamide /--o ' ci N-N
\ \ \ CONH2 ~N\/"~,g ! N NI/

The title compound was synthesized from 0.36 g of the title compound of step 1 of Example 262, and the title compound of step 4 of Example 161 (0.35 g) by the same procedure used for Example 260. The title compound is a white solid (0.51 g, 86%). Its structure was confirmed by 'H NMR and LC/MS: 1H NMR (d6-DMSO):
S 2.18 (s, 6H), 2.55 (m, 2H), 2.85 (m, 4H), 3.24 (m, 2H), 6.10 (s, 2H), 6.90-7.08 (m, 2H), 7.14 (s, 1H), 7.22-7.35 (m, 211), 7.36-7.47 (m, 3H), 7.52 (s, 1H), 7.84 (d, IH, J
= 9 Hz), 10.40 (s, IH). ESI mass spectrum for C29H28C1N6O4S+: 591 (M + 1).

[00104] Example 219 1-(1,3-benzodioxol-5-yl)-8-{ [(3-chloro-6-morpholin-4-ylpyridin-2-yl)carbonyl] amino } -4,5-dihydro-lH-benzo[g]indazole-3-carboxamide O
~/
CI
\
I ~ H N-N
O
~N N N \ \

O

The title compound was synthesized from 0.27 g of morpholine and the title compound of Example 216 (0.522 g) by the same procedure used for Example 207 except that EtOH was replaced by 0.5 ml of DMA. The reaction was carried out at 80 C for 36 hours. The title compound, isolated by preparative HPLC, is a white solid (0.30 g, 52%), m.p. 260-262 C (decomposition). Its structure was confirmed by 1H NMR and LC/MS: 1H NMR (CDC13) S 2.96 (m, 2H), 3.15 (m, 2H)), 3.48 (m, 4H), 3.86 (m, 4H), 5.41 (s, 1H), 6.74-6.86 (m, 2H), 6.90-7.04 (m, 2H), 7.16 (d, 1H, J = 1 Hz), 7.28-7.35 (m, 2H), 7.54-7.22 (m, 2H), 9.32 (s, 1H). ESI mass spectrum for C29H26C1N6O5+: 573 (M + 1).

[00105] Example 220 1-(1,3-benzodioxol-5-yl)-8-({ [3-chloro-6-(methylamino)pyridin-2-yl]carbonyl } amino)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide /--O
O

~~ ~
N-N

The title compound was synthesized from N-methylamine (6 mL of 33 w% solution in EtOH) and the compound of Example 216 (1.04 g) by the same procedure used for Example 207 except that 1 mL of DMA was added. The reaction was carried out at 82 C for 5 days. The title compound, isolated by preparative HPLC, is a white solid (0.29 g, 52%), M.p. 269-270 C (decomposition). Its structure was confirmed by 1H NMR and LC/MS: 'H NMR (d6-DMSO): S 2.76 (d, 3H, J = 5.5 Hz), 2.84-3.99 (m, 4H), 6.16 (s, 2H), 6.57 (d, 1H, J = 9 Hz), 6.91-7.04 (m, 3H), 7.12 (d, 1H, J = 1 Hz), 7.22-7.34 (m, 3H), 7.46-7.54 (m, 3H), 10.19 (s, 1H).
ESI
mass spectrum for C26H22C1N6O4+: 517 (M + 1).
[00106] Example 221 SCHEME XXIV

CI CI O~ rNH CI O~
CO2H ~ ~ I\ O iN O

conc. H2SO4 Pd2(dba)3 Br 70% Br BINAP 'N) Na BuO
rN
95%

R
R.
ci O
N-N H N-N
11~H HN CONH2 N
TFA I\ CONH2 /

88% ~ J \ I N--) R= 4-F, 4-SO2Me, 3,4-MDO, etc.

/-O
O

N N
O N

CI

N-N\
iii [00107] Step 1: A solution of 2-chloro-5-bromobenzoic acid (23.6 g, 0.1 mol), conc. sulfuric acid (5 mL) and condensed isobutene (400 mL) was prepared in a pressure vessel and stirred at room temperature under 12 psi for 2 days. The vessel was opened and the excess isobutene was released. The remaining liquid was treated with sat. NaHCO3 solution and extracted with methylene chloride. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuum to give 20.5 g of the crude product as brown oil, which was used without further purification (70%).

[00108] Step 2: A mixture of tert-butyl 2-chloro-5-bromobenzoate (2.95 g, 0.01 mol), N-methylpiperazine (1.5 g, 0.015 mol), NatBuO (1.5 g, 0.015 mol), Pd2(dba)3 (0.18 g, 0.0002 mol) and BINAP (0.2 g, 0.0003 mol) in toluene was heated at under nitrogen for 16 h. The solution was cooled to room temperature and filtered through a pad of Celite . The filtrate was concentrated and the residue was partitioned between methylene chloride and water. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuum to give 3.0 g of the crude product as a dark brown oil (97%). The NMR and MS
were consistent with the proposed structure.

[00109] St~: To a solution of tert-butyl 2-chloro-5-(4-methylpiperazin-l-yl)benzoate (7.3 g, 0.023 mol) in methylene chloride (150 mL) was added trifluoroacetic acid (62 mL, 0.8 mol) dropwise at 0-5 C. The reaction mixture was stirred overnight while allowing to warm up to room temperature. Solvent and excess TFA was removed and the residue was triturated with ether to give 7.5 g of acid as a light brown solid;'H NMR (DMSO, 400 MHz) S: 10.11 (s, 1H), 7.39 (d, J
= 8.9 Hz, 1H), 7.33 (d, J 3.1 Hz, 1H), 7.16 (dd, J= 3.1, 8.9 Hz, 1H), 3.90 (d, J=
12.2 Hz, 2H), 3.52 (d, J 11.1 Hz, 2H), 3.15 (m, 2H), 2.98 (m, 2H), 2.87 (s, 3H);
Anal. Calcd. for C12H15C1N202 + 1.0 TFA: C, 45.60; H, 4.37; N, 7.60. Found: C, 45.99; H, 4.62; N, 7.21.

[00110] St~: To a mixture of 2-chloro-5-(4-methylpiperazin-1-yl)benzoic acid (0.9 g, 0.0035 mol), the title compound of step 4 of Example 161 (0.82 g, 0.0024 mol) and 1 mL of diisopropylethylamine in 25 mL of DMF was added HATU (1.3 g, 0.0035 mol) in one portion. The reaction mixture was stirred at room temperature for 16 h. Solvent was removed and the residue was purified on preparative HPLC to give 1.25 g of the product as a pale white solid (89%
yield);

mp: 185-187 C; 'HNMR (DMSO + TFA-d, 400 MHz) S: 10.26 (s, 1H), 9.81 (brs, 1H), 7.52 (brs, 1H), 7.44 (dd, J= 2.0, 8.1 Hz, 1H), 7.37 (d, J= 8.6 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 7.12 (d, J = 2.0 Hz, 1H), 7.09 (m, 2H), 7.03 (d, J = 8.2 Hz, 1H), 6.98 (dd, J = 2.1, 8.2 Hz, 1H), 6.11 (s, 2H), 3.90 (m, 2H), 3.50 (m, 2H), 3.14 (m, 2H), 2.96 (m, 6H), 2.86 (s, 3H).
[00111] The bioactivity in the IKK2 Resin assay for the compounds of Examples 207-221 is shown in Table 5.

Table 5 Structure Mol. Compound Name(s) IKK2 wt. Resin Avg. Example IC50 (uM) o,-0 482.50 1-(1,3-benzodioxol-5-yl)-8- <1 M 207 ~ ~ [2-(methylamino)pyridin-3--H 0 ~ N-N yl]carbonyl}amino)-4,5-H NHz dihydro-lH-benzo[g]indazole-" 0 3-carboxamide o/- 512.53 1-(1,3-benzodioxol-5-yl)-8- 51 M 208 OH tz [({2-[(2-hydroxyethyl)amino]pyridin-NH 0 H N-N NHZ 3-yl}carbonyl)amino]-4,5-N e-, "\ ) o dihydro-1H benzo[g]indazole-3-carboxamide - 588.63 1-(1,3-benzodioxol-5-yl)-8- 10 < 100 209 '1 b [(12-[(4- M
NH o H N-N N~ methoxybenzyl)amino]pyridin N ~ N \ ~ ~ -3-yl}carbonyl)amino]-4,5-dihydro-1 H-b en zo [ g]indazole-3-carboxamide /-o 468.48 8-{ [(2-aminopyridin-3- 1< 10 pM 210 /~ ~ yl)carbonyl]amino}-1-(1,3-benzodioxol-5-yl)-4,5-J N-N dihydro-lH-benzo[g]indazole-o ~
HZN ~ ~ \ NHZ 3-carboxamide N~

o~0 522.35 1-(1,3-benzodioxol-5-yl)-8- <1 M 211 [(2,5-~ dichloroisonicotinoyl)amino]-ci 0 N N NHZ 4,5-dihydro-lH-N'' o benzo[g]indazole-3-" carboxamide ci 573.01 1-(1,3-benzodioxol-5-yl)-8- 51 M 212 ~ [(5-chloro-2-morpholin-4-o~ ylisonicotinoyl)amino]-4,5-~
ci 0 \N NHZ dihydro-lH-benzo[g]indazole-i 0 3-carboxamide N

Co~
0 0 534.99 1-(1,3-benzodioxol-5-yl)-8- <1 M 213 ~ ({[5-chloro-2-/ ~ (methylthio)pyrimidin-4-ci 0 N-N NHZ yl]carbonyl}amino)-4,5-i\ H~ \ o dihydro-lH-benzo[g]indazole-"Y" \ 3-carboxamide ,S

0 /-0 586.06 1-(1,3-benzodioxol-5-yl)-8- <1 M 214 {[5-chloro-2-(4-~ methylpiperazin-l-cl 0 H N N NH2 yl)isonicotinoyl]amino}-4,5-~ " \ ) o dihydro-lH-benzo[g]indazole 3-carboxamide C ~
N

o 572.03 1-(1,3-benzodioxol-5-yl)-8- <1 M 215 [(5-chloro-2-piperazin-l-, ylisonicotinoyl)amino]-4,5-c~ o H \N NH2 dihydro-lH-benzo[g]indazole-~ " ) 0 3-carboxamide N

C ~
N
H
o,.o 522.35 1-(1,3-benzodioxol-5-yl)-8- 1< 10 M 216 {[(3,6-dichloropyridin-2-ci / yl)carbonyl]amino}-4,5-, H N-N o dihydro-lH-benzo[g]indazole-ci N N / NH 3-carboxamide z ,1 586.06 1-(1,3-benzodioxol-5-yl)-8- <1 M 217 ({[3-chloro-6-(4-[3-chloro-6-(4-ci N_N methylpiperazin-1-yl)pyridin-NN~ 2-yl]carbonyl}amino)-4,5-i"~J dihydro-lH-benzo[g]indazole-õ 591.09 1-(1,3-benzodioxol-5-yl)-8- <1 M 218 {[(3-chloro-6-{[2-N (dimethylamino)ethyl]thio}py \ O1 N-N
CONHi ridin-2-yl)carbonyl]amino}-" ( 4,5-dihydro-lH-benzo[g]indazole-3-carboxamide - 573.01 1-(1,3-benzodioxol-5-yl)-8- <1 M 219 { [(3-chloro-6-morpholin-4-I C1 / N-N ylpyridin-2-O -4,5-NN ~, \ NH yl)carbonyl]amino}
J = dihydro-1H-benzo[g]indazole-3-carboxamide ,- 516.95 1-(1,3-benzodioxol-5-yl)-8- <1 M 220 ({[3-chloro-6-~ (methylamino)pyridin-2-~ I H N N. yl]carbonyl}amino)-4,5-H N CONHx dihydro-lH-benzo[g]indazole-3-carboxamide o 585.07 1-(1,3-benzodioxol-5-yl)-8- <1 M 221 {[2-chloro-5-(4-~ N-N methylpiperazin-l-N CONHZ yl)benzoyl]amino}-4,5-ci dihydro-lH-benzo[g]indazole-~ 3-carboxamide N,_ [00112] Examples 222-243 Examples 222-243 shown in Table 6 were synthesized with the corresponding starting compounds using the following synthesis procedure similar to Scheme I
where R9 is the appropriate aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or cycloalkyl.

[00113] SCHEME XXV
F
O O 4-(fluoro)- /
phenylhydrazine N-N OEt O2N / OEt AcOH, 4 02N
~ 51YO
ethyl (7-nitro-l-oxo-1,2,3, 4-tetrahydronaphthalen-2-yl) (oxo)acetate 1 F F
Pd(OH)2 )2 NH3, MeOH /
N-N OEt H2 HZN ~~ 700 psi H N-N NH2 5:~, N~
F

Q
R9CO2H, HATU or R9 N N-N NH2 O
O
R9COCI, Pyridine Table 6 Structure Mol. Wt. Compound Name(s) IKK2 Example Resin IC50 ( \S O F 522.99 8-{[2 chloro-5 <1 M 222 (methylsulfinyl)benzoyl] a N-N mino } 1 (4-fluorophenyl)-~ N N NH2 4,5-dihydro-lH-~ benzo[g]indazole-3-CI 0 O carboxamide F 496.33 8-{ [(2,5-dichloropyridin-3- <1 M 223 yl)carbonyl]amino}-1-(4-fluorophenyl)-4,5-dihydro-N-N 1H benzo[g]indazole-3-N ~ ~ ~ carboxamide CI ~ ~ NHz N
CI

Structure Mol. Wt. Compound Name(s) IKK2 Example Resin IC50 ( F 504.90 8{[(6-chloro 1,3 <1 M 224 benzodioxol-5-yl)carbonyl]amino }-1-(4-O H N O fluorophenyl)-4,5-dihydro-CI N 1H-benzo[g]indazole-3-' ~ NH2 carboxamide O,/O

F 461.88 8-{[(2-chloropyridin-3- <1 M 225 yl)carbonyl]amino}-1-(4--~ fluorophenyl)-4,5-dihydro-N-N 1H-benzo[g]indazole-3-N \ carboxamide N

F ~ 538.99 8-1[2-chloro-4- <1 M 226 0 -o (methylsulfonyl)benzoyl]a ~
H N-N mino}-1-(4-fluorophenyl)-N NH 4,5-dihydro-lH-c- 0 benzo[g]indazole-3-carboxamide F 475.91 8-{ [(2-chloro-6- <1 M 227 ~ methylpyridin-3-yl)carbonyl]amino }-1-(4-CI 0 H N-N NH2 fluorophenyl)-4,5-dihydro-N 0 1H-benzo[g]indazole-3-~ carboxamide F 498.35 8-[(3- <1 M 228 chloroisonicotinoyl)amino]
-1-(4-fluorophenyl)-4,5-N N-N dihydro-lH-/ N 2 benzo[g]indazole-3-cl 0 carboxamide hydrochloride HCI

F 475.91 8-[(3-amino-2- <1 M 229 chlorobenzoyl)amino]-1-N-N (4-fluorophenyl)-4,5-N O dihydro-lH-CI benzo[g]indazole-3-NH2 carboxamide HzN

Structure Mol. Wt. Compound Name(s) IKK2 Example Resin IC50 ( F 460.90 8-[(2- <1 M 230 chlorobenzoyl)amino]-l-(4-fluorophenyl)-4,5-N- dihydro-lH-N i ~ o benzo[g]indazole-3-ci NH2 carboxamide F 456.48 1-(4-fluorophenyl)-8-[(3- <1 M 231 hydroxy-2-methylbenzoyl)amino]-4,5-N-N dihydro-1 H-O
N o benzo[g]indazole-3-/ NH2 carboxamide HO

F 475.91 8-[(4-amino-2- <1 M 232 chlorobenzoyl)amino]-1-(4-fluorophenyl)-4,5-0 N-N dihydro-lH-N o benzo[g]indazole-3-Cil NH2 carboxamide F 490.92 8-[(2-chloro-4- <1 M 233 metho xybenzoyl) amino]-1-N_N (4-fluorophenyl)-4,5-o N ~ \ dihydro 1H-c, I NH benzo[g]indazole-3-carboxamide \

F 529.88 8-({ [2-chloro-6- <1 M 234 (trifluoromethyl)pyridin-3-~- yl]carbonyl } amino)-1-(4-ct 0 N- ~ NHZ fluorophenyl)-4,5-dihydro-N 1H-benzo[g]indazole-3-I ,~ carboxamide \S F 506.99 8-{ [2-chloro-5- <1 M 235 (methylthio)benzoyl]amino i H N-N )-1-(4-fluorophenyl)-4,5-N NH2 dihydro-lH-benzo[g]indazole 3 CI 0 carboxamide Structure Mol. Wt. Compound Name(s) IKK2 Example Resin IC50 ( F 475.91 8-[(5-amino-2- <1 M 236 chlorobenzoyl)amino]-1-(4-fluorophenyl)-4,5-N-N dihydro-lH-N ~ p benzo[g]indazole-3-cI NH2 carboxamide F 503.97 8-{[2-chloro-5- <1 [tM 237 N~ (dimethylamino)benzoyl]a mino }-1-(4-fluorophenyl)-N-N 4,5-dihydro-lH-~ N CONH2 benzo[g]indazole-3-CI p ~ carboxamide F 495.34 8-[(2,3- <1 M 238 dichlorobenzoyl)amino]-1-(4-fluorophenyl)-4,5-N-N dihydro-lH-p N , \ ~NH2 o benzo[g]indazole-3-CI carboxamide CI

F 520.95 8-[(2-chloro-4,5- <1 M 239 \N dimethoxybenzoyl)amino]-1-(4-fluorophenyl)-4,5-N-N dihydro-lH-p N benzo[g]indazole-3-CI NH2 carboxamide -o I

F 440.48 1-(4-fluorophenyl)-8-[(2- <1 M 240 methylbenzoyl)amino]-4,5-dihydro-lH-N-N benzo[g]indazole-3-\ o carboxamide I \

Structure Mol. Wt. Compound Name(s) IKK2 Example Resin IC50 ( F 505.89 8-[(2-chloro-3- <1 M 241 nitrobenzoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-N-N 1H-benzo[g]indazole-3-0 N \ a carboxamide CZ NH

N O

F 400.43 1-(4-fluorophenyl)-8- 1< 10 M 242 [(methylsulfonyl)amino]-4,5-dihydro-lH-N-N benzo[g]indazole-3-carboxamide O, O+S~,N

F 427.44 1-(4-fluorophenyl)-8- 1< 10 M 243 (isonicotinoylamino)-4,5-dihydro-lH-N-N benzo[g]indazole-3-0 ~ O carboxamide N

[00114] Example 244 8-amino- i-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide F
r H2N 106~

This material was prepared from 4-fluorophenyl hydrazine by the method described for Example 92.

[00115] Example 245 1-(4-fluorophenyl)-8-{ [(2-piperazin-l-ylpyridin-3-yl)carbonyl]amino }-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide F
H N-N
HN--'-) O N I\ \\ CONH2 N~

The title compound was synthesized by the same procedure as in Example 207 starting with the title compound of Example 225 (0.81 g, 0.017 mol) and piperazine (3 g, 0.0348 mol) in 4 mL Et OH to afford 0.523 g of title compound (yield: 58 %). Mp: 156-157 C.

1H NMR (300 MHz, d6-DMSO): 6 2.63 (t, 4H, J= 4.5 Hz), 2.86-2.93 (m, 4H), 3.08 (t, 4H, J = 4.5 Hz), 6.86-6.90 (dd, 1H, J = 7.4 Hz, 4.8 Hz), 7.23 (s, 1H), 7.28 (s, 1H), 7.32 (d, 1H, J = 8.3 Hz), 7.40 (t, 2H, J = 8.7 Hz), 7.54-7.6 (m, 4H), 7.63-7.66 (dd, 1H, J
= 7.4 Hz, 1.7 Hz), 8.22-8.25 (dd, 1H, J= 4.8 Hz, 1.9 Hz), 10.25 (s, 1H). M + 1 = 512.

[00116] Example 246 8- { [(6-chloro-4-methylpyridin-3-yl)carbonyl] amino } -1-(4-fluorophenyl)-4,5-dihydro-lH-benzo [g] indazole-3-carboxamide F
CI r H N_\
O
N

[00117] Step 1 6-Hydroxy-4-methylnicotinic acid I oH
HO N
A modification of the procedure of Weglinski and Talik (Rocz. Chem. 1977, 51, 2401) was used. Potassium carbonate powder (-325 mesh) was dried under vacuum at 200 C
overnight prior to use. A layer of the dried potassium carbonate (28.56 g, 0.207 mol) was placed in the bottom of a 300-mL Hastelloy-B autoclave followed by a layer of 2-hydroxy-4-methylpyridine (28.51 g, 0.2612 mol) mixed with dried potassium carbonate (28.70 g, 0.208 mol). The vessel was sealed, carefully purged with dry carbon dioxide (5 x 80 psig), pressurized with dry carbon dioxide to 800 psig, and heated to 130 C for 18 h. After cooling and careful venting, the product mixture was dissolved in water (560 mL) and added to 132 mL of 6 N HCl with vigorous stirring over about 20 min. The pH of the resulting slurry was 2.43 and potassium carbonate (ca. 0.25 g) was added to pH=2.53.
After stirring the slurry for 1 h at 25 C, the precipitate was recovered by vacuum filtration, washed with water (3 x 35 mL), and dried in vacuo at 100 C to afford 7.11 g of a tan powder. 1H NMR analysis of the tan powder was consistent with a mixture of about 5.6 mol% 2-hydroxy-4-methylpyridine and 94.4 mol% of the desired 2-hydroxy-4-methyl-5-pyridinecarboxylic acid. The yield was estimated to be 17.0% based on the NMR
assay of the recovered product. 1H NMR (400 MHz, d6-DMSO) S 2.36 (d, T= 1 Hz, 3H), 6.19 (apparent s, 1H), 7.99 (s, 1H), 12.2 (broad s, 2H). 13C NMR (100 MHz, d6-DMSO) 8 21.6, 109.1, 119.5, 141.1, 151.8, 161.8, 165.8.

[00118] Step 2 4-Methyl-6-chloronicotinic acid O

OH
CI N

6-Hydroxy-4-methylnicotinic acid (10 g, 65.3 mmol) and phosphorus oxychloride (33 mL) were combined and refluxed for 3 hours. The reaction solution was poured into 300 mL of ice and then 600 mL of water was added. The solution was boiled for 30 minutes before cooling and extracting the product into ether. The solvent was removed and the residue was recrystallized from 900 mL of hot water. Yellow solid, 9.06g (81% yield).
Mp 170-172 C. 1H NMR (CD3OD): S 2.61 (s, 3H), 7.41 (s, 1H), 8.80 (s, IH). LC-MS, M +
1=
172.

[00119] Step 3 8- { [(6-chloro-4-methylpyridin-3-yl)carbonyl] amino 1- 1 -(4-fluorophenyl)-4,5-dihydro- I H-benzo [g] indazole-3-carboxamide F

~ ~
~ N_ \
CI / H O
N' N

The compound of example 244 (3.872 mmoles), 4-methyl-6-chloronicotinic acid from step 2 (5.828 mmoles), and HATU (5.844 mmoles) were dissolved in 20 mL DMF followed by the addition of 1.9 mL triethylamine. The mixture was stirred at room temperature overnight. The solvent was then stripped and the residue suspended in water, filtered, and washed with water. The solid was recrystallized from acetonitrile, then redissolved in acetonitrile, decolorized with decolorizing carbon, and dried over anhydrous MgSO4. The solvent was then stripped down to a solid. Mp: 280-284 C. 1H NMR (d6-DMSO, 400 MHz): S 2.28 (s, 3H); 2.84-2.98 (m, 4H); 7.25-7,44 (m, 6H); 7.49 (s, 1H); 7.51-7.62 (m, 3H); 8.35 (s, 1H); 10.31 (s, 1H). 13C NMR (DMSO, 100 MHz): S 19.13, 20.35, 29.67, 115.01, 117.07, 117.30, 120.08, 121.34, 126.19, 126.60, 128.72, 128.81, 129.58, 132.80, 133.42, 136.81, 136.84, 137.64, 139.71, 143.19, 148.42, 149.96, 151.59, 161.44, 163.88, 164.47, 164.78. M + 1= 476.

[00120] Example 247 1-(4-fluorophenyl)-8-{ [(4-methyl-6-morpholin-4-ylpyridin-3-yl)carbonyl]amino }-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide F
C
O N-N
O
NN

The title compound of Example 246 (1.47 mmoles) and morpholine (23.1 mmoles) were dissolved in 10 mL of N,N-dimethylacetamide. The reaction mixture was then placed under nitrogen and stirred in an oil bath at 100 C for 27 h. The mixture was partially stripped of solvent then added to water, filtered, and washed with water. The solid was recrystallized from acetonitrile, then dissolved in acetonitrile and dried over anhydrous MgSO4. The solvent was then stripped down to a solid. Mp: 301 C (decomp.) 1H
NMR
(d6-DMSO, 400 MHz): S 2.22 (s, 3H); 2.80-2.94 (m, 4H); 3.46 (t, 4H, J = 4.8 Hz); 3.62 (t, 4H, J= 4.8 Hz); 6.67 (s, 1H); 7.22-7.27 (m, 3H); 7.31-7.38 (m, 2H); 7.42 (dd, 1H, J =
1.9Hz, 8.2Hz); 7.49-7.57 (m, 3H); 8.11 (s, 1H); 9.92 (s, 1H). 13C NMR (d6-DMSO, 100 MHz): S 20.35, 20.38, 29.63, 45.55, 66.54, 108.46, 114.91, 117.02, 117.25, 119.91, 121.23, 122.78, 126.42, 128.64, 128.73, 129.36, 132.60, 136.82, 136.85, 138.38, 139.82, 143.15, 147.70, 148.03, 160.04, 161.39, 163.84, 164.47, 166.18. M+ 1= 527 [00121] Example 248 8-[(2,5-dichloroisonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide F a_ H N N

CI

N CI

2,5-Dichloroisonicotinic acid (1.65g, 0.0086 mol), HATU (3.27g, 0.0086 mol), and Et3N
(2.32 mL, 0.0166 mol) were added to a solution of the title compound of Example 244 (1.85g, 0.00574 mol) in 29 mL of DMF. The reaction mixture was stirred at room temperature for 3 h. The completion of the reaction was confirmed by monitoring the disappearance of the title compound of Example 246 step 2 in LC/MS. The crude reaction mixture was concentrated to about 10 mL of DMF. Upon addition of water to this DMF
residue, a white solid was formed. This white solid was triturated in water for 20 min and filtered. The solid was collected, dissolved in THF, and dried with MgSO4.
Removal of the solvent afforded a brown solid that was crystallized from CH3CN to give 2.1 g of the title compound as white needles (yield 73%). 1H NMR (300 MHz, d6-DMSO): 2.86-2.91 (m, 4H), 7.18 (d, 1H, J= 1.2 Hz), 7.25 (s, 1H), 7.32-7.36 (m, 4H), 7.52-7.56 (m, 3H), 7.75 (s, 1H), 8.57 (s, 1H), 10.49 (s, 1H). M + 1= 497.

[00122] Example 249 8-[(5-chloro-2-morpholin-4-ylisonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide F
N \ CI N_' O
N
N

Oi O

The title compound of Example 244 (0.757 mmoles), 5-chloro-2-morpholin-4-ylisonicotinic acid, (1.38 mmoles), and HATU (1.57 mmoles) were dissolved in 5 mL
DMF followed by the addition of 0.4 mL of triethylamine. The mixture was stirred at room temperature for 3 hrs and partially stripped of DMF. The reaction mixture was then added to water, filtered, and washed with water. The solid was dissolved in THF, decolorized with decolorizing carbon, and dried over anhydrous MgSO4. The THF was stripped and the solid triturated in diethyl ether three times, then triturated in ethanol, and twice more with acetonitrile, filtered and dried under vacuum. Mp: 309-313 C. 'H NMR (d6-DMSO, 400 MHz): 8 2.80-2.95 (m, 4H); 3.42 (t, 4H, J = 5 Hz); 3.62 (t, 4H, J = 5 Hz);
6.88 (s, 1H); 7.17-7.21 (m, 1H); 7.23-7.41 (m, 5H); 7.49-7.58 (m, 3H); 8.14 (s, 1H);

10.31 (s, 1H).
13C NMR (d6- DMSO, 100 MHz): 5 20.34, 29.70, 45.74, 66.50, 106.55, 114.97, 115.87, 117.09, 117.32, 120.05, 121.41, 126.67, 128.64, 128.73, 129.62, 133.47, 136.80, 136.82, 137.48, 139.64, 143.21, 145.28, 147.54, 158.30, 161.39, 163.85, 164.45. M + 1 = 547.
[00123] Example 250 8- { [5-chloro-2-(4-methylpiperazin- 1 -yl)isonicotinoyl] amino } -1-(4-fluorophenyl)-4,5dihydro-1 H-benzo[g]indazole-3-carboxamide F
H N-N

O N ID~
CI N N-[00124] Step 1 5-chloro-2-(4-methylpiperazin- 1 -yl)isonicotinic acid hydrochloride CI
I = HCI
N N

5-chloro-2-(4-methylpiperazin-1-yl)isonicotinic acid hydrochloride was synthesized by the same procedure as for example 212 step 1 starting with 2,5-dichloroisonico-tinic acid (3 g, 0.0156 mol) N-methylpiperazine (30.7g, 0.30 mol) in 10 mL of N,N-dimethylacetamide.
The reaction was carried out at 100 C for 8 days. The volatiles were removed under vacuum. The resulting residue was washed with a saturated solution of K2C03 and with CH2C12. The solvents were removed under vacuum and the resulting residue dissolved in the minimum amount of water, acidified to pH = 1 with an aqueous solution of HCl (1N) and washed with CH2C12. Upon standing at room temperature, the acidic aqueous layer afforded 2g (yield: 44%) of title compound. 1H NMR (300 MHz, D20): S 2.85 (s, 3H), 3.13 (t, 2H, J= 12.28 Hz), 3.34 (t, 2H, J= 14.3 Hz), 3.56 (d, 2H, J= 12.28 Hz), 4.18 (d, 2H, J = 14.3 Hz), 7.08 (s, 1H), 8.00 (s, 1H). 13C NMR (75 MHz, D20): 8 43.1, 43.4, 52.54, 109.5, 117.6, 142.3, 147.9, 154.4, 169.5.

[00125] Step 2 8-{ [5-chloro-2-(4-methylpiperazin- 1 -yl)isonicotinoyl] amino } -1-(4-fluorophenyl)-4,5 dihydro-1 H-benzo [g] indazole-3-carboxamide F O N )aN-N

C!

N
N~
The title compound was synthesized by the same procedure as in Example 211 starting with 5-chloro-2-(N-methyl-piperazinyl)isonicotinic acid hydrochloride from step 1)) (0.59 g, 0.00202 mol), the title compound of Example 244 (0.432 g, 0.00134 mol), HATU
(0.755g, 0.00198mo1) and Et3N (1.09 mL, 0.0078 mol) in DMF (8 mL) to yield 0.305 g of the title compound (yield: 40%). 1H NMR (300 MHz, d6-DMSO): 6 2.17 (s, 3H), 2.33 (t, 4H, J = 4.8 Hz), 2.87-2.93 (m, 4H), 3.47 (t, 4H, J = 4.8 Hz), 6.87 (s, 1H), 7.2 (d, 1H, J =
1.9 Hz), 7.27 (s, 1H), 7.29-7.41 (m, 5H), 7.53-758 (m, 3H), 8.13 (s, 1H), 10.31 (s, 1H). M
+1=561.
[00126] Example 251 1-(4-fluorophenyl)-8-{ [2-(4-methylpiperazin- 1 -yl)isonicotinoyl] amino } -4,5-dihydro- 1 H-benzo[g] indazole-3-carboxamide = F

):~Y H N N N O
\ \
O I /
/NJ

[00127] Step 1 8-[ (2-chloroisonicotinoyl) amino] - 1 -(4-fluorophenyl)-4,5-dihydro- 1 H-benzo[g]indazole-3-carboxamide F

O
N N
H
CI / N \ \

This material was prepared from Example 244 (8-amino-l-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide) and 2-chioroisonicotinic acid by the method described for Example 246 step 3.

[00128] Step 2 The material from step 1 (2.17 mmoles) and N-methyl piperazine (32.9 mmoles) were dissolved in 5.0 mL N,N-dimethylacetamide. The reaction mixture was then placed under nitrogen and stirred in an oil bath at 100 C for 88 h. The mixture was partially stripped of solvent then added to water, filtered, and washed with water. The solid was then dissolved in acetonitrile, decolorized with decolorizing carbon, and dried over anhydrous MgSO4.

The solvent was stripped, then the solid residue was recrystallized from acetonitrile. Mp:
277-279 C. 1H NMR (400 MHz, d6-DMSO): S 2.17 (s, 3H); 2.35 (t, 4H, J = 5 Hz);
2.82-2.95 (m, 4H); 3.47 (t, 4H, J = 5 Hz); 6.85 (d, 1H, J = 5 Hz); 7.01 (s, 1H);
7.21-7.44 (m, 6H); 7.50-7.59 (m, 3H); 8.16 (d, 1H, J = 5 Hz); 10.10 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): S 20.32, 29.69, 45.20, 46.46, 55.00, 105.43, 111.23, 115.50, 117.07, 117.30, 120.66, 121.37, 126.54, 128.60, 128.69, 129.48, 133.36, 136.82, 136.85, 137.70, 139.71, 143.19, 144.36, 148.89, 159.88, 161.37, 163.81, 164.44, 165.15. M + 1 526.

[00129] Example 252 8- { [5-chloro-2-(4-methyl- 1,4-diazepan- 1 -yl)isonicotinoyl] amino } -1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide F llz:~

H N_N

O N ID~
CI J
N N
C
'N
The title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 248 (1 g, 0.0020 mol) and 1-methylhomopiperazine (4.6 g, 0.040 mol). The reaction was run at 95 C for 24 h. After allowing the reaction mixture to cool, the volatiles were removed under vacuum. The residue was triturated with H2O to yield 0.899 g of the title compound as a tetrahydrate (yield: 71%). 1H
NMR (300 MHz, d6-DMSO): S 1.81-1.83 (m, 2H), 2.21 (s, 3H), 2.41 (t, 2H, J= 5.5 Hz), 2.53 (t, 2H, J
= 4.56 Hz), 2.87-2.93 (m, 4H), 3.53 (t, 2H, J = 5.5 Hz), 3.63-3.67 (m, 2H), 6.62 (s, 1H), 7.19 (d, 1H, J = 1.9 Hz), 7.27-7.38 (m, 4H), 7.42-7.45 (dd, IH, J= 8.12 Hz, 1.88 Hz), 7.53-7.58 (m, 3H), 8.07 (s, 1H), 10.31 (s, 1H). M + 1= 575.
[00130] Example 253 8-[(5-chloro-2-piperazin-1-ylisonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g] indazole-3-carboxami de F a H N-N
O N I \ \ ~ CONH2 CI

N N' ~~NH
The title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 248 (lg, 0.0020 mol) and piperazine (3.44g, 0.040 mol) in 5 mL of EtOH. The reaction was run at 100 C for 24 h. The off-white precipitate that formed in the crude reaction mixture was filtered and washed with EtOH to afford 0.579 g of title compound (yield: 53%). 1H NMR (300 MHz, d6-DMSO): 2.67 (t, 4H, J=
4.9 Hz), 2.85-2.90 (m, 4H), 3.36 (t, 4H, J= 4.9 Hz), 6.80 (s, 1H), 7.18-7.19 (m, 1H), 7.25 (s, 1H), 7.27-7.35 (m, 3H), 7.37-7.39 (dd, 1H, J = 8 Hz, 2Hz), 7.51-7.55 (m, 3H), 8.09 (s, 1H), 10.28 (s, 1H). M= 1= 547 [00131] Example 254 8-( { 5-chloro-2-[[2-(dimethylamino)ethyl] (methyl)amino]isonicotinoyl }
amino)-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide F

N-N

CI / I /
ZI
N N~
~-N

The title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 248 (0.8 g, 0.0016 mol) and N,N,N'-trimethylethylene diamine (3.3 g, 0.032 mol). The reaction was run at 100 C for 24 h. After removal of the volatiles under vacuum, the residue was partitioned between water and CH2C12.
The organic layer was washed an additional time with water and dried over MgSO4.
The crude product mixture was purified by preparative HPLC to give 0.424 g of the title product, yield: 47%. 1H NMR (400 MHz, d6-DMSO): 2.13 (s, 6H), 2.34 (t, 2H, J = 6.7 Hz), 2.87-2.95 (m, 4H), 2.96 (s, 3H), 3.59 (t, 2H, J = 6.7 Hz), 6.58 (s, IH), 7.2 (d, 1H, J = 2Hz), 7.27 (s, 1H), 7.29-7.37 (m, 3H), 7.41-7.44 (dd, 1H, J = 8 Hz, 2 Hz), 7.53-7.58 (m, 3H), 8.13 (s, 1H), 10.36 (s, 1H). M + 1= 563.

[00132] Example 255 8- {[(3-chloro-6-morpholin-4-ylpyridin-2-yl)carbonyl] amino } - 1-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide F
CI
N_N
(~N N CONH2 IO~ I
[00133] Step 1 3-chloro-6-morpholinyl-2-pyridine carboxylic acid ci ~ ~
N N OH
O

3,6 Dichloropyridine-2-carboxylic acid (0.55g, 2.86 mmol), morpholine (1.37g, 15.7 mmol) and N,N dimethylacetamide (1.37 mL) were combined and stirred for 24 h at 80 C. An additional volume of morpholine (1.39 g, 15.7 mmol) was added and heating continued for 40 hours more. After cooling the DMA was removed in the presence of toluene. The residue was dissolved in water and extracted with ether to remove excess morpholine. The aqueous was acidified to pH = 2 and the product extracted into ether.
Crystallization from water gave a white solid, 369 mg (53% yield). 1H NMR
(CD3OD): S
3.52 (t, 4H), 3.78 (t, 4H), 6.97 (d, l H), 7.65 (d, l H). LC-MS, M + H: 243.

[00134] Step 2 8-1 [(3-chloro-6-morpholin-4-ylpyridin-2-yl)carbonyl]amino}-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo [g]indazole-3-carboxamide F
ci I ~ H N-N
~N N N CONH2 OJ O

The title compound was synthesized from 0.294 g of 3-chloro-6-morpholinyl-2-pyridine carboxylic acid (from step 1) and (0.258 g) of the title compound of example 244 by the same procedure used for Example 211 except that HATU was replaced by HBTU
(BF4).

The title compound is a brown solid (0.37 g, 84%), m.p. 252-254 C. Its structure was confirmed by 1H NMR and LC/MS: 1H NMR (CDC13): S 2.95 (m, 2H), 3.12 (m, 2H), 3.48 (m, 4H), 3.88 (m, 414), 5.39 (s, 1H), 6.65-6.82 (m, 3H), 7.16 7.18-7.23 (m, 3H), 7.43-756 (m, 3H), 7.62 (m, 1H), 9.18 (s, IH). ESI mass spectrum for C28H25C1FN6O3+: 547 (M +
1).
[00135] Example 256 8-( { [3-chloro-6-(4-methylpiperazin-1-yl)pyridin-2-yl]carbonyl } amino)-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide F
CI
N-N
rNI N-- N CONH2 O

The title compound was synthesized from 0.501 g of 3-chloro-6-piperazinyl-2-pyridine carboxylic acid, obtained by acidification of its K-salt (from step 1 of Example 217), and the title compound of Example 244 (0.37 g) by the same procedure used for Example 217.

The title compound is a brown solid (0.56 g, 88%), m.p. 218-220 C. Its structure was confirmed by 'H NMR and LC/MS: 'H NMR (d6-DMSO): 8 2.19 (s, 3H), 2.38 (m, 4H), 2.85 (m, 4H), 3.45 (m, 4H), 6.95 (d, 1H, J = 9 Hz), 7.20 (d, 1H, J = 2 Hz), 7.26-7.40 (m, 4H), 7.49-7.62 (m, 4H), 7.63 (d, 1H, J = 9 Hz), 10.20 (s, 1H). ESI mass spectrum for C29H28C1FN7O2+: 560 (M + 1).

[00136] Example 257 8- { [(3-chloro-6- { [2-(dimethylamino)ethyl]thio }pyridin-2-yl)carbonyl]amino }-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide F
CI
N~ Nr N N-N

; S

[00137] Step 1 2-[(6-carboxy-5-chloropyridin-2-yl)thio]-N,N-dimethylethanaminium chloride cl ci I O
g N
i~H OH
3,6-Dichloropyridine-2-carboxylic acid (1.0g, 5.23 mmol.), sodium hydroxide (1.64g, 15.7 mmol.), and anhydrous THF (10 mL) were combined before slowly adding the N,N-dimethylaminoethanethiol (1.9 g, 18.3 mmol). After stirring for several hours under nitrogen, two aliquots of DMF (101nL each) were added. Several hours later, additional DMF (10 mL) and dimethylaminoethanethiol (1.9 g, 18.3 mmol) were added. The reaction was stirred overnight at room temperature. The solution was diluted with water and extracted three times with methylene chloride. The aqueous was acidified to pH
5 and extracted four times with methylene chloride. The aqueous was acidified to pH
1, the solvent was removed, and the residue was recrystallized from hot water. Yellow solid, 0.786 g (51% yield). 1H NMR (300 MHz, CD3OD): S 2.98 (s, 6H), 3.53 (m, 4H), 7.50 (d, 1H), 7.85 (d, 1H). 13C NMR (75 MHz, CD3OD): S 24.4, 42.8, 58.2, 125.7, 128.1, 140.0, 147.3, 158.2, 166Ø

[00138] Step 2 8-{ [(3-chloro-6-{ [2-(dimethylamino)ethyl]thio }pyridin-2-yl)carbonyl]amino}-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide F
CI \
N-N
N )C(Y- CONH2 o 10 The title compound was synthesized from 0.355 g of the title compound of Step 1 and the title compound of Example 244 (0.32 g) by the same procedure used in Example 255. The title compound is a white solid (0.49 g, 87%). Its structure was confirmed by 1H NMR and LC/MS: 1H NMR (CD3CN): S 2.18 (s, 6H), 2.57 (m, 2H), 2.85 (m, 4H), 3.00 (m, 4H), 3.26 (m, 2H), 5.88 (s, 1H), 6.94 (d, 1H), 7.27-7.38 (m, 5H), 7.47-7.62 (m, 3H), 7.69 (d, 1H, J
9 Hz), 9.40 (s, 1H). ESI mass spectrum for C28H27CIFN6O2S+: 565 (M + 1).

[00139] Example 258 N-N

CI

N' This compound was synthesized by using the same procedure described for Example 221;
mp: 194-195 C; 1HNMR (DMSO + TFA-d, 400 MHz) S: 10.24 (s, 1H), 9.69 (s, 1H), 7.60 (m, 2H), 7.46 (d, J = 4.2 Hz, 1H), 7.38 (m, 411), 7.10 (dd, J= 2.6, 8.9 Hz, 1H), 7:06 (s, 1H), 3.90 (d, J = 13.0 Hz, 2H), 3.50 (d, J = 12.0 Hz, 2H), 3.12 (m, 2H), 2.95 (m, 411), 2.91 (s, 3H), 2.86 (s, 2H).

[00140] The IKK2 bioactivity for Examples 245-257 is shown in Table 7.
Table 7 Structure Mol. Wt. Compound Name(s) IKK2 Example Resin IC50 F 511.56 1-(4-fluorophenyl)-8- <1 M 245 Q {[(2-piperazin-l-N-N ylpyridin-3-~-> o N yl)carbonyl]amino}-4,5-N \ NHZ dihydro-lH-N benzo[g]indazole-3-carboxamide F 475.91 8-{ [(6-chloro-4- <1 M 246 methylpyridin-3-c' / N-N o yl)carbonyl]amino}-1-(4-N. fluorophenyl) 4,5-0 NH2 dihydro-lH-benzo[g]indazole-3-carboxamide F 526.58 1-(4-fluorophenyl)-8- <1 M 247 ~ ~ { [(4-methyl-6-morpholin-N N I N N-N 4-ylpyridin-3-yl)carbonyl]amino}-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide F 496.33 8-[(2,5- <1 M 248 dichloroisonicotinoyl)ami N ci N N-N o no]-1-(4-fluorophenyl)-ci 4,5-dihydro-lH-0 NHz benzo[g]indazole-3-carboxamide F 546.99 8-[(5-chloro-2-morpholin- <1 M 249 4-ylisonicotinoyl)amino]-N C1 y N-N 1-(4-fluorophenyl)-4,5-rN N dihydro-lH-'J benzo[g]indazole-3-carboxamide F 560.04 8-{[5-chloro-2-(4- <1 M 250 / methylpiperazin-l-ci 0 N-N NH yl)isonicotinoyl]amino}-N Z 1-(4-fluorophenyl)-4,5-N I ~ dihydro-lH-CNJ \ benzo[gjindazole-3-carboxamide N

F 525.59 1-(4-fluorophenyl)-8-{[2- <1 M 251 (4-methylpiperazin-l-N N-N o yl)isonicotinoyl]amino}-~N J o NHz 4,5-dihydro-lH-benzo[gjindazole-3-carboxamide F 574.06 8-{ [5-chloro-2-(4-methyl- <1 M 252 1,4-diazepan-l-ci 0 N-N yI)isonicotinoyljamino}-H ~ N ~~ NHZ 1-(4-fluorophenyl)-4,5-N dihydro-lH-C benzo[g]indazole-3-carboxamide N

F 546.01 8-[(5-chloro-2-piperazin- <1 M 253 1 1-ylisonicotinoyl)amino]-ci o N-N 1-(4-fluorophenyl)-4,5-N ~ NHz dihydro-lH-N benzo[g]indazole-3-CN\ carboxamide NJ
H
F 562.05 8-({5-chloro-2-[[2- <1 M 254 (dimethylamino)ethyl](m ci 0 N-N ethyl)amino]isonicotinoyl } amino)-1-(4-NHZ
N fluorophenyl)-4,5-~N\ dihydro-lH-benzo[g]indazole-3-N
carboxamide F_ 546.99 8-{ [(3-chloro-6- 1< 10 M 255 cI ~ / morpholin-4-ylpyridin-2-~ H N-" yl)carbonyl]amino}-1-(4-N"N-/~( N coNHz fluorophenyl)-4,5-01-li O dihydro-lH-benzo[g]indazole-3-carboxamide F_ 560.04 8-({[3-chloro-6-(4- <1 M 256 \ ~i I methylpiperazin-l-~N I N N N CON~ yl)pyridin-2-NJ o I yl]carbonyl}amino)-1-(4-~ fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide F_ 565.07 8-{[(3-chloro-6-{[2- <1 M 257 c, ~ ~ (dimethylamino)ethyl]thi ON~~S N q \\N caNHi o}pyridin-2-o yl)carbonyl]amino}-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide I 559.05 8-{ [2-chloro-5-(4- <1 M 258 methylpiperazin-l-O N N-N yl)benzoyl]amino}-1-(4-~ CONH2 fluorophenyl)-4,5-c- dihydro-lH-benzo[g]indazole-3-carboxamide ~ a______________ [00141] Examples 259-263 Examples 259-263 were synthesized with the corresponding starting compounds using the following synthesis procedures similar to scheme I where R9 is the appropriate aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or cycloalkyl.

14112?PCT

N-N OEt arYihydrazine O AcOH, fl 02N O
OEt OZN O
~...
ethyl(7-nitro-1-o)(O 1,2,3, 4-tetrahydronaPhthalen 2 Yl) (Oxo)acetate 1 2 RiC-U/
2 NH3, MeOH N-N NH2 Pd(OH)2 OEt 700 H2N
t t2 HaN O

2.
R1 ~d N-N NHz HATl, or R9COaH, O
0 R9COCi PYridine SCHEME XXVII

~
0 0 ~\ NHNH2'HCI N-N OEt O2N OEt R ; / O2N ~
\ I O \ ~ O
ethyl (7-nitro-l-oxo-1,2,3, AcOH, reflux 4-tetrahydronaphth ale n-2-yl) (oxo)acetate 1 HO \ I HO CQ P

d(OH)2 N-N OEt NH3, MeOH N-N NH2 - - ~ 2 H
2 H2N \ I \ O 700 psi H2N OJ \ O
TBDMSOQF/ TB
DMSCI, imidazole N-N 1) R9CO2H, HATU

DMF, RT H2N / I \
O 2) TBAF/THF
HO \ I R10 \

H N-N NH2 RiCI or R"OTs H N-N NH2 O\/N / I \ O Base, DMF O~N / I \ O
'R( \ R
OH

MeOH, reflux ON

R = 3- or 4-benzyloxyl [00142] Example 259 1- [4-(benzyloxy)phenyl]-8- [(2-chlorobenzoyl)amino] -4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide 0,, ~I
N-N
N ~ ~ I CONHZ
Cj I /

[00143] St~: A mixture of 4-benzyloxylphenylhydrazine hydrochloride (6.42 g, 0.03 mol) and ethyl (7-nitro-l-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate 1 (9.2 g, 0.03 mol) in 200 mL of acetic acid was refluxed for 16 h, then cooled to room temperature. The precipitate was collected by filtration and air-dried to give 8.5 g of product as a light green solid (60% yield); 1HNMR
(DMSO, 400 MHz) S: 8.07 (dd, 1H), 7.66 (d, 1H), 7.35-7.53 (m, 8H), 7.24 (dd, 2H), 5.26 (s, 2H), 4.32 (q, 2H), 3.11 (m, 2H), 3.30 (m, 2H), 1.32 (t, 3H).

[00144] Step 2: A mixture of the product from step 1(15.0 g, 0.032 mol) and tin chloride (21.6 g, 0.096 mol) in 400 mL of ethanol was heated at reflux overnight. Another two equivalent of tin chloride was added and stirred for 6 h.
The reaction mixture was cooled to room temperature and the precipitate was filtered and washed with ether to give 13.5 g of the amine as a light yellow solid (96% yield); 1HNMR (DMSO, 400 MHz) 8: 8.07 (dd, 1H), 7.66 (d, 1H), 7.35-7.53 (m, 8H), 7.24 (dd, 2H), 5.26 (s, 2H), 4.32 (q, 2H), 3.11 (m, 2H), 3.30 (m, 2H), 1.32 (t, 3H).

[00145] Step 3: A sealed reaction vessel containing the product from step (6.2 g, 0.014 mol) and 40.mL of liquid ammonia in 200 mL of absolute alcohol was heated at 120 C and 600 psi for 24 h. After cooling, solvent was removed and the residue was purified by chromatography on silica gel (ethyl acetate/hexane, 6:4) to give 4.0 g of product as a pale yellow solid (70% yield); 1HNMR (CDC13, 400 MHz) b: 7.35-7.47 (m, 7 H), 7.07 (m, 3H), 6.81 (s, 1H), 6.50 (dd, 1H), 6.07 (d, 1H), 5.49 (s, 1H), 5.15 (s, 2H), 3.37 (s, 2H), 3.08 (m, 2H), 2.86 (m, 2H).

[00146] Step 4: To a solution of the product from step 3(7.08 g, 0.017 mol) in 100 mL of pyridine was added 2-chlorobenzoyl chloride (3.4 g, 0.019 mol) in one portion and the reaction mixture was stirred at room temperature overnight.
Solvent was removed and the residue was stirred with water. The precipitate was collected by filtration and air-dried to give 7.5 g of product as a white solid (80%
yield);

1HNMR (DMSO, 400 MHz) 8: 10.29 (s, 1H), 7.15-7.51 (m, 18 H), 5.16 (s, 2H), 2.90 (m, 4H); Anal. Calcd. for C32H25C1N403: C, 70.01; H, 4.59; N, 10.20.
Found:
C, 69.62; H, 4.44; N, 10.24.

[00147] Example 260 1-[4-(benzyloxy)phenyl]-8- { [(2-chloropyridin-3-yl)carbonyl] amino 1-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide r ~ ' N-N

N'~
CI / / r This compound was synthesized by following the same procedure as Example 259 except using 2-chloronicotinyl chloride in step 4; 1HNMR (DMSO, 400 MHz) S:
10.42 (s, 1H), 8.50 (d, 1H), 7.96 (d, 1H), 7.16-7.54 (m, 15H), 5.16 (s, 2H), 2.93 (m, 4H); Anal. Calcd. for C31H24C1N503: C, 67.70; H, 4.40; N, 12.73. Found: C, 66.75;
H, 4.17; N, 12.41.
[00148] Example 261 8-[(2-chlorobenzoyl)amino]-1-(4-hydroxyphenyl)-4,5-dihydro-lH-benzo [g] indazole-3-carboxamide HO,,a N-N
N \ \ I CONH2 CI /

The final product from Example 259 (7.5 g, 0.014 mol) was dissolved of TFA
(120 mL) and the dark brown solution was stirred at room temperature for 84 h.
Solvent was removed and the residue was taken up with 200 mL of water. The solid was collected and air-dried to give 6.5 g of product as a pale white solid (83%
yield);
'HNMR (DMSO, 400 MHz) S: 10.29 (s, 1H), 9.84 (s, 1H), 7.24-7.51 (m, 11 H), 6.87 (d, 2H), 2.90 (m, 4H); Anal. Calcd. for C25H19C1N4O3 + 1.0 H20: C, 62.96;
H, 4.44; N, 11.75. Found: C, 62.92; H, 4.28; N, 11.76.
[00149] Example 262 8-[(2-chlorobenzoyl)amino]-1-(3-hydroxyphenyl)-4,5-dihydro-1 H-benzo [g] indazole-3 -carboxamide OH

N
bN- H
~
O N \ \ CONH2 CI I /

This compound was synthesized by following the same procedure as Example 261 except using 3-benzyloxyphenyhydrazine hydrochloride in step 1; 1HNMR (DMSO, 400 MHz) S: 10.31 (s, 1H), 7.27-7.54 (m, lOH), 6.89 (m, 3H), 2.92 (m, 4H);
Anal.
Calcd. for C25HI9C1N403 + 0.5 H20: C, 64.17; H, 4.31; N, 11.97. Found: C, 64.29;
H, 4.36; N, 11.63.

[00150] Example 263 8- { [(2-chloropyridin-3-yl)carbonyl] amino }-1-(4-hydroxyphenyl)-4,5-dihydro-lH-benzo [g]indazole-3-carboxamide HO a I

N-N
O N ~ CONH2 CI I i N~ I
This compound was synthesized by following the same procedure as Example 261 except using 2-chioronicotinyl chloride in step 4; 1HNMR (DMSO, 400 MHz) b:
10.31 (s, 1H), 7.27-7.54 (m, 10H), 6.89 (m, 3H), 2.92 (m, 411); Anal. Calcd.
for C24H18C1N5O3: C, 62.68; H, 3.95; N, 15.23. Found: C, 62.03; H, 3.89; N, 14.83.

[00151] The bioactivity in the IKK2 resin assay of Examples 259-263 is shown Table 8.

Table 8 Compound No., Structure Mol. Compound Name(s) IKK2 MS Example Wt. Resin (M+H) \ 549.03 1-[4-(benzyloxy)phenyl]-8-[(2- > 10 550 259 ~ ~ chlorobenzoyl)amino]-4,5-/ N-~ dihydro-lH-benzo[g]indazole- PM
b / \ N"~ 3-carboxamide ci~ \ ~ o 550.02 1-[4-(benzyloxy)phenyl]-8- 1< 10 551 260 {[(2-chloropyridin-3- M
\ yl)carbonyl]amino}-4,5-I / dihydro-lH-benzo[g]indazole-I / N-N 3-carboxamide cl \ \ I O

Compound No., Structure Mol. Compound Name(s) IKK2 MS Example Wt. Resin (M+H) 458.91 8-[(2-chlorobenzoyl)amino]-1- <1 gM 459 261 (4-hydroxyphenyl)-4,5-"o \ dihydro-lH-benzo[g]indazole-N-N 3-carboxamide O N 1 NHa CI~ I / O

458.90 8-[(2-chlorobenzoyl)amino]-1- <1 M 459 262 (3-hydroxyphenyl)-4,5-o" dihydro-lH-benzo[g]indazole-I 3-carboxamide N-N
O N ~ NFL
CI \ \ O

459.89 8-{[(2-chloropyridin-3- <1 M 460 263 yl)carbonyl] amino } -1-(4-"o \ hydroxyphenyl)-4,5-dihydro-I
" / N-N 1H-benzo[g]indazole-3-0 N NHz carboxamide CI \ \ O
I
N

[00152] Example 264 8-[(2-chlorobenzoyl)amino]-1-[4-(2-morpholin-4-ylethoxy)phenyl]-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide N~~O
~ HN' IN
O N ~ ~ CONH2 To a suspension of the product from Example 261 (0.6 g, 0.001 mol) and cesium carbonate in 10 mL of DMF was added 4-(2-chloroethyl)morpholine hydrochloride (0.19 g, 0.001 mol) in one portion. The reaction mixture was stirred at room temperature overnight. After the removal of solvent, the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. This crude was purified by HPLC to give 0.15 of product as a light yellow (26% yield);1HNMR (DMSO, 400 MHz) S:

11.49 (brs, 1H), 10.33 (s, 1H), 7.14-7.54 (m, 10H), 4.53 (s, 2H), 3.82 (m, 2H), 3.58 (m, 8H), 3.08 (m, 2H), 2.93 (m, 4H); Anal. Calcd. for C31H30C1N5041.0 H20- 1.0 HC1: C, 59.43; H, 5.31; N, 11.18. Found: C, 59.58; H, 5.26; N, 10.92.
[00153] Example 265 8-[(2-chlorobenzoyl)amino]-1-{ 4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]phenyl }-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide oJ,o \ I N-N

CI

This compound was synthesized by following the same procedure as Example 264 except using 2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate (78%
yield);
1HNMR (CDC13, 400 MHz) 5: 7.69 (d, 1H), 7.59 (m, 211), 7.44 (d, 2H), 7.30-7.40 (m, 3H), 7.05 (d, 211), 6.83 (d, 2H), 4.52 (m, 1H), 4.13 (m, 2H), 4.02 (m, 2H), 3.93 (m, 2H), 3.14 (m, 2H), 2.98 (m, 2H), 1.46 (s, 3H), 1.26 (s, 3H); Anal. Calcd.
for C31H29C1N405: C, 64.98; H, 5.10; N, 9.78. Found: C, 64.56; H, 4.97; N, 9.68.
[00154] Example 266 8-[(2-chlorobenzoyl)amino]-1-[4-(2,3-dihydroxypropoxy)phenyl]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide OH
HO,,~,,O~

N-N
O N ~ Z~-, CONH2 CI I i To a suspension of the product from Example 265(0.36 g, 0.00063 mol) in methanol was added 1N HC1 and the mixture was heated at reflux for 16 h.
Solvent was removed and the crude was recrystallized from water and methanol to give 0.24 g of the desired product as a white solid (72%); 'H NMR (DMSO, 400 MHz) S:
10.30 (s, 1H), 7.36-7.57 (m, 6H), 7.33 (d, 1H), 7.28 (brs, 1H), 7.18 (d, 1H), 7.09 (d, 2H), 4.98 (d, 1H), 4.68 (t, 1H), 4.10 (q, 1H), 4.05 (dd, 1H), 3.92 (dd, 1H), 3.83 (m, 1H), 3.45 (t, 1H), 3.16 (d, 2H), 2.94 (m, 4H); Anal. Calcd. for C28H25C1N405:
C, 63.10; H, 4.73; N, 10.51. Found: C, 62.81; H, 4.45; N, 10.16.

[00155] The compounds of Examples 267-275 were synthesized as described in Example 264 using the appropriate aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted arylalkyl, substituted heteroarylalkyl, or cycloalkyl.

[00156] The bioactivity in the IKK2 Resin assay for the compounds of Examples 264-275 is shown in Table 9.

Table 9 Compound No., Structure Mol. Compound Name(s) IKK2 MS Example Wt. Resin (M+H) o N-N 572.07 8-[(2-chlorobenzoyl)amino]-1- <1 M 573 264 ~ J 1 [4-(2-morpholin-4-0v~
o r", I N~ ylethoxy)phenyl]-4,5-dihydro-cJ 1 0 1H benzo[g]indazole 3 1 carboxamide 573.05 8-[(2-chlorobenzoyl)amino]-1- <1 M 574 265 'xo {4-[(2,2-dimethyl-1,3-~ 1 N-N dioxolan-4-o r, NF~ yl)methoxy]phenyl}-4,5-ci 1 o dihydro-lH-benzo[g]indazole-~ 1 3-carboxamide Ho 532.99 8-[(2-chlorobenzoyl)amino]-1- <1 M 533 266 HoD~"c i [4-(2,3-~ 1 N-N dihydroxypropoxy)phenyl]-4,5-0 rNi ~ 6 fl NH, dihydro-1H-benzo[g]indazole-ci e 1 ~ 0 3-carboxamide Compound No., Structure Mol. Compound Name(s) IKK2 MS Example Wt. Resin (M+H) Ho 533.98 8-[(3- <1 M 534 267 Ho~ chloroisonicotinoyl)amino]-1-~ [4-(2,3-\
o r" N-N NH, dihydroxypropoxy)phenyl]-4,5-c,~ o dihydro-lH-benzo[g]indazole-l= 3-carboxamide N

Ho 611.08 8-{[2-chloro-4- <1 M 612 268 Ho~ (methylsulfonyl)benzoyl]amino N-N }-1-[4-(2,3-w NH, dihydroxypropoxy)phenyl]-4,5-ci (.~ o dihydro-lH-benzo[g]indazole-~ 3-carboxamide 0=5.

Ho 548.00 8-[(5-amino-2- <1 M 548 269 Ho~ chlorobenzoyl)amino]-1-[4-~ N-N (2,3-o r, , NHz dihydroxypropoxy)phenyl]-4,5-ci o dihydro-lH-benzo[g]indazole-~ ~ 3-carboxamide NHz Ho 533.98 8-([(2-chloropyridin-3- <1 M 534 270 Ho~ yl)carbonyl]amino}-1-[4-(2,3-~ I N-N dihydroxypropoxy)phenyl]-4,5-o rHi NHz dihydro-lH-benzo[g]indazole-ci~ 0 3-carboxamide N_\J~
N''1 530.03 8-[(2-chlorobenzoyl)amino]-l- 1< 10 530 271 H I N-N {4-[2-.~
0 N NHz (dimethylamino)ethoxy]phenyl M
C1 ~ }-4,5-dihydro-lH-~~
benzo[g]indazole-3-carboxamide 544.06 8-[(2-chlorobenzoyl)amino]-1- 1< 10 544 272 -N-~, O
- {4-[3 M
o H \ ~ N N N NHz (dimethylamino)propoxy]pheny C1 ~ ~ 0 1}-4,5-dihydro-lH-~ benzo[g]indazole-3-carboxamide 4 651.14 8-{[2-chloro-4- 1 < 10 651 273 s' ~ O (methylsulfonyl)benzoyl]amino M
N-N }-1-{4-[(2,2-dimethyl-l,3-~ON):~~NH, dioxolan-4-C1 yl)methoxy]phenyl}-4,5-dihydro-1 H-benzo [g] indazole-o 3-carboxamide Compound No., Structure Mol. Compound Name(s) IKK2 MS Example Wt. Resin (M+H) \~ 574.04 8-{[(2-chloropyridin-3- 1< 10 574 274 ~' ~ 0 yl)carbonyl]amino}-1-{4-[(2,2- M
H N-N dimethyl-1,3 dioxolan 4 C1" I "", yl)methoxy]phenyl}-4,5-N I dihydro-lH-benzo[g]indazole-3-carboxamide '1/'0 574.04 8-[(3- 1< 10 574 275 6N-N chloroisonicotinoyl)amino]-1-{3-[(2,2-dimethyl-1,3- M
" JI ""2 dioxolan-4-C1 ~ yl)methoxy]phenyl}-4,5-" dihydro-lH-benzo[g]indazole-3-carboxamide [001571 Example 276 8-[(2-chlorobenzoyl)amino]-1-(4-cyanophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide HO~

N-N
H

CI

[00158] Stepl: The product (45.0 g, 0.096 mol) from step 1 of Example 261 was hydrogenated in 400 mL of acetic with Pd(OH)2/C as catalyst for 17 h under 15 psi in a Parr shaker. After the removal of solvent, the residue was triturated with a mixture of methanol and ether (1:2) to give 23.0 g of the desired product as a white solid (68% yield); 1HNMR (DMSO, 400 MHz) 8: 10.06 (s, 1H), 7.27 (d, 2H), 6.98 (d, 1H), 6.92 (d, 2H), 6.43 (dd, 1H), 6.02 (d, 1H), 4.82 (brs, 2H), 4.29 (q, 2H), 2.75 (m, 2H), 1.30 (t, 3H).

[00159] Step 2: A sealed reaction vessel containing the product from step 1 (25.0 g, 0.072 mol) and 40 mL of liquid ammonia in 250 mL of absolute alcohol was heated at 120 C and 600 psi for 30 h. After cooling, the precipitate was collected by filtration to give 16.7 g of product as a pale yellow solid (73%
yield);
1HNMR (CDC13, 400 MHz) S: 7.44 (s, 1H), 7.27 (d, 2H), 7.20 (s, 1H), 6.97 (d, 1H), 6.91 (d, 2 H), 6.40 (d, 1H), 6.03 (s, 1H), 4.77 (brs, 2H), 2.85 (m, 2H), 2.72 (m, 2H).

[00160] Step 3: To a solution of the product form step 1 (5.25 g, 0.016 mol) and TBDMSCI (3.0 g, 0.02 mol) in 100 mL of DMF was added imidazole (2.72 g, 0.04 mol) in one portion. The reaction mixture was stirred at room temperature for 36 h. Solvent was removed and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. This crude was purified by chromatography on silica gel (ethyl acetate/hexane, 1:1) to give 4.0 g of product as a white solid (57% yield).
The NMR was consistent with the proposed structure.

[00161] Step 4: To a mixture of the product from step 3 (1.05 g, 0.0024 mol) and 2-chloro-4,5-methylenedioxanylbenzoic cid (0.73 g, 0.0036 mol) in 25 mL of DMF was added 1 mL of diisopropylethylamine, followed by the addition of HATU
(1.37 g, 0.0036 mol). The reaction was stirred at room temperature for 16 h and concentrated. The residue was partitioned between water and ethyl acetate and the organic phase was concentrated. This crude was then dissolved in 20 mL of THF
and treated with 10 eq of TBAF for lh at RT. After the removal of solvent, the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and triturated with a mixture of acetonitrile to give 1.04 g of desired product as an off-white solid (86% yield);1HNMR (DMSO, 400 MHz) S: 10.17 (s, 1H), 9.85 (s, 1H), 7.47 (m, 2H), 7.27 (m, 5H), 7.14 (s, 1H), 7.04 (s, 1H), 6.88 (d, 2H), 6.12 (s, 2 H), 2.92 (m, 4H).

[00162] Example 277 8- { [(6-chloro-1,3-benzodioxol-5-yl)carbonyl]amino}-1-(3-hydroxyphenyl)-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide OH
/ I

\ N-N
O N ~ I CONH2 CI I /

O

This compound was synthesized by following the same procedure as Example 276 except using 3-benzyloxyphenyhydrazine hydrochloride in step 1; iHNMR (DMSO, 400 MHz) S: 10.19 (s, 1H), 9.86 (s, 1H), 7.51 (m, 2H), 7.31 (m, 3H), 7.24 (d, 1H), 7.14 (s, 1H), 7.04 (s, 1H), 6.88 (m, 3H), 6.12 (s, 2 H), 2.91 (m, 4H); Anal.
Calcd.
for C26H19C1N405: C, 62.10; H, 3.81; N, 11.14. Found: C, 61.52; H, 3.53; N, 11.11.
[00163] Example 278 8-[(2-chloro-5-nitrobenzoyl)amino]-1-(4-hydroxyphenyl)-4,5-dihydro-lH-benzo [g] indazole-3-carboxamide HO,~Ci N-N
H ~
0- N ~ ~ CONH2 CI I /

This compound was synthesized by following the same procedure as Example 276 except using 2-chloro-5-nitrobenzoic acid in step 4; Anal. Calcd. for C25H18C1N505'1.5 H20: C, 56.56; H, 3.99; N, 13.19. Found: C, 56.89; H, 4.45;
N, 12.81.

[00164] Example 279 8-{ [2-chloro-5-(methylsulfinyl)benzoyl]amino}-1-(4-hydroxyphenyl)-4,5-dihydro-1H-benzo [g]indazole-3-carboxamide CLNN
H I
O N CONHZ
CI SOMe This compound was synthesized by following the same procedure as Example 276 except using 2-chloro-5-(methylthio)benzoic acid in step 4 and then oxidized to the desired product with mCPBA; 'HNMR (DMSO, 400 MHz) 8: 10.43 (s, 1H), 9.85 (s, 1H), 7.26-7.79 (m, 10H), 6.88 (d, J = 8.5 Hz, 2H), 2.92 (m, 4H), 2.80 (s, 3H);
Anal. Calcd. for C26H21C1N404S: C, 59.94; H, 4.06; N, 10.75; S, 6.15. Found:
C, 59.48; H, 4.09; N, 10.54; S, 6.18.

[00165] Example 280 8- [ (5-amino-2-chlorobenzoyl) amino] -1-(4-hydroxyphenyl)-4,5-dihydro-1 H-benzo [g] indazole-3 -carboxamide N-N
0 N ~ CONH2 CI

This compound was synthesized by following the same procedure as Example 276 except using 5-[(tert-butoxycarbonyl)amino]-2-chlorobenzoic acid in step 4 and then deprotected with 4N HCI in dioxane; 1HNMR (DMSO, 400 MHz) 8: 10.19 (s, 1H), 9.84 (s, 1H), 7.49 (d, 1H), 7.46 (d, 1H), 7.28-7.31 (m, 5H), 7.12 (d, 1H), 6.88 (d, 2H), 6.64 (m, 2H), 2.90 (m, 4H), 2.80; Anal. Calcd. for Ca5H2OC1N5O3'3.0 H20:
C, 56.87; H, 4.96; N, 13.26. Found: C, 56.18; H, 5.10; N, 13.09.

[00166] The compounds of Examples 281-287 listed in the Table 10 were prepared according to the procedure of Example 276 using the appropriate acylating agent.

[00167] The bioactivity in the IKK2 Resin assay for the compounds of Examples 276-287 is shown in Tab1e10.

Table 10 Compound No., Structure Mol. Compound Name(s) IKK2 MS Example Wt. Resin (M+H) HO 502.91 8-{ [(6-chloro-1,3- <1 M 503 276 _ benzodioxol-5-o r", ~ N N,6 yl)carbonyl]amino}-1-(4-oi o hydroxyphenyl)-4,5-dihydro-~ 1H-benzo[g]indazole-3-J carboxamide oH 502.92 8-{[(6-chloro-1,3- <1 M 503 277 6N-N benzodioxol-5-yl)carbonyl]amino}-1-(3-o r", NH, hydroxyphenyl)-4,5-dihydro-oi 0 1H-benzo[g]indazole-3-~ carboxamide o~

HO 503.91 8-[(2-chloro-5- <1 M 504 278 s _ nitrobenzoyl)amino]-1-(4-o rHi N~ N NHz hydroxyphenyl) 4,5 dihydro :rI
1H-benzo[g]indazole 3-carboxaniide O

HO 521.00 8-{ [2-chloro-5- <1 M 521 279 N-N (methylsulfinyl)benzoyl]amin o r", ~ ~ NHo}-1-(4-hydroxyphenyl)-4,5-~ o dihydro-lH-~ benzo[g]indazole-3-s carboxamide Ho 473.92 8-[(5-amino-2- <1 M 474 280 _ chlorobenzoyl)amino]-1-(4-N Z'-'I , N~ N,~ hydroxyphenyl)-4,5-dihydro 1H-benzo[g]indazole-3 ca rboxamide NHs OH 459.90 8-[(3- <1 M 460 281 6,N- chl oroisonicotinoyl)amino]-N 1-(3-hydroxyphenyl)-4,5-0 r "~ NHz dihydro-lH-c~~ o benzo[g]indazole-3-~) carboxamide N

Compound No., Structure Mol. Compound Name(s) IKK2 MS Example Wt. Resin (M+H) oH 510.38 8-[(5-amino-2- <1 M 511 282 chlorobenzoyl)amino]-1-(3-H 6 N-N hydroxyphenyl)-4,5-dihydro-o N N~ 1H-benzo[g]indazole-3-ol o carboxamide hydrochloride NHz HCI
OH 488.94 8-[(2-chloro-4- <1 M 489 283 / methoxybenzoyl)amino]-1-H N-N (3-hydroxyphenyl)-4,5-o I NHs dihydro-lH-ol o benzo[g]indazole-3-~ carboxamide o1~

OH 459.90 8-{ [(2-chloropyridin-3- <1 M 460 284 6,1-- yl)carbonyl]amino}-1-(3-N-N hydroxyphenyl)-4,5-dihydro-0 0, / ~ NHz 1H-benzo[g]indazole-3-ci o carboxamide oH 398.44 1-(3-hydroxyphenyl)-8- 1< 10 399 285 6N-N [(methylsulfonyl)amino]-4,5-dihydro-lH- pM
.r"~ NH2 benzo[g]indazole-3-0 o carboxamide OH 518.96 8-[(2-chloro-3,4- <1 M 519 286 6~N-N dimethoxybenzoyl)amino]-1-(3-hydroxyphenyl)-4,5-o rHi NHz dihydro-lH-ci benzo[g]indazole-3-o carboxamide o~

OH 473.92 8-{ [(2-chloro-4- <1 M 474 287 6,N- met hylpyridin-3-/ N yl)carbonyl]amino}-1-(3-No~/r"~ ~ NHz hydroxyphenyl)-4,5-dihydro-Tci (of 1H-benzo[g]indazole-3-carboxamide [00168] Example 288 8- { [(2-chloropyridin-3-yl)carbonyl] amino 1- 1 -(4-morpholin-4-ylphenyl)-4,5-dihydro-IH-benzo [g]indazole-3 -carboxamide O<:~N-N
N ~ ~ I CONH2 ci I /
N, This compound was synthesized in an analogous manner to Example 3 by substituting 4-morpholinylphenylhydrazine hydrochloride and 2-chloronicotinyl chloride.; 'HNMR (DMSO, 400 MHz) 8: 10.39 (s, 1H), 8.50 (d, 1H), 7.94 (d, 1H), 7.05-7.53 (m, 10H), 3.74 (m, 4H), 3.18 (m, 4H), 2.92 (m, 4H); Anal. Calcd. for C28H25C1N603: C, 63.57; H, 4.76; N, 15.89. Found: C, 63.19; H, 4.61; N, 15.48.
IKK-2 resin IC50 1<10 M.
[00169] Example 289 8-[(2-chlorobenzoyl)amino]-1- { 4-[( IE)-3-hydroxy-3-methylbut-l-enyl]phenyl }
-4,5-dihydro- IH-benzo[g]indazole-3-carboxamide OH
py N N NH2 15 CI O O

A 50 mL round bottomed flask with a magnetic stir bar was charged with 1-(4-bromophenyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (987 mg, 1.89 mmol), palladium (II) acetate (44 mg, 0.19 mmol), 1,1'-biphenyl-2-yl[di(tert-butyl)]phosphine (254 mg, 0.822 mmol), and dimethylformamide (20 mL). The resulting solution was sparged with argon for minutes. To the solution was added 2-methyl-3-buten-2-ol (823 mg, 6.07 mmol) and triethylamine (614 mg, 6.07 mmol). The solution was sparged with argon for an additional 2 minutes. The flask was sealed with a rubber septum and heated to 100 C in an oil bath for 90 minutes. The reaction was allowed to cool to room temperature and water was added. The resulting precipitate was collected and purified by silica gel chromatography (100% hexane to 100% ethyl acetate). The pure fractions were combined, concentrated to dryness, triturated with diethyl ether, and dried under vacuum to give 215 mg of 8-[(2-chlorobenzoyl)amino]-1-{4-[(lE)-3-hydroxy-3-methylbut-l-enyl]phenyl }-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (0.408 mmol, 21% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) S 1.29 (s, 6 H), 2.88-2.98 (m, 4 H), 4.76 (s, 1 H), 6.48 (d, 1 H), 6.58 (d, 1 H), 7.23 (d, 1 H), 7.30-7.50 (m, 8 H), 7.53-7.59 (m, 3 H), 10.28 (s, 1 H); MS (ESI+) for C30H27C1N403 m/z 527 (M+H)+.

[00170] The compounds of Example 290-308 listed in the Table 11 were prepared according to the procedure of Example 289 using the appropriate alkene.
[00171] The bioactivity in the IKK2 Resin assay for the compounds of Examples 289-308 is shown in Tablel 1.

Table 11 Compound No., Structure Mol. Compound Name IKK2 MS Example Wt. Resin (M+H) o" 527.03 8-[(2-chlorobenzoyl)amino]-1- <1 M 527 289 / { 4-[(1E)-3-hydroxy-3-_ methylbut-l-enyl]phenyl}-4,5-~ / dihydro-lH-benzo[g]indazole-Q--Ir H N-N NHz 3-carboxamide N

CI O

541.01 ethyl (2E)-3-(4-{3- 1< 10 541 290 o (aminocarbonyl)-8-[(2- M
o / chlorobenzoyl)amino]-4,5-~ dihydro-lH-benzo[g]indazol-l-~ / yl}phenyl)prop-2-enoate \ I CI N \N NHz \
O /

Compound No., Structure Mol. Compound Name IKK2 MS Example Wt. Resin (M+H) oH 512.96 (2E)-3-(4-{3-(aminocarbonyl)- <1 M 513 291 ~ 8-[(2-chlorobenzoyl)amino]-~ 4,5-dihydro-lH-~ / benzo[g]indazol-l-~ c+ N ~" ""2 yl}phenyl)prop-2-enoic acid o 511.97 1-{4-[(lE)-3-amino-3- <1 M 512 292 ~ oxoprop-l-enyl]phenyl}-8-[(2-~ chlorobenzoyl)amino]-4,5-cl dihydro-lH-benzo[g]indazole-\ n"~ " N"2 3-carboxamide O
O /

'N 535.01 8-[(2-chlorobenzoyl)amino]-1- <1 M 535 293 {4-[(E)-2-(1H-imidazol-l-~ yl)ethenyl]phenyl}-4,5-~ / dihydro-lH-benzo[g]indazole-/ ~ O1 H "-" NHz 3-carboxamide N
I/

o 539.00 8-[(2-chlorobenzoyl)aniino]-1- 1< 10 539 294 {4-[(E)-(2-oxodihydrofuran- M
3(2H)-ylidene)methyl]phenyl}-C1 ~ / 4,5-dihydro-lH-~ N ~" "", benzo[g]indazole-3-o I 1~ o carboxamide 513.00 8-[(2-chlorobenzoyl)amino]-1- <1 M 513 295 { 4-[( lE)-3-hydroxybut-l-~ enyl]phenyl}-4,5-dihydro-lH-benzo[g]indazole-3-ci ~ I N ~" "H= carboxamide o 513.00 8-[(2-chlorobenzoyl)amino]-1- <1 M 513 296 [4-(3-oxobutyl)phenyl]-4,5-~ dihydro-lH-benzo[g]indazole-c~ ~ / 3-carboxamide ~ \ N-N NHz N \
\ \
O I /

H,N 0 547.04 8-[(2-chlorobenzoyl)amino]-1- <1 M 547 297 , { 4-[(E)-2-"'N I I \ (methylsulfonyl)ethenyl]phenyl }-4,5-dihydro-lH-~ HN o benzo[g]indazole-3-~ Ci carboxamide o:
Oa8\

Compound No., Structure Mol. Compound Name IKK2 MS Example Wt. Resin (M+H) H~N 513.00 8-[(2-chlorobenzoyl)aniino]-1- <1 M 513 298 {4-[(lE)-4-hydroxybut-l-"'N enyl]phenyl}-4,5-dihydro-lH-~ benzo[g]indazole-3-~ HN o carboxamide ~cl Ho HzN 529.00 8-[(2-chlorobenzoyl)amino]-1- <1 M 529 299 [4-(4-hydroxy-3-"'N oxobutyl)phenyl]-4,5-dihydro-~ 1H-benzo[g]indazole-3-~ / HN o carboxamide ~I ~ cl Ho 499.96 8-{[(2-chloropyridin-3- <1 M 500 300 Ho yl)carbonyl]amino}-1-{4-N-N [(1Z)-3-hydroxyprop-l-0 N ~ ~ enyl]phenyl}-4,5-dihydro-1H-cl N' i I NHz benzo[g]indazole- 3-carboxamide N 0 526.99 8-{ [(2-chloropyridin-3- <1 M 527 301 H yl)carbonyl]amino}-1-{4-_ [(1E)-3-(methylamino)-3-~ / oxoprop-l-enyl]phenyl}-4,5-N-N dihydro-lH-benzo[g]indazole-N) N \ \N
3-carboxamide 513.99 8-{[(2-chloropyridin-3- <1 M 514 302 yl)carbonyl]amino }-1-[4-(3-- oxobutyl)phenyl]-4,5-dihydro-~ 1H-benzo[g]indazole-3-N N ~" carboxamide \ 11 / F~
cl 0 N

F'N 512.96 1-{4-[(1E)-3-amino-3- <1 M 513 303 ~ oxoprop-l-enyl]phenyl}-8-_ { [(2-chloropyridin-3-~ yl)carbonyl]amino}-4,5-N N \" dihydro-lH-benzo[g]indazole-~
cl 0 / NH2 3-carboxaniide H 528.01 8-{[(2-chloropyridin-3- 1< 10 528 304 yl)carbonyl]amino}-1-{4- M
[(1E)-3-hydroxy-3-methylbut-1-enyl]phenyl}-4,5-dihydro-N N ~", 1H-benzo[g]indazole-3-"H= carboxamide cl 0 Compound No., Structure Mol. Compound Name IKK2 MS Example Wt. Resin (M+H) 541.01 8-{[(2-chloropyridin-3- 1< 10 541 305 i yl)carbonyl]amino}-1-{4 M
, [(1E)-3-(dimethylamino)-3-~ ~ oxoprop-l-enyl]phenyl}-4,5-N N N-" NHz dihydro-lH-benzo[g]indazole-\ ~ 3-carboxamide ci 0 452.54 8-[(methylsulfonyl)amino]-1- 1< 10 453 306 [4-(3-oxobutyl)phenyl]-4,5- M
~ dihydro-lH-benzo[g]indazole-3-carboxamide H N-N NHz S.N
O'0 465.54 1-{4-[(1E)-3-(methylamino)-3- <1 [LM 566 307 H / oxoprop-l-enyl]phenyl}-8-_ [(methylsulfonyl)amino]-4,5-~ / dihydro-lH-benzo[g]indazole-H N-N NHZ 3-carboxanlide S.N
O'0 562.50 8-[(2-chlorobenzoyl)amino]-1- 1< 10 526 308 i I ~ {4-[(1E)-3-qj'~ N N-" NH, (dimethylamino)prop-l- M
c o\ I o enyl]phenyl}-4,5 dihydro 1H
benzo[g]indazole-3-HO1 carboxamide hydrochloride [00172] Example 309 8-[(2-chlorobenzoyl)amino]-1-(4-{ ( lE)-3-[(2-methoxyethyl)amino]-3-oxoprop-l-enyl }phenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide ~o 0 N
H
N NHZ
p cl O

To a 50 mL syringe barrel equipped with a fritted disk was added 2.02 g of PS-MB-CHO (Argonaut Technologies, 1.46 mmol/g loading). The resin was washed with N,N-dimethylformamide. To the resin was added a solution of sodium triacetoxyborohydride (3.20 g, 15.1 mmol) dissolved in trimethylorthoformate (1.5 mL), acetic acid (1.5 mL), and N,N-dimethylformamide (12 mL). 2-Methoxyethylamine (1.11 g, 14.8 mmol) was added to the mixture. The mixture was allowed to shake on an orbital shaker for 16 hrs. The solution was drained from the resin and washed with a solution of 8 parts N,N-dimethylfromamide to part trimethylorthoformate to 1 part acetic acid. The resin was then washed with N,N-dimethylformamide, 1 part N,N-dimethylformamide to 1 part triethylamine, N,N-dimethylformamide, dichloromethane, and diethyl ether. The resin was dried under vacuum.

[00173] To a 4 mL peptide flask was added 100mg of the resin. A solution of HBTU (127 mg, 0.336 mmol), 1-hydroxybenzotriazole (52 mg, 0.38 mmol), triethylamine (34 mg, 0.34 mmol), and (2E)-3-(4-{3-(aminocarbonyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-lH-benzo[g]indazol-l-yl }phenyl)prop-2-enoic acid (172 mg, 0.335 mmol) in 2mL of N,N-dimethylformamide was added to the resin. The peptide flask was agitated on an orbital shaker for 16 hrs, after which the solution was drained and the resin was washed with DMF, dichloromethane, and diethyl ether. The resin was dried under vacuum.

[00174] The resin was suspended in 2 mL of 90% aqueous trifluoroacetic acid and agitated for 30 minutes. The solution was filtered. The resin was washed with 2 mL of 90% aqueous trifluoroacetic acid, with the wash being collected.
The TFA solutions were combined, diluted to 15 mL with water, and concentrated to dryness. The resulting oil was triturated with methanol to yield the title compound.
MS (ESI+) for C31H28C1N504 m/z 570.2 (M+H)+.

[00175] The compounds of Examples 310-315 listed in the Table 12 were prepared according to the procedure of Example 309 using the appropriate amine.

[00176] The bioactivity in the IKK2 Resin assay for the compounds of Examples 309-315 is shown in Table 12.

Table 12 Compound No., Structure Mol. Compound Name(s) IKK2 MS Example Wt. Resin (M+H) -O\-\ 0 570.0 8-[(2-chlorobenzoyl)amino]-1-(4- <1 M 570 309 a / {(1E)-3-[(2-methoxyethyl)amino]-_ 3-oxoprop-1-enyl }phenyl)-4,5-~ / dihydro-lH-benzo[g]indazole-3-\ NHz carboxaniide l\
ci o 0 ~ / 0 592.1 8-[(2-chlorobenzoyl)amino]-1-(4- <1 M 592 310 b / {(lE)-3-[(2-furylmethyl)amino]-3-_ oxoprop-l-enyl}phenyl)-4,5-~ / dihydro-lH-benzo[g]indazole-3-\ \ carboxaniide ot o NH, 526.0 8-[(2-chlorobenzoyl)amino]-1-{4- <1 M 526 311 / [(1E)-3-(methylamino)-3-_ oxoprop-l-enyl]phenyl}-~ / 4,5-dihydro-lH-benzo[g]indazole-\ \ 0 NHz 3-carboxamide ct o N 540.0 8-[(2-chlorobenzoyl)amino]-1-{4- <1 M 540 312 H / [(lE)-3-(ethylamino)-3-oxoprop-_ 1-enyl]phenyl}-4, 5-dihydro-lH-benzo[g]indazole-3-\ NHz carboxanude e \

ci o 0 602.1 1-{4-[(1E)-3-(benzylamino)-3- 1< 10 602 313 oxoprop-l-enyl]phenyl}-8-[(2-chlorobenzoyl)amino]- PM
\ / 4,5-dihydro-IH-benzo[g]indazole-\ \ ~ NHz 3-carboxamide ci o I\

s ra- 387.44 8-amino-l-{4-[(lE)-3- 1 < 10 388 314 / (methylamino)-3-oxoprop-l- M
_ enyl]phenyl}-4,5-dihydro-lH-~ / benzo[g]indazole-3-N-N
HzN \ \ ' carboxamide O

479.56 1-{4-[(lE)-3-(dimethylamino)- 1< 10 480 315 N
. 3-oxoprop-1-enyl]phenyl}-8-[(methylsulfonyl)amino]-4,5-H N-N N~ M
i dihYdro-lH-benzoLg1ndazole-\S.N
3-carboxamide [00177] Example 316 8-{ [(2-chloropyridin-3-y1)carbonyl]amino}-1-[4-(3-hydroxypropyl)phenyl]-4, 5-dihydro-1 H-benzo [g] indazole-3-carboxamide HO
-N

CI NHZ
/ ~
N~

Using standard hydrogenation conditions 8-{ [(2-chloropyridin-3-yl)carbonyl] amino }-1-{ 4-[(1Z)-3-hydroxyprop-l-enyl]phenyl }-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide was converted to 8-{ [(2-chloropyridin-3-yl)carbonyl]amino}-1-[4-(3-hydroxypropyl)phenyl]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide. MS (ESI+) for ni/z 502 (M+H)+. IKK-2 resin ICSO<1 M.

[00178] Example 317 8-[(2-chlorobenzoyl)amino]-1-[4-(3-furyl)phenyl]-4,5-dihydro-lH-benzo [g]indazole-3-carboxamide U
~
CI H ~ / N-N
I N J' NH2 O ) / O

[00179] Step 1: A suspension of ethyl 1-(4-bromophenyl)-8-nitro-4,5-dihydro-lH-benzo[g]indazole-3-carboxylate (4.4 g) in THF (80 mL) was treated with 1 N aq. NaOH (80 mL) and stirred vigorously overnight. The reaction mixture was diluted with ethyl acetate and acidified to pH = 2 with 1 N aq. HCI. The organic layer was separated and the aqueous fraction extracted with EtOAc (3x).

Combined extracts were washed with brine, dried over NazSO4, filtered and concentrated in vacuo to afford 4.0 g (97%) of 1-(4-bromophenyl)-8-nitro-4,5-dihydro-IH-benzo[g]indazole-3-carboxylic acid as a solid: MS(ESI+) 414 [M+H]+.
1H NMR (400 MHz, d6 DMSO) S 8.07 (dd, IH), 7.83 (d, 2H), 7.66 (d, 1H), 7.56 (d, 2H), 7.42 (d, 1H), 3.10 (m, 2H), 2.99 (m, 2H).

[00180] Step 2: A suspension of Rink amide resin (5.3g, 2.5 mmol, 0.47 meq/g, NovaBiochem), in 30 % piperidine/DMF was prepared in a solid phase reactor equipped with an overhead stirrer. The mixture was stirred for 15 min, filtered, and treated a second time with 30 % piperidine/DMF for 15 min. The solvent was removed by filtration and the resin washed with DMF ( 3x), MeOH
(3x), and DCM (4x). A solution of 1-(4-bromophenyl)-8-nitro-4,5-dihydro-IH-benzo[g]indazole-3-carboxylic acid (2.07 g) in 1:1 DCM/DMF (10 mL) was prepared and added to the resin, followed by 1M HOBt in DMF (5 mL) and 1M
DIC in DMF (5 mL). The resin was stirred at RT. After stirring for 16 h, the resin was washed with DMF (3x), MeOH (3x), DCM (4x), and filter to afford loaded resin. Resin loading was determined by direct cleavage 'H NMR: 0.569 mmol/g.
Evaporated direct cleavage NMR sample from the resin gave an oil: MS(ESI+) 413 [M+H]+. 'H NMR (400 MHz, 10%TFA/CDC13): 6 8.10 (dd, 1H), 7.76 (d, 2H), 7.63 (d, 1H), 7.53 (d, 1H), 7.41 (d, 2H), 3.16 (m, 4H).

[00181] Step 3: In a solid phase reactor equipped with an overhead stirrer to a suspension of resin from step 2 (7.8 g, 4.43 mmol) in NMP (15 mL) was added 2M SnC12 in NMP (15 mL). The mixture was stirred for 1 h, filtered, and retreated with 2M SnC12 in NMP (15 mL). After stirring overnight the resin was filtered, washed with DMF (3x), MeOH (3x), DCM (4x), filtered, and air dried to afford the intermediate amine resin. Determined resin loading by direct cleavage 'H NMR:
0.414 mmol/g. In a solid phase reactor equipped with an overhead stirrer was prepared a suspension of 0.4 g of the amine resin in NMP.

[00182] Step 4: The resin was allowed to stir for 5 min and subsequently treated with a solution of 2-chlorobenzoic acid (126 mg) in NMP (1 mL). The mixture was treated with HATU (307 mg), DIEA (0.28 mL) and stirred for lh. The resultant resin was filtered, subjected to a second treatment of 2-chlorobenzoic acid, HATU and DIEA in NMP, and allowed to stir. After stirring overnight, the resin was filtered, washed with DMF (3x), MeOH (3x), and DCM (4x). The resin was filtered and air dried to afford resin. Determined resin loading by direct cleavage 'H
NMR: 0.702 mmol/g.

[00183] Step 5: To a reaction vessel was added resin from step 4 (0.20g, 0.09 mmol) in a suspension of toluene/EtOH (2:1). The vessels were purged with argon for 5 min and subsequently treated with Pd(PPh3)4 (41.6 mg, 0.036mmol), an 3-furylboronic acid (0.2mmo1), and 2M Na.ZCO3 (200 L, 0.4mmol). The vessels were heated to 100 C and allowed to agitate for 30 h. Each vessel was quenched with 25% NH4OH for 30min, filtered and washed three times each with DMF, MeOH, MeOH:H20 (1:1), 0.2N HCt, MeOH:H20 (1:1), MeOH and DCM. The resins were allowed to dry and cleaved with 10% TFA/DCM (2 mL) for 30 min.
The resins were washed twice with 0.5 mL DCM and the combined filtrates concentrated to afford the desired final product.

[00184] The compounds of Examples 318-323 listed in the Table 13 were prepared according to the procedure of Example 317 using the appropriate boronic acid in step 5.

[00185] The bioactivity in the TKK2 Resin assay for the compounds of Examples 316-323 is shown in Table 13.

Table 13 Compound No., Structure Mol. Compound Name IKK2 MS Example Wt. Resin (M+H) 501.96 8-{ [(2-chloropyridin-3- <1 M 502 316 Ho yl)carbonyl]amino}-1-[4-(3-p \ N hydroxypropyl)phenyl]-4,5-0 dihydro-lH-benzo[g]indazole-C1 N \ ~ NHz 3-carboxaniide 0 508.97 8-[(2-chlorobenzoyl)amino]-1- 1< 10 509 317 ~ [4-(3-furyl)phenyl]-4,5-~ / dihydro-lH-benzo[g]indazole- M
\ ~ C1 N N-N N~ 3-carboxamide o ~ i ,N 520.00 8-[(2-chlorobenzoyl)amino]-1- 1< 10 520 318 ~ (4-pyridin-3-ylphenyl)-4,5- M
/ dihydro-lH-benzo[g]indazole-N
\ ~ C1 N-N NH2 3-carboxamide o I i oH 549.03 8-[(2-chlorobenzoyl)amino]-1- 1< 10 549 319 [3'-(hydroxymethyl)-1,1'- M
\ / biphenyl-4-yl]-4,5-dihydro-lH-benzo[g]indazole-3-\ ' 01 N-N NH2 carboxamide \

o /

""= 534.02 1-(3'-amino-1,1'-biphenyl-4- 1< 10 534 320 yl)-8-[(2- M
- chlorobenzoyl)amino]-4,5-, cl N-N dihydro-lH-benzo[g]indazole-N \ ~ ' ""~ 3-carboxamide o ~,~ o oH 563.02 4'-{3-(aminocarbonyl)-8-[(2- 1< 10 563 321 chlorobenzoyl)amino]-4,5- M
dihydro-lH-benzo[g]indazol-l-yl}-1,1'-biphenyl-3-carboxylic \ C1 N ~N NHz acid O

563.02 4'-{3-(aminocarbonyl)-8-[(2- 1< 10 563 322 "o chlorobenzoyl)amino]-4,5- M
dihydro-lH-benzo[g]indazol-l-N " yl}-1,1'-biphenyl-4-carboxylic H \ NHacid o Compound No., Structure Mol. Compound Name IKK2 MS Example Wt. Resin (M+H) ~ o- 579.06 8-[(2-chlorobenzoyl)amino]-1- 1 < 10 579 323 0 (3',4'-dimethoxy-1,1'-biphenyl- M
, 4-yl)-4,5-dihydro-IH-benzo[g]indazole-3-a \ N N-N
NHz carboxamide p ~ O

[00186] The compounds of Examples 324-366 in Table 14 were prepared in a manner analogous to Example 3 using the appropriate hydrazine and acylating or sulfonating agent. The bioactivity in the IKK2 Resin assay for the compounds of Examples 324-366 is shown in Table 14.

Table 14 Compound No., Structure Mol. Wt. Compound Name(s) IKK2 MS Example Resin (M+H) No2 487.91 8-[(2-chlorobenzoyl)amino]- <1 gM 488 324 / 1-(4-nitrophenyl)-4,5-~ N-N o dihydro-IH-" - ~ N,~ benzo[g]indazole-3 ci 0 ~ ~ carboxamide 2 487.91 8-[(2-chlorobenzoyl)amino]- 1< 10 488 325 C~ 1-(3-nitrophenyl)-4,5- M
N-N dihydro-lH-~ ~ N ~\ cONH, benzo[g]indazole-3-O1 0 ~ s carboxamide ci 511.80 8-[(2-chlorobenzoyl)amino]- 1< 10 512 326 O1-(3,4-dichlorophenyl)-4,5-dihydro-lH- M
P-ir " ~ ~ N"~ benzo[g]indazole-3-cl 0 ~ carboxamide N~ 443.90 8-[(2-chlorobenzoyl)amino]- 1< 10 444 327 ~~ 1 pyridin 3-y1-4,5-dihydro M
N ~" NHz 1H-benzo[g]indazole-3- o ~ I o carboxamide a ~ 442.91 8-[(2-chlorobenzoyl)amino]- <1 M 443 328 ~ / 1-phenyl-4,5-dihydro-lH-ci 01 ly N ~" N~ benzo[g]indazole-3-0 0 o carboxamide Compound No., Structure Mol. Wt. Compound Name(s) IKK2 MS Example Resin (M+H) 0 486.92 4-{3-(aminocarbonyl)-8-[(2- 1< 10 487 329 Hp- chlorobenzoyl)amino]-4,5-~ ~ dihydro-lH-benzo[g]indazol- M
1-yl}benzoic acid pioyi N NH
CI

\ 382.44 8-[(methylsulfonyl)amino]-1- 1< 10 383 330 ~ e phenyl-4,5 dihydro-lH-N N-N NNZ benzo[g]indazole-3- M
N / \
o'o \ o carboxamide 443.90 8-[(3- <1 M 444 331 chloroisonicotinoyl)amino]-I hen 14 5 dih dro-1H-~ N \ "\ " ~ coNt~ P Y-~- Y
ol o benzo[g]indazole-3-carboxamide c( ~ 477.35 8-[(2-chlorobenzoyl)amino]- <1 M 478 332 r/~~~ ---\)~" 1-(4-chlorophenyl)-4,5-N-N dihydro-lH-o " o benzo[g]indazole-3-o' N~ carboxamide F~o 526.91 8-[(2-chlorobenzoyl)amino]- 1< 10 527 333 F 1-[4 M
(trifluoromethoxy)phenyl]-o N ~ ~" 0 4,5-dihydro-lH-o~ \ I N~ benzo[g]indazole-3-I carboxamide 477.35 8-[(2-chlorobenzoyl)amino]- <1 M 478 334 ci 1-(3-chlorophenyl)-4,5-0 N ~ N dihydro-lH-o~ ~ I NNO benzo[g]indazole-3-~ \ carboxamide 456.94 8-[(2-chlorobenzoyl)amino]- <1 M 457 335 1 1-(4-methylphenyl)-4,5-N-N dihydro-lH-o N \ ' o benzo[g]indazole-3-oi\ N~ carboxamide 456.94 8-[(2-chlorobenzoyl)amino]- <1 M 457 3336 1-(3-methylphenyl)-4,5-dihydro-lH-o r, ~ " o benzo[g]indazole-3-CI \ NHz carboxamide Compound No., Structure Mol. Wt. Compound Name(s) IKK2 MS Example Resin (M+H) 484.99 8-[(2-chlorobenzoyl)amino]- 1< 10 485 337 1-(4-isopropylphenyl)-4,5- M
dihydro-lH-N-N benzo[g]indazole-3-carboxamide CI~" k2 43.89 8-[(2-chlorobenzoyl)amino]- 1 M 444 338 1-pyridin-4-y1-4,5-dihydro-Q
N-N 1H-benzo[g]indazole-3-N / carboxaniide CI \ I NH
~ \
/

460.89 8-[(2-chlorobenzoyl)amino]- <1 M 461 339 1-(3-fluorophenyl)-4,5-N-N dihydro-lH-~ benzo[g]indazole-3-"
0 N / \
cl NI~ carboxamide 11'"J/, F F 372.35 8-amino-l-[4- 1< 10 373 340 F (trifluoromethyl)phenyl]-4,5- M
dihydro-lH-N-" o benzo[g]indazole-3-H~N N"z carboxamide I~ F 460.89 8-[(2-chlorobenzoyl)amino]- <1 M 461 341 ~ 1-(2-fluorophenyl)-4,5-N-N dihydro-lH-"
O N \ benzo[g]indazole-3 CI \ N"2 carboxamide F 462.43 8-[(2,3- 1< 10 463 342 difluorobenzoyl)amino]-1-(3--~ fluorophenyl)-4,5-dihydro- M
N / ~" 1H-benzo[g]indazole-3-F \ \ ~ Nr carboxamide F ~

F 498.51 3-({[3-(aminocarbonyl)-1-(3- 1< 10 499 343 cz fluorophenyl)-4,5-dihydro- M
1H-benzo[g]indazol-8-~ N yl]amino}carbonyl)-2-H methylphenyl acetate o~
o--4-Compound No., Structure Mol. Wt. Compound Name(s) IKK2 MS Example Resin (M+H) F 495.34 8-[(2,3- 1< 10 496 344 dichlorobenzoyl)amino]-1-(3-fluorophenyl)-4,5-dihydro-N ~M
o H I~" 0 1H-benzo[g]indazole-3-/
N~ carboxamide c~

F 461.88 8-{ [(2-chloropyridin-3- <1 M 462 345 yl)carbonyl]amino}-1-(3-fluorophenyl)-4,5-dihydro-O H ~ " 0 1H-benzo[g]indazole-3-ci " N~ carboxamide N

F 478.88 8-[(2-chlorobenzoyl)amino]- <1 M 479 346 1-(3,5-difluorophenyl)-4,5-F 0 dihydro-1 H-~ H ~ " o benzo[g]indazole-3-N /
c~~ NHz carboxamide F 479.87 8-{ [(2-chloropyridin-3- <1 M 480 347 ~ \ yl)carbonyl]amino}-1-(3,5-F difluorophenyl)-4,5-dihydro-0 H ~ " c 1H-benzo[g]indazole-3-/
ci "~ NNz carboxamide i~

F 513.33 8-[(2,3- 1< 10 513 348 ~ \ dichlorobenzoyl)amino]-1- M
F (3,5-difluorophenyl)-4,5-H
ci ~ " dihydro-lH-c NHz benzo[g]indazole-3-~ carboxaniide a /

F F 510.91 8-[(2-chlorobenzoyl)amino]- 1< 10 511 349 1-[4- M
1 (trifluoromethyl)phenyl]-4,5-N-N
H ~ dihydro-lH-o N ~ o benzo[g]indazole-3-ci , ""~ carboxamide I/

sr 521.81 1-(4-bromophenyl)-8-[(2- <1 M 521 350 chlorobenzoyl)amino]-4,5-\ O1 N \N N~ dihydro-lH-o benzo[g]indazole-3-0 carboxamide Compound No., Structure Mol. Wt. Compound Name(s) IKK2 MS Example Resin (M+H) er 501.39 1-(4-bromophenyl)-8-[(2- <1 M 502 351 a methylbenzoyl)amino]-4,5-, ~ I H N-N dihydro-lH-benzo[g]indazole-3-~ "
carboxamide B' 383.25 8-amino-l-(4-bromophenyl)- 1< 10 383 352 0 4,5-dihydro-lH-~N \ ~", NHz benzo[g]indazole-3- M
~ o carboxamide F 478.89 8-[(2-chlorobenzoyl)amino]- <1 M 479 353 1-(2,4-difluorophenyl)-4,5-~
cl 0 H \N NN dihydro-lH-I " o benzo[g]indazole-3-carboxamide F 479.87 8-[(3- <1 gM 480 354 F ~ chloroisonicotinoyl)amino]-I
N 01 N\NcoN 1-(3,4-difluorophenyl)-4,5-"~ dihydro-IH-benzo[g]indazole-3-carboxamide F 479.87 8-[(3- <1 M 480 355 loroisonicotinoyl)amino]-b ch HF N-N 1-(3,5-difluorophenyl)-4,5-~ " ~ 0ON1~ dihydro-lH-benzo[g]indazole-3-carboxamide FCl 495.34 8-[(2-chlorobenzoyl)amino]- <1 M 495 356 1-(3-chloro-4-fluorophenyl)-\ N \N N,~ 4,5-dihydro-lH-benzo[g]indazole-3-cl 0 o carboxamide o 436.42 8-aniino-1-14- 1< 10 437 357 cFs s [(trifluoromethyl)sulfonyl]ph N-N enyl}-4,5-dihydro-1H- M
""~ benzo[g]indazole-3-carboxamide 0 0 612.42 8-[(3- <1 M 576 358 cF~- s chloroisonicotinoyl)amino]-1-{4-N N-N NH~ [(trifluoromethyl)sulfonyl]ph ci H enyl}-4,5-dihydro-lH-N benzo[g]indazole-3-carboxamide hydrochloride o 575.96 8-{ [(2-chloropyridin-3- <1 M 576 359 cFs s yl)carbonyl]amino}-1-{4-[(trifluoromethyl)sulfonyl]ph N N-N NHenyl}-4,5-dihydro-lH-c~ benzo[g]indazole-3-"J carboxamide Compound No., Structure Mol. Wt. Compound Name(s) IKK2 MS Example Resin (M+H) 1 478.34 1-(4-chlorophenyl)-8-{ [(4- <1 M 478 360 chloropyridin-3-\ 0 N ~N. N~ yl)carbonyl]amino}-4,5-N o dihydro-lH-benzo[g]indazole-3-carboxamide 0' 472.94 8-[(2-chlorobenzoyl)amino]- 1< 10 473 361 Q 1-(3-methoxyphenyl)-4,5- M
N-N dihydro-lH-r, benzo[g]indazole-3-c~ carboxamide F 478.88 8-[(3-chloro-2- 1 < 10 479 362 / fluorobenzoyl)amino]-1-(3-/ N-N fluorophenyl)-4,5-dihydro- pM
ra ' 1H-benzo[g]indazole-3-F~ N carboxamide F, ~ 478.88 8-[(2-chlorobenzoyl)amino]- 51 M 479 363 ]I"~~ 1-(3,4-difluorophenyl)-4,5-N-N dihydro-lH-N benzo[g]indazole-3-C1H N~ carboxamide ~

p F 479.87 8-{ [(2-chloropyridin-3- <1 M 480 364 0 yl)carbonyl]amino}-1-(3,4-N-N difluorophenyl)-4,5-dihydro-0 N 1H-benzo[g]indazole-3-C1 NH~ carboxanllde N i F F 513.33 8-[(2,3- 1< 10 513 365 0 dichlorobenzoyl)amino]-1-N-N (3,4-difluorophenyl)-4,5- M
N ' dihydro-lH-01H N"~ benzo[g]indazole-3-c~ carboxaniide F F 479.88 8-{ [(2-chloropyridin-3- <1 M 480 366 yl)carbonyl]amino } -1-(2,4-o H N-N, difluorophenyl)-4,5-dihydro-C1 NHz 1H-benzo[g]indazole-3-N carboxamide [00187] Example 367 8-[(2-chlorobenzoyl)amino]-1-[5-(methylsulfonyl)pyridin-2-yl]-4,5-dihydro- lH-benzo[g]indazole-3-carboxamide O1, N-N
N

[00188] Step 1 ~ "'0 S I ~N
~ Br To a suspension of 2,5-dibromopyridine (12.0 g, 0.05 mol) in ether was added nBuLi (32 mL of 1.6 N in hexane, 0.05 mol) at -78 C dropwise. The purple suspension was stirred for 1 hour and then treated with dimethyl disulfide.
The reaction mixture was kept at this temperature for 1 h and 1/a h at 0 C. The reaction was quenched with a mixture of concentrated HCI and ether. The organic phase was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated to give 10.3 g of crude as brown oil, which was used without purification. To a solution of this crude (10.0 g, 0.05 mol) in methanol (200 mL) was added a solution of OXONE in 300 mL of water. The reaction was stirred at room temperature for 72 h. Solvent was removed and the residue was basified with 50% NaOH solution. The precipitate was collected by filtration, air-dried to give 8.2 g of product as a white crystal (72% yield over two step). NMR spectrum was consistent with the proposed structure.

[00189] Step 2 0, 00 S N
~

A mixture of the product from step 1(8.0 g, 0.034 mol) and hydrazine (2.3 g, 0.068 mol) in 100 mL of ethanol was heated at reflux for 2 h. cooled to room temperature, and the solid was collected by filtration, washed with sat. NaHCO3, water, air-dried to give 4.0 g of crude as a pale white solid (63% yield); NMR spectrum was consistent with the proposed structure.

[00190] Step 3 O111,O

N-N
z~
02N C02Et A mixture of the product from step 2(1.4 g, 0.007 mol) and ethyl (7-nitro-l-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate (2.03 g, 0.007 mol) in 75 mL of acetic acid was heated at reflux under nitrogen for 3 h. The solvent was removed and the residue was treated with a mixture of methanol/ethyl acetate/ether to give 1.67 g of the product as a yellow solid (54% yield); 1HNMR (DMSO, 400 MHz) S:

8.98 (dd, 1H), 8.68 (dd, 1H), 8.21 (d, 1H), 8.13 (dd, 1H), 7.95 (d, 1H), 7.68 (d, 1H), 4.37 (q, 2H), 3.42 (s, 3H), 3.11 (m, 2H), 3.00 (m, 2H), 1.35 (t, 3H); Anal.
Calcd. for C20H18N406S: C, 54.29; H, 4.10; N, 12.66; S, 7.23. Found: C, 53.71; H, 4.41;
N, 12.56; S, 7.14.

[00191] Step 4 Q. ,o iS
~
N-N
H2N CO2Et The product from step 3(1.6 g, 0.0036 mol) was hydrogenated in a Parr shaker with 20% Pd(OH)2/C in acetic acid for 2 h at 5 psi. After the removal of solvent, the residue was triturated with a mixture of methanol and ether to give 1.0 g of the product as a white solid (67% yield): 1HNMR (DMSO, 400 MHz) S: 9.01 (dd, IH), 8.62 (dd, 1H), 8.07 (dd, 1H), 7.01 (d, IH), 6.46 (dd, 1H), 6.12 (d, 1H), 4.90 (brs, 2H), 4.33 (q, 2H), 3.42 (s, 3H), 2.87 (m, 2H), 2.78 (m, 2H), 1.33 (t, 3H);
Anal.
Calcd. for C20H2ON404S: C, 58.24; H, 4.89; N, 13.58; S, 7.77. Found: C, 57.70;
H, 4.68; N, 13.43; S, 7.60.

[00192] Step 5 o, o iS / N
\ I
N-N

To a suspension of the product from step 4(0.95 g, 0.0023 mol) in 25 mL of methanol was added liquid ammonia through a dry-ice condenser. The solution was sealed with a septum and stirred at room temperature for 48 h. Solvent was removed and the solid was triturated with methanol to give 0.68 g of product as a yellow solid (77% yield): 1HNMR (CDC13, 400 MHz) 8: 8.99 (d, 1H), 8.63 (ddd, 1H), 8.10 (d, 1H), 7.66 (s, 1H), 7.43 (s, 1H), 7.00 (d, IH), 6.45 (d, 1H), 6.22 (s, 1H), 4.89 (s, 2H), 3.41 (s, 3H), 2.86 (m, 2H), 2.74 (m, 2H); Anal. Calcd. for C18H17N503S: C, 56.39; H, 4.47; N, 18.27; S, 8.36. Found: C, 55.48; H, 4.29;
N, 17.84; S, 8.19.

[00193] Step 6 o, ,so N-N
N \ \ I CONH2 CI

To a suspension of the product from step (0.62 g, 0.0016 mol) in 10 mL of pyridine was added 2-chlorobenzoyl chloride (0.29 g, 0.0016 mol) in one portion and the reaction mixture was stirred at room temperature overnight. Solvent was removed and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate) to give 0.6 g of the product as a yellow solid (72% yield); iHNMR (DMSO, 400 MHz) S: 10.36 (s, 1H), 9.00 (d, 1H), 8.62 (dd, 1H), 8.15 (d, 1H), 7.74 (s, 1H), 7.39-7.54 (m, 7 H), 7.34 (d, 1H), 3.32 (s, 3H), 2.93 (m, 4H); Anal. Calcd. for C25H20C1N504S:

C, 57.53; H, 3.86; N, 13.42; S, 6.14. Found: C, 56.69; H, 4.37; N, 12.82; S, 5.86.
IKK-2 resin IC50 <1 M.

[00194] Example 368 8-[(2-chlorobenzoyl)amino]-1-[6-(methylsulfonyl)pyridin-3-yl]-4,5-dihydro-lH-benzo [g] indazole-3-carboxamide O1, SO N

I
N-N
N \ ~ I CONH2 CI / I /

[00195] Step 1 o\SO Na,-_ N

A mixture of 2-chloro-5-nitropyridine (20.5 g, 0.13 mol) and sodium thiomethoxide (10.9 g, 0.16 mol) in DMS was heated at 100 C under nitrogen for 3 h. Cooled to room temperature and water was added. The precipitate was collected, air-dried to give 14.5 g of product as a brown solid. To a solution of this solid (16.5 g, 0.097 mol) in 100 mL of acetone was added 170 mL of 2N sulfuric acid solution. Then a solution of K1VInO4 (20.0 g, 0.126 mol) in 375 mL of water was added dropwise to the above suspension. The reaction mixture was stirred at RT overnight and then it was filtered. The solid was stirred with 400 mL of hot ethanol, then cooled and filtered. The filtrate was concentrated to half volume and the precipitate was collected and air-dried to give 12.5 g of the desired product as a pale yellow solid, which was used without further purification. The NMR and MS were consistent with the proposed structure.

[00196] Step 2 OSO N\
I /

A mixture of the product from step 1(12.3 g, 0.061 mol), iron (6.5 g, 0.11 mol) and 1 mL of acetic acid in 250 mL of water was heated at reflux for 4 h. Cooled to room temperature, 400 mL of sat. NaHCO3 solution was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated to give 3.5 g of crude as a dark brown solid. To a solution of this crude in conc. HCI at -10 C was added a solution of NaNO2 dropwise. The mixture was stirred at this temperature for 2 h and then a solution tin chloride in conc. HCI
was added slowly to keep the temperature under -5 C. The reaction was stirred overnight while allowing to warm up to RT. NaOH solution was added to adjust pH to 9 and filtered through a pad of Celite . The aqueous phase was extracted with THF and the organic layer was washed with brine, dried over MgSO4, and concentrated. The crude was triturated with methanol to give the hydrazine as a yellow solid. The NMR and MS were consistent with the proposed structure.
[00197] Steps 3-6 0S~ N
\ I
H N-N
O N \ \ CONH2 CI I /

The title compound was synthesized by using the same procedure from step 3 to step 6 for Example 367 except using the above hydrazine; 1H NMR (DMSO, 400 MHz) 10.38 (s,1H), 9.08 (s, 1H), , IH), 8.41 (d, 1H), 8.25 (d, 1H), 7.71 (s, 1H), 7.35-7.53 (m, 8H), 3.28 (s, 3H), 2.96 (m, 4H); Anal. Calcd. for C25H2OCIN5O4S:
C, 57.53; H, 3.86; N, 13.42; S, 6.14. Found: C, 56.62; H 4.09; N, 13.09; S, 5.99.
IKK-2 resin IC50 < 1 M.

[00198] Example 369 8-[(2-chlorobenzoyl)amino]-1-(4-cyanophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide NC~n T'~~i N-N
0 \ NH2 . HN
CI O
~
N~ ~
1-(4-Brornophenyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (5.2g) and Zn(CN)2 (0.9g) were dissolved in 100m1 DMF under NZ.
Then Pd(Ph3P)4 (1.38g) was added. The reaction mixture was heated up to 100 C

under NZ for 12 hours. After the reaction is completed by HPLC, the solvent was evaporated, and the residue was suspended in ethyl acetate and water. After filtration, and washing with water and ethyl acetate, the filtrate of the organic layer was separated and dried with NazSO4. After filtration and evaporation of solvent, the residue was triturated with ether. Solid obtained was filtered and washed with ether, then dried under vacuum. The desired compound (3.4g) was obtained and characterized by 'H NMR, LC-MS (468, M+1), and CHN analysis. IKK-2 resin IC50 < 1 M.

[00199] The compounds of Examples 370-380 in the Table 15 were prepared by the reduction and/or acylation or sulfonation from either Example 324 or Example 325 using standard conditions. The bioactivity in the IKK2 Resin assay for the compounds of Examples 370-380 is shown in Table 15.

Table 15 Compound No., Structure Mol. Compound Name(s) IKK2 MS Example Wt. Resin (M+H) H2N 457.92 1-(4-aminophenyl)-8-[(2- <1 M 458 370 / chlorobenzoyl)amino]-4,5-I H N-N dihydro-lH-benzo[g]indazole-i N \ ~ CONHz ol o ~ 3-carboxamide 499.96 1-[4-(acetylamino)phenyl]-8- <1 pM 500 371 [(2-chlorobenzoyl)amino]-4,5-N-N dihydro-lH-benzo[g]indazole-( N ~ CONH6 3-carboxaniide ci 0 CH,S y 536.01 8-[(2-chlorobenzoyl)amino]-1- <1 M 536 372 o N {4-/ [(methylsulfonyl)amino]phenyl H N-N }-4,5-dihydro-lH-f, N ooN", benzo[g]indazole-3-ci o carboxamide ~ 562.03 1-[4-(benzoylamino)phenyl]-8- 1< 10 562 373 ~ [(2-chlorobenzoyl)amino]-4,5- M
o dihydro-lH-benzo[g]indazole-N N 3 carboxamide P-r N CONHx o~N 529.99 8- (2-chlorobenzoyl)amino]-1- <1 M 530 374 {
N_N [(methoxyacetyl)amino]phenyl ~N ooN~ }-4,5-dihydro-lH-Cl 0 ~ benzo[g]indazole-3-carboxamide NHz 457.92 1-(3-aminophenyl)-8-[(2- <1 M 458 375 chlorobenzoyl)an-uno]-4,5-~ N-N dihydro-lH-benzo[g]indazole-~ r, oONHs 3-carboxaniide oi c Q-Y 596.48 8-[(2-chlorobenzoyl)amino]-1- 1< 10 596 376 r, ~ {4-[(2-ci 0 chlorobenzoyl)amino]phenylQ }- uM
H N-N 4,5-dihydro-lH-N ~ CONHi ol 0 ~ benzo[g]indazole-3-carboxamide 507.98 8-[(2-chlorobenzoyl)amino]-1- 1< 10 508 377 N [4-(1 H-pyrrol-1-yl)phenyl]-~ / M
4,5-dihydro-1 H-I " N " benzo[g]indazole-3-/ N t CONHz a 0 1 carboxaniide Compound No., Structure Mol. Compound Name(s) IKK2 MS Example Wt. Resin (M+H) 606.09 1-(4- 1< 10 606 378 o~o {[(benzyloxy)acetyl]amino}ph HN M
enyl)-8-[(2-I ~ H \ / N-N chlorobenzoyl)amino]-4,5-~N ~ ~ ooN~ dihydro-lH-benzo[g]indazole-01 o I ~ 3-carboxamide 657.18 8-[(2-chlorobenzoyl)amino]-1- 1< 10 657 379 {4-[(5-{[(2,2-H-r;o dimethylpropanoyl)oxy]amino} M
pentanoyl)amino]phenyl}-4,5-dihydro-1 H-benzo [ g] indazole-HN o 3-carboxamide \ ~l N-N
N CONHz 0 593.52 8-[(2-chlorobenzoyl)amino]-1- 1< 10 557 380 H [4-({ [2-~ N-N (dimethylamino)ethyl]amino}c M
0 arbonyl)phenyl]-4,5-dihydro-oi 1H-benzo[g]indazole-3-carboxamide hydrochloride HCI

[00200] Example 381 1-(6-aminopyridin-3-yl)-8-[(3-chloroisonicotinoyl)amino]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide N-N
O N I \ \

CI / /
~ I
N
[00201] Step 1: A 100 mL 3-neck flask was charged with (in order) Cul (300 mg, 1.6 mmol), 1,10-phenanthroline (350 mg, 1.94 mmol) and 25 mL DMF. A
dark cherry red solution resulted. To this solution was added (in order) 2-Chloro-5-iodopyridine (2.0 g, 8.4 mmol), t-butyl carbamate (1.33 g, 10.1 mmol), 25 mI, DMF

and Cs2CO3 (4.75 g, 14.6 mmol). To the flask was attached a reflux condenser with a nitrogen inlet, a thermometer and a glass stopper. With stirring the slurry was heated to 70 C for 3 h. The reaction was allowed to cool to room temperature.
The crude reaction mixture was poured into 200 mL water giving a rust colored solid.

The product was extracted from this aqueous slurry using 2 x 200 mL diethyl ether.
The ether layers were extracted with 200 mL water, dried over MgSO4, filtered, and then concentrated giving a dark oil. The oil was chromatographed on silica gel (25g) using 20% EtOAc/80% hexane giving 0.9 g (3.7 mmol, 44%) of product (light yellow oil which slowly solidified). NMR and MS were consistent with the proposed structure.

[00202] Step 2: To a mixture of the product from step 1(6.35 g, 0.023mo1) and ethyl (7-nitro-l-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate (6.6 g, 0.023 mol) in 200 mL of ethanol was added 10 mL of 1N HCI and the reaction mixture was heated at reflux under nitrogen for 6 h. After the solution was cooled, the precipitate was collected by filtration and air-dried to give 7.5 g of the product as a yellow crystal (83% yield); IHNMR (DMSO, 400 MHz) S: 8.76 (dd, 1H), 8.22 (dd, 1H), 8.12 (dd, 1H), 7.85 (dd, 1H), 7.71 (d, 1H), 7.44 (d, 1H), 4.35 (q, 2H), 3.14 (m, 2H), 3.03 (m, 2H), 1.33 (t, 3H); Anal. Calcd. for C19H15CIN404: C, 57.22;
H, 3.79; N, 14.05; Cl, 8.89. Found: C, 57.03; H, 3.95; N, 13.71; Cl, 9.04.

[00203] Step 3: The product from step 2(7.5 g, 0.019 mol) was hydrogenated in a Parr shaker with 5% Pt/C in acetic acid for 2 h at 5 psi.
After the removal of solvent, the residue was triturated with a mixture of methanol and ether to give 6.5 g of the product as a pale yellow solid (94% yield): 1HNMR (DMSO, 400 MHz) S: 8.64(dd, 1H), 8.09 (dd, 1H), 7.75 (dd, 1H), 7.02 (d, 1H), 6.45 (dd, 1H), 6.03 (d, 1H), 4.99 (brs, 2H), 4.31 (q, 2H), 2.88 (m, 2H), 2.78 (m, 2H), 1.31 (t, 3H); Anal. Calcd. for C19H17C1N402: C, 61.88; H, 4.65; N, 15.19; Cl, 9.61.
Found:
C, 60.97; H, 5.06; N, 14.65; Cl, 9.50.
[00204] Step 4: To a mixture of the product from step 3(0.96 g, 0.0026 mol) and 3-chloroisonicotinic cid (0.65 g, 0.004 mol) in 25 mL of DMF was added 1 1mI, of diisopropylethylamine, followed by the addition of HATU (1.50 g, 0.004 mol).
The reaction was stirred at room temperature for 16 h and concentrated. The residue was triturated with methanol and acetonitrile to give 1.08 g of product as a pale yellow solid (82% yield); IHNMR (DMSO, 400 MHz) S: 10.56 (s, IH), 8.76 (s, 1H), 8.69 (d, 1H), 8.63 (d, 1H), 8.14 (dd, 1H), 7.76 (d, 1H), 7.56 (d, 1H), 7.53 (dd, 1H), 7.40 (d, 1H), 7.26 (d, 1H), 4.32 (q, 2H), 2.97 (s, 4H), 1.31 (t, 3H).

[00205] Step 5: A sealed reaction vessel containing the product from step 4 (0.8 g, 0.0016 mol) and 10 mL of liquid ammonia in 50 mL of absolute alcohol was heated at 120 C and 600 psi for 24 h. After cooling, solvent was removed and the residue was triturated with a niixture of methanol and acetonitrile to give 0.38 g of product as a pale yellow solid (52% yield);1HNMR (DMSO, 400 MHz) 8: 10.57 (s, 1H), 8.75 (s, 1H), 8.63 (d, 1H), 8.02 (d, 1H), 7.47-7.56 (m, 3H), 7.35 (d, 1H), 7.32 (d, 1H), 7.27 (s, 1H), 6.54 (d, 1H), 6.36 (s, 2H), 2.92 (m, 4H); Anal. Calcd.
for C23H18C1N702: C, 60.07; H, 3.95; N, 21.32. Found: C, 59.26; H, 3.99; N, 20.85.
[00206] Example 382 8- [(3-chloroisonicotinoyl)amino]-1-thien-2-yl-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide S N-N

CI

N
~ooxo~~ Ste_p 1: To a mixture of tert-butyl 1-thien-2-ylhydrazinecarboxylate (3.9 g, 0.016 mol, synthesized by using the same method as the previous example) and ethyl (7-nitro-l-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate (4.6 g, 0.016 mol) in 100 mL of ethanol was added 5 mL of 1N HCl and the reaction mixture was heated at reflux under nitrogen for 6 h. After the solution was cooled, the precipitate was collected by filtration and air-dried to give 2.6 g of the product as a brown solid (44% yield). This solid was refluxed with 3eq of tin chloride in ethanol under nitrogen for 3 h. Solvent was removed and the residue was partitioned between THF and sat. NaHCO3 solution. Organic layer was washed with brine, dried over MgSO4, and concentrated to give 1.4 g of crude as a yellow solid, used without further purification. The MS and NMR were consistent with the proposed structure.

[00208] Step 2: A sealed reaction vessel containing the crude product from step 1(1.3 g, 0.004 mol) and 10 mL of liquid ammonia in 50 mL of absolute alcohol was heated at 120 C and 600 psi for 24 h. After cooling, solvent was removed and the residue was triturated with a mixture of methanol and acetonitrile to give 1.0 g of product as a pale yellow solid. To a mixture of this solid (0.56 g, 0.0018 mol) and 3-chloroisonicotinic cid (0.39 g, 0.0027 mol) in 20 mL of DMF
was added 1 mL of diisopropylethylamine, followed by the addition of HATU
(1.03 g, 0.0027 mol). The reaction was stirred at room temperature for 16 h and concentrated. The residue was triturated with methanol and water to give 0.31 g of product as pale yellow solid (38% yield); 1HNMR (DMSO, 400 MHz) S: 10.55 (s, IH), 8.75 (s, IH), 8.62 (d, 1H), 7.67 (d, 1H), 7.62 (s, 1H), 7.55 (d, 1H), 7.44 (s, 3H), 7.42 (s, 1H), 7.35 (m, 3H), 7.12 (m, 1H), 2.93 (m, 4H); Anal. Calcd. for C22H16C1N502S: C, 58.73; H, 3.58; N, 15.57. Found: C, 58.26; H, 3.62; N, 15.48.
[00209] Example 383 8-[(3-chloroisonicotinoyl)amino]-1-thien-3-yl-4,5-dihydro-lH-benzo[g]indazole-carboxamide sa__ N-N
O N

cl N

This compound was synthesized by using the same method as previously described in Example 381. 1HNMR (DMSO, 400 MHz) 8: 10.54 (s, 1H), 8.75 (s, 1H), 8.62 (d, 1H), 7.85 (dd, 1H), 7.75 (dd, 1H), 7.58 (s, 1H), 7.54 (d, 1H), 7.38 (m, 3H), 7.31 (s, 1H), 7.28 (dd, 1H), 2.92 (m, 4H); Anal. Calcd. for C22HI6C1N502S: C, 58.73; H, 3.58; N, 15.57. Found: C, 58.65; H, 3.77; N, 15.59.

[00210] Example 384 1-(4-amino-3,5-difluorophenyl)-8-[(3-chloroisonicotinoyl)amino]-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide F O
N-N

CI

N
[00211] Step 1: 1-Bromo- 3,4,5 trifluorobenzene (5 g, 24 mmol) was added to a slurry of Pd(OAc)2 (0.269 g , 5 mol %), bisdiphenylphosphino-ferrocene (1.0 g, 7 mol %) in anhydrous toluene (50 mL) at rt. Benzophenone hydrazone (4.9 g) was added, stirred for 5 min following by addition of dried cesium acetate (9.33 g) and toluene (40 mL). The flask was removed from a glove box and heated to 86 C
for 72 hours. The reaction was monitored by disappearance of bromotrifluourobenzene by LC (210 nm) or 19 F NMR. The reaction mixture was cooled down to room temperature and filtered through a sintered glass funnel. The solvent was removed under the vacuum. The orange solid residue was re-dispersed in ether (15 mL) and hexane (150 mL) and heated up to 58 C, stirred for 20 min. The hot solution was quickly filtered, solid discarded and the solution was allowed to cool to room temperature, stirred for 30 min, then 1 hour at 4 C. The formed slurry was filtered, washed with cold hexane (2x25 mL). Crystals were dried in air then in the vacuum at 80 C for 1 hour to give 5 g of diphenylmethanone (3,4,5-trifluorophenyl)hydrazone (64 % yield) as a yellowish solid.

[00212] Step 2: The product from step 1(1.9 g) and ethyl (7-nitro-l-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate (1.66 g) were dispersed in 1M

in ethanol (125 mL), heated to reflux, and stirred until the starting material disappeared (overnight). The solution was cooled down to 4 C and stirred for 2 hrs.
The cold slurry was filtered, solid washed with anhydrous ethanol (2x25 mL), dried on air and in the vacuum oven at 70 C for 1 hour to give 1.4 g of 8-nitro-1-(3,4,5-trifluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide as a brown powder (58 % yield).

[00213] Step 3: The product from step 2(1.17 g, 0.0028mo1) was hydrogenated in a Parr shaker with 5% Pt/C in acetic acid for 4 h at 5 psi.
After the removal of solvent, the residue was triturated with a mixture of methanol and ether to give 1.0 g of the product as a pale yellow solid. A sealed reaction vessel containing this solid and 10 mL of liquid ammonia in 50 mL of absolute alcohol was heated at 120 C and 600 psi for 24 h. After cooling, solvent was removed and the residue was triturated with a mixture of methanol and acetonitrile to give 0.8 g of 8-amino-l-(4-amino-3,5-difluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide as a pale yellow solid (80% yield over two steps); NMR spectrum was consistent with the proposed structure.

[00214] Step 4: To a mixture of the product from step 3(0.75 g, 0.0021 mol) and 3-chloroisonicotinic cid (0.33 g, 0.0023 mol) in 20 mL of DMF was added 1 mL of diisopropylethylamine, followed by the addition of HATU (0.9 g, 0.0023 mol). The reaction was stirred at room temperature for 16 h and concentrated.
The crude was purified by reverse phase HPLC to give 0.15 g of 1-(4-amino-3,5-difluorophenyl)-8-[(3-chloroisonicotinoyl)amino]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide as a pale white solid (15% yield); 1HNMR
(DMSO, 400 MHz) S: 10.56 (s, 1H), 8.76 (s, 1H), 8.63 (d, 1H), 8.56 (s, 1H), 7.54 (d, 1H), 7.49 (dd, 1H), 7.35 (m, 2H), 7.31 (s, 1H), 6.71 (m, 2H), 5.88 (s, 2H), 2.92 (m, 4H); Anal. Calcd. for Ca4H17FC1N602 + 0.5 H20: C, 57.21; H, 3.60; N, 16.68.
Found: C, 56.91; H, 3.70; N, 16.64.

[00215] Example 385 1-(4-amino-2,5-difluorophenyl)-8-[(3-chloroisonicotinoyl)amino]-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide F F
N N-N
O I \ \

CI

N
[00216] This compound was synthesized by using the same method as Example 384; mp: 289-290 C; 1HNMR (DMSO, 400 MHz) S: 10.55 (s, 1H), 8.75 (s, 1H), 8.63 (d, 1H), 7.57 (d, 1H), 7.55 (s, 1H), 7.39 (m, 4H), 7.29 (s, 1H), 6.70 (m, 1H), 5.90 (brs, 211), 2.89(s, 4H); Anal. Calcd. for CZ4H17FC1N602: C, 58.25;
H, 3.46; N, 16.98. Found: C, 57.65; H, 3.73; N, 16.82.

[00217] Additional analytical data is presented in Table 16 for the compounds of Examples 381-385.

Table 16 Compound No., Structure Mol. Compound Name(s) IKK2 MS Example Wt. Resin (M+H) HzN N~ 459.90 1-(6-aminopyridin-3-yl)-8- <l M 460 381 I [(3-o r", /~ N chloroisonicotinoyl)amino]-~ 1 H2 4,5-dihydro-lH-ci benzo[g]indazole-3-N carboxamide Compound No., Structure Mol. Compound Name(s) IKK2 MS Example Wt. Resin (M+H) IC50 449.92 8-[(3- <1 M 450 382 H s N-N chloroisonicotinoyl)amino]-o N r, ~ NH6 1-thien-2-yl-4,5-dihydro-lH-ci benzo[g]indazole-3-N carboxamide s 449.92 8-[(3- <1 M 450 383 ~ N-N chloroisonicotinoyl)amino]-o rv " NHZ 1-thien-3-yl-4,5-dihydro-1H-cl o benzo[g]indazole-3-~ N carboxamide F 494.89 1-(4-amino-3,5- <1 M 495 384 H" )J~ difluorophenyl)-8-[(3-F ~ N.-N chloroisonicotinoyl)amino]-o r", NHz 4,5-dihydro-lH-cl~ benzo[g]indazole-3-~ carboxamide N

H." 494.89 1-(4-amino-2,5- <1 M 495 385 F F difluorophenyl)-8-[(3-chIoroisonicotinoyl)amino]-N-N
NHz 4,5-dihydro-lH-' benzo[g]indazole-3-carboxamide [00218] Example 386 8-{ [(2-chloropyridin-3-yl)carbonyl]amino}-1-[4-(3-hydroxyprop-1-ynyl)phenyl]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide HO

N-N
O N O
CI ~ I NHZ
~
N ~

The following scheme was used for the synthesis of the title compound of Example 386.

SCHEME XXVIII
Br N-N Pd(PPh3)4 H2N CONH2 CuI-DMF O CI
TBSO HzN N- CI
CO

8-amino-l-(4-bromop henyl) -4,5-dihydro-1 H-benzo[g]indazole-<X~
3-carboxamide Pyr TBSO \\\ NO N

kll / TBAF ~ /
H N-N H N-N
N~. CONH2 40% N/ ~ CONH2 CI 3 steps cl I
N'~ N, I

Example 386 A stirred solution of 8-amino-l-(4-bromophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (2.30 g, 6 mmol) and tert-butyldimethyl-(2-propynl-oxy)silane (1.12 g, 6.6 mmol) in DMF-triethylamine (6 mL-6 mL) was added CuI (114 mg, 0.6 mmol) and tetrakis(triphenylphosphine) palladium (346 mg, 0.3 mmol) and the resulted mixture was heated at 100 C for 14 h before cooled to rt. The mixture was filtered through silica gel pad, washed with EtOAc, and concentrated. The crude material was taken into pyridine (20 mL), treated 2-chloronicotinyl chloride (1.23g, 7 mmol) at RT for 14 h. Tetrabutylammonium fluoride (25 mL of 1M THF solution, 25 mmol) was added at RT and stirred overnight. Aqueous ammonium chloride was added, the mixture extracted with EtOAc (5x30 mL). The organic portions were combined, dried over MgSO4, filtered, and separated by silica gel column (EtOAc). This gave 8-{ [(2-chloropyridin-3-yl)carbonyl]amino }-1-[4-(3-hydroxyprop-1-ynyl)phenyl]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide as a pale yellow solid (1.19g, 40%
over 3 steps). 1H NMR was consistent with its structure.

[00219] Example 387 8- { [(2-chloropyridin-3-yl)carbonyl]amino 1-1-[4-(5-hydroxypent-l-ynyl)phenyl]-4,5-dihydro- l H-benzo [g] indazole-3-carboxamide HO /~
N-N
N
CI NHz N, /

The compound was prepared in a similar manner as Example 386. 1H NMR was consistent with its structure.

[00220] Example 388 8-{ [(2-chloropyridin-3-yl)carbonyl] amino } -1-(4-ethynylphenyl)-4,5-dihydro-lH-benzo [g] indazole-3 -c arboxamide N-N
o N \ t O
/

A stirred solution of 8-amino-l-(4-bromophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (5.74 g, 15 mmol) and tert-butyldimethylsilylacetylene (2.31 g, 16.5 mmol) in DMF-triethylamine (20 mL-10 mL) was added CuI (285 mg, 1.5 mmol) and tetrakis(triphenylphosphine) palladium (870 mg, 0.75 mmol) and the resulted mixture was heated at 100 C for 14 h before cooled to rt. The mixture was filtered through silica gel pad, washed with EtOAc, and concentrated. The crude material was taken into pyridine (30 mL), treated with 2-chloronicotinyl chloride (2.90 g, 16.5 mmol) at RT for 14 h.
Tetrabutylammonium fluoride (25 mL of 1M THF solution, 25 mmol) was added at RT and stirred overnight. Aqueous ammonium chloride was added, the mixture extracted with EtOAc (5x30 mL). The organic portions were combined, dried over MgSO4, filtered, and separated by silica gel column (EtOAc). This gave product as a pale yellow solid (3.5 g, 49% over 3 steps). 1H NMR was consistent with its structure. CNH calculated for C26H18N502C1(H20)1.3: C(63.5%), H(4.2%), N(14.3%); found: C(63.6%), H(4.0%), N(14.3%).

[00221] Example 389 8- { [(2-chloropyridin-3-yl)carbonyl]amino }-1-(4-vinylphenyl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide N-N
O N / ~ I
O
CI NHZ
N ~

A solution of 8-{ [(2-chloropyridin-3-yl)carbonyl]amino}-1-(4-ethynylphenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (557 mg, 1.19 mmol) in DMF-DMSO
(20 mL - 1 mL) was treated at RT with H2 (5 psi) and Pd-CaSO4 (5%, 100 mg) for 12 min. The mixture was filtered through celite pad, concentrated and added water.
The solid product was collected via filtration, washed with water and ether, and dried to give product (262 mg, 47%). 1H NMR was consistent with its structure.
[00222] Example 390 1-(4-acetylphenyl)-8-{ [(2-chloropyridin-3-yl)carbonyl] amino } -4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide O

/ ~
~
N-N
O O
Cl NHZ
/ ~
N ~

A mixture of 8-{[(2-chloropyridin-3-yl)carbonyl]amino}-1-(4-ethynylphenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (442 mg, 1.2 mmol), water (65 mg, 3.6 mmol), and triflic acid (270 mg, 1.8 mmol) in dioxane (10 mL) was heated to 100 C for 18 h. The mixture was cooled to RT, aqueous NaHCO3 was added, and filtered. The product was washed with water and ether, and dried. This gave product (293 mg, 67%). 1H NMR was consistent with its structure.

[00223] Example 391 8- { [(2-chloropyridin-3-yl)carbonyl]amino }-1-[4-(1-hydroxyethyl)phenyl]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide OH

N-N
O N 0[~ N

CI NHZ
1 ~
N

A mixture of 1-(4-acetylphenyl)-8-{ [(2-chloropyridin-3-yl)carbonyl]amino}-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (200 mg, 0.41 mmol) in MeOH
(3 mL) and water (0.3 mL) was added NaBH4 (10 mg, 0.25 mmol) at RT and stirred for 14 h. The mixture was separated on silica gel column (EtOAc) to give product (100 mg, 50%). 'H NMR was consistent with its structure.

[00224] Additional analytical data for the compounds of Examples 386-391 is presented in Table 17 Table 17.

Compound No., Structure Mol. Compound Name(s) IKK2 MS Example Wt. Resin (M+H) Ho ~ 497.94 8-{ [(2-chloropyridin-3- 51 M 498 386 yl)carbonyl]amino}-1-[4-(3-hydroxyprop-1-ynyl)phenyl]-"-" 4,5-dihydro-lH-o, o o benzo[g]indazole-3-~ ~ N~4 N ~ carboxamide 525.99 8-{ [(2-chloropyridin-3- <1 pM 526 387 -Ho yl)carbonyl] amino }- 1-[4-(5 ~ hydroxypent-1-ynyl)phenyl]-H 4,5-dihydro-lH-"-"
o " N~ benzo[g]indazole-3-01 -- carboxamide N~

~ 467.91 8-{[(2-chloropyridin-3- 1< 10 468 388 y1)carbonyl]amino}-1-(4-/ N-N ethynylphenyl)-4,5-dihydro- M
o 0 1H-benzo[g]indazole-3-cl NHz carboxamide ~
N/~

469.93 8-{[(2-chloropyridin-3- <1 gM 470 389 yl)carbonyl]amino}-1-(4-vinylphenyl)-4,5-dihydro-lH-"-" benzo[g]indazole-3-H CI O N~ ~ \ N~ carboxamide N ~

0 485.93 1-(4-acetylphenyl)-8-{ [(2- 1< 10 486 390 chloropyridin-3-yl)carbonyl]amino}-4,5- pM
N-N
o o dihydro-lH-benzo[g]indazole-cl NHZ 3-carboxanude w ~

OH 487.95 8-{ [(2-chloropyridin-3- <1 M 488 391 yl)carbonyl]amino}-1-[4-(1-hydroxyethyl)phenyl]-4,5-N ~" o dihydro-lH-benzo[g]indazole-ol NHz 3-carboxamide N~

[00225] Example 392 8-{ [5-(acetylamino)-2-chlorobenzoyl] amino }-1-[4-(ethylsulfonyl)phenyl]-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide n 00 NH

N /\N NH2 O
CI O \

[00226] Step 1 F
S

To a stirring solution of NaOH (11.26 g, 281.6 mmol) in water (500 mL) was added dropwise a solution of 4-fluorothiophenol (25 mL, 234.6 mmol) in methanol (50 mL). After 15 minutes ethyl bromide (14.4 mL, 281.6 mmol) was added. After 6 hours more NaOH (1 g) was added and the reaction mixture was extracted with ether (3 X 300 mL). The combined organic extracts were treated with brine followed by MgSO4 then concentrated down to give 1-(ethylthio)-4-fluorobenzene (29 g, 80%) as a slightly yellow colored liquid.
[00227] Step 2 ~ F
O~ (/
0= ~

To a solution of the crude product of step 1 in CH2Cl2 (500 mL) was added m-CPBA (82 g of 77% max powder, 368 mmol) portion-wise with vigorous stirring. After 5 hours the reaction mixture was concentrated down and ethyl acetate (750 mL) was added. The organic phase was then washed with 4% aqueous NaOH (2 X 100 mL), water (100 mL), then brine (75 mL), and finally dried over MgSO4. The solution was concentrated down to yield a white solid (17.9 g) that was carried onto the next step without purification.

[00228] Step 3 0 ' 0=S
\
The crude product of step 2 was dissolved in ethanol (200 mL) and hydrazine (24 mL, 758 mmol) was added. The reaction mixture was heated to reflux for 6 hours then left at room temperature overnight. The ethanol was concentrated down to a smaller volume then water was added. A white precipitate formed and was collected (12.87 g, 68%). The desired compound (1-[4-(ethylsulfonyl)phenyl]hydrazine) was used in the next step without purification.

[00229] Step 4 ~ ~ ,o NH

~N NH2 CI O
o-Ir N
O

The title compound was prepared in a manner analogous to Example 3 using 1-[4-(ethylsulfonyl)phenyl]hydrazine and the appropriate acylating agent. The desired product crystallizes out of the reaction media in 81% yield. Anal. Calcd for C29H26C1NSO5S (MW = 591.13): C, 58.83; H, 4.43; N, 11.83. Found: C, 58.69;
H, 4.46; N, 12.16.

[00230] Example 393 8-[(2-chlorobenzoyl)amino]-1-[4-(isopropylsulfonyl)phenyl]-4,5-dihydro-lH-benzo [g] indazole-3-carboxamide ?O
N ~N NHz O
cl O

[00231] Step 1 O ~ F
~ /
0=S

To a 250 mL round-bottomed flask was placed KH (35 wt % in mineral oil) (1.64 g, 14.35 mmol). The solid was washed with hexane (2 X 10 mL) under nitrogen.
THF (50 mL) was added and the suspension was cooled to 0 C. lodomethane (0.89 mL, 14.35 mmol) followed by a solution of 4-fluorophenylmethylsulfone (1.25 g, 7.17 mmol) in THF (10 mL) was added. The reaction mixture was stirred at 0 C
for 1 hour then allowed to warm to room temperature overnight. A mixture of ethyl and isopropyl sulfone was observed, so LiHMDS (7.2 mL, 14.35 mmol) and iodomethane (0.45 mL, 14.35 mmol) were added. After 2.5 hours water was added to the reaction mixture and the aqueous phase was extracted with ether (3 X

mL). The combined organic extracts were treated with brine and dried over MgSO4. The ether solution was concentrated down to give the desired compound as a yellow solid. The crude material was used in the nest step without further purification.

[00232] Step 2 N, NHNH2 0=S

The product of step 1 (640 mg, 3.15 mmol) was dissolved in absolute ethanol (12 mL), the system was flushed with N2 and hydrazine ( 404 mg, 12.6 mmol) was added and the reaction refluxed overnight. HPLC showed 78% product and 21%
starting material. To drive the reaction to completion 2 equivalents of additional hydrazine was added and reaction was refluxed for additional 5 hours, at this time HPLC indicated 95% product. The reaction mixture was concentrated and the residue was stirred with water. A white solid, 390 mg (58%) was isolated. HPLC
indicated 86% product and 14% starting material. The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The organic phase was dried over MgSO4, and concentrated to yield 258 mg (38%) of 1-[4-(isopropylsulfonyl)phenyl]hydrazine with 99% purity. MH+ = 215. The 390 mg was re-dissolved in 10 mL ethanol and treated once more with additional hydrazine to obtain additional product with the desired purity.

[00233] Step 3 \/
I N ~N NH2 CI O ~ I O
~ I O

The title compound was prepared in a manner analogous to Example 3 using 1-[4-(isopropylsulfonyl)phenyl]hydrazine and the appropriate acylating agent. The desired compound was recovered in 86% yield. HPLC indicated the compound had 94% purity. Anal. Calcd for C28H25C1N404S +.1 H20 (MW = 550.05): C, 61.05; H, 4.61; N, 10.17. Found: C, 60.67; H, 4.44; N, 10.14.

[00234] Example 394 1-{ 4-[(3-aminopropyl)sulfonyl]phenyl } -8-{ [(2-chloropyridin-3-yl)carbonyl]amino } -4,5-dihydro-lH-benzo[g]indazole-3-carboxamide hydrochloride O!O
H-CI

0/, N H2 / I
N~ N ~
C! O ~ I O
[00235] Stgp 1 Br"v~NHBoc Commercially available 3-bromopropylamino hydrogen bromide (10 g, 45.7 mmol) was suspended in CH2C12 (125 mL). Triethylamine (10 mL, 98 mmol) was added followed by (Boc)20 (11g, 50 mmol) as a solid. After stirring overnight at room temperature the reaction mixture was diluted with CH2Cl2 (100 mL). The organic phase was washed with 1M HCl (100 mL), sat. aq. NaHCO3 (50 mL), and brine (50 mL) then dried over MgS04. Evaporation under reduced pressure yielded the desired compound as a slightly yellow liquid (10.55g, 97%) and no purification was necessary.
[00236] Ste p 2 F
S

BocHN
To a stirring solution of NaOH (624 mg, 15.6 mmol) in water (20 mL) was added drop-wise a solution of 4-fluorobenzenethiol (2 g, 15.6 mmol) in methanol (5 mL) at room temperature. After 30 minutes a solution of the product of step 2 (3.71 g, 15.6 mmol) in methanol (5 mL) was added drop-wise and the reaction mixture was allowed to stir at room temperature overnight. Ether (450 mL) was added and the aqueous layer separated. The organic phase was then washed successively with NaOH (75 mL), conc. aq. NH4C1 (75 mL), and brine (50 mL). The solution was dried over MgSO4 and concentrated down to give the desired compound as a colorless liquid (3.2 g, 72%). The compound was used in the next step without further purification.
[00237] Step 3 ~ F
O ~ , 0=
BocHN

To a stirring solution of the product of step 2 (3.2 g, 11.2 mmol) in CH2C12 (150 mL) was added m-CPBA (77% max powder) (9.56 g, mmol) portion-wise at room temperature. The reaction was left overnight then it was concentrated down and ethyl acetate (750 mL) was added. The organic phase was then washed with 4%
aqueous NaOH (2 X 100 mL), water (100 mL), then brine (75 mL), and finally dried over MgSO4. The solution was concentrated down to yield a white solid that was carried onto the next step without purification.

[00238] Step 4 ~ NHNH2 ~ /
0=S
BocHN

[00239] All of the crude material from step 3 was dissolved in ethanol (30 mL) and hydrazine (2.4 mL, 75 mmol) was added. The reaction mixture was refluxed overnight then concentrated down to a volume of 5 mL and added to water.

The resulting precipitate was collected to yield tert-butyl 3-[(4-hydrazinophenyl)sulfonyl]propylcarbamate as a white solid (1.88 g, 51%). The compound was used in the next step without further purification.

[00240] Step 5 IWO
H-CI

/ I
N-N
N y N NH2 CI 0 ~ I O

The title compound was prepared in a manner analogous to Example 3 using tert-butyl 3-[(4-hydrazinophenyl)sulfonyl]propylcarbamate and the appropriate acylating agent. The title compound was isolated as a tan colored HCl salt following standard Boc deprotection using 4N HCI in dioxane.

[00241] The compounds of Examples 395-409 in Table 18 were prepared in a manner analogous to Examples 392, 393, and 394 using the appropriate hydrazine and acylating agent.

[00242] The bioactivity in the IKK2 Resin assay for the compounds of Examples 392-409 is shown in Table 18.

Table 18 Compound No., Structure Mol. Compound Name IKK2 MS Example Wt. Resin (M+H) o 0 592.08 8-{[5-(acetylamino)-2- <1 pM 592 392 /- NH I~S ~ ~ cblorobenzoyl]amino}-1-[4-~ ~ H ~ N-N (ethylsulfonyl)phenyl]-4,5-~ N N'~ dihydro-lH-benzo[g]indazole-ci 0 3-carboxamide 0 0 550.05 8-[(2-chlorobenzoyl)amino]-1- <1 M 550 393 [4-(isopropylsulfonyl)phenyl]-N-N 4,5-dihydro-lH-"
~ r, ~ \ ~ NHz benzo[g]indazele-3-ci o ~ ~ carboxaniide Compound No., Structure Mol. Compound Name IKK2 MS Example Wt. Resin (M+H) 601.52 1-{4-[(3- 1< 10 565 394 H-Cl aminopropyl)sulfonyl]phenyl }-o. ,0 8-1 [(2-chloropyridin-3- M
yl)carbonyl]amino}-4,5-N N """ NHz dihydro-lH-benzo[g]indazole-ol 0 I~ 0 3-carboxamide hydrochloride 0 0 535.03 8-[(2-chlorobenzoyl)amino]-1- <1 M 535 395 / [4-(ethylsulfonyl)phenyl]-4,5-/ H N-N dihydro-lH-benzo[g]indazole-" NHz 3-carboxamide ci 0 0 0 536.01 8-{ [(2-chloropyridin-3- <1 M 536 396 -,_'s / yl)carbonyl]amino}-1-[4-H \ N-N (ethylsulfonyl)phenyl]-4,5-") " ~ ~ "H, dihydro-lH-benzo[g]indazole-ci 0 / 0 3-carboxamide o, 0 650.16 tert-butyl 3-[({3- <1 M 650 397 ci S \ ~ (aminocarbonyl)-1-[4-N "-N NF~ (ethylsulfonyl)phenyl]-4,5-HN o o ~ o dihydro-lH-benzo[g]indazol-8-yl } amino)carbonyl]-4-chlorophenylcarbamate o. 0 550.04 8-[(5-amino-2- <1 M 550 398 0 chlorobenzoyl)amino]-1-[4-~ H N-N (ethylsulfonyl)phenyl]-4,5-HzN" ~ 6 "'~ dihydro-lH-benzo[g]indazole-o 0 3-carboxamide 0 0 474.56 1-[4-(ethylsulfonyl)phenyl]-8- 1< 10 475 399 ~'s [(methylsulfonyl)amino]-4,5 N_N dihydro-lH-benzo[g]indazole- M
H
~ "'~ 3-carboxamide o S-" ~/ o o 0 0 549.05 8-[(2-chlorobenzoyl)amino]-1- <1 M 549 400 [4-(propylsulfonyl)phenyl]-4,5-\ N-N dihydro-lH-benzo[g]indazole-~ " N
"H, 3-carboxamide ci 0 0 0 550.04 8-{ [(2-chloropyridin-3- 1< 10 550 401 -'~s yl)carbonyl]aniino}-1-[4 ~ N-N (propylsulfonyl)phenyl]-4,5- M
N) N NHz dihydro-lH-benzo[g]indazole-ol 0 3-carboxamide Compound No., Structure Mol. Compound Name IKK2 MS Example Wt. Resin (M+H) o. ~ 678.09 8-[(5-amino-2- <1 pM 678 402 S
0 ci chlorobenzoyl)amino]-1-[4-F'O,k.H=N 1 p ~" NH, (propylsulfonyl)phenyl]-4,5-~ r 0 dihydro-lH-benzo[g]indazole-3-carboxamide trifluoroacetate 0 0 488.59 8-[(methylsulfonyl)amino]-1- 1< 10 489 403 [4-(propylsulfonyl)phenyl]-4,5 dih dro-lH-benzo M
H y [g]indazole-s "'~ 3-carboxamide o r o H-oi q. 0 600.53 1-{4-[(3- <1 gM 564 404 H2N'-'~9 ~ aminopropyl)sulfonyl]phenyl}-~ ~ I N N 8-[(2-chlorobenzoyl)amino]-~ r", NF6 4,5-dihydr6-1H-oi o benzo[g]indazole-3-carboxamide hydrochloride =lo 563.08 1-[4-(butylsulfonyl)phenyl]-8- 1< 10 563 405 wS
[(2-chlorobenzoyl)amino]-4,5-~ N "-" N,~ dihydro-lH-benzo[g]indazole- M
c~ o . \ 0 3-carboxamide o, 0 396.47 8-amino-l-[4- 1< 10 397 406 "'S ~I
~ (ethylsulfonyl)phenyl]-4,5-" " dihydro-lH-benzo[g]indazole- M
HzN I/ o NHz 3-carboxamide o, 0 410.50 8-amino-l-[4- 1<10 411 407 (propylsulfonyl)phenyl]-4,5-1 j~N,~ dihydro-lH-benzo[g]indazole- uM
~~ \ 0 3-carboxamide =-9 664.19 tert-butyl 3 [({3- 1< 10 664 408 ~ ~S ~ N N (aminocarbonyl)-1-[4- M
HN ~ " N"6 (propylsulfonyl)phenyl]-4,5-( o dihydro-lH-benzo[g]indazol-8 -I yl } amino)carbonyl]-4-chlorophenylcarbamate 0 0 561.06 8-[(2-chlorobenzoyl)amino]-1- 1< 10 561 409 {4-~ N \ N-N NN [(cyclopropylmethyl)sulfonyl]p M
~~ o ~ o henyl}-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide [00243] Example 410 8-[(2-chlorobenzoyl)amino]-1-[4-(methylthio)phenyl]-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide N N-N NHZ

CI O O
[00244] Step 1 IaNHNH2 4-Methylthiol-aniline (10.0 g; 7.2 mmoles) was suspended in 6N HCI (50 mL).
The solution was cooled to 0 C and sodium nitrite (5.26 g; 7.6 mmoles) dissolved in water (20 mL) was added dropwise keeping the temperature at 0 C. When the addition is complete, the reaction mixture is homogeneous and has changed from a dark brown to an orange color. After letting this stir for an hour, SnC12.2H20 (42.5 g; 18.8 mmoles) dissolved in conc. HCl (35 mL) was added to the cold solution over a period of 15 minutes. The reaction was allowed to stir for 2 hours allowing the temperature to reach room temperature. The white solid was filtered of and suspended in ice water (300 mL). 50% NaOH solution was added till reaction mixture becomes basic (pH - 12). Any undissolved solid was filtered off and the aqueous phase was extracted with ethyl ether (3 x 300 mL). The organic phase was dried over MgSO4 and concentrated to a yellow solid (7.8 g; 71 %
yield) HPLC indicated that product is 64% pure and has M+1=155 (other impurity was starting material); 1H NMR (CDC13) b 2.44 (s, 3H), 6.78 (m, 2 H), 7.23 (m, 2H).
[00245] Step 2 \ N N-N NHZ
CI O I / O

The title compound was prepared in a manner analogous to Example 3 using 1-[4-methylsulfonyl)phenyl]hydrazine and the appropriate acylating agent.

[00246] The compounds of Examples 411-414 in Table 19 were prepared in a manner analogous to Examples 410 using the appropriate acylating agent.

[00247] The bioactivity in the IKK2 Resin assay for the compounds of Examples 410-414 is shown in Table 19.

Table 19 Compound No., Structure Mol. Compound Name IKK2 MS Example Wt. Resin (M+H) s ~ 489.00 8-[(2-chlorobenzoyl)amino]-1- 1< 10 489 410 ~ [4-(methylthio)phenyl]-4,5- M
r", \\" N"2 dihydro-lH-benzo[g]indazole-o~ o I~ 0 3-carboxaniide 428.54 8-[(methylsulfonyi)amino]-1- <1 M 429 411 N-N [4-(methylthio)phenyl]-4,5-,N \ \ ~ NHZ dihydro-lH-benzo[g]indazole-~ 3-carboxamide ,s 526.45 8-[(3- <1 pM 490 412 HCI I chloroisonicotinoyl)amino]-1-N~ N "-N NHz [4-(methylthio)phenyl]-4,5-ci o I \ dihydro-lH-benzo[g]indazole-3-carboxamide hydrochloride ~s 533.01 8-{[(6-chloro-l,3-benzodioxol- <1 M 533 413 ~ N-N 5-yl)carbonyl]amino}-I-[4-~ ~ ,"~ \ \ N,6 (methylthio)phenyl]-4,5-oi o dihydro 1H-benzo[g]indazole-3-carboxamide s 540.48 8-[(5-amino-2- <1 M 504 414 i N-N chlorobenzoyl)amino]-1-[4-~ I N \ \ NN (methylthio)phenyl]-4,5-c~ o dihydro-IH-benzo[g]indazole-HoI 3-carboxamide hydrochloride [00248] The compounds of Examples 415-420 in Table 20 were prepared by oxidation with m-CPBA with the appropriate sulfide.

[00249] The bioactivity in the IKK2 Resin assay for the compounds of Examples 415-420 is shown in Table 20.

Table 20 Compound No., Structure Mol. Compound Name(s) IKK2 MS Example Wt. Resin (M+H) 0 444.54 1-[4-(methylsulfinyl)phenyl]-8- 1< 10 445 415 [(methylsulfonyl)amino]-4,5- pM
H N_N dihydro-lH-benzo[g]indazole--~ N,~\NHz 3 carboxamide S

o o HCI 542.45 8-[(3- <1 M 543 416 "5 ~ ~ chloroisonicotinoyl)amino]-1-~H ~ N_N [4-(methylsulfinyl)phenyl]-4,5-N NHi dihydro-lH-benzo[g]indazole-cl o ( 0 3-carboxamide hydrochloride 0 549.01 8-{[(6-chloro-1,3-benzodioxol- <l M 550 417 ro 5 5-yl)carbonyl]amino}-1-[4-N_N (methylsulfinyl)phenyl]-4,5-N NF~ dihydro-lH-benzo[g]indazole-cl o 3-carboxamide 0 556.48 8-[(5-amino-2- <1 M 557 418 HCI NHa s ~ chlorobenzoyl)amino]-1-[4-N-N (metbylsulfinyl)phenyl]-4,5-~ NH4 dihydro-lH-benzo[g]indazole-ei 0 3-carboxan-ude hydrochloride 0 505.00 8-[(2-chlorobenzoyl)amino]-1- <1 M 505 419 ~s ~ [4-(methylsulfinyl)phenyl]-4,5-\ N N-N N~ dihydro-lH-benzo[g]indazole-~ 3-carboxarmde I ~ o cl 0 0 505.99 8-{ [(2-chloropyridin-3- <1 M 506 420 ~s yl)carbonyl]amino}-1-[4-\ N N_N N~ (methylsulfinyl)phenyl]-4,5-~ dihydro 1H-benzo[g]indazole-i 0 3-carboxamide [00250] Example 421 1-{4-[(allylamino)sulfonyl]phenyl } -8-[(2-chlorobenzoyl)amino]-4,5-dihydro-lH-benzo [g] indazole-3-carboxamide \ oSo ~\H .N 0 N

N
C! O

[00251] Step 1 AH.S ( \
/
N'NH2 H
\ N a~c ct O 10 To a stirring solution of 1-[4-(aminosulfonyl)phenyl]-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (2967 mg, 5.7 mmol) in THF
(120 mL) was added DMAP (348 mg, 2.8 mmol), then tri-ethyl amine (0.95 mL, 6.8 mmol), followed by acetic anhydride (1.62 mL, 17.1 mmol). The reaction mixture was stirred at room temperature for overnight and then concentrated. To the residue was added 5 % aq. NaHCO3 (100 mL). All compounds were dissolved. The aq.
Layer was washed with EA (100 mL x 2), CH2C12 (100 mL). The aq. layer was separated. To the aq. Layer was added 1N HCl to pH=6. A white precipitate was formed. It was filtered and washed with ether to give a white solid. The solid was dried under reduced pressure at 45 C to give 1-{4-[(acetylamino)sulfonyl]phenyl}-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (2255.4 mg, 70%).

[00252] Step 2 O Cs+
~ S/o N'~

N- N NHO

CI O
To a stirring solution of 1-{4-[(acetylamino)sulfonyl]phenyl}-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (563 mg, 1 mmol) in H20 (5 mL) was added cesium carbonate (163 mg, 0.5 mmol). The suspension was stirred at room temperature for overnight. All compounds were dissolved. It was dried to give the Cs+ salt (650 mg, 93 %).

[00253] Step 3 oso ~N I \
O
/O / N.N

N

To a stirring solution of the Cs+ salt of 1-{4-[(acetylamino)sulfonyl]phenyl}-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (637 mg, 0.92 mmol ) in DMF (8 mL) was added a solution of allyl bromide (111 mg, 0.92 mmol). The solution was stirred at room temperature for over the weekend and concentrated. To the mixture was added MeOH- H20 (2:1). A precipitate was formed. It was filtered to give a yellow solid of 1-(4-[acetyl(allyl)amino] sulfonyl }phenyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-benzo[g]indazole-3-carboxamide (360 mg, 65%.) [00254] Step 4 ~S~

H I / N.N

N
CI O

A solid of 1-(4-{[acetyl(allyl)amino]sulfonyl}phenyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (360 mg, 0.6 mmol) was dissolved in 0.5 N solution of NaOH in EtOH (10 mL) 'and stirred at room temperature for overnight. The mixture was concentrated. It was purified by HPLC
to give the desired compound (210 mg, 62 %.) IKK-2 resin IC50 < 1 M.

[00255] Example 422 8-[(2-chlorobenzoyl)amino]-1- { 4-[(methylamino)sulfonyl]phenyl }-4,5-dihydro-lH-benzo [g] indazole-3-carboxamide O~ o0 N \
H ~ / N~N O
~ NHp N
cl O
[00256] St~
oo N
,~, 'O I ~ N' N p H N
ci o To a stirring solution of 1-{4-[(acetylamino)sulfonyl]phenyl}-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (563 mg, 1 mmol ) in DMF (20 mL) was added NaH2 (40 mg, 1 mmol). The mixture was stirred at room temperature for 1 h. To the mixture was added a solution of lodomethane (170.3 mg, 1.2 mmol) in DMF (1 mL). The solution was stirred at room temperature for 4 h and concentrated. It was purified by HPLC to give a solid of the desired compound 1-(4-{ [acetyl(methyl)amino]sulfonyl}phenyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (155 mg, 27 %.) [00257] Step 2 o, vo ~ is H N

N
cl O

[00258] A solid of 1-(4-{[acetyl(methyl)amino]sulfonyl}phenyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide was dissolved in 0.5 N solution of NaOH in EtOH (3 mL) and stirred at room temperature for 2 h. A suspension was formed. It was filtered and washed to give the desired compound (29 mg, 53 %.) IKK-2 resin IC50 < 1 M.
[00259] The compounds of Examples 423-433 in Table 21 were prepared in a manner analogous to Example 46 using the appropriate alkylating agent and when appropriate acylating or sulfonating agent.

Table 21 Compound No., Structure Mol. Compound Name IKK2 Resin MS Example Wt. IC50 (M+H) o,0 435.51 8-amino-l-[4-(2,5- 1 < 10 M 436 423 G""S dihydro-lH-pyrrol-l-ylsulfonyl)phenyl]-4,5-~" N~ dihydro-IH-~ I o benzo[g]indazole-3-carboxamide 0 0 453.52 8-amino-1-[4- 1< 10 M 454 424 ~"" S ~/ \) (morpholin-4-ylsulfonyl)phenyl]-4,5-N-" NF~
dihydro-IH-\ I o benzo[g]indazole-3-carboxamide o,0 459.53 8-amino-l-{4-[(diprop- <1 pM 460 425 N.s' 2-~ N- " NH2 ynylamino)sulfonyl]phe fizN L ~-< o nyl}-4,5-dihydro-1H-/ ' benzo[g]indazole-3-carboxamide Compound No., Structure Mol. Compound Name IKK2 Resin MS Example Wt. IC50 (M+H) 0 0 489.58 1-{4- <1 M 490 426 [(dimethylamino)sulfon yl]phenyl}-8-N-S~
H "'", [(methylsulfonyl)amino -3-N \ o ]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide 550.04 8-[(2- <1 M 550 427 -" o chlorobenzo 1 amino oS/~ 1{4- y) l / N-N [(dimethylamino)sulfon N ~ \ ""~ yl]phenyl}-4,5-dihydro-t / \ \ ~ 1H-benzo[g]indazole-3-carboxamide 0; ;0 593.11 8-[(2- <1 M 594 428 '",,,'H=S chlorobenzoyl)amino]-N 1-[4-({[2-o N ~" o (dimethylamino)ethyl]a ol I NH, mino } sulfonyl)phenyl]-~ ~ 4,5-dihydro-IH-~ benzo[g]indazole-3-carboxamide 0 550.04 8-[(3- 15 10 M 550 429 N-S~
' ~ ~ chlorobenzoyl)amino]-H N-N 1-{4-o N / \ ' NHZ [(dimethylamino)sulfon ~ yl]phenyl}-4,5-dihydro-oI 1H-benzo[g]indazole-3-carboxamide s..o 453.52 8-(acetylamino)-1-{4- 15 10 M 454 430 /t ) [(dimethylamino)sulfon H N-N yl]phenyl}-4,5-dihydro-~" 1H-benzo[g]indazole-~ 3-carboxamide 0 541.65 1-{4- 1< 10 M 542 431 N.s J [(diallylamino)sulfonyl]
o= N N-N phenyl}-8-0 ''" o "~ [(methylsulfonyl)amino ]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide ~N 8<o 598.08 8-[(2- 1 10 M 598 432 a chlorobenzoyl)amino]-N N-N 1-{4-[(diprop-2-0 " ynylamino)sulfonyl]phe "., nyl}-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide Compound No., Structure Mol. Compound Name IKK2 Resin MS Example -Wt. IC50 (M+H) H 9..0 454.56 8-amino-l-[4-({ [2- 1< 10 M 455 433 N~/ N-S' (dimethylamino)ethyl]a N-N mino}sulfonyl)phenyl]-",N 4,5-dihydro-+H-benzo[g]indazole-3-carboxamide [00260] The following scheme was used for the synthesis of Examples 434 SCHEME XXIX
0 0 O o ~ I H2gO4 02N LiHMDS 02N OEt \ KNO3 iCO O
~O
~ O O~
AcOH ~ ~ ~
-_ y ~~
O NHNH2 N-N OEt SnCI2 H N N-N OEt O 02N \ I \ O EtOH \ I \ O

O O
/\p -- cl ~ ~ oN-/ O
NH3, EtOH O N-N NH CI H N-N NH2 H2N N( II N/
O
O Pyridine ci O

[00261] Example 434 1 -(1,3-benzodioxol-5-yl)-8-{ [(2-chloropyridin-3-yl)carbonyl]amino}-5,5-dimethyl-4,5-dihydro- IH-benzo[g]indazole-3-carboxamide 0 /'-O

N-N

cl 0 / I
N~
[00262] Step 1 4,4-dimethyl-tetralone (6g) was suspended in 120m1 conc. HZSOQ at 0 C, then KNO3(3.8g)/H2SO4 (15m1) solution was added drop wise at 0 C. The reaction mixture was stirred at 0 C for three hours until the starting material was gone, then poured into about 100g of ice. After cooling down, the mixture was filtered, and the solid obtained was washed with water, hexane, and then dried under vacuum.
5.6g of desired product was obtained. It was used as it was without further purification.
They structure was proved by LC-MS(220, M+1), HPLC, 'HNMR.

[00263] Step 2 The title compound of Step 1(5.6g) was dissolved in 100m1 THF, then (COOEt)Z
(5.6g) was added. The mixture was cooled down to -40 C, and then, LiHMDS/1M
THF solution (40m1) was added slowly. The reaction mixture was warmed up to r.
t.
slowly, then stirred overnight, and then neutralized with 2N aq. HCI. The mixture was extracted with EA (3x200m1). The EA solution was dried over Na.ZSO4. After filtration and evaporation of solvent, the residue was purified by HPLC
(50%CH3CN to 90%CH3CN in 30 minutes). 1.3g of desired product was obtained.
The structure was proved by LC-MS(320, M+1) and HPLC.

[00264] Step 3 The title compound of step 2(1.3g) and 3,4-methylenedioxyphenylhydrazine hydrochloride ( 0.85g ) were suspended in 100 ml of HOAc. The mixture was heated up to reflux for 3 hours, and then the solvent was evaporated, and the residue was purified by HPLC (50% CH3CN/H2O to 90%CH3CN/HZO in 30 minutes). 0.65g of desired product was obtained and characterized by LC-MS(436, M+1), 'HNMR, HPLC analysis.

[00265] Step 4 The title compound of step 3 (0.65g) was suspended in 100m1 of EtOH, and then SnClZ (1.2g) were added. The reaction mixture was refluxed overnight. Then the solvent was evaporated, and residue was dissolved in 15m1 CH3CN and filtered.
The solution was purified by HPLC (40% CH3CN/HZO to 90% CH3CN/H2O in 30 minutes). 0.25g of desired product was obtained and characterized by HPLC and LC-MS(406, M+1).

[00266] Step 5 The title compound of step 4 (0.25g) was dissolved in EtOH and liquid ammonia, and heated up to 100C under 600 PSI for 36 hours. After releasing pressure and evaporating solvent, the residue is purified by HPLC (5% CH3CN/H2O to 60%
CH3CN/H20 in 30 minutes). 200mg of desired product was obtained, and characterized by LC-MS(376, M+1) and HPLC analysis.

[00267] Step 6 The title compound of step 5 ( 90mg) was dissolved in pyridine(5m1), then 2-chloro-nictinoyl chloride (52mg) were added. The reaction mixture was stirred overnight, and then solvent was evaporated. The residue was purified by HPLC(30% CH3CN/H2O to 90%CH3CN/Hz0 in 30 minutes) 49 mg of desired compound 1-(1,3-benzodioxol-5-yl)-8-{ [(2-chloropyridin-3-yl)carbonyl]amino}-5,5-dimethyl-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide O/'-O
N-N

cl O
N

The resulting compound was obtained and analyzed by 'HNMR, LC-MS(516, M+l), HPLC and CHN analysis.

[00268] Example 435 1-(1,3-benzodioxol-5-yl)-8-[(3-chloroisonicotinoyl)amino]-5,5-dimethyl-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide O~O
\ ~

\ I N

cl O ~ \ O

The tile compound of Example 332 (90mg) was dissolved in 5ml DMF, then 2-chloroisonicotinic acid(100mg), HATU(150mg) and diiospropylethylamine(0.5m1) were added. The reaction mixture was stirred at r. t. for two days. After the reaction was complete, solvent was evaporated, and the residue was purified by HPLC(30%

CH3CN/HO to 90% CH3CN/HZO in 30 minutes). 100mg of product was obtained and characterized by'HNMR, LC-MS (516, M+1), HPLC, CHN analysis.

[00269] The compounds of Examples 436-443 in Table 22 were prepared in a manner analogous to Examples 434 and 435 [00270] The bioactivity ilr the IKK2 Resin assay for the compounds of Examples 434-443 is shown in Table 22.

Table 22 Compound No., Structure Mol. Compound Name IKK2 MS Example Wt. Resin (M+H) 0 515.96 1-(1,3-benzodioxol-5-yl)-8- <1 p.M 516 434 J { [(2-chloropyridin-3-yl)carbonyl] amino }-5,5-N ~N NHZ dimethyl-4,5-dihydro-lH-~ benzo[g]indazole-3-oi I ~ o carboxamide N.

0 >'0 515.96 1-(1,3-benzodioxol-5-yl)-8- <1 M 552 435 [(3-chloroisonicotinoyl)amino]-N ~N NHz 5,5-dimethyl-4,5-dihydro-lH-benzo[g]indazole-3-cl o carboxamide N
F 475.91 8-[(3- <1 M 476 436 J chloroisonicotinoyl)amino]-1-~ o ~ N_N NH (4-fluorophenyl)-5-methyl-4,5-Ci HN ~ ~ ~ z dihydro-lH-benzo[g]indazole-~ 0 3-carboxamide F 475.91 8-{[(2-chloropyridin-3- <1 M 476 437 Q yl)carbonyI]amino}-1-(4-N y llo N-N fluorophenyi)-5-methyl-4,5-Ci HN / ~ ~ NHZ dihydro-lH-benzo[g]indazole-~ 0 3-carboxamide F F 354.36 8-amino-l-(2,4- nd 355 438 di#luorophenyl)-5-methyl-4,5-N-N NH dihydro-lH-benzo[g]indazole-HzN , r Z
3-carboxamide ~ HzN 351.39 8-amino-l-(4-amino-2- nd 352 439 fluorophenyl)-5-methyl-4,5-Q_F fluorophenyl)-5-methyl-4,5-N-N NHz dihydro-lH-benzo[g]indazole-H2N 3-carboxamide Compound No., Structure Mol. Compound Name IKK2 MS Example Wt. Resin (M+H) F 493.90 8-[(3- <1 M 494 440 / chloroisonicotinoyl)amino]-1-~ o N-N NH2 (2,4-difluorophenyl)-5-methyl-Ci HN 4,5-dihydro-lH-~ o benzo[g]indazole-3-carboxamide I 573.08 8-{[2-chloro-5-(4- <1 M 574 441 N methY1P erazin-l-1 iP
NJ F yl)benzoyl]amino}-1-(4-n\ fluorophenyl)-5-methyl-4,5-~ o ~ dihydro-lH-benzo[g]indazole-CI HN N-N NHZ 3-carboxamide O

HzN F 490.93 1-(4-amino-2-fluorophenyl)-8- <1 M 491 442 N~ ' \
[(3-N-N NH chloroisonicotinoyl)amino]-5-a HN / ' Z methyl-4,5-dihydro-IH-~ o benzo[g]indazole-3-carboxamide F 493.90 8-{[(2-chloropyridin-3- nd 494 443 ~ / \ F yl)carbonyl]amino}-1-(2,4-Ny I C ~
N-N NHZ difluorophenyl)-5-methyl-4,5-ci HN dihydro-lH-benzo[g]indazole-~ 0 3-carboxamide nd = not determined [00271] Example 444 1-(1,3-benzodioxol-5-yl)-8-[(N-isopropylglycyl)amino]-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide 0 /,--o N_N
NHN CONHZ

[00272] Step 1 To a solution of 8-amino-l-(1,3-benzodioxol-5-yl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (1.00 g, 2.87mmol) in DMA (5.0 mL) was added chloroacetyl chloride (0.27 mL, 3.44 mmol) and triethylamine (0.48 mL, 3.44 mmol) and the mixture was stirred at RT overnight. The reaction mixture was triturated with distilled water (3x40 mL) and the solid product precipitated out once the water was added. The mixture was filtered and the solid was dried under the vacuum oven overnight to give 8-[(chloroacetyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide. MS (ESI+) for C21H17C1N404 m/z 425 (M+H)+.

[00273] Step 2 To a solution of product from step 1(0.10 g, 0.24 mmol) dissolved in DMA (2.0 mL) was added isopropyl amine (3.0 eq) followed by the PS-DIEA resin (2.0 eq).
The mixture was stirred and heated at 100 C overnight. The reaction mixture was cooled to RT and the solution was filtered. The filtrate was then evaporated under a stream of nitrogen overnight. The sample was purified on the SPE silica column.
The clean fractions were combined and concentrated to give the title material.

NMR (CD3OD) 8 7.38 (dd, 1H), 7.28 (d, 1H), 7.18 (d, 1H), 7.0 (t, 1H), 6.96 (d, 2H), 6.12 (s, 2H), 3.29 (s, 2H), 3.04 (m, 2H), 2.95 (m, 2H), 2.79 (m, 1H), 1.08 (d, 6H); MS (ESI+) for C24H25N504 m/z 448 (M+H)+.

[00274] The compounds of Examples 445-4521isted in the table below where prepared according to the procedure of Example 444 using the appropriately substituted aniline and appropriate amine.

[00275] The bioactivity in the IKK2 Resin assay for the compounds of Examples 444-452 is shown in Table 23 Table 23 Compound No., Structure Mol. Compound Name(s) IKK2 LCMS Example Wt. Resin (M+H) 0 0 447.50 1-(1,3-benzodioxol-5- <1 M 448 444 / yl)-8-[(N-~ isopropylglycyl)amino]-I N-N 4,5-dihydro-lH-~N~N ~ ~ CONH2 benzo[g]indazole-3-" 0 carboxamide os1o 495.97 1-(1,3-benzodioxol-5- <1 M 460 445 yl)-8-[(N-H-Cl cyclobutylglycyl)amino]
N-N -4,5-dihydro-lH-~H~rHi CONHz benzo[g]indazole-3-0 carboxamide hydrochloride 0 o 495.97 1-(1,3-benzodioxol-5- 1< 10 460 446 HCI yl)-8-[(pyrrolidin-l- pM
/ ~ ylacetyl)amino]-4,5-~ N_N dihydro-lH-r~ CONH2 benzo[g]indazole-3-CN0 carboxamide hydrochloride 0 524.02 1-(1,3-benzodioxol-5- 1< 10 488 447 yl)-8-[(N-HCI cyclohexylglycyl)amino M
~H.~rHi ~N CONHa ]-4,5-dihydro-lH-benzo[g]indazole-3-0 carboxamide hydrochloride os.o 455.91 1-(1,3-benzodioxol-5- 1< 10 420 448 yl)-8-[(N- M
HCI ~ methylglycyl)amino]-N_N 4,5-dihydro-lH-H~r"~ \ CONH2 benzo[g]indazole-3-o I carboxamide hydrochloride 0 /.0 495.97 1-(1,3-benzodioxol-5- 1< 10 460 449 / \' yl)-8-{ [N- M
HCI (cyclopropylmethyl)glyc N- N yl] amino } -4,5-dihydro-N ~
coNH2 1H-benzo[g]indazole-3-~ -o carboxamide hydrochloride o~o 461.53 1-(1,3-benzodioxol-5- <1 M 462 450 \' yl)-8- { [N-(tert-butyl)glycyl]amino } -N- N 4,5-dihydro-1 H-xN~ r"i ~ ~ CoNHz benzo[g]indazole-3-o carboxamide Compound No., Structure Mol. Compound Name(s) IKK2 LCMS Example Wt. Resin (M+H) ,-0 461.53 1-(1,3-benzodioxol-5- 51 M 462 451 / ~ ~ 1)8-[(N-Y
isobutylglycyl)amino]-H N-N 4,5-dihydro-lH-\~HN CONHZ benzo[g]indazole-3-IT o~ i carboxamide F 433.49 8-[(N- <1 M 434 452 OY\' cyclobutylglycyl)amino]
N-N -1-(4-fluorophenyl)-4,5-N \ CONN dihydro-lH-H~ 2 benzo[g]indazole-3-carboxamide Example 453 8- { [5-Chloro-2-(4-methylpiperazin-1-yl)isonicotinoyl]amino}-1-[4-(methylsulfonyl)phenyl]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide Step 1 8- [(2, 5-Dichloroisonicotinoyl)amino]-1- [4-(methylsulfonyl)phenyl]-4, 5-dihydro-1 H-benzo [g] indazole-3-carboxamide Q. O

N' I C~ H N-N
CI ~ N
~ I NH2 [00276] The product of Example 92 (8-amino-l-[4-(methylsulfonyl)phenyl]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide hydrochloride) (1.20 mmol), 2,5-dichloroisonicotinic acid (1.83 mmol), HATU (1.83 mmol), and 0.7 mL

triethylamine were dissolved in 10 mL DMF. The mixture was stirred at r.t.
overnight before more triethylamine (0.4 rnL), HATU (1.29 mmol), and 2,5-dichloroisonicotinic (2.24 mmol) were added to drive the reaction. After another 2.5 h, the mixture was added to water, causing a precipitate, which was filtered and washed with water. After trituration in water, the product was dissolved in tetrahydrofuran, decolorized with activated carbon, dried over MgSO4, and the solvent stripped. The solid was dissolved in anhydrous acetonitrile, filtered, and the acetonitrile stripped. The residue was purified by recrystallizations from absolute ethanol followed by triturations with anhydrous acetonitrile. Mp: 215-222 C.
Mass spectrum: M + 1 = 556. 1H NMR (S, d6-DMSO, 400 MHz): 2.87-2.98 (m, 4H); 3.18 (s, 3H); 7.29-7.38 (m, 4H); 7.60 (s, 1H); 7.76 (s, 1H); 7.80-7.85 (m, 2H);
8.06-8.11 (m, 2H); 8.58 (s, 1H); 10.56 (s, 1H).

Step 2 8- { [5-Chloro-2-(4-methylpiperazin-l-yl)isonicotinoyl]amino}-1-[4-(methylsulfonyl)phenyl]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide N~ Ci H N-N
N

[00277] The product of step 1 (0.92 mmol) and N-methylpiperazine (9.0 mmol) were combined with 2.6 mL DMA. The reaction mixture was placed under nitrogen and stirred in an oil bath at 100 C for 15 h. The mixture was then added to water, causing a precipitate, which was filtered and washed with water. The solid was dissolved in acetonitrile, dried over MgSO4, and the solvent stripped.
Mass spectrum: M + 1= 620.
Example 454 1-(1,3-Benzodioxol-5-yl)-8-{ [(6-chloro-4-methylpyridin-3-yl)carbonyl] amino }-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide O~ ~O
/ ~
CI I N_N O
\
O ~ i NH2 [00278] The product of Example 161, Step 4(5.93 mmol), 6-chloro-4-methylnicotinic acid (Example 246, Step 1) (8.91 mmol), HATU (8.73 mmol), and 3.0 mL triethylamine were dissolved in 30 mL DMF. The mixture was stirred at r.t.
for 5.4 h. The solvent was then partially stripped and the residue suspended in water, filtered, and washed with water. The solid was dissolved in tetrahydrofuran, decolorized with activated carbon, dried over MgSO4, and-the solvent stripped.
The product was purified by recrystallizations in tetrahydrofuran and a trituration in ethanol/water. Mp: 303 C (decomp.). Mass spectrum: M + 1 = 502. 1H NMR (S, d6-DMSO, 400 MHz): 2.28 (s, 3H); 2.81-2.96 (m, 4H); 6.06 (s, 2H) ; 6.90-6.94 (m, 1H); 6.97-7.01 (m, 1H); 7.08 (d, 1H, J = 2.0 Hz); 7.20-7.39 (m, 4H); 7.45-7.49 (m, 2H); 8.34 (s, 1H); 10.30 (s, 1H) [00279] Examples 455, 456, and 457 were synthesized by the following general synthesis procedure, illustrated for Example 455:

Zn2 / CI $N-N Pd2(a)a)s> dPPf / CI N H2, 5%Pd/C
~ H
CI N N/ CONH2 DMF/BN, 90 C~ N N D
N/ CONH2 HCI, rt O

\
/ CI H N-N

Example 455 [00280] 8-({ [6-(Aminomethyl)-3-chloropyridin-2-yl]carbonyl}amino)-1-(1,3-benzodioxol-5-yl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide Step 1 1-(1,3-Benzodioxol-5-y1)-8-{ [(3-chloro-6-cyanopyridin-2-yl)carbonyl]amino }-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide / H N-N
Cl I

O

[00281] The product of Example 216 (1-(1,3-benzodioxol-5-yl)-8-{ [(3,6-dichloropyridin-2-yl)carbonyl]amino } -4,5-dihydro- 1 H-benzo[g]indazole-3-carboxamide) (1.045 g, 2 mmol), Zn(CN)2 (0.138 g, 1.2 mmol), Pd2(dba)3 (0.0904 g, 0.1 mmol) (dba = dibenzylideneacetone), and dppf (dppf =

bis[diphenylphosphino]ferrocene) (0.121 g, 0.22 mmol) were mixed in a flask containing stir bar. The mixture was placed under vacuum then nitrogen three times to remove oxygen. Degassed anhydrous solvents (9 mL of DMF and 3 mL of benzonitrile) were added under N2, and the flask was placed in an oil bath at for 6 h. After 6 h solvent was removed under vacuum, 50 n1L of ether was added and stirred 3 h. Ether was removed by filtration, and the solid was triturated with 50 mL of water 3 h, dried and purified by HPLC. The title compound is a yellow solid (0.234 g, 23%). 1H NMR (d6-DMSO): 8 2.82-3.01 (m, 4H), 6.09 (s, 2H), 6.97-7.07 (m, 2H), 7.14 (d, 1H, J= 3 Hz), 7.27 (s, 1H), 7.33-7.40 (m, 3H), 7.52 (s, 1H), 8.21 (d, 1H, J= 8 Hz), 8.39 (d, 1H, J = 8 Hz), 10.60 (s, 1H). ESI mass spectrum for C26H18C1N6O4+: 513 (M + 1).
Step 2 8-( { [6-(Aminomethyl)-3-chloropyridin-2-yl]carbonyl } amino)-1-(1,3-benzodioxol-5-yl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxatnide /lo ~
CI ~ 1N-H
/ ~

[00282] The product of step 1 (0.24 g, 0.47 mmol) was dissolved in a mixture of anhydrous solvents, containing glyme (3 mL), methanol (9 mL), and 1.2 M
solution of HCl in methanol (3 mL). The mixture was placed under N2, in Fisher-Potter bottle, containing magnetic stir bar and 0.02g of 5% Pd/C catalyst (Degussa -Frankfurt, Germany). Previously, the catalyst was dried and preactivated (H2, psi, 30 minutes). The hydrogenation was carried out under 3 psi pressure for 3 hours at room temperature. The catalyst was removed by filtration, and the filtrate was purified by HPLC to give 0.152 g of TFA salt of 8-({ [6-(Aminomethyl)-3-chloropyridin-2-yl] carbonyl } amino)-1-(1,3-benzodioxol-5-yl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide, which was triturated in water-triethyl amine mixture (2:1) for 30 minutes. The title compound (0.12 g, 49%) was obtained as the free base (a white solid) after filtration and drying. 1H NMR (db-DMSO): S
2.03 (s, 2H), 2.82-3.00 (m, 4H)), 3.80 (s, 2H), 6.09 (s, 2H), 6.92-7.03 (m, 2H), 7.15 (d, 1H, J = 2 Hz), 7.25 (s, 1H), 7.28-7.44 (m, 3H), 7.49 (s, 1H), 7.58 (d, 1H, J =
8.5 Hz), 7.96 (d, 1H, J= 8.5 Hz), 10.40 (s, 1H). ESI mass spectrum for C26H22C1N6O4+: 517 (M + 1).

Example 456 8- { [2-(Aminomethyl)-5-chloroisonicotinoyl] amino }-1-(4-fluorophenyl)-4,5-dihydro-IH-benzo[g]indazole-3-carboxamide Step 1 8-[(5-Chloro-2-cyanoisonicotinoyl) amino] -1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g]indazole-3-carboxamide F
N~ CI N-N
N \ N / I \ CONH2 O

[00283] The compound of step 1 was synthesized by the same procedure as in step 1 of Example 455 for l-(1,3-Benzodioxol-5-yl)-8-{ [(3-chloro-6-cyanopyridin-2-yl)carbonyl] amino } -4,5-dihydro-lH-benzo[g]indazole-3-carboxamide starting with the compound of Example 248 (8-[(2,5-dichloroisonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-car'boxamide) (1.67 g, 3.2 mmol), Zn(CN)2 (0.230 g, 2 mmol), Pd2(DBA)3 (0.203 g, 0.22 mmol), and DPPF (0.121 g, 0.52 mmol), in a mixture of DMF (6 mL) and benzonitrile (2 mL). The mixture was heated at 90 C for 6 h. Solvents were removed under reduced pressure. The residue was triturated with 50 mL of ether overnight and filtered to give 2.2 g of a brown solid. The title compound, isolated from 0.8 g of the crude reaction mixture by preparative HPLC, is a white solid (0.30 g), M.p. 275-276 C. 1H NMR (CD3OD): b 2.94 - 3.17 (m, 4H)), 7.20-7.48 (m, 9H), 8.01 (s, 1H), 8.82 (s, 1H). ESI mass spectrum for Ca5H17C1FN6O2+: 487 (M + 1).
Step 2 8- { [2-(Aminomethyl)-5-chloroisonicotinoyl] amino } -1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide N~ I CI N-N

HCI

[00284] The title compound was synthesized by the same procedure as in step 2 of Example 455 for 8-( {[6-(Aminomethyl)-3-chloropyridin-2-yl]carbonyl }
amino)-1-(1,3-benzodioxol-5-yl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide starting with 1.2 g of the crude reaction mixture containing the compound of step 1 and 0.4 g of 10% Pd/C (Aldrich) in a mixture of glyme (3 mL), methanol (14 mL), and 1.2 M solution of HCI in methanol (6 mL). The hydrogenation was carried out under psi pressure for 8 h at room temperature. The catalyst was removed by filtration, and the filtrate was purified by HPLC to give 0.43 g of the TFA salt of 8-{[2-(Aminomethyl)-5-chloroisonicotinoyl] amino } -1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide, which was triturated in 2N HCl for 3 hours.
The title compound (0.35 g) as the HCI salt (white solid) was obtained after filtration and drying. M.p., 312-314 C. 1H NMR (CD3OD): 6 2.91 - 3.15 (m, 4H), 4.33 (s, 2H), 6.09 (s, 2H), 7.22 - 7.42 (m, 5H), 7.38 - 7.52 (m, 3H), 8.78 (s, 1H). ESI
mass spectrum for C25H21C1FN6O2+: 491 (M + 1).
Example 457 8- { [2-(Aminomethyl)-5-chloroisonicotinoyl]amino 1- l-(l,3-benzodioxoI-5-yI)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide Step 1 1-(1,3-Benzodioxol-5-yl)-8-[(5-chloro-2-cyanoisonicotinoyl)amino]-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide /'-O
J Ci N
N

O

[00285] The compound of step 1 was synthesized by the same procedure as in step 1 of Example 455 for 1-(1,3-Benzodioxol-5-yl)-8-{ [(3-chloro-6-cyanopyridin-2-yl) c arb onyl] amino }-4, 5-dihydro-1 H-benzo [g] indaz ole-3 -carboxamide starting with the compound of Example 211 (1-(1,3-benzodioxol-5-yl)-8- [(2, 5-dichloroisonicotinoyl)amino] -4, 5-dihydro-1 H-benzo[g]indazole-3-carboxamide) (2.16 g, 4.1 mmol), Zn(CN)2 (0.287 g, 2.5 mmol), Pd2(DBA)3 (0.203 g, 0.24 mmol), and DPPF (0.121 g, 0.55 mmol), in a mixture of DMF (9 mL) and benzonitrile (3 mL). The mixture was heated at 90 C
for 6 hours. Solvents were removed under reduced pressure. The residue was triturated with 50 mL of ether overnight and filtered to give 2.8 g a brown solid.
The product, isolated from 0.9 g of the crude reaction mixture by preparative HPLC, is a white solid (0.35 g), M.p. 321-322 C. 1H NMR (d6-DMSO): S 2.82-3.01 (m, 4H)), 6.10 (s, 2H), 6.94-7.06 (m, 2H), 7.11 (d, 1H, J = 2 Hz), 7.24-7.38 (m, 4H), 7.52 (s, 1H), 8.38 (s, 1H), 8.97 (s, 1H). ESI mass spectrum for C26H18C1N6O4+:

(M+1).

Step 2 8-{[2-(Aminomethyl)-5-chloroisonicotinoyl]amino}-1-(1,3-benzodioxol-5-yl)-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide /--O
N~ I Ci H N-N
~ N / ~ ONH2 H2 O ~ I

[00286] The title compound was synthesized by the same procedure as in step 2 of Example 455 for 8-({[6-(Aminomethyl)-3-chloropyridin-2-yl]carbonyl}amino)-1-(1,3-benzodioxol-5-yl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide starting with 1.4 g of the crude reaction mixture containing the compound of step 1 and 0.6 g of 10% Pd/C (Aldrich) in a mixture of glyme (20 mL), methanol (30 mL), and 1.2 M solution of HC1 in methanol (10 mL). The hydrogenation was carried out under 5 psi pressure for 8 h at room temperature. The catalyst was removed by filtration, and the filtrate was purified by HPLC to give 0.52 g of TFA salt of the title compound, which was triturated in 1N HC1(2:1) for 3 h. The title compound (0.40 g) as the HCl salt (a white solid) was obtained after filtration and drying.
M.p., 125-130 C. 1H NMR (CD3OD): S 2.90 -3.16 (m, 4H), 4.34 (s, 2H), 6.09 (s, 2H), 6.92 - 7.03 (m, 3H), 7.38(s, 2H), 7.40 (s, 1H), 7.57 (s, 1H), 8.78 (s, 1H).
ESI mass spectrum for C26H23C1N6O4+: 518 (M + 1).

[00287] Examples 458 and 459 were synthesized by the following synthesis procedure, illustrated for Example 458.

SCHEME XXX

CO2H CO2Et 1. Zn(CN)2, Pd2(dba)3 C02Et CI SOCI2 CI dppf, DMF, PhCN CI
N I CI CZH50H~ N I CI 2. H2, 10% Pd/C C2H5OH N NH2 CO2 Et CO2H
(Br(CH2)z)20 CI O HCI O
(i-Pr)~EtN, MeCN N N reflux NJ
F
F
N
H2N \~ CONH N CI N-N

~ I O N N/ \ t CONH2 HBTU (BF~ ), DMSO, NEt3 O \ I

Example 458 8-( { [3-Chloro-6-(morpholin-4-ylmethyl)pyridin-2-yl] carbonyl } amino)- 1 -(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide Step 1 Ethy12,5-dichloroisonicotinate C02Et CI
I
N CI

[00288] 2,5-Dichloroisonicotinic acid (7.2 g, 37.5 mmol) and 180 mL of anhydrous C2H5OH were placed in a flask containing magnetic stir bar under N2.
The mixture was cooled to 0 C and 5.6 mL of SOC12 (38 mmol) was added dropwise. The solution was heated under reflux overnight. Volatiles were partially evaporated to decrease the volume to 30 mL. The residue was partitioned between a water solution of Na2CO3 with pH = 8.5 (75 mL) and CH2C12 (75 mL). The organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2 x mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo to give 7.8 g of product (97.5% yield). 'H NMR (DCC13): S 1.42 (t, 3H, J
= 7 Hz), 4.44 (q, 2H, J = 7 Hz), 7.68 (s, 1H), 8.50 (s, 1H). ESI mass spectrum for C8H8C12NO2+: 220 (M + 1).

Step 2 Ethy12-(aminomethyl)-5-chloroisonicotinate hydrochloride CO2Et CI HCI

[00289] All dried reagents (7.8 g (35.45 mmol) of ethyl 2,5-dichloroisonicotinate, 4.5 g (3.5 mmol) of Zn(CN)2, 0.226 g (0.41 mmol) of dppf (dppf = bis[diphenylphosphino]ferrocene), and 0.170 g(0.19 mmol) of Pd2(dba)3) (dba = dibenzylideneacetone) were mixed in a flask containing a stir bar.
Degassed anhydrous solvents (10 mL of DMF and 3.3 mL of benzonitrile) were added under N2, and the flask was placed in an oil bath at 90 C for 6 h. After 6 h solvents were removed under vacuum, then 100 mL of water was added and the residue was triturated for 3 h. After filtration, the solid was dried under reduced pressure to give about 7 g of product mixture, which was used for reduction without further purification. Both starting material and ethyl dicyanoisonicotinate were detected.
[00290] This product mixture (7 g) was placed in a Fisher-Porter bottle with 1.8 g of 10% Pd/C (Aldrich) in 120 mL of EtOH and 30 mL of Et,)O-HC1(2M

solution) under a hydrogen atmosphere (2-3 psi) and stirred at RT for 3 hours.
After removing solvent, the oil was triturated with ether to give a brownish solid, which, after filtration, was triturated with 10 mL of CH3CN to give 4.2 g of the title compound as the HCl salt (47% yield). 1H NMR (CD3OD): 8 1.41 (t, 3H, J = 7 Hz), 4.38 (s, 2H), 4.46 (q, 2H, J = 7 Hz), 7.80 (s, 1H), 8.78 (s, 1H). ESI
mass spectrum for C9H12C1aN2O2+: 215 (M + 1).

Step 3 Ethy15-chloro-2-(morpholin-4-ylmethyl)isonicotinate trifluoroacetate CO2Et CF3CO2H
CI / ~O
N

[00291] The product from step 2 (1.77 g, 7 mmol), 2-bromoethyl ether (2.18 g, 9.5 mmol), and ethyldiisopropylamine (2.5 g, 19 mmol) in 10 mL of acetonitrile were placed in a flask containing magnetic stir bar. The reaction mixture was stirred for 8 days at room temperature. Volatiles were removed under reduced pressure, and the desired product (solid, 1.3 g, 65% yield) was isolated with preparative HPLC as the TFA salt. 1H NMR (CD3OD): S 1.42 (t, 3H, J = 7 Hz), 3.41 (s, broad, 4H), 4.46 (q, 2H, J = 7 Hz), 4.58 (s, 2H), 4.88 (s, broad, 4H), 7.90 (s, 1H), 8.83 (s, 1H). ESI mass spectrum for C13H18ClN2O3+: 285 (M + 1).
Step 4 5-Chloro-2-(morpholin-4-ylmethyl)isonicotinic acid hydrochloride CI / ,/~O -I
\N NJHCI

[00292] The compound of step 3 (2.69 g, 10.3 mmol) as a suspension in 3N
HCl (15 mL) was heated under reflux for 3 hours. Volatiles were removed under reduced pressure to give 1.88 g (95% yield) of the title compound. 1H NMR
(CD3OD): S 3.30 (s, broad, 2H), 3.41 (s, broad, 2H), 3.83 (s, broad, 2H), 4.05 (s, broad, 2H), 4.58 (s, 2H), 7.92 (s, 1H), 8.83 (s, 1H). ESI mass spectrum for C1iH14C1N2O3+: 257 (M + 1).

Step 5 8-( { [3-Chloro-6-(morpholin-4-ylmethyl)pyridin-2-yl]carbonyl } amino)-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g]indazole-3-carboxamid.

F
CI
N H N-N

lo ~ o \ I

[00293] The title compound was synthesized from 0.94 g (3.2 mmol) of 5-chloro-2-(morpholin-4-ylmethyl)isonicotinic acid hydrochloride (step 4) and the compound of Example 244 (8-amino-l-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide) (0.69 g, 2.1 mmol) by the same procedure used for Example 255 except that DMF was replaced with DMSO (4 mL). The title compound is a brownish solid (0.31 g, 26%), M.p., 310-315 C(decomp.). 1H
NMR (CD3OD): S 2.78 - 2.82 (m, 4H), 2.92 - 3.12 (m, 4H), 3.76 - 3.80 (m, 4H), 3.98 (s, 2H), 7.21 - 7.42 (m, 5H), 7.50 - 7.63 (m, 3H), 8.63 (s, 1H). ESI mass spectrum for C?9HZ7CIFN6O3+: 561 (M + 1).
Example 459 1-(1,3-Benzodioxol-5-yl)-8-({ [3-chloro-6-(morpholin-4-ylmethyl)pyridin-2-yl]carbonyl } amino)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide O O

2 HC1 \ /
CI N
N x5H
[00294] The title compound was synthesized from 1.0 g (3.4 mmol) of 5-chloro-2-(morpholin-4-ylmethyl)isomicotinic acid hydrochloride (step 4 of Example 458) and the product of Example 161, Step 3 (0.78 g, 2.2 mmol) by the same procedure used for Example 255 except that DMF was replaced with DMSO (5 mL). The title compound was initially isolated as the TFA salt by preparative HPLC. After trituration with 2N HCI (2 x 20 mL) it was filtered and dried under reduced pressure to give the product as the bis(hydrochloride) tetrahydrate (0.35 g, 22% yield), M.p., 231-235 C(decomp.). 1H NMR (CD3OD): S 2.50 - 2.54 (m, 4H), 2.92 - 3.12 (m, 4H), 3.76 - 3.80 (m, 6H), 6.09 (s, 2H), 6.90 - 7.10 (m, 3H), 7.38 - 7.42 (m, 3H), 7.58 (s, IH), 8.60 (s, 1H). ESI mass spectrum for C30H28C1N605+: 587 (M + 1).

Examples 460 and 461 were synthesized by the following synthesis procedure, illustrated for the synthesis of Example 461.

SCHEME XXXI
CO2Me CO2Me tributylvinyl tin, CO2Me CI , SOCI2, MeOH CI / Pd(Ph3)4, dioxane CI

CI ~N I CI N

O O
~
O O
CO2H ~ / ~ N-N CI IN~ ~
HN ~ CONH2 O N N-N
1. morpholine, ~ CONH2 AcOH, EtOH HCI
2. NaOH, EtOH
3. HCI OJ HATU, DMF, NEt3 N N
O
Example 460 1-(1,3-Benzodioxol-5-y1)-8- { [5-chloro-2-(2-morpholin-4-ylethyl)isonicotinoyl]amino}-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide Step 1 Methyl 2,5-dichloroisonicotinate CO2Me CI , I
N CI

[00295] Thionyl chloride (9.13 g, 5.6 mL, 76 mmol) was added at 0 C to a suspension of 2,5-dichloroisonicotinic acid (7.3 g, 38 mmol) in 170 mL of MeOH.
The reaction mixture was refluxed overnight. The volatiles were evaporated and the resulting residue was basified (pH = 9) with a saturated aqueous solution of Na2CO3 and extracted with CH2CL.2. The organic extract was dried over MgSO4.
Purification by chromatography on silica gel (hexanes / EtOAc : 4/1) afforded the title compound as a white solid, yield 89%. 1H NMR (300 MHz, CDC13): 8 3.98 (s, 3H), 7.7 (s, 1H), 8.49 (s, 1H), 13C NMR (300 MHz, CDC13): 8 53.4, 125.2, 129.2, 139.3, 150.1, 151.1, 163.4. Mass spectrum, M+ 1= 207.
Step 2 Methyl 2-vinyl-5-chloroisonicotinate CO2Me CI
. ~ /
N

[00296] Pd(PPh3)4 (263 mg, 0.6 %) was added to a degassed mixture of methy12,5-dichloroisonicotinate (step 1) (8.39 g, 40.7 mmol) and tributyl(vinyl)tin (15.4 g, 14.24 mL, 48.5 mmol) in 100 mL THF. The reaction mixture was stirred at 60 C for 4 days. The solvent was evaporated and the resulting residue partitioned between CH2C12 and a saturated aqueous solution of KF. The CH2C12 extract was washed with H20 and dried over MgSO4. Purification by chromatography on silica gel (hexanes / EtOAc : 20/1 to 10/1) afforded the title compound as a colorless oil, yield 74 %. 1H NMR (300 MHz, CDC13): S 3.96 (s, 3H), 5.55 (d, 1H, Jc,s = 10.8 Hz), 6.24 (d, 1H, JTrans = 17.5 Hz), 6.78 (dd, 1H, JT,-QõS = 17.5 Hz, Jcis =
10.8 Hz), 7.65 (s, 1H), 8.62 (s, 1H), 13C NMR (300 MHz, CDC13): 8 53.2, 120.2, 121.9, 128.6, 135.3, 137.2, 151.1, 154.7, 164.8.1H-13C and 1H-15N correlation spectroscopy (ghmbc) confirmed the structure.

Step 3 2-(Morpholin-4-ylethyl)-5-chloroisonicotinic acid hydrochloride CI , = HCI
~ ~

N Oo [00297] A mixture of the material from step 2 (1.5 g, 7.5 mmol), morpholine (0.97 g, 0.97 mL, 11 mmol) and acetic acid (0.66 g, 0.63 mL, 11 mniol) in 7 mL
EtOH was refluxed for 2 days. The reaction mixture was concentrated under vacuum and the resulting residue basified to pH = 8 to 9 with a saturated aqueous solution of Na2CO3 and extracted with CHaC12. The organic extracts were dried over MgSO4. The crude product, consisting of a mixture of methyl and ethyl5-chloro-2-(morpholinoethyl)-isonicotinic esters, and was stirred with NaOH (1 mol/L, 7.5 mL, 7.5 mmol) in 20 mL of EtOH, at room temperature for 2 h. The volatiles were removed and the basic aqueous residue washed once with CH2C12.
The aqueous phase was acidified to pH = 3 with an aqueous solution of HC1(1N) and washed with CH2C12 before concentration under vacuum affording a white solid, which was washed with MeOH to give the title product, yield 49%. 1H NMR

(300 MHz, d6-DMSO): S 2.47-2.48 (m, 2H), 2.82-2.87 (m, 4H), 2.96-3.015 (m, 2H), 3.6-3.3-63 (m, 2H + H20), 7.49 (s, 1H), 8.53 (s, 1H),13C NMR (300 MHz, D20 ): S 30.3, 52.0, 56.1, 63.9, 121.4, 125.6, 147.9, 149.0, 154.9, 172.6.
Mass spectrum, M + 1 = 271.

Step 4 1-(1,3-Benzodioxol-5-yl)-8-{ [5-chloro-2-(2-morpholin-4-ylethyl)isonicotinoyl] amino }-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide O~O

\ ~
H N-N

C! 1)~

N co [00298] The product of step 4 was synthesized by the same procedure as in Example 211, starting with 8-amino-1 -(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (0.3 g, 0.86 mmol), 2-(Morpholin-4-ylethyl)-5-chloroisonicotinic acid hydrochloride (step 2) (0.399 g, 0.86 mmol), HATU
(0.48 g, 1.28 mmol) and Et3N (0.511 g, 0.70 mL, 5.05 mmol) in 6 mL of DMF. Purification by chromatography on silica gel (CH2C12 / MeOH: 11/1) afforded the title compound as a yellow solid, yield 41%. 1H NMR (300 MHz, d6-DMSO): 6 2.38 (s (broad), 4H), 2.62 (t, 2H, J= 7.12 Hz), 2.87-2.92 (m, 4H + 2H), 3.52 (t, 4H, J=
3.23), 6.07 (s, 2H), 6.94 (dd, 1H, J= 8.2 Hz, 1.88 Hz), 6.99-7.01 (m, 1H), 7.09 (d, 1H, J= 1.88 Hz), 7.24 (s, IH), 7.27-7.31 (m, 2H), 7.38 (dd, 1H, J= 8.2 Hz, 1.88 Hz), 7.43 (s, 1H), 7.49 (s,1H), 8.58 (s, 1H), 10.44 (s, 1H). Mass spectrum, M
+ 1 262.

Example 461 8- { [5-Chloro-2-(2-morpholin-4-ylethyl)isonicotinoyl]amino }-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g]indazole-3-carboxamide \ ~
~
H F\ N-N

O N CO

CI lxr N N~
~O
[00299] The title compound was synthesized by the same procedure as in Example 211, starting with 8-amino-l-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (0.489 g, 1.52 mmol), 2-(Morpholin-4-ylethyl)-5-chloroisonicotinic acid hydrochloride (step 3 of Example 460) (0.7 g, 2.27 mmol), HATU (0.852 g, 2.24 mmol) and Et3N (0.885 g, 1.22 mL, 8.75 mmol) in 10 mL of DMF. Purification by preparative reverse phase HPLC afforded the title compound as a white solid, yield 25 %. 'H NMR (300 MHz, d6-DMSO): S 2.35 (s (broad), 4H), 2.58 (t, 2H, J = 7.58 Hz), 2.84-2.90 (m, 4H + 2H), 3.54 (t, 4H, J= 4.36 Hz), 7.18 (s, 1H), 7.25 (s, 1H), 7.28-7.37 (m, 4H), 7.39 (s, 1H), 7.53-7.56 (rn, 3H), 8.55 (s, 1H), 10.41 (s, 1H). Mass spectrum, M + 1= 576.

Example 462 was prepared using a synthesis method similar to that of Example and 461, differing only in the amine added to the methyl 2-vinyl-5-chloropyridine.
SCHEME XXXII

CO2Me CO2Me CO2H
CI CI , Cf , = HCI
N NMe2H, AcOH, N N 1. NaOH, EtOH ~N N
MeOH, 37% ~ 2. HCI
40%

Example 462 8-({ 5-Chloro-2-[2-(dimethylamino)ethyl]isonicotinoyl } amino)-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo [g]indazole-3-carboxamide Step 1 Methyl 5-chloro-2-[2-(dimethylamino)ethyl]isonicotinate CO2Me CI

N N

[00300] A mixture of inethyl2-vinyl-5-chloroisonicotinate (step 2 of Example 460) (2.48 g, 12.5 mmol), methylamine (2 M solution in MeOH) (11.5 mL, 23 mmol) and acetic acid (1.38 g, 1.32 mL, 23 mmol) in 3 mL MeOH was heated at 78 C in a sealed tube for 3 days. The reaction mixture was concentrated under vacuum and the resulting residue basified to pH = 8 to 9 with a saturated aqueous solution of Na2CO3 and extracted with CH2C12. The organic extracts were dried over MgSO4. Purification by chromatography on silica ge1(CH2C12) afforded the title compound in 37% yield. 1H NMR (400 MHz, CDC13 ): S 2.29 (s, 6H), 2.71 (t, 2H, J = 7.36 Hz), 2.97 (t, 2H, J = 7.36 Hz), 3.9 (s, 3H), 7.5 (s, 1H), 8.56 (s, 1H), 13C NMR (300 MHz, CDC13): S 35.5, 45.4, 53.1, 59.0, 123.8, 127.8, 137.1, 150.8, 159.3, 164.9. Mass spectrum, M + 1 = 243.

Step 2 5-Chloro-2-[2-(dimethylamino)ethyl]isonicotinic acid hydrochloride CI / = HCI
~N N"

[00301] An aqueous solution of NaOH (1 mol/L) (5.8 mL, 5.8 mmol) was added to a solution of inethyl5-chloro-2-[2-(dimethylamino)ethyl]isonicotinate (step 1) (1.41 g, 5.8 mmol) in 15 mL MeOH. The reaction mixture was stirred at room temperature for 3 h and concentrated under vacuum. The basic aqueous residue was washed once with CHaC12. The aqueous phase was acidified to pH = 3 with an aqueous solution of HCl (1N) and washed with CH2Cl2 before concentration under vacuum affording a white solid, which was washed with MeOH
to give the title product, yield 40 %. iH NMR (300 MHz, D20): S 2.76 (s, 6H), 3.12 (t, 2H, J= 7.24 Hz), 3.38 (t, 2H, J= 7.24 Hz), 7.30 (s, 1H), 8.40 (s, 1H).
Mass spectrum, M + 1= 229.
Step 3 8-( { 5-Chloro-2-[2-(dimethylamino)ethyl]isonicotinoyl } amino)-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g] indazole-3 -carboxamide F
H N-N
O N ' CONH2 CI
I
N Ni [00302] The title compound was synthesized by the same procedure as in Example 211, starting with 8-amino-l-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (0.3 g, 0.86 mmol) (0.478 g, 1.48 mmol), 2-(Morpholin-4-ylethyl)-5-chloroisonicotinic acid hydrochloride (step 3 of Example 460) (0.59 g, 2.22 mmol), HATU (0.833 g, 2.19 mmol) and Et3N (0.871 g, 1.2 mL, 8.6 mmol) in DMF (8 mL). Purification by preparative reverse phase HPLC

afforded the title compound as a white solid in 33% yield. 1H NMR (300 MHz, d6-DMSO): S 2.10 (s, 6H), 2.54 (t, 2H, T= 7 Hz), 2.81-2.90 (m, 6H), 7.18 (s, 1H), 7.26-737 (m, 6H), 7.52-7.56 (m, 3H), 8.54 (s, 1H), 10.42 (s, 1H). Mass spectrum, M+1=534 Example 463 8-{ [(5-Chloro-2,4'-bipyridin-4-yl)carbonyl] amino }-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g]indazole-3-carboxamide Step 1 Methyl 5-chloro-2,4'-bipyridine-4-carboxylate C02Me CI

N
N

[00303] The product of step 1 was synthesized by the same procedure as for methyl 2-vinyl-5-chloroisonicotinate (step 2 of Example 461) starting with methyl 2,5-dichloroisonicotinate (step 1 of Example 460) (1.4 g, 6.8 mmol), 4-tributylstanylpyridine (2.5 g, 6.8 mmol) and Pd(PPh3)4 (45 mg) in 20 mL of dioxane. The reaction mixture was refluxed for 7 days. Purification by chromatography on silica gel (CH2CI2/MeOH: 18/1) afforded the title compound as a colorless oil, yield 44 %.1H NMR (300 MHz, CDC13): S 4.02 (s, 3H), 7.89-7.91 (m, 2H), 8.17 (s, 1H), 8.76 (d, broad, 2H, J = 6.0 Hz), 8.81 (s, 1H). Mass spectrum, M+1 =249.

Step 2 5-Chloro-2,4'-bipyridine-4-carboxylic acid hydrochloride CI HCI

N
N

[00304] The compound of step 2 was synthesized by the same procedure as for 5-chloro-2-[2-(dimethylamino)ethyl]isonicotinic acid hydrochloride (step2 of Example 462) starting with the product of step 1 (0.755 g, 3 mmol) and NaOH (1 mol/L) (4.5 mL, 4.5 mxnol) in 5 mL MeOH. The reaction mixture was stirred at room temperature for lh before acidification to pH = 2 with an aqueous HCl (1N) solution. The acidic mixture was washed once with CH2C12. White needles crystallized from the acidic aqueous layer. These needles were filtered and washed with water to give the title compound in 36% yield. 1H NMR (300 MHz, CDC13): S
8.1 (dd, 2H, J = 4.6 Hz, 1.6 Hz), 8.4 (s, 1H), 8.72 (dd, 2H, J = 4.6 Hz, 1.6 Hz), 8.9 (s, 1H). Mass spectrum, M + 1(-HCl) = 235.

Step 3 8- { [(5-Chloro-2,4'-bipyridin-4-yl)carbonyl] amino } - 1 -(4-fluorophenyl)-4,5-dihydro-1H-benzo [g] indazole-3-carboxamide F

-H N N

CI

N NII
[00305] The title compound was synthesized by the same procedure as in Example 211 starting with 8-amino-l-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (0.3 g, 0.86 mmol) (0.227 g, 0.7 mmol), the product of step 2 (0.287 g, 1.0 mmol), HATU (0.395 g, 1 mmol) and Et3N (0.413 g, 1.2 mL, 4 mmol) in DMF (6 mL). Crystallization from CH3CN afforded the title compound as a white solid, yield 45%. 1H NMR (400 MHz, d6-DMSO): S 2.9-2.95 (m, 4H), 7.26 (d, 1H, J = 2 Hz), 7.28 (s, 1H), 7.34-7.42 (m, 4H), 7.55 (s, 1H), 7.57-7.6 (m, 2H), 8.07 (dd, 2H, J= 4.6 Hz, 1.5 Hz), 8.3 (s, 1H), 8.7 (dd, 2H, J=
4.6 Hz, 1.5 Hz), 8.86 (s, 1H), 10.5 (s, 1H). Mass spectrum, M + 1 = 539.
[00306] Example 464 was synthesized by the following synthesis method.
The first two bicyclic compounds were not isolated pure, but subjected to successive reactions as described in step 3 to give 8-{ [(5-chloro-1'-methyl-1',2',3',6'-tetrahydro-2,4'-bipyridin-4-yl)carbonyl] amino } -1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g]indazole-3-carboxamide.

0 OTf SnMe3 Me6Sn2, Pd(PPh3)4, LHMDS, PhN(OTf)2 ~ LiCI, dioxane, 98 C 65 1 ~ N
CO2Me cl C02Me C02H
N I CI CI i I 1. NaOH, MeOH CI
Pd(PPh3)4, N 2. HCI N
dioxane 98 C N HCI N
F _ F

\
N-N H N-N

cl ~
HATU, Et3N, DMF -N

Step 1 1-Methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate OTf \
N

[00307] LiHMDS (1M, THF) (48.6 mL, 48.6 mmol) was added to a solution of 1-methyl-4-piperidone (5 g, 5.43 mL, 44.2 mmol) in 80 mL THF at -75 C. The mixture was stirred at this temperature for 2 h and warmed up to -50 C. A
solution of N-phenyltrifluoro-methanesulfonimide (17.36 g, 48.6 mmol) in 55 mL THF was added to the reaction mixture, which was then allowed to warm up to room temperature over a period of 3 h. The volatiles were removed under vacuum.
Purification of the resulting residue by chromatography on silica gel (EtOAc/hexanes: 7/3) afforded the title compound in 73% yield. 1H NMR (300 MHz, CDC13): S 2.36 (s, 3H), 2.43-2.45 (m, 2H), 2.65 (t, 2H, J= 5.8 Hz), 3.05-3.07 (m, 2H), 5.68 - 5.70 (m, 1H).

Step 2 1 -Methyl-4-(trimethylstannyl)- 1,2,3,6-tetrahydropyridine SnMe3 N
) [00308] Pd(PPh3)4 (0.31 g, 0.26 mmol) was added to a degassed mixture of 1-methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (step 1) (3.28 g, 13.3 mmol), hexamethylditin (4.60 g, 14 mmol), LiCI (1.73 g, 40 mmol) and a few crystals of 2,6-di-tert-butyl-4-methylphenol in 60 mL dioxane. The reaction mixture was heated at 98 C for 4 h. After cooling the reaction mixture was poured into an aqueous solution of KF and extracted with Et20. The organic extracts were washed once with H20 and once with brine before being dried over MgSO4. The residue obtained after removal was purified by chromatography on silica gel (CH2C12/MeOH : 10/1) to afford the title compound in a 41% yield. 1H NMR (300 MHz, CDC13): S 0.0 (t, 9H, Jsn-x = 26.4 Hz), 2.21 (s, 3H), 2.23-2.27 (m, 2H), 2.39 (t, 2H, J = 5.6 Hz), 2.82-2.85 (m, 2H), 5.70 - 5.72 (m, 1H).

Step 3 8-{ [(5-chloro-1'-methyl-1',2',3',6'-tetrahydro-2,4'-bipyridin-4-yl)carbonyl]amino }-1-(4-fluorophenyl)-4, 5-dihydro-1 H-benzo [g] indazole-3-carboxamide F
H N-N
O N ~ CONH2 CI ~ /

N
N
[00309] Pd(PPh3)4 (30 mg, 0.025 mmol) was added to a degassed mixture of the product of step 2 (1.82 g, 7 mmol) and methy12,5-dicloroisonicotinate (step 1 of Example 460) (0.96 g, 4.66 mmol) in 10 mL of dioxane. The reaction mixture was kept at 98 C overnight. After cooling the reaction mixture was poured into an aqueous solution of KF and extracted with EtOAc. The organic extracts were washed once with H20 and once with brine before being dried over MgSO4. The residue, obtained after removal of the solvents, was purified by chromatography on silica gel (CH2C12/MeOH: 15/1) to afford 0.606 g of a 2/1 mixture of the methyl 5-chloro-1'-methyl-1',2',3',6'-tetrahydro-[2,4']bipyridinyl-4-carboxylate and the product of step 2 which was dissolved in 5 mL of MeOH and reacted at room temperature with an aqueous solution of NaOH (1M) (2.5 mL, 2.5 mmol) for 1.5 h.
The reaction mixture was acidified to pH = 2 with an aqueous solution of HCI
(1N) and concentrated to give a white solid residue. This residue was reacted with amino-l-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (0.52 g, 1.6 mmol) in 10 niL DMF in the presence of Et3N (0.94 g, 1.3 mL, 9.3 mmol) and HATU (0.906 g, 2.38 mmol). After stirring 1.5 h, the mixture was concentrated and a white solid precipitated upon addition of water. The solid was filtered, dissolved in THF and dried over MgSO4. Preparative HPLC afforded the title compound in 36% yield. 'H NMR (400 MHz, d6-DMSO): S 2.25 (s, 3H), 2.51-2.53 (m, 4H), 2.86-2.91 (m, 4H), 3.04 (s, broad, 2H), 6.73 (s, broad, 1H), 7.19 (t, 1H, J
2.5 Hz), 7.25 (s, 1H), 7.29-7.38 (m, 4H), 7.52-7.56 (m, 3H), 7.59 (s, IH), 8.59 (s, 1H), 10.4 (s, 1H). Mass spectrum, M + 1= 558 Example 465 1-(4-Fluorophenyl)-8- [(2-morpholin-4-ylisonicotinoyl)amino] -4, 5-dihydro-1 H-benzo[g]indazole-3-carboxamide Step l 8-[(2-Chloroisonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide N-N
~ N
C~ O NH2 [00310] The product of Example 244 (8-amino-l-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide) (8.46 nunol), 2-chloroisonicotinic acid (12.70 mmol), HATU (12.63 mmol), and 4.2 mL triethylamine were dissolved in 42 mL of DMF. The mixture was stirred at r.t. for 4 h. The solvent was then partially stripped and the residue suspended in water, filtered, and washed with water. The solid was triturated in water, dissolved in acetonitrile, decolorized with activated carbon, dried over MgSO4, and recrystallized from acetonitrile. Mp:

262 C. Mass spectrum: M + 1= 462. 'H NMR (S, d6-DMSO, 400 MHz): 2.83-2.95 (m, 4H); 7.26 (s, 1H); 7.30-7.42 (m, 5H); 7.50-7.58 (m, 3H); 7.65-7.68 (m, IH);
7.78 (s, 1H); 8.53 (d, 1H, J = 5.1 Hz); 10.36 (s, 1H).
Step 2 1-(4-Fluorophenyl)-8-[(2-morpholin-4-ylisonicotinoyl)amino]-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide F
NH N-N 0~N N

, \ NH
O~ 0 [00311] The product of step 1 (2.17 mmol) and morpholine (32.7 mmol) were dissolved in 10 mL N,N-dimethylacetamide. The reaction mixture was placed under nitrogen and stirred in an oil bath at 80 C for 160 h then 100 C for 172 h.

The mixture was partially stripped of solvent then added to water causing a precipitate, filtered, and washed with water. The solid was recrystallized from acetonitrile, and triturated in diethyl ether, ethyl acetate, acetonitrile, and ethanol.
The product was dissolved in tetrahydrofuran, dried over MgSO4, and the solvent stripped. Finally, the product was dissolved in ethanol followed by stripping to remove trapped solvents. Mp: 269-274 C (decomp.). Mass spectrum: M + 1= 513.
1H NMR (S, d6-DMSO, 400 MHz): 2.56-2.59 (m, 4H); 3.44 (t, 4H, J = 4.8 Hz);
3.66 (t, 4H, J = 4.8 Hz); 6.88-6.92 (m, 1H); 7.02 (s, 1H); 7.24-7.43 (m, 6H); 7.50-7.58 (m, 3H); 8.19 (d, 1H, J = 5.1 Hz); 10.12 (s, 1H).
Example 466 8- { [5-chloro-2-(1,4-diazepan-1-yl)isonicotinoyl]amino }-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide F

N
N O
N

"
NH
C

[00312] The title compound was synthesized by the same procedure as in Example 214 starting with 8-[(2,5-dichloroisonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (Example 248) (1 g, 2 mmol) and homopiperazine (4 g, 40 mmol) in 5 mL EtOH. The reaction was run at 100 C for 24 h. The white precipitate that formed in the crude reaction mixture was filtered and washed with EtOH to afford the title product, yield: 82%. 1H NMR (400 MHz, d6-DMSO): 6 1.68-1.72 (m, 2H), 2.63 (t, 2H, J= 5.84 Hz), 2.79 (t, 2H, J= 5 Hz), 2.91-2.93 (m, 4H), 3.59 (t, 2H, J= 5 Hz), 3.64 (t, 2H, J= 5.84 Hz), 6.62 (s, 1H), 7.2 (d, 1H, J = 2 Hz), 7.28-7.4 (m, 4H), 7.44 (dd, 1H, J = 8.2 Hz, 2 Hz), 7.55-7.60 (m, 3H), 8.08 (s, 1H), 10.32 (s, 1H). Mass spectrum, M + 1= 561.

Example 467 8-({ 5-Chloro-2-[4-(2-hydroxyethyl)piperazin-1-yl]isonicotinoyl } amino)-1-(4-fluorophenyl)-4, 5-dihydro-1 H-benzo [g] indazole-3 -carboxamide F
H N-N

O N [/
CI
I
N N~
''NNO~OH

[00313] The title compound was synthesized by the same procedure as in Example 214 starting with 8-[(2,5-dichloroisonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (Example 248) (0.8 g, 1.6 mmol) and 1-(2-hydroxyethyl)piperazine (4.19 g, 3.94 mL, 32 mmol). The reaction was run at 100 C for 24 h. The white precipitate that formed in the crude reaction mixture was filtered and washed with EtOH and finally triturated with CHC13 to afford the title product, yield: 66%. 1H NMR (400 MHz, d6-DMSO): S 2.38 (t, 2H, J = 6.2 Hz), 2.44 (t, 4H, J= 4.7Hz), 2.87-2.93 (m, 4H), 3.45-3.52(m, 4H + 2H), 4.39 (t, 1H, J= 5.3 Hz), 6.87 (s, 1H), 7.2 (d, 1H, J= 2 Hz), 7.27 (s, 1H), 7.29-7.38 (m, 3H), 7.4 (dd, 1H, J= 8.2 Hz, 2 Hz), 7.54-7.58 (m, 3H), 8.12 (s, 1H), 10.31 (s, 1H).
Mass spectrum, M + 1 = 591.

Example 468 8-( { 5-Chloro-2- [4-(2-methoxyethyl)piperazin-1-yl]isonicotinoyl } amino)- 1 -(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide F
N~ CIH N-N
rN i N
~J O I i \ NH2 OS N

[00314] The title compound of Example 248 (8-[(2,5-dichloroisonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-IH-benzo[g]indazole-3-carboxamide) (1.61 mmol) and 1-(2-methoxyethyl)-piperazine (16.25 mmol) were combined with 4.0 mL of DMA. . The reaction mixture was placed under nitrogen and stirred in an oil bath at 100 C for 25 h. The mixture was added to water causing a precipitate, filtered, and washed with water. The product was dissolved in , tetrahydrofuran, dried over MgSO4, and the solvent stripped. The product was purified by nearly dissolving in ethanol, adding acetonitrile, the solid triturated in the solvent mix, the solvent partially stripped, and slurry filtered.
Elemental analysis: 61.65% C, 5.22% H, 16.04% N (theory: 61.64% C, 5.17% H, 16.23% N).
Mp: 238-240 C. Mass spectrum: M + 1 = 604.

Example 469 8-[(5-Chloro-2-{ [2-(dimethylamino)ethyl]amino }isonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide F

H N-N
O N I ~ CONH2 CI /
N I H~
/1 \

[00315] The title compound was synthesized by the same procedure as in Example 214 starting with 8-[(2,5-dichloroisonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (Example 248) (1 g, 2 mmol) and N,N-dimethylethylenediamine (3.55 g, 4.42 mL, 40 mmol). The reaction was run at 100 C for 24 h. The white precipitate that formed in the crude reaction mixture was filtered and washed with EtOH and finally purified by reverse phase preparative HPLC to afford the title product, yield: 14%. 1H NMR (400 MHz, d6-DMSO): S
2.13 (s, 6H), 2.34 (t, 2H, J= 6.5 Hz), 2.87 - 2.92 (m, 4H), 3.29 - 3.30 (m, 2H), 6.49 (s, 1H), 6.78 (t, 1H, J= 5.3 Hz), 7.2 (d, 1H, J= 2 Hz), 7.27 (s, 1H), 7.29 -7.40 (m, 4H), 7.53 - 7.58 (m, 3H), 7.99 (s, 1H), 10.3 (s, 1H). Mass spectrum, M + 1=
549.
Example 470 8-({5-Chloro-2-[(3R)-3-methylpiperazin-1-yl]isonicotinoyl}amino)-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo [g]indazole-3-caxboxamide F
Q
CI H N-~ ON 1)6--c2 ~

[00316] The title compound of Example 248 (8-[(2,5-dichloroisonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide) (2.62 mmol) and (R)-2-methylpiperazine (25.6 mmol) were combined with 6.5 mL of DMA. The reaction mixture was placed under nitrogen and stirred in an oil bath at 100 C for 15.5 h. The mixture was then added to water, causing a precipitate, which was filtered and washed with water. The solid was dissolved in acetonitrile, dried over MgSO4, and the solvent stripped. Mp., 278 C (decomp.). Mass spectrum: M + 1 = 560.
Example 471 8-( { 5-Chloro-2-[(3S)-3-methylpiperazin-1-yl]isonicotinoyl } amino)-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide F
/ ~
N~ CI H ~ N-N
~N N
~ ~
HNJ O J i NH2 [00317] The title compound of Example 248 (8-[(2,5-dichloroisonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g]indazole-3-carboxamide) (2.63 mmol) and (S)-2-methylpiperazine (25.1 mmol) were combined with 6.5 mL N,N-dimethylacetamide. The reaction mixture was placed under nitrogen and stirred in an oil bath at 100 C for 15.5 h. The mixture was then added to water causing a precipitate, which was filtered, and washed with water.
The solid was dissolved in acetonitrile, dried over MgSO4, and the solvent stripped.
Mp: 275-278 C (decomp.). Mass spectrum: M + 1 = 560.
Example 472 8-( { 5-Chloro-2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]isonicotinoyl } amino)-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide F
CIH -N

H

[00318] The title compound of Example 248 (8-[(2,5-dichloroisonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g]
indazole-3-carboxamide) (2.62 mmol) and cis-2,6-dimethyl piperazine (26.2 mmol), were combined with 6.5 mL DMA. The reaction mixture was placed under nitrogen and stirred in an oil bath at 100 C for 24 h. The mixture was then added to water, causing a precipitate, which was filtered and washed with water. The solid was dissolved in acetonitrile, dried over MgSO4, and the solvent stripped. Mp: 250 C
(decomp.). Mass spectrum: M+' 1 = 574.

[00319] Examples 473, 474, 475 were synthesized by the following synthesis method, illustrated for 473.

SCHEME XXXIII

r-~ CbzCI, Et3N /-\ CH2O, NaBH(OAc)3 Pd/C, H2(15 psi), ~
HN NH CHCI3 Cbz-N NH DCE, rt, 2h Cbz-N/ N- rt HN N-~{' F \ H F
I ~ N
I ~ N-N
H
O N \ \ N CONH2 ;N' O N \ ~\ CONH2 ci ! / C1 EtOH, 100 C
N CI N
N' Example 473 8-( { 5-Chloro-2-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]isonicotinoyl } amino)-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide Step 1 Benzyl (3R,5S)-3,5-dimethylpiperazine-l-carboxylate Cbz-N NH
' [00320] Benzyl chloroformate (9.7g, 8.12 mL, 54.1 mmol) was slowly added to a mixture of 2,6-dimethylpiperazine (6.25g, 54.7 mmol) and Et3N (5.53g, 7.6 mL, 54.7 mmol) in 100 mL CHC13. The reaction mixture was stirred at room temperature for 4h. Water was added and the organic phase separated and dried over MgSO4. Purification by chromatography on silica gel (CH2C12/MeOH: 12/1) afforded the title compound in 60% yield. 1H NMR (300 MHz, CDC13): S 1.04 (d, 6H, J = 6.2 Hz), 1.46 (s, broad, 1H), 2.38 (m, broad, 2H), 2.78 (s, broad, 2H), 3.99 -4.03 (m, broad, 2H), 5.12 (s, 2H), 7.34 - 7.36 (m, 5H), 13C NMR (300 MHz, CDC13): S 19.5, 50.9, 67.3, 128.1, 128.2, 128.7, 137.0, 155.3.
Step 2 Benzyl (3R,5S)-3,4,5-trimethylpiperazine-l-carboxylate Cbz-N N-[00321] NaBH(OAc)3 (2.96 g, 14 mmol) was added to a mixture of the product of step 1 (2.34 g, 10 mmol) and formaldehyde (0.86 g, 0.79 mL, 10 mmol) in 35 mL dichloroethane. The reaction mixture was stirred at room temperature for 1 h 40 min and quenched by adding an aqueous saturated solution of NaHCO3. The product was extracted with EtOAc and dried over MgSO4. Evaporation of the volatiles afforded the titled compound in 76% yield. 1H NMR (300 MHz, CDC13):
S
1.09 (d, 6H, J= 6.1 Hz), 2.16-2.17 (m, 2H), 2.25 (s, 3H), 2.65 (m, broad, 2H), 3.95 (m, broad, 2H), 5.13 (s, 2H), 7.33 - 7.36 (m, 5H). Mass spectrum, M + 1 = 263.

Step 3 (2R,6S)-1,2,6-Trimethylpiperazine HN N-[00322] A mixture of the product of step 2(2.75 g, 10 mmol) and Pd/C (5%, 1.1 g) in 20 mL MeOH was reacted for 2 h at room temperature under H2 (15psi).
The mixture was filtered through Celite and the filtrate evaporated to afford the title compound in 80% yield. 1H NMR (400 MHz, CDC13): S 1.0 (d, 6H, J = 6.1 Hz), 1.78 (m, broad, 1H), 2.0-2.05 (m, 2H), 2.21 (s, 3H), 2.5 (t, 2H, J = 10.7), 2.82 (dd, 2H, J = 12.5 Hz, 1.8 Hz). Mass spectrum, M + 1 = 129.

Step 4 8-({5-Chloro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]isonicotinoyl}amino)-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide F

_ H N N

O N jEI5CONH2 CI

N N
NI-I
1-f I

[00323] The title compound was synthesized by the same procedure as in Example 214 starting with 8-[(2,5-dichloroisonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide) (0.49 g, 1.0 mmol) and (2R,6S)-1,2,6-trimethylpiperazine (step 3) (1.03 g, 8.0 mmol) in 5 mL of EtOH. The reaction was run at 100 C for 5 days. The off-white precipitate that formed in the crude reaction mixture was filtered and washed with EtOH to afford the title compound in 77% yield. 1H NMR (400 MHz, d6-DMSO): 81.01 (d, 6H, J= 12.3 Hz), 2.05 (m, broad, 2H), 2.13 (s, 3H), 2.47-2.53 (2H, m, overlaps with DMSO), 2.88-2.93 (m, 4H), 4.11 (d, 2H, J= 12.3 Hz), 6.92 (s, 1 H), 7.21 (d, 1 H, J=
2.0Hz), 7.27 (s, 1H), 7.3-7.38 (m, 3H), 7.41 (dd, 1H, J= 8.2 Hz, 2.0 Hz), 7.54-7.58 (m, 3H), 8.11 (s, 1H), 10.32 (s, 1H). HRMS calc. for C31H32C1FN702 588.2285, found 588.2212.

Example 474 8-({5-Chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]isonicotinoyl}amino)-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g]indazole-3-carboxamide Step 1 Benzyl (3R)-3-methylpiperazine-l-carboxylate Cbz-N NH

[00324] The product of step 1 was synthesized by the same procedure as for compound of step 1 of Example 473 starting with 2-(R)-methylpiperazine (6 g, 59.9 mmol), triethylamine (6.04 g, 8.32 mL, 59.7 mmol) and benzyl chloroformate (10.62 g, 59.2 mmol) in 100 mL of CHC13. Purification by chromatography on silica gel (CH2C12/MeOH: 12/1) afforded the title compound in 30% yield.1H NMR (300 MHz, CDC13): 8 1.05 (d, 3H, J= 6.2 Hz), 1.59 (s, 1H), 2.47 (s, broad, 1H), 2.71 -2.9 (m, 4H), 4.02 (s, broad, 1H), 5.13 (s, 2H), 7.30 - 7.36 (m, 5H).

Step 2 Benzyl (3R)-3,4-dimethylpiperazine-l-carboxylate Cbz-N N-[00325] The title compound of,step 2 was synthesized by the same procedure as for the compound of step 2 of Example 473 starting with compound of step 1 (3.77 g, 16 mmol), formaldehyde (1.46 g, 1.34 mL, 16 mmol), and NaHB(OAc)3 (4.98 g, 23 mmol) in 60 mL of dichioroethane to afford the title compound in 95 %

yield. 1H NMR (300 MHz, CDC13): S 1.05 (d, 3H, J= 6.24 Hz), 2.02 - 2.08 (m, 1H), 2.13-2.21 (m, 1H), 2.28 (s, 3H), 2.72-2.76 (m, 2H), 3.08 (t, 1H, J= 1.2 Hz), 3.95 - 3.99 (m, 2H), 5.12 (s, 2H), 7.32 - 7.36 (m, 5H).

Step 3 (2R)-1,2-Dimethylpiperazine HN N-[00326] The title compound of step 3 was synthesized by the same procedure as fo'r step 3 of Example 473 starting with the compound of step 2 (3.78 g, 15.2 mmol), (Pd/C (5%, 1.6g) in 30 mL of MeOH under H2 (15 psi). The reaction mixture was stirred 4 h to afford the title compound in 53% yield. 1H NMR (300 MHz, CDC13): S 1.03 (d, 3H, J= 6.24 Hz), 1.96-2.03 (m, 1H), 2.12 - 2.21 (m, 1H), 2.27 (s, 1H), 2.34 (s, broad, 1H), 2.45 - 2.52 (m, 1H), 2.73 - 2.92 (m, 4H).
Mass spectrum, M + 1= 115. HRMS calc. for C6H15N2115.1230, found 115.1199.
Step 4 8-( { 5-Chloro-2-[(3R)-3,4-dimethylpiperazin-l-yl]isonicotinoyl } amino)-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide F

_ H N N

CI

J
N
("'N
[00327] The title compound was synthesized by the same procedure as in Example 214 starting with 8-[(2,5-dichloroisonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (Example 248) (0.434 g, 0.87 mmol) and (2R)-1,2-dimethylpiperazine (step 3) (0.9 g, 7.8 mmol) in 5 mL of EtOH. The reaction was run at 100 C for 4 days. The off-white precipitate that formed in the crude reaction mixture was filtered and washed with EtOH to afford the title compound in 55% yield. 1H NMR (400 MHz, d6-DMSO): S 1.0 (d, 3H, J

6.17 Hz), 1.96 - 2.0 (m, 1 H), 2.05 - 2.06 (m, IH), 2.15 (s, 3H), 2.48 - 2.54 (m, 1 H), 2.74 (d, broad, 1H, J= 11.5 Hz), 2.85 - 2.93 (m, 4H), 4.01-4.09 (m, 2H), 6.89 (s, 1 H), 7.21 (d, 1 H, J= 2.0 Hz), 7.27 (s, 1 H), 7.29 - 7.38 (m, 2H), 7.41 (dd, 1 H, J=
8.2 Hz, 2.0 Hz), 7.53 - 7.58 (m, 2H), 8.11 (s, 1H), 10.33 (s, 1H). HRMS calc.
for C30H30C1FN702 574.2128, found 574.2094.

Example 475 8-( { 5-Chloro-2-[(3S)-3,4-dimethylpiperazin-l-yl]isonicotinoyl } amino)-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide Step 1 Benzyl (3S)-3-methylpiperazine-l-carboxylate /-\
Cbz-N NH

[00328] The compound of step 1 was synthesized by the same procedure as for step 1 of Example 473 starting with 2-(S)-methylpiperazine (6 g, 59.9 mmol), triethylamine (6.04 g, 8.32 mL, 59.7 mmol) and benzyl chloroformate (10.62 g, 59.2 mmol) in 100 mL CHC13. Purification by chromatography on silica gel (CH2C12/MeOH: 12/1) afforded the title compound in 22% yield. 1H NMR (300 MHz, CDC13): 8 1.05 (d, 3H, J= 6.2 Hz), 1.89 (s, 1H), 2.48 (s, broad, 1H), 2.7-2.97 (m, 4H), 4.02 (s, broad, 1H), 5.12 (s, 2H), 7.32 - 7.35 (m, 5H).

Step 2 Benzyl (3S)-3,4-dimethylpiperazine-l-carboxylate Cbz-N N-[00329] The compound of step 2 was synthesized by the same procedure as for step 2 for Example 473 starting with the compound of step 1 (3.1 g, 13 mmol), formaldehyde (1.2 g, 1.1 mL, 13 mmol), and NaHB(OAc)3 (4.09 g, 19 mmol) in 50 mL dichloroethane to afford the title compound in 96 % yield. 1H NMR (300 MHz, CDC13): S 1.05 (d, 3H, J= 6 Hz), 2.02-2.05 (m, 1H), 2.13-2.21 (m, 1H), 2.28 (s, 3H), 2.71-2.75 (m, 2H), 3.08 (t, 1H, J= 1.5 Hz), 3.95 - 3.99 (m, 2H), 5.12 (s, 2H), 7.32 - 7.36 (m, 5H).

Step 3 (2S)-2-Methylpiperazine H N-[00330] (2S)-2-Methylpiperazine was synthesized by the same procedure as for step 3 of Example 473 starting with the material from step 2 (3.1 g, 12.4 mmol), (Pd/C (5%, 1.37g) in 25 mL MeOH under H2 (15 psi). The reaction mixture was stirred 4 h to afford the title compound in 55% yield. 1H NMR (300 MHz, CDC13):
S 1.03 (d, 3H, J= 6.24 Hz), 1.97 - 2.03 (m, 1H), 2.12 - 2.21 (m, 1H), 2.27 (s, 1H), 2.42 (s, broad, 1H), 2.45 - 2.52 (m, 1H), 2.73 - 2.92 (m, 4H). Mass spectrum, M +
1=115.

Step 4 8-( { 5-Chloro-2-[(3S)-3,4-dimethylpiperazin-l-yl]isonicotinoyl } amino)-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide F
_ H N N

CI

N N

[00331] The title compound was synthesized by the same procedure as in Example 214 starting with 8-[(2,5-dichloroisonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (Example 248) (0.380 g, 0.76 mmol) and (2S)-2-methylpiperazine (step 3) (0.79 g, 6.8 mmol) in 3 mL of EtOH.
The reaction was run at 100 C for 3 days. The off-white precipitate that formed in the crude reaction mixture was filtered and washed with EtOH to afford the title compound in 55% yield. 1H NMR (400 MHz, d6-DMSO): 81.0 (d, 3H, J= 6.17 Hz), 1.96-1.98 (m, 1H), 2.02 - 2.09 (m, 1H), 2.16 (s, 3H), 2.48 - 2.54 (m, 1H), 2.74 (d, broad, IH, J= 11.7 Hz), 2.85-2.93 (m, 4H), 4.02-4.09 (m, 2H), 6.89 (s, 1H), 7.21 (d, 1H, J= 2.0 Hz), 7.27 (s, 1H), 7.29 - 7.38 (m, 2H), 7.41 (dd, 1H, J=
8.2 Hz, 2.0 Hz), 7.54 - 7.58 (m, 2H), 8.11 (s, 1H), 10.33 (s, 1H). HRMS calc. for C30H30C1FN702 574.2128, found 574.2098.

Example 476 8-{ [5-Chloro-2-(4-ethylpiperazin-1-yl)isonicotinoyl]amino }-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g] indazole-3-carboxamide F
/ ~
N~ I CIH N_N N N

I ~ \ 10"
~N"o [00332] The title compound of Example 248 (8-[(2,5-dichloroisonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide) (1.81 mmol) and 1-ethyl piperazine (18.1 mmol) were combined with 4.5 mL of DMA. The reaction mixture was placed under nitrogen and stirred in an oil bath at 100 C for 21 h. The mixture was added to water, causing a precipitate, which was filtered and washed with water. The solid was dissolved in acetonitrile, dried over MgSO4, filtered, and washed with acetonitrile. Mp: 251-254 C. Mass spectrum: M + 1 = 574.
Example 477 8- { [5-Chloro-2-(4-isopropylpiperazin-1-yl)isonicotinoyl]amino}-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g] indazole-3 -carboxamide F
N~ ~ CIH / N-N O
N ~ N

-y [00333] The title compound of Example 248 (8-[(2,5-dichloroisonicotinoyl) amino]-1-(4-fluorophenyl)-4, 5-dihydro-1 H-benzo [g]
indazole-3-carboxamide) (1.81 mmol) and (1-isopropyl) piperazine (18.1 mmol) were combined with 4.5 mL of DMA. The reaction mixture was placed under nitrogen and stirred in an oil bath at 100 C for 21 h. The mixture was added to water, causing a precipitate, which was filtered and washed with water. The solid was dissolved in acetonitrile, dried over MgSO4, and the solvent stripped. The product was then filtered and washed with acetonitrile. Mp: 220-226 C. Mass spectrum:
M
+1=588.

Example 478 8-1 [5-Chloro-2-(4-methylpiperazin- 1 -yl)isonicotinoyl] amino } -1-pyridin-4-yl-4, 5-dihydro-1H-benzo[g]indazole-3-carboxamide Step 1 8-[(2,5-Dichloroisonicotinoyl)amino]-1-pyridin-4-yl-4,5-dihydro-1 H-benzo [g]indazole-3-carboxamide H N-N
O N ~ CONH2 ci I

N CI

[00334] The compound of step 1 was synthesized by the same procedure as in Example 211, starting with 8-amino-1-pyridin-4-yl-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (1.56 g, 5.1 mmol), 2,5-dichloroisonicotinic acid (1.47 g, 7.6 mmol), HATU (2.91 g, 7.3 mmol) and Et3N (2.85 g, 2.07 mL, 28 mmol) in DMF (25 mL). The crude reaction mixture was concentrated and the product precipitated upon addition of water and filtered. Trituration in 250 mL hot CH3CN afforded the title compound as a yellow solid, yield 40%. 1H NMR (400 MHz, d6-DMSO): S 2.92 (s, 4H), 7.33-7.4 (m, 3H), 7.52 (dd, 1H, J= 8.15 Hz, 2 Hz), 7.62-7.64 (m, 3H), 7.8 (s, 1H), 8.61 (s, 1H), 8.74 (dd, 2H, J= 4.6 Hz, 1.5 Hz), 10.61 (s, 1H). Mass spectrum, M + 1 480.

Step 2 8-{ [5-Chloro-2-(4-methylpiperazin-1-yl)isonicotinoyl]amino}-l-pyridin-4-yl-4,5-dihydro-1 H-benzo jg] indazole-3-carboxamide H N-N

CI
I
N N ~

[00335] The title compound was synthesized by the same procedure as in Example 214 starting with the compound of step 1 (0.8 g, 1.66 mmol) and N-methylpiperazine (3 g, 3.34 mL, 30mmol) in 1.5 mL EtOH. The reaction was run at 100 C for 2 days. The white precipitate that formed in the crude reaction mixture was filtered and washed with EtOH to afford the title product, yield: 73%. 1H
NMR
(400 MHz, d6-DMSO): S 2.16 (s, 3H), 2.32 (t, 4H, J= 4.8 Hz), 2.9 (s, 4H), 3.47 (t, 4H, J= 4.8 Hz), 6.89 (s, 1H), 7.34-7.38 (m, 3H), 7.54 (dd, 1H, J = 8.3 Hz, 2 Hz), 7.60-7.61 (m, 3H), 8.12 (s, 1H), 8.72 (dd, 2H, J= 4.5 Hz, 1.6 Hz), 10.4 (s, 1H).
Mass spectrum, M + 1= 544.
Example 479 1-(1,3-Benzodioxol-5-yl)-8-( { [5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]carbonyl } amino)-4,5-dihydro-1 H-benzo [g]indazole-3-carboxamide Step 1 5-Chloro-2-(methylsulfonyl)-4-pyrimidinecarboxylic acid O OH

CI N
~ i N O,S~

[00336] 5-Chloro-2-(methylsulfonyl)-4-pyrimidinecarboxylic acid was prepared by the method of Liang Yong-min, Luo Sheng-jun, Zhang Zhao-xin and Ma Yong-xiang, Synthetic Commun., 32 (1), 153-157, 2002.

Step 2 1-(1,3-Benzodioxol-5-yl)-8-({ [5-chloro-2-(methylsulfonyl)pyrimidin-4-yl]carbonyl } amino)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide /-O
O

H N-N

CI N

N OSO
[00337] The title compound of step 2 was synthesized by the same procedure as in Example 211 starting with 5-chloro-2-(methylsulfonyl)-4-pyrimidinecarboxylic acid (step 1) (0.987 g, 4.17 mmol), Example 161, step 3(8-amino-1 -(1,3-benzodioxol-5-yl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide) (0.968 g, 2.78 mmol), HATU (1.58 g, 4.15 mmol) and Et3N (1.54 g, 1.12 mL, 15 mmol) in DMF (8 mL). Trituration with CH2C12 afforded the title compound in 38% yield. 1H NMR (400 MHz, d6-DMSO): 6 2.86-2.91 (m, 4H), 3.42 (s, 1H), 6.05 (s, 2H), 6.94 (dd, 1H, J = 8.2 Hz, 2 Hz), 7 (d, 111, J = 2.2 Hz), 7.1 (d, 1H, J = 2 Hz), 7.23-7.26 (m, 2H), 7.31-7.37 (m, 2H), 7.48 (s, 1H), 9.35 (s, 1H), 10.73 (s, 1H).

Mass spectrum, M + 1 = 567.
Step 3 1-(1,3-Benzodioxol-5-yl)-8-( { [5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]carbonyl } amino)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide /-O
O

H N-N
O N I \ CONH2 CI N /

N N
~N~
[00338] The title compound was synthesized by the same procedure as in Example 214 starting with the compound of step 2 (0.625 g, 1.1 mmol) and N-methylpiperazine (1.98 g, 2.2 mL, 20 mmol) in 3 mL EtOH. The reaction was run at 95 C for 2.5 h. The volatiles were removed and the residue partitioned between H20 and CHZCI2. The organics were dried over MgSO4. Purification by reverse phase preparative HPLC afforded the title product in 16% yield. 1H NMR (400 MHz, d6-DMSO): S 2.18 (s, 3H), 2.33 (t, 4H, J = 4.7 Hz), 2.86-2.92 (m, 4H), 3.67 (t, 4H, J = 4.7 Hz), 6.08 (s, 2H), 6.94 (dd, 1H, J = 8.2 Hz, 2.1 Hz), 7 (d, 1H, J = 8.2 Hz), 7.1 (d, 1H, J = 2 Hz), 7.27-7.31 (m, 2H), 7.4 (dd, 1H, J = 8.2 Hz, 2 Hz), 7.49 (s, 1H), 8.5 (s, 1H), 10.34 (s, 1H). Mass spectrum, M + 1 = 567.

Example 480 8-({ [5-Chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]carbonyl}amino)-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide Step 1 8-({ [5-Chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]carbonyl } amino)-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide F a-H N N
O N N~ CONH2 CI N /

N OAS~O

[00339] The compound of step 1 was synthesized by the same procedure as in Example 211 starting with the compound of step 1 of Example 479 (2.7 g, 11.4 mmol), 8-amino-l-(1,3-benzodioxol-5-yl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide (2.45 g, 7.6 mmol), HATU (4.32 g, 11.3 mmol) and Et3N (2.17 g, 3 mL, 21 mmol) in DMF (8 mL). Purification by preparative reverse phase HPLC
afforded the title compound in 62% yield. 1H NMR (400 MHz, d6-DMSO): 8 2.88-2.92 (m, 4H), 3.41 (s, 3H), 7.22 (s, broad, 1H), 7.25 (s, broad, 1H), 7.34-7.37 (m, 4H), 7.52-7.58 (m, 3H), 9.34 (s, IH), 10.72 (s, 1H). Mass spectrum, M + 1=
541.

Step 2 8-( { [5-Chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]carbonyl } amino)-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo [g]indazole-3 -carboxamide F

_ H N N
O N ~ \ ~ CONH2 CI / N

N N "') ~N'~' [00340] The title compound was synthesized by the same procedure as in Example 214 starting with the material from step 1 (0.9 g, 1.66 mmol) and N-methylpiperazine (1.66 g, 1.84 mL, 16.5 mmol) in 3 mL EtOH. The reaction was run at 45 C for 7 h. The yellow precipitate that formed in the crude reaction mixture was filtered and purified by reverse phase preparative HPLC to afford the title product in 15% yield. 1H NMR (400 MHz, d6-DMSO): S 2.18 (s, 3H), 2.32 (t, 4H, J = 4.9 Hz), 2.88-2.93 (m, 4H), 3.68 (t, 4H, J= 4.9 Hz), 7.18 (t, 1H, J = 2.4 Hz), 7.27 (s, 1H), 7.31-7.39 (m, 3H), 7.42 (dd, 1H, J = 8.2 Hz, 2 Hz), 7.53-7.59 (m, 3H), 8.49 (s, 1H), 10.412 (s, 1H). Mass spectrum, M + 1 = 562.

[00341] The bioactivity in the IKK2 Resin assay for the compounds of Examples 452-480 is shown in Table 24 Table 24 Compound No., Structure Compound Name IKK2 Resin Example 0 $-[(2,$- <1 M 453 step I
Dichloroisonicotinoyl) amino]-1-[4-N' H N-N O (methylsulfonyl)pheny N 1]-4,5-dihydro-lH-0 NH2 benzo[g]indazole-3-carboxamide 0 8-{ [5-Chloro-2-(4- <i M 453 OY\' methylpiperazin-l-ci N-N yl)isonicotinoyl]amin N ~ 0}-1-[4-~N NH2 (methylsulfonyl)pheny 1]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide O~O 1-(1,3-Benzodioxol-5- <i M 454 yl)-8-{[(6-chloro-4-CI ~ methylpyridin-3-Nol N N-N O yl)carbonyl]amino}-O ~ NH2 4,5-dihydro-lH-benzo[g]indazole-3-carboxamide 1-(1,3-Benzodioxol-5- 1< 10 M 455 step 1 yl)-8-{[(3-chloro-6-r c~ N-N cyanopyridin-2-~ n~i yl)carbonyl]amino}-N N o \~ ONH2 4,5-dihydro-lH-benzo[g]indazole-3-carboxamide O 8-( {[6- 1< 10 M 455 (Aminomethyl)-3-~ a ~ N-N chloropyridin-2-, N yl]carbonyl } amino)-1-N ~ CONH2 (1,3-benzodioxol-5-NH2 0 ~ yl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide Compound No., Structure Compound Name IKK2 Resin Example F 8-[(5-Chloro-2- <1 M 456 step 1 ci cyanoisonicotinoyl)am H ino]-1-(4-N N CONH2 fluorophenyl)-4,5-o Z~' dihydro-1 H-benzo[g]indazole-3-carboxamide 8-{ [2-(Aminomethyl)- <1 M 456 ANr'II 5-r"~ CONH2 chloroisonicotinoyl]a "c~
NHZ 0 mino }-1-(4-~ I
fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide 1-(1,3-Benzodioxol-5- <1 M 457 step 1 yl)-8-[(5-chloro-2-Nr ci ~ N cyanoisonicotinoyl)am N N/ CONHZ ino]-4,5-dihydro-1H-0 benzo[g]indazole-3-carboxamide 8-{ [2-(Aminomethyl)- 51 M 457 N~ ci N chloroisonicotinoyl]a $N-~ ~ N mino}-1-(1,3-CONHZ
benzodioxol-5-yl)-N"2 0 4,5-dihydro-lH-benzo[g]indazole-3-carboxamide ~ 8-({ [3-Chloro-6- <1 M 458 N~ ~ cl H~ N-N (morpholin-4-vN_/~N .CONH ylmethYl)pyridin-2-~ Y1]carbonY1 } amino)-1-(4-fluorophenyl)-4, 5-dihydro-lH-benzo[g]indazole-3-carboxamid o 1-(1,3-Benzodioxol-5- <1 M 459 ZxC, yl)-8-({[3-chloro-6-~ cl " N-N NH2 (morpholin-4-0 ylmethyl)pyridin-2-0 y1]carbony1} amino)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide Compound No., Structure Compound Name IKK2 Resin Example 0 O 1-(1,3-Benzodioxol-5- <1 M 460 y1)-8-{[5-chloro-2-(2-~ morpholin-4-H N-N ylethyl)isonicotinoyl]a O N CONH2 mino}-4,5-dihydro-CI 1H-benzo[g]indazole-3-carboxamide N co F 8-{[5-Chloro-2-(2- <1 M 461 morpholin-4-H N-N ylethyl)isonicotinoyl]a O N CONHZ mino}-1-(4-CI fluorophenyl)-4,5-~ dihydro-lH-N N) benzo[g]indazole-3-~'O carboxamide 8-( { 5-Chloro-2-[2- <1 M 462 / (dimethylamino)ethyl]
H N-N isonicotinoyl } amino)-O N CONH2 1-(4-fluorophenyl)-J 4,5-dihydro-lH-CI benzo [g]indazole-3-N carboxamide 8-{[(5-Chloro-2,4'- <i M 463 N-N bipyridin-4-o N yl)carbonyl]amino}-1-I CONH2 (4-fluorophenyl)-4,5-CI dihydro-~ 1H-benzo[g]indazole-N 3-carboxamide N
F 8-{[(5-chloro-1'- <1 M 464 methyl-1',2',3',6'-N-N tetrahydro-2,4'-N bipyridin-4-CI O J CONH2 yl)carbonyl]amino}-1-i (4-fluorophenyl)-4,5-N dihydro-1 H-N", benzo[g]indazole-3-carboxamide Compound No., Structure Compound Name IKK2 Resin Example F 1-(4-Fluorophenyl)-8- 51 M 465 ~\
~ [(2-morpholin-4-N H N-N o ylisonicotinoyl)amino ~J o N O13'iH2 ]-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide F 8-{[5-chloro-2-(1,4- <1 M 466 diazepan-l-ci 0 N-N NH yl)isonicotinoyt]amin H ~ 2 0 } -1-(4-fluorophenyl)-N N 0 4,5-dihydro-lH-N~ benzo[g]indazole-3-\\\~~~~ carboxamide NH

F.
8-( { 5-Chloro-2-[4-(2- 51 pM 467 hydroxyethyl)piperazi H N-N n-1-O N CONH2 yl]isonicotinoyl}amin Ci o)-1-(4-~ fluorophenyl)-4,5-N N dihydro-1 H-~N,~oH benzo[g]indazole-3-carboxamide F 8-({5-Chloro-2-[4-(2- <_1 M 468 ci N-N methoxyethyl)piperazi N o n-1-N JN 0 1) NH2 yl]isonicotinoyl}amin o f o)-1-(4-fluorophenyl)-4,5-dihydro-1 H-benzo[g]indazole-3-carboxamide F 8-[(5-Chloro-2-{[2- <1 M 469 Q (dimethylamino)ethyl]
H N-N amino } isonicotinoyl)a O N CONH2 mino]-1-(4-Cl fluorophenyl)-4,5-~ dihydro-lH-N N) benzo[g]indazole-3-N*~' carboxamide Compound No., Structure Compound Name IKK2 Resin Example F~ 8-({5-Chloro-2-[(3R)- 51 M 470 3-methylpiperazin-1-N% N N-N o yl]isonicotinoyl}amin NH o)-1-(4-fluorophenyl)-~ o 2 4,5-dihydro-lH-benzo[g]indazole-3-carboxamide F ~ 8-({5-Chloro-2-[(3S)- <1 M 471 3-methylpiperazin-l-ci H N-N o yl]isonicotinoyl}amin HN,) o N I~ \ NH2 o)-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo [g]indazole-3-carboxamide F ~ 8-({5-Chloro-2- <1 gM 472 , [(3R,5S)-3,5-N~ H N-N o dimethylpiperazin-l-N I ~ \ NH yl]isonicotinoyl}amin HN~ o ~ 2 o)-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide F ~ 8-({5-Chloro-2- <1 M 473 ~ ~ _ [(3R,5S)-3,4,5-O N ~ N trimethylpiperazin-l-CONH2 yl]isonicotinoyl}amin CI ~ o)-1-(4-I fluorophenyl)-4,5-N N~ dihydro-lH-N", benzo[g]indazole-3-carboxamide F I~ 8-( { 5-Chloro-2-[(3R)- <1 M 474 _ 3,4-O N N dimethylpiperazin-l-CONH2 yl]isonicotinoyl}amin cl o)-1-(4-~ ~ fluorophenyl)-4,5-N ~ dihydro-lH-N benzo[g]indazole-3-~ carboxamide Compound No., Structure Compound Name IKK2 Resin Example 8-({5-Chloro-2-[(3S)- <1 [tM 475 3,4-H N_N dimethylpiperazin-l-O CONH2 y1]isonicotinoyl}amin cl o)-1-(4-~ ~ fluorophenyl)-4,5-N N dihydro-1 H-benzo[g]indazole-3-N carboxamide F 8-{ [5-Chloro-2-(4- <1 M 476 ci ethylpiperazin-1-N H N-N O yl)isonicotinoyl]amin ~NJ \ ~ N \ NH2 o}-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide F ~ 8-{[5-Chloro-2-(4- <1 M 477 c ~, isopropylpiperazin-l-N H N-N
o yl)isonicotinoyl]amin NJ o N NH2 01-1-(4-fluorophenyl)-4,5-dihydro-lH-benzo[g]indazole-3-carboxamide 8-[(2,5- <1 M 478 step 1 Dichloroisonicotinoyl) H N-N amino]-1-pyridin-4-yl-O N CONH2 4,5-dihydro-lH-CI benzo[g]indazole-3-~ ~ carboxamide N Cl N 8-{ [5-Chloro-2-(4- <1 M 478 methylpiperazin-l-H N-N yl)isonicotinoyl]amin O N CONH2 o}_1-pyridin-4-yl-4,5-CI dihydro-lH-benzo[g]indazole-3-carboxamide N ON, Compound No., Structure Compound Name IKK2 Resin Example /_O 1-(1,3-Benzodioxol-5- <1 M 479 step 2 0 yl)-8-({[5-chloro-2-I (methylsulfonyl)pyrim H O N ~ N idin-4-0 yl]carbonyl}amino)-CI N 4,5-dihydro-lH-~ benzo[g]indazole-3-~N o S o carboxamide /-O 1-(1,3-Benzodioxol-5- <1 M 479 0 yl)-8-({[5-chloro-2-(4-I methylpiperazin-l-H N N CONH yl)pyrimidin-4-2 yl]carbonyl } amino)-cl N I 4,5-dihydro-lH-~ benzo[g]indazole-3-N carboxamide NNI
8-({ [5-Chloro-2-(4- <1 M 480 ~ , methylpiperazin-l-H N-N yl)pyrimidin-4-0 N CONH2 yl]carbonyl}amino)-1-CI N (4-~ ~ fluorophenyl)-4,5-N N~ dihydro-lH-~ N ~ benzo[g]indazole-3-carboxamide BIOLOGICAL EVALUATION

Materials [00342] SAM2 TM 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 (IKKy) (FL-419), IKK1(H-744), IKK2(H-470) and ItcBoc(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 [00343] cDNAs of human IKK1 and IKK2 were amplified by reverse transcriptase-polymerase chain reaction from human placental RNA (Clonetech).
hIKK1 was subcloned into pFastBac HTa (Life Technologies) and expressed as N-terminal His6-tagged fusion protein. The hIKK2 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 rhIKK activity were demonstrated. Cell lysates were stored at -80 C until purification of the recombinant proteins was undertaken as described below.
Enzyme Isolation [00344] All purification procedures were carried out at 4 C unless otherwise noted. Buffers used are: buffer A: 20 mM Tris-HC1, pH 7.6, containing 50 mM

NaC1, 20 mM NaF, 20 mM (3-Glycerophosphate, 500 uM sodiumortho-vanadate, 2.5 mM metabisulfite, 5 mM benzamidine, 1 mM EDTA, 0.5 mM EGTA, 10%
glycerol, 1 mM DTT, 1X CompleteTm protease inhibitors; buffer B: same as buffer A, except 150 mM NaCl, and buffer C: same as buffer A, except 500 mM NaC1.
Isolation of rhIKKl hofnodimer [00345] Cells from an 8-liter fermentation of baculovirus-expressed IKK1 tagged with His peptide were centrifuged and the cell pellet (MOI 0.1, I=72 hr) was re-suspended 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 inl of 50 mM imidazole in buffer C. rhIKKl homodimer was eluted using 300 mM invidazole 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 of rhIKK2 homodim.er [00346] A 10-liter culture of baculovirus-expressing IKK2 tagged with FLAG
peptide was centrifuged and the cell pellet (MOI=0.1 and 1=72 hrs) was re-suspended 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 -C.

Isolation of rhIKK1/IKK2 heteroditner [00347] The heterodimer enzyme was produced by coinfection in a baculovirus system (FLAG IKK2/IKK1 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 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 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 cut-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 [00348] 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 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. For experiments, cells were plated in 6 well plates at 1x106 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 NaC1 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 0-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.

Irnrnunoprecipitation and Western Blotting [00349] 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 supematant 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, IKK1 H-744). Native IKK2, IxBa, and NEMO proteins from cytosolic lysates (20-80 g) were separated by SDS-PAGE and visualized by chemiluminescense using specific antibodies.

Phosphatase Treatment [00350] Immunoprecipitated rhIKKs were washed 2 times in 50 mM Tris-HCI, pH 8.2 containing 0.1 mM EDTA, 1 mM DTT, 1 mM PMSF and 2 mM
MnC12 and resuspended in 50 l. Phosphatase (XPPase, 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 l of the buffer used for the in vitro kinase assay.
IKKa SAM Enzynie Assay [00351] IKKa kinase activity was measured using a biotinylated IxBa 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 Tm 96 Biotin capture plate and a vacuum system. The standard reaction mixture contained 5 M biotinylated IxBa peptide, 1 M [7-33P] ATP (about 1 X 105 cpm), 1 mM DTT, 50 mM KCI, 2 mM MgC12, 2 mM MnC12, 10 mM NaF, 25 mM Hepes buffer, pH. 7.6 and enzyme solution (1-10 1) in a final volume of 50 l. After incubation at 25 C for 30 min, 25 l of the reaction mixture was withdrawn and added to a SAM2 'rm 96 Biotin capture 96-well plate. Each well was then washed successively with 800 12 M NaCl, 1.2 ml of NaC1 containing 1 Io H3PO4, 400 l H20, and 200 195 Io ethanol. The plate was allowed to dry in a hood at 25 C for 1 hr and then 25 l of scintillation fluid (Microscint 20) was added to each well. Incorporation of [7-33P] ATP was measured using a Top-Count NXT (Packard). Under each assay condition, the degree of phosphorylation of IxBa 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-IKBa1_54 and [y-32P] ATP. The resulting radiolabeled substrate was quantitated by Phosphoimager (Molecular Dynamics). An ion exchange resin assay was also employed using [y-33P] ATP and GST-IxBal_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 IxBa peptide per min. Specific activity was expressed as units per mg of protein.
For experiments related to K. determination of purified enzymes, various concentrations of ATP or IxBa peptide were used in the assay at either a fixed IxBa or ATP concentration. For IxBa peptide Km, assays were carried out with 0.1 g of enzyme, 5 M ATP and IxBa peptide from 0.5 to 20 M. For ATP Km, assays were carried out with 0.1 g of enzyme, 10 M ItxBa peptide and ATP from 0.1 to 10 M. For Km determination of rhIKKl homodimer, due to its low activity and higher Km for IKBa peptide, rhIKKl homodimer (0.3 g) was assayed with 125 M
IKBa peptide and a 5-fold higher specific activity of ATP (from 0.1 to 10 M) for ATP Km experiments and a 5-fold higher specific activity of 5 gM ATP and IxBa peptide (from 5 to 200 M) for IxBa peptide Km experiments.

271 ' IKKfl Resin Enzyme Assay [00352] IKK(3 kinase activity was measured using a biotinylated IxBa 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 M biotinylated IxBa peptide, 0.1 Ci/reaction W3P]
ATP (Amersham) (about 1 X 105 cpm), 1 M ATP (Sigma), 1 mM DTT (Sigma), 2 mM MgC12 (Sigma), 2 mM MnC12 (Sigma), 10 mM NaF (Sigma), 25 mM Hepes (Sigma) buffer, pH 7.6 and 20 1 enzyme solution and 10 ul inhibitor in a final volume of 50 1. After incubation at 25 C for 30 min, 150 l 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 l of scintillation fluid (Microscint 40) (Packard) was added to each well.
Incorporation of [y-33P] ATP was measured using a Top-Count NXT (Packard).
IKK heterodimer Resin Enzyme Assa.y [00353] IKK heterodimer kinase activity was measured using a biotinylated IxBa 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 M biotinylated IrxBa peptide, 0.1 Ci/reaction [y-33P] ATP (Amersham) (about 1 X 105 cpm), 1 M ATP (Sigma), 1 mM DTT (Sigma), 2 mM MgC12 (Sigma), 2 mM MnC12 (Sigma), 10 mM NaF
(Sigma), 25 mM Hepes (Sigma) buffer, pH 7.6 and 20 1 enzyme solution and 10 l inhibitor in a final volume of 50 l. After incubation at 25 C for 30 min, 150 t 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 l of scintillation fluid (Microscint 40) (Packard) was added to each well. Incorporation of [y-33P] ATP was measured using a Top-Count NXT
(Packard).

Claims (34)

CLAIMS:

1. The compound 8-{[5-Chloro-2-(4-methylpiperazin-1-yl)isonicotinoyl]amino}-1-[4-(methylsulfonyl)phenyl]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

2. The compound 8-[(2,5-Dichloroisonicotinoyl)amino]-1-[4-(methylsulfonyl)phenyl]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

3. The compound 1-(1,3-Benzodioxol-5-yl)-8-{[(6-chloro-4-methylpyridin-3-yl)carbonyl]amino}-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

4. The compound 8-({[6-(Aminomethyl)-3-chloropyridin-2-yl]carbonyl}amino)-1-(1,3-benzodioxol-5-yl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

5. The compound 8-{[2-(Aminomethyl)-5-chloroisonicotinoyl]amino}-1-(1,3-benzodioxol-5-yl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

6. The compound 1-(1,3-Benzodioxol-5-yl)-8-({[3-chloro-6-(morpholin-4-ylmethyl)pyridin-2-yl]carbonyl}amino)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

7. The compound 1-(1,3-Benzodioxol-5-yl)-8-{[5-chloro-2-(2-morpholin-4-ylethyl)isonicotinoyl]amino}-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

8. The compound 1-(1,3-Benzodioxol-5-yl)-8-{[(3-chloro-6-cyanopyridin-2-yl)carbonyl]amino}-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

9. The compound 1-(1,3-Benzodioxol-5-yl)-8-[(5-chloro-2-cyanoisonicotinoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

10. The compound 1-(1,3-Benzodioxol-5-yl)-8-({[5-chloro-2-(methylsulfonyl)pyrimidin-4-yl]carbonyl}amino)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

11. The compound 1-(1,3-Benzodioxol-5-yl)-8-({[5-chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]carbonyl}amino)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

12. The compound 8-{[5-Chloro-2-(4-methylpiperazin-1-yl)isonicotinoyl]amino}-1-pyridin-4-yl-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

13. The compound 8-[(2,5-Dichloroisonicotinoyl)amino]-1-pyridin-4-yl-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

14. The compound 1-(4-Fluorophenyl)-8-[(2-morpholin-4-ylisonicotinoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

15. The compound 8-{[2-(Aminomethyl)-5-chloroisonicotinoyl]amino}-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

16. The compound 8-({[3-Chloro-6-(morpholin-4-ylmethyl)pyridin-2-yl]carbonyl}amino)-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

17. The compound 8-{[5-Chloro-2-(2-morpholin-4-ylethyl)isonicotinoyl]amino}-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

18. The compound 8-({5-Chloro-2-[2-(dimethylamino)ethyl]isonicotinoyl}amino)-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

19. The compound 8-{[(5-Chloro-2,4'-bipyridin-4-yl)carbonyl]amino}-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

20. The compound 8-{[(5-chloro-1'-methyl-1',2',3',6'-tetrahydro-2,4'-bipyridin-4-yl)carbonyl]amino)-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

21. The compound 8-{[5-chloro-2-(1,4-diazepan-1-yl)isonicotinoyl]amino}-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

22. The compound 8-({5-Chloro-2-[4-(2-hydroxyethyl)piperazin-1-yl]isonicotinoyl}amino)-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

23. The compound 8-({5-Chloro-2-[4-(2-methoxyethyl)piperazin-1-yl]isonicotinoyl}amino)-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

24. The compound 8-[(5-Chloro-2-{[2-(dimethylamino)ethyl]amino}isonicotinoyl)amino]-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

25. The compound 8-({5-Chloro-2-[(3R)-3-methylpiperazin-1-yl]isonicotinoyl}amino)-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

26. The compound 8-({5-Chloro-2-[(3S)-3-methylpiperazin-1-yl]isonicotinoyl}amino)-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

27. The compound 8-({5-Chloro-2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]isonicotinoyl}amino)-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

28. The compound 8-({5-Chloro-2-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]isonicotinoyl}amino)-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

29. The compound 8-({5-Chloro-2-[(3R)-3,4-dimethylpiperazin-1-yl]isonicotinoyl}amino)-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

30. The compound 8-({5-Chloro-2-[(3S)-3,4-dimethylpiperazin-1-yl]isonicotinoyl}amino)-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

31. The compound 8-{[5-Chloro-2-(4-ethylpiperazin-1-yl)isonicotinoyl]amino}-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

32. The compound 8-{[5-Chloro-2-(4-isopropylpiperazin-1-yl)isonicotinoyl]amino}-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

33. The compound 8-({[5-Chloro-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl]carbonyl}amino)-1-(4-fluorophenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, or a pharmaceutically acceptable salt thereof.

34. A composition comprising the compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.