PATENT DOCUMENT

Abstract:
Compounds of Formulas I-XLIII are identified as direct inhibitors of p97 ATPase or of the degradation of a p97-dependent ubiquitin-proteasome system (UPS) substrate. Methods and compositions are disclosed for inhibiting p97 ATPase and the degradation of a p97-dependent UPS substrate, and for identifying inhibitors thereof

Full Description:
CROSS-REFERENCE TO RELATED APPLICATION(S) 
       [0001]    This application claims priority to and the benefit of U.S. Provisional Application Ser. No. 61/332,667, filed on May 7, 2010, the entire contents of which are incorporated herein by reference. 
     
    
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
       [0002]    This invention was made with government support under MH085687 awarded by National Institutes of Health. The government has certain rights in the invention. 
     
    
     TECHNICAL FIELD 
       [0003]    Embodiments of this invention are directed to selective inhibitors of the ubiquitin-proteasome system (UPS). In particular, inhibitors of the transitional endoplasmic reticulum (p97) ATPase and an ubiquitin substrate are identified. 
       TECHNICAL BACKGROUND 
       [0004]    The ubiquitin-proteasome system (UPS) comprises one of the most important mechanisms for post-translational regulation of protein function in eukaryotic cells. The UPS comprises hundreds of enzymes that promote covalent attachment of ubiquitin and ubiquitin-like proteins (UBL) to target proteins, as well as enzymes that reverse the modification. Conjugation of ubiquitin to target proteins is a multi-step process (Weissman, 2001,  Nat. Rev. Mol. Cell. Biol.,  2:169-178; Finley, 2009,  Annu. Rev. Biochem.,  78:477-513; Schrader et al., 2009,  Nat. Chem. Biol.,  5:815-822; Deshaies et al., 2009,  Annu. Rev. Biochem.,  78: 399-434). The most intensively-studied consequence of ubiquitination is protein degradation. Given the importance of the UPS to regulatory biology there has been considerable interest in developing small molecule inhibitors as potential therapies for a range of human diseases. The UPS has been validated as an important target in cancer by clinical use of the proteasome inhibitor, bortezomib (Velcade), for the treatment of multiple myeloma and mantle cell lymphoma (Kane et al., 2003,  Oncologist,  8:508-513; Colson et al., 2004,  Clin. J. Oncol. Nurs., 8:473-480). 
         [0005]    The AAA (ATPase associated with diverse cellular activities) ATPase p97 is conserved across all eukaryotes and is essential for life in budding yeast (Giaever et al., 2002,  Nature,  418:387-391) and mice (Muller et al., 2007,  Biochem. Biophys. Res. Commun.,  354:459-465). p97 (also referred to as the transitional endoplasmic reticulum ATPase) is overexpressed in several cancers supporting the idea that it could be a target of general importance in oncology (Yamamoto et al., 2004,  Clin. Cancer Res.,  10:5558-5565; Yamamoto et al., 2003,  J. Clin. Oncol.,  21:447-452). Elevated expression levels of p97 have been associated with poor prognosis of cancer (Yamamoto et al., 2004,  Ann. Surg. Oncol.  11:697-704; Tsujimoto et al., 2004,  Clin. Cancer Res.,  10:23007-3012). Additionally, p97 is an essential ATP hydrolase and thus, it should be druggable and have antiproliferative activity. Furthermore, p97 is essential for endoplasmic reticulum associated degradation (ERAD) (Ye et al., 2004,  Nature,  429:841-847; Ye et al., 2003,  J. Cell Biol.,  162:71-84; Neuber et al., 2005,  Nat. Cell Biol.,  7:993-998). Blockade of ERAD is thought to be a key mechanism underlying the anti-cancer effects of bortezomib (Nawrocki et al., 2005,  Cancer Res.,  65:11510-11519). Given that p97 is implicated in ERAD, but otherwise has a more restricted role in the UPS compared to the proteasome, it is possible that drugs that target p97 might retain much of the efficacy of bortezomib but with less toxicity. 
       SUMMARY 
       [0006]    In one embodiment of the present invention, a method of decreasing p97 ATPase activity and/or degradation of a p97-dependent ubiquitin-proteasome system (UPS) substrate in a human cell, is provided, including administering to a human an effective amount of at least one of (i) a compound represented by any of Formulas I-VII, IX, XI-XLIII, (ii) a PEGylated analog of the compound, (iii) a pharmaceutically acceptable salt of said compound or analog, or (iv) an isomer of said compound, analog, or salt, wherein, for Formula I, R 1 , R 2 , R 3 , R 4 , and R 5  are selected from the combinations listed in Tables 1.1, 12.1, and 18.1; wherein, for Formula II, R 1  is selected from the groups listed in Tables 2.1, 13.1, and 19.1; wherein, for Formula III, R 1  is selected from the groups listed in Table 3.1; wherein, for Formula IV, R 1  is selected from the groups listed in Table 4.1; wherein, for Formula V, R 1  is selected from the groups listed in Table 5.1; wherein, for Formula VI, R 1  is selected from the groups listed in Tables 6.1 and 20.1; wherein, for Formula VII, R 1 , n, X, and Y are selected from the combinations listed in Tables 7.1 and 14.1; wherein for Formula XI, R 2  is selected from the groups listed in Tables 9.1 and 21; wherein for Formula XII, R 4  is selected from the groups listed in Tables 10.1 and 22.1; wherein, for Formula XXI, R1 is 5,6-dimethyl; and wherein, for Formula XXV, R 1  is chlorine at position 3 and R 2  is selected from hydrogen and methoxy at position 4. 
         [0007]    In one embodiment, the preceding method is provided wherein the compound decreases p97 ATPase activity and degradation of a p97-dependent UPS substrate in a human cell, and the compound is represented by any of Formulas I-VII, IX, and XI-XIX, wherein: for Formula I, R 1 , R 2 , R 3 , R 4 , and R 5  are selected from the combinations listed in Table 1.1, for Formula II, R 1  is selected from the groups listed in Table 2.1, for Formula III, R 1  is selected from the groups listed in Table 3.1, for Formula IV, R 1  is selected from the groups listed in Table 4.1, for Formula V, R 1  is selected from the groups listed in Table 5.1, for Formula VI, R 1  is selected from the groups listed in Table 6.1, for Formula VII, R 1 , n, X, and Y are selected from the combinations listed in Table 7.1, for Formula XI, R 2  is selected from the groups listed in Table 9.1, and for Formula XII, R 4  is selected from the groups listed in Table 10.1. 
         [0008]    In one embodiment, the preceding method is provided wherein the isomer is a regioisomer or a stereoisomer. 
         [0009]    In one embodiment, a method of identifying an inhibitory compound that decreases p97 activity in a human cell is provided, including: (a) forming a p97 protein control solution; (b) forming a test solution comprising p97 protein and at least one of (i) a compound represented by any of Formulas LII through LXVI, (ii) a PEGylated, biotinylated, or fluorescently labeled analog of the compound, (iii) a pharmaceutically acceptable salt of said compound or analog, or (iv) an isomer of said compound analog, or salt; (c) measuring p97 activity of the control solution and of the test solution in the presence of ATP and a kinase; and (d) comparing the measured activities, wherein for Formula LII, n is selected from 0, 1, and 2; wherein, for Formula LIII, R 1  and R 2  are independently selected from hydrogen, methyl, ethyl, propyl and butyl; wherein, for Formula LIV, R 1  is selected from hydrogen, methyl, fluorine, chlorine, bromine, and OMe (methoxy), and R 2  is selected from hydrogen, methyl, ethyl, propyl, and butyl; wherein, for Formula LV, R 1  is selected from hydrogen, methyl, fluorine, chlorine, bromine, and OMe (methoxy), and R 2  is selected from hydrogen, methyl, ethyl, propyl, and butyl; wherein, for Formula LVI, R 1  and R 2  are independently selected from hydrogen, methyl, fluorine, chlorine, bromine, and OMe (methoxy); wherein, for Formula LVII, X is oxygen, NMe (nitrogen-methyl), NEt (nitrogen-ethyl), NPh (nitrogen-phenyl); n is selected from −1, 0, 1, and 2; m is selected from 1, 2, 3, and 4; and R 1  and R 2  are independently selected from hydrogen, methyl, fluorine, chlorine, bromine and methoxy; wherein, for Formula LVIII, X is selected from oxygen, NMe (nitrogen-methyl), NEt (nitrogen-ethyl), and NPh (nitrogen-phenyl); n is selected from −1, 0, 1, and 2; m is selected from 1, 2, 3, and 4; and R 1  is selected from hydrogen, methyl, fluorine, chlorine, bromine, and methoxy; wherein, for Formula LIX, R 1 , R 2  and R 3  are independently selected from hydrogen, A(CH 2 ) n CH 3 , and A(CH 2 ) n X, where n is selected from 0, 1, 2, 3, 4 and 5, A is O, S or NH and X is selected from heteroaryl, O(alkyl), S(alkyl), (O-alkyl) 2 , and (S-alkyl) 2 ; wherein, for Formula LX, A 1  is selected from O, S, Se, N, NH, CH, CH 2 , CHalkyl, and Calkyl, wherein n is 1 or 2; A 2  is selected from N, NH, CH, and Calkyl; and R 1  is selected from H, A(CH 2 ) n CH 3 , or A(CH 2 ) n X, where A is O, S or NH and X is heteroaryl, O(alkyl), S(alkyl), (O-alkyl) 2 , or (S-alkyl) 2 ; and n is 0, 1, 2, 3, 4, or 5; wherein, for Formula LXI, R 1 , R 2  and R 3  are independently selected from alkyl, alkoxyalkyl, and aminoalkyl; wherein, for Formula LXII; n is selected from −1, 0, 1, and 2; m is selected from 0, 1, and 2; and X is selected from CH 2 , O, NMe, NEt, and NPh; wherein, for Formula LXIII, R 1  and R 2  are independently selected from H, Me, Et, Pr, and Bu; X is selected from CH 2 , O, NMe, NEt, and NPh; and n is selected from −1, 0, 1 and 2; wherein, for Formula LXIV, R 1  is selected from H, Me, F, Cl, Br, and OMe; R 2  is selected from H, Me, Et, Pr, and Bu; X is selected from CH 2 , O, NMe, NEt, and NPh; and n is selected from −1, 0, 1, and 2; wherein, for Formula LXV, R 1  is selected from H, Me, F, Cl, Br, and OMe; R 2  is selected from H, Me, Et, Pr, and Bu; X is selected from CH 2 , O, NMe, NEt, and NPh; and n is selected from −1, 0, 1, and 2; and, wherein, for Formula LXVI, R 1  and R 2  are independently selected from H, Me, F, Cl, Br, and OMe; X is selected from CH2, O, NMe, NEt, and NPh; and n is selected from −1, 0, 1, and 2. 
         [0010]    In one embodiment, the preceding composition is provided wherein the isomer is a regioisomer or a stereoisomer. 
         [0011]    In one embodiment, a composition for decreasing p97 ATPase activity and/or degradation of a p97-dependent UPS substrate is provided, including: at least one of (i) a compound selected from any of Formulas II-VII, IX, XI, XII, XX, XXI, XXIV, XXV, XLII, and XLIII, (ii) a PEGylated, biotinylated, or fluorescently labeled analog of the compound, (iii) a pharmaceutically acceptable salt of said compound or analog; or (iv) an isomer of said compound analog, or salt, wherein, for Formula II, R 1  is selected from the groups listed in Tables 2.2, 13.1, and 19.1; wherein, for Formula III, R 1  is selected from the groups listed in Table 3.1; wherein, for Formula IV, R 1  is selected from the groups listed in Table 4.1; wherein, for Formula V, R 1  is selected from the groups listed in Table 5.1; wherein, for Formula VI, R 1  is selected from the groups listed in Tables 6.1 and 20.1; wherein, for Formula VII, R′, n, X, and Y are selected from the combinations listed in Tables 7.1 and 14.1; wherein, for Formula XI, R 2  is selected from the groups listed in Tables 9.1 and 21; wherein, for Formula XII, R 4  is selected from the groups listed in Tables 10.1 and 22.1; and wherein, for Formula XXV, R 1  is chlorine at position 3 and R 2  is selected from hydrogen and methoxy at position 4. 
         [0012]    In one embodiment, the preceding composition for decreasing p97 ATPase activity and/or degradation of a p97-dependent UPS substrate is provided further including a pharmaceutically acceptable carrier. 
         [0013]    In one embodiment, the preceding composition for decreasing p97 ATPase activity and/or degradation of a p97-dependent UPS substrate is provided, wherein the isomer is a regioisomer or a stereoisomer. 
         [0014]    In one embodiment, the preceding composition decreases p97 ATPase activity and degradation of a p97-dependent UPS substrate, and the compound is represented by any of Formulas II-VII, IX, XI, and XII, wherein, for Formula II, R 1  is selected from the groups listed in Table 2.2; for Formula III, R 1  is selected from the groups listed in Table 3.1; for Formula IV, R 1  is selected from the groups listed in Table 4.1; for Formula V, R 1  is selected from the groups listed in Table 5.1; for Formula VI, R 1  is selected from the groups listed in Table 6.1; for Formula VII, R 1 , n, X, and Y are selected from the combinations listed in Table 7.1; for Formula XI, R 2  is selected from the groups listed in Table 9.1; and for Formula XII, R 4  is selected from the groups listed in Table 10.1. 
         [0015]    In one embodiment, the preceding composition that decreases p97 ATPase activity and degradation of a p97-dependent UPS substrate is provided, further including a pharmaceutically acceptable carrier. 
         [0016]    In one embodiment, the preceding composition that decreases p97 ATPase activity and degradation of a p97-dependent UPS substrate is provided, wherein the isomer is a regeoisomer or a stereoisomer. 
         [0017]    In one embodiment, a composition for identifying an inhibitor that decreases p97 ATPase activity and/or degradation of a p97-dependent UPS substrate is provided, including: at least one of (i) a compound selected from any of Formulas LII-LXVI, (ii) a PEGylated, biotinylated, or fluorescently labeled analog of the compound, (iii) a pharmaceutically acceptable salt of said compound or analog; or (iv) a isomer of said compound, analog, or salt: wherein for Formula LII, n is selected from 0, 1, and 2; wherein, for Formula LIII, R 1  and R 2  are independently selected from hydrogen, methyl, ethyl, propyl and butyl; wherein, for Formula LIV, R 1  is selected from hydrogen, methyl, fluorine, chlorine, bromine, and OMe (methoxy), and R 2  is selected from hydrogen, methyl, ethyl, propyl, and butyl; wherein, for Formula LV, R 1  is selected from hydrogen, methyl, fluorine, chlorine, bromine, and OMe (methoxy), and R 2  is selected from hydrogen, methyl, ethyl, propyl, and butyl; wherein, for Formula LVI, R 1  and R 2  are independently selected from hydrogen, methyl, fluorine, chlorine, bromine, and OMe (methoxy); wherein, for Formula LVII, X is oxygen, NMe (nitrogen-methyl), NEt (nitrogen-ethyl), NPh (nitrogen-phenyl); n is selected from −1, 0, 1, and 2; m is selected from 1, 2, 3, and 4; and R 1  and R 2  are independently selected from hydrogen, methyl, fluorine, chlorine, bromine and methoxy; wherein, for Formula LVIII, X is selected from oxygen, NMe (nitrogen-methyl), NEt (nitrogen-ethyl), and NPh (nitrogen-phenyl); n is selected from −1, 0, 1, and 2; m is selected from 1, 2, 3, and 4; and R 1  is selected from hydrogen, methyl, fluorine, chlorine, bromine, and methoxy; wherein, for Formula LIX, R 1 , R 2  and R 3  are independently selected from hydrogen, A(CH 2 ) n CH 3 , and A(CH 2 ) n X, where n is selected from 0, 1, 2, 3, 4 and 5, A is O, S or NH and X is selected from heteroaryl, O(alkyl), S(alkyl), (O-alkyl) 2 , and (S-alkyl) 2 ; wherein, for Formula LX, A 1  is selected from O, S, Se, N, NH, CH, CH 2 , CHalkyl, and Calkyl, wherein n is 1 or 2; A 2  is selected from N, NH, CH, and Calkyl; and R 1  is selected from H, A(CH 2 ) n CH 3 , or A(CH 2 ) n X, where A is O, S or NH and X is heteroaryl, O(alkyl), S(alkyl), (O-alkyl) 2 , or (S-alkyl) 2 ; and n is 0, 1, 2, 3, 4, or 5; wherein, for Formula LXI, R 1 , R 2  and R 3  are independently selected from alkyl, alkoxyalkyl, and aminoalkyl; wherein, for Formula LXII; n is selected from −1, 0, 1, and 2; m is selected from 0, 1, and 2; and X is selected from CH 2 , O, NMe, NEt, and NPh; wherein, for Formula LXIII, R 1  and R 2  are independently selected from H, Me, Et, Pr, and Bu; X is selected from CH 2 , O, NMe, NEt, and NPh; and n is selected from −1, 0, 1 and 2; wherein, for Formula LXIV, R 1  is selected from H, Me, F, Cl, Br, and OMe; R 2  is selected from H, Me, Et, Pr, and Bu; X is selected from CH 2 , O, NMe, NEt, and NPh; and n is selected from −1, 0, 1, and 2; wherein, for Formula LXV, R 1  is selected from H, Me, F, Cl, Br, and OMe; R 2  is selected from H, Me, Et, Pr, and Bu; X is selected from CH 2 , O, NMe, NEt, and NPh; and n is selected from −1, 0, 1, and 2; and, wherein, for Formula LXVI, R 1  and R 2  are independently selected from H, Me, F, Cl, Br, and OMe; X is selected from CH 2 , O, NMe, NEt, and NPh; and n is selected from −1, 0, 1, and 2. 
         [0018]    In one embodiment, the preceding composition for identifying an inhibitor is provided, further including a pharmaceutically acceptable carrier. 
         [0019]    In one embodiment, the preceding composition for identifying an inhibitor is provided, wherein the isomer is a regeoisomer or a stereoisomer. 
         [0020]    In one embodiment, a method of decreasing p97 ATPase activity and/or degradation of a p97-dependent ubiquitin-proteasome system (UPS) substrate in a human cell is provided, including: administering to a human an effective amount of at least one of (i) a compound represented by any of Formulas VIII, X, XI, and XII, (ii) a PEGylated analog of the compound, (iii) a pharmaceutically acceptable salt of said compound or analog; or (iv) an isomer of said compound, analog, or salt, wherein, for Formula XI, R 2  is selected from the groups listed in Tables 9.2 and 15.1; and wherein, for Formula XII, R 4  is selected from the groups listed in Tables 10.2 and 22.2. 
         [0021]    In one embodiment, a composition for decreasing p97 ATPase activity and/or degradation of a p97-dependent UPS substrate is provided, including at least one of (i) a compound selected from any of Formulas VIII, X, XI, XII, (ii) a PEGylated, biotinylated, or fluorescently labeled analog of the compound, (iii) a pharmaceutically acceptable salt of said compound, or (iv) an isomer of said compound, analog, or salt, wherein, for Formula XI, R 2  is selected from the groups listed in Tables 9.2 and 15.1, and wherein, for Formula XII, R 4  is selected from the groups listed in Tables 10.2 and 22.2. 
         [0022]    In one embodiment, the preceding composition for decreasing p97 ATPase activity and/or degradation of a p97-dependent UPS substrate is provided, further including a pharmaceutically acceptable carrier. 
         [0023]    In one embodiment, the preceding composition for decreasing p97 ATPase activity and/or degradation of a p97-dependent UPS substrate is provided, wherein the isomer is a regeoisomer or a stereoisomer. 
     
    
     DETAILED DESCRIPTION 
       [0024]    Utilizing a set of dual-reporter human cell lines and a chase protocol to quantify and distinguish p97-specific inhibitors of proteasomal degradation, compounds that directly inhibit p97 and inhibit the degradation of a UPS substrate that depends on p97 were identified and characterized. 
         [0025]    Compounds were identified as “inhibitors” if the compound had an IC 50  of 20 μM or less (potency). Inhibition was measured using a p97 ATPase assay and a p97-dependent Ub G76V -GFP assay that measures Ub G76V -GFP turn over. In one embodiment, a compound of the present invention decreases p97 activity and/or p97-dependent Ub G76V -GFPdegradation turn-over to 20 μM or less. In another embodiment, the compound decreases the p97 ATPase activity and/or p97-dependent Ub G76V -GFPdegradation turn-over to 15 μM or less. In another embodiment, the compound decreases the p97 ATPase activity and/or p97-dependent Ub G76V -GFP degradation turn-over to 10 μM or less. In a preferred embodiment, the compound decreases the p97 ATPase activity and/or p97-dependent Ub G76V -GFP degradation turn-over is decreased to 5 μM or less. In a most preferred embodiment, the compound decreases the p97 ATPase activity and/or p97-dependent Ub G76V -GFP degradation turn-over to 2 μM or less. 
         [0026]    Compounds were categorized into three types of inhibitors: 1) inhibitors of both p97 and Ub G76V -GFP turn-over (degradation); 2) inhibitors of p97 that do not inhibit Ub G76V -GFP turn over; and 3) inhibitors of Ub G76V -GFP turn-over that do not inhibit p97. Comparative Examples are shown in Tables 28-33, listing compounds assayed that did not decrease either p97 or Ub G76V -GFP turnover to at least 20 μM. 
         [0027]    In one embodiment, a method for decreasing p97 ATPase activity and/or decreasing the degradation of the p97-dependent UPS substrate (Ub G76V -GFP), is carried out using a compound represented by one of Formulas I-XLIII and, where applicable, having variable groups as shown in Tables 1-26. 
         [0028]    As shown in the tables throughout, compounds and variable groups are characterized using abbreviations, which are defined as follows. In the * column of the tables, “P” refers to a purchased compound and “S” refers to a synthesized compound. R groups include H (hydrogen), C (carbon) N (nitrogen) Cl (chlorine), F (flourine), Br (bromine), NO 2  (nitro), Me (methyl), OMe (methoxy), Ph (phenyl), PhOMe (methoxyphenyl). Standard IUPAC nomenclature is followed for all chemical abbreviations unless indicated otherwise. Numbers preceding the atom groups indicate the position for that atom. Specific compound data is found in the enclosed NMR data (Example 9, Appendix). 
         [0029]    Inhibitors of p97 and p97-Dependent UPS Substrate (Ub G76V -GFP) 
         [0030]    Tables 1-11 show compounds represented by Formulas I-XIX having an IC 50  of 20 μM or less in both a p97 ATPase assay (Example 7) and a p97-dependent Ub G76V -GFP degradation turn-over assay (Example 8). 
         [0031]    Formula I 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 FORMULA I: 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                 KU 
                   
                   
                   
                   
                   
                   
                   
                 Ub G76V -GFP 
               
               
                 Cpd 
                 CID 
                 SID 
                 SCC # 
                 * 
                 R1 
                 R2 
                 R3 
                 R4 
                 R5 
                 ATPase 
                 turn over 
               
               
                   
               
             
          
           
               
                 I-1 
                 8868 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 2-F 
                 H 
                 H 
                 H 
                   3 ± 0.8 
                 9.0 ± 1.3 
               
               
                   
                 13 
                 231 
                 150 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 I-1 
                 8868 
                 96022 
                 KSC-16- 
                 S 
                 H 
                 2-F 
                 H 
                 H 
                 H 
                 1.1 ± 0.3 
                   8 ± 1.7 
               
               
                   
                 13 
                 089 
                 88 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 I-2 
                 7806 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 H 
                 H 
                 H 
                 H 
                 4.2 ± 2.3 
                 12 ± 3  
               
               
                   
                 43 
                 227 
                 145 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 I-3 
                 1894 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 2-Cl 
                 H 
                 H 
                 H 
                 1.2 ± 0.6 
                 8 ± 3 
               
               
                   
                 007 
                 228 
                 146 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 I-4 
                 2927 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 3-NO 2   
                 H 
                 H 
                 H 
                 5.9 ± 3   
                 4.0 ± 1.6 
               
               
                   
                 831 
                 230 
                 149 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 I-5 
                 4084 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 3-Me 
                 H 
                 H 
                 H 
                 4.2 ± 0.2 
                 17 ± 4  
               
               
                   
                 712 
                 265 
                 226 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 I-6 
                 1591 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 4-Cl 
                 H 
                 H 
                 H 
                 5.5 ± 1.9 
                 20 ± 3  
               
               
                   
                 117 
                 273 
                 236 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 I-8 
                 1187 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 4-NO 2   
                 H 
                 H 
                 H 
                 11 ± 6  
                 19 ± 7  
               
               
                   
                 251 
                 271 
                 234 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 I-9 
                 9497 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 4-OMe 
                 H 
                 H 
                 H 
                 1.6 ± 0.3 
                 15 ± 2  
               
               
                   
                 42 
                 266 
                 227 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 I-10 
                 3395 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 4-Me 
                 H 
                 H 
                 H 
                 5.7 ± 0.7 
                 13 ± 2  
               
               
                   
                 671 
                 263 
                 224 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 I-13 
                 2452 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 H 
                 H 
                 H 
                 4-F 
                 11 ± 3  
                 19 ± 3  
               
               
                   
                 802 
                 251 
                 212 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 I-17 
                 2096 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 4-OMe 
                 H 
                 H 
                 4-F 
                 7.8 ± 0.4 
                 9.8 ± 3   
               
               
                   
                 3125 
                 258 
                 219 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 I-20 
                 2096 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 4-OMe 
                 H 
                 H 
                 4- 
                 13 ± 4  
                 15 ± 5  
               
               
                   
                 3158 
                 259 
                 220 
                   
                   
                   
                   
                   
                 OMe 
                   
                   
               
               
                 I-21 
                 2096 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 4-OMe 
                 H 
                 H 
                 4-Me 
                 8 ± 2 
                 12 ± 2  
               
               
                   
                 3177 
                 260 
                 221 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 I-22 
                 2096 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 4-OMe 
                 H 
                 H 
                 4-Cl 
                 8 ± 2 
                 9.3 ± 1   
               
               
                   
                 3187 
                 261 
                 222 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 I-23 
                 2096 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 4-Cl 
                 H 
                 H 
                 4-F 
                   8 ± 0.2 
                 20 ± 5  
               
               
                   
                 3255 
                 262 
                 223 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 I-24 
                 4084 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 3-Me 
                 H 
                 H 
                 4-F 
                 15 ± 2  
                  12 ± 0.8 
               
               
                   
                 711 
                 264 
                 225 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 I-30 
                 2790 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 4-Me 
                 H 
                 Me 
                 H 
                 7 ± 4 
                 17 ± 4  
               
               
                   
                 952 
                 274 
                 237 
               
               
                   
               
             
          
         
       
     
         [0032]    Formula II 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 FORMULA II: 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Ub G76V - 
               
               
                   
                   
                   
                 KU 
                   
                   
                   
                 GFP 
               
               
                 Cpd # 
                 CID 
                 SID 
                 SCC # 
                 * 
                 R1 
                 ATPase 
                 turn over 
               
               
                   
               
             
          
           
               
                 II-1 
                 2909 
                 87796 
                 KSC-1- 
                 P 
                 H 
                 2.3 ± 1   
                 3.1 ± 0.4 
               
               
                   
                 934 
                 234 
                 153 
                   
                   
                   
                   
               
               
                 II-2 
                 9295 
                 87796 
                 KSC-1- 
                 P 
                 4-Me 
                 2.2 ± 0.4 
                 6.3 ± 1.4 
               
               
                   
                 48 
                 285 
                 251 
                   
                   
                   
                   
               
               
                 II-3 
                 2351 
                 87796 
                 KSC-1- 
                 P 
                 4-Cl 
                 5.4 ± 2   
                 5.9 ± 1.2 
               
               
                   
                 737 
                 281 
                 246 
                   
                   
                   
                   
               
               
                 II-4 
                 7976 
                 87796 
                 KSC-1- 
                 P 
                 4-F 
                 3.8 ± 1.2 
                 9.4 ± 1   
               
               
                   
                 50 
                 284 
                 249 
                   
                   
                   
                   
               
               
                 II-5 
                 1943 
                 87796 
                 KSC-1- 
                 P 
                 4-Br 
                 1.8 ± 0.4 
                 6.0 ± 0.8 
               
               
                   
                 389 
                 280 
                 245 
                   
                   
                   
                   
               
               
                 II-6 
                 1330 
                 92093 
                 KSC-1- 
                 P 
                 4-OMe 
                 3.8 ± 0.5 
                 4.5 ± 1.1 
               
               
                   
                 474 
                 141 
                 250 
                   
                   
                   
                   
               
               
                 II-6 
                 1330 
                 92252 
                 KSC-1- 
                 S 
                 4-OMe 
                 3.5 ± 0.5 
                 4.8 ± 0.7 
               
               
                   
                 474 
                 642 
                 290 
                   
                   
                   
                   
               
               
                 II-7 
                 9494 
                 87796 
                 KSC-1- 
                 P 
                 2-Me 
                 3.4 ± 1.5 
                 10 ± 2  
               
               
                   
                 45 
                 286 
                 252 
                   
                   
                   
                   
               
               
                 II-9 
                 8861 
                 87796 
                 KSC-1- 
                 P 
                 2-F 
                 0.85 ± 0.17 
                 10 ± 2  
               
               
                   
                 96 
                 282 
                 247 
                   
                   
                   
                   
               
               
                 II-11 
                 1415 
                 87796 
                 KSC-1- 
                 P 
                 2-OMe 
                 2.2 ± 0.9 
                 11 ± 3  
               
               
                   
                 819 
                 283 
                 248 
                   
                   
                   
                   
               
               
                 II-12 
                 9500 
                 87796 
                 KSC-1- 
                 P 
                 3-Me 
                 1.7 ± 0.5 
                 3.0 ± 0.7 
               
               
                   
                 33 
                 287 
                 253 
                   
                   
                   
                   
               
               
                 II-13 
                 1633 
                 87796 
                 KSC-1- 
                 P 
                 3-Cl 
                 0.48 ± 0.16 
                 7.8 ± 1.3 
               
               
                   
                 082 
                 279 
                 244 
                   
                   
                   
                   
               
               
                 II-14 
                 1164 
                 92252 
                 KSC-1- 
                 S 
                 3-F 
                 1.6 ± 0.1 
                 2.7 ± 0.4 
               
               
                   
                 5888 
                 644 
                 292 
                   
                   
                   
                   
               
               
                 II-15 
                 4510 
                 92252 
                 KSC-1- 
                 S 
                 3-Br 
                 2.5 ± 0.5 
                 4.3 ± 0.8 
               
               
                   
                 8365 
                 645 
                 293 
                   
                   
                   
                   
               
               
                 II-16 
                 3986 
                 92252 
                 KSC-1- 
                 S 
                 3-OMe 
                 2.5 ± 0.2 
                 4.3 ± 0.7 
               
               
                   
                 1404 
                 643 
                 291 
                   
                   
                   
                   
               
               
                 II-17 
                 1571 
                 87796 
                 KSC-1- 
                 P 
                 3,4-di-Cl 
                 8.1 ± 2.6 
                 12 ± 2  
               
               
                   
                 079 
                 290 
                 259 
                   
                   
                   
                   
               
               
                 II-18 
                 4510 
                 92252 
                 KSC-1- 
                 S 
                 3-Cl-6-F 
                 13 ± 3  
                 13 ± 2  
               
               
                   
                 8364 
                 647 
                 295 
                   
                   
                   
                   
               
               
                 II-19 
                 4510 
                 92252 
                 KSC-1- 
                 S 
                 3,5-di-Cl 
                 8.2 ± 0.3 
                 13 ± 1  
               
               
                   
                 8364 
                 647 
                 294 
                   
                   
                   
                   
               
               
                 II-22 
                 4685 
                 99239 
                 KSC-16- 
                 S 
                 3-NO 2   
                 5.2 ± 0.5 
                 19 ± 2  
               
               
                   
                 0871 
                 933 
                 155 
               
               
                   
               
             
          
         
       
     
         [0033]    Formula III 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                   
                 FORMULA III:                          
 
                   
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R1 
                 ATPase 
                 Ub G76V -GFP turn over 
               
               
                   
               
               
                 III-1 
                 4617 
                 9602 
                 KSC-16-72 
                 S 
                 4-Me 
                 1.4 ± 0.3 
                  12 ± 2 
               
               
                   
                 3070 
                 2083 
                   
                   
                   
                   
                   
               
               
                 III-2 
                 4617 
                 9602 
                 KSC-16-89 
                 S 
                 4-Cl 
                 2.8 ± 0.9 
                 7.6 ± 2.4 
               
               
                   
                 3066 
                 2090 
                   
                   
                   
                   
                   
               
               
                 III-3 
                 4617 
                 9602 
                 KSC-16-98 
                 S 
                 4-F 
                 1.5 ± 0.3 
                 5.7 ± 1.3 
               
               
                   
                 3057 
                 2093 
                   
                   
                   
                   
                   
               
               
                 III-4 
                 4617 
                 9602 
                 KSC-16-101 
                 S 
                 4-Br 
                 7.4 ± 2 
                  10 ± 3 
               
               
                   
                 3059 
                 2096 
                   
                   
                   
                   
                   
               
               
                 III-5 
                 4617 
                 9602 
                 KSC-16-79 
                 S 
                 4-OMe 
                 2.3 ± 0.6 
                  11 ± 4 
               
               
                   
                 3063 
                 2086 
                   
                   
                   
                   
                   
               
               
                 III-6 
                 4617 
                 9602 
                 KSC-16-63 
                 S 
                 2-Me 
                 4.2 ± 1.1 
                  11 ± 3 
               
               
                   
                 3069 
                 2080 
                   
                   
                   
                   
                   
               
               
                 III-7 
                 4617 
                 9602 
                 KSC-16-84 
                 S 
                 2-Cl 
                 4.7 ± 1.4 
                  18 ± 5 
               
               
                   
                 3062 
                 2087 
                   
                   
                   
                   
                   
               
               
                 III-8 
                 4617 
                 9602 
                 KSC-16-92 
                 S 
                 2-F 
                 1.8 ± 0.5 
                 7.8 ± 2.1 
               
               
                   
                 3072 
                 2091 
                   
                   
                   
                   
                   
               
               
                 III-9 
                 4617 
                 9602 
                 KSC-16-99 
                 S 
                 2-Br 
                   4 ± 1.7 
                  12 ± 5 
               
               
                   
                 3058 
                 2094 
                   
                   
                   
                   
                   
               
               
                 III-10 
                 4617 
                 9602 
                 KSC-16-75 
                 S 
                 2-OMe 
                 1.6 ± 0.4 
                  11 ± 2 
               
               
                   
                 3067 
                 2084 
                   
                   
                   
                   
                   
               
               
                 III-11 
                 4617 
                 9602 
                 KSC-16-66 
                 S 
                 3-Me 
                 2.3 ± 0.6 
                 9.7 ± 2.7 
               
               
                   
                 3061 
                 2081 
                   
                   
                   
                   
                   
               
               
                 III-12 
                 4617 
                 9602 
                 KSC-16-87 
                 S 
                 3-Cl 
                   5 ± 1.2 
                  15 ± 4 
               
               
                   
                 3068 
                 2088 
                   
                   
                   
                   
                   
               
               
                 III-13 
                 4617 
                 9602 
                 KSC-16-95 
                 S 
                 3-F 
                 1.2 ± 0.2 
                 6.3 ± 1.7 
               
               
                   
                 3060 
                 2092 
                   
                   
                   
                   
                   
               
               
                 III-14 
                 4617 
                 9602 
                 KSC-16-100 
                 S 
                 3-Br 
                 3.7 ± 0.9 
                 9.9 ± 2 
               
               
                   
                 3065 
                 2095 
                   
                   
                   
                   
                   
               
               
                 III-15 
                 4617 
                 9602 
                 KSC-16-78 
                 S 
                 3-OMe 
                   1 ± 0.1 
                 9.9 ± 1.6 
               
               
                   
                 3071 
                 2085 
               
               
                   
               
             
          
         
       
     
         [0034]    Formula IV 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                   
                 FORMULA IV:                          
 
                   
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R1 
                 ATPase 
                 Ub G76V -GFP turn over 
               
               
                   
               
               
                 IV-1 
                 2514 
                 9337 
                 KSC-1-300 
                 S 
                 4-Me 
                   3 ± 0.3 
                 1.5 ± 0.4 
               
               
                   
                 4450 
                 4186 
                   
                   
                   
                   
                   
               
               
                 IV-2 
                 4538 
                 9337 
                 KSC-16-33 
                 S 
                 4-Cl 
                 3.1 ± 0.2 
                 2.1 ± 0.4 
               
               
                   
                 2112 
                 4224 
                   
                   
                   
                   
                   
               
               
                 IV-3 
                 4538 
                 9337 
                 KSC-16-38 
                 S 
                 4-F 
                 2.6 ± 0.2 
                 3.4 ± 0.5 
               
               
                   
                 2121 
                 4227 
                   
                   
                   
                   
                   
               
               
                 IV-4 
                 4538 
                 9337 
                 KSC-16-42 
                 S 
                 4-Br 
                 4.3 ± 0.9 
                 3.9 ± 0.3 
               
               
                   
                 2119 
                 4230 
                   
                   
                   
                   
                   
               
               
                 IV-5 
                 4538 
                 9337 
                 KSC-16-2 
                 S 
                 4-OMe 
                   3 ± 0.5 
                 1.3 ± 0.2 
               
               
                   
                 2111 
                 4187 
                   
                   
                   
                   
                   
               
               
                 IV-6 
                 4538 
                 9337 
                 KSC-16-8 
                 S 
                 2-Me 
                 2.7 ± 0.5 
                 1.9 ± 0.4 
               
               
                   
                 2120 
                 4191 
                   
                   
                   
                   
                   
               
               
                 IV-7 
                 4538 
                 9337 
                 KSC-16-31 
                 S 
                 2-Cl 
                 5.3 ± 1.2 
                 2.9 ± 0.9 
               
               
                   
                 2117 
                 4222 
                   
                   
                   
                   
                   
               
               
                 IV-8 
                 4538 
                 9337 
                 KSC-16-35 
                 S 
                 2-F 
                 2.9 ± 0.4 
                 2.8 ± 0.4 
               
               
                   
                 2108 
                 4225 
                   
                   
                   
                   
                   
               
               
                 IV-9 
                 4538 
                 9337 
                 KSC-16-40 
                 S 
                 2-Br 
                 2.0 ± 0.3 
                 3.8 ± 0.7 
               
               
                   
                 2107 
                 4228 
                   
                   
                   
                   
                   
               
               
                 IV-10 
                 4538 
                 9337 
                 KSC-16-29 
                 S 
                 2-OMe 
                 3.6 ± 0.8 
                 1.9 ± 0.2 
               
               
                   
                 2105 
                 4193 
                   
                   
                   
                   
                   
               
               
                 IV-11 
                 4538 
                 9337 
                 KSC-16-28 
                 S 
                 3-Me 
                 2.3 ± 0.4 
                 2.5 ± 0.5 
               
               
                   
                 2113 
                 4192 
                   
                   
                   
                   
                   
               
               
                 IV-12 
                 4538 
                 9337 
                 KSC-16-32 
                 S 
                 3-Cl 
                 2.7 ± 0.1 
                 2.5 ± 0.4 
               
               
                   
                 2114 
                 4223 
                   
                   
                   
                   
                   
               
               
                 IV-13 
                 4538 
                 9337 
                 KSC-16-36 
                 S 
                 3-F 
                 3.1 ± 0.4 
                 2.8 ± 0.4 
               
               
                   
                 2110 
                 4226 
                   
                   
                   
                   
                   
               
               
                 IV-14 
                 4538 
                 9337 
                 KSC-16-41 
                 S 
                 3-Br 
                 3.7 ± 0.4 
                 2.8 ± 0.4 
               
               
                   
                 2118 
                 4229 
                   
                   
                   
                   
                   
               
               
                 IV-15 
                 4538 
                 9337 
                 KSC-16-30 
                 S 
                 3-OMe 
                 4.5 ± 0.8 
                 2.5 ± 0.8 
               
               
                   
                 2116 
                 4221 
                   
                   
                   
                   
                   
               
               
                 IV-16 
                 4538 
                 9337 
                 KSC-16-6 
                 S 
                 4-CF 3   
                 2.6 ± 0.4 
                 2.3 ± 0.3 
               
               
                   
                 2109 
                 4190 
                   
                   
                   
                   
                   
               
               
                 IV-17 
                 4538 
                 9337 
                 KSC-16-3 
                 S 
                 3,4-di-Cl 
                   3 ± 0.5 
                 1.9 ± 0.2 
               
               
                   
                 2106 
                 4188 
                   
                   
                   
                   
                   
               
               
                 IV-18 
                 4538 
                 9337 
                 KSC-16-4 
                 S 
                 4-Cl-3-CF 3   
                 4.7 ± 1 
                 2.2 ± 0.4 
               
               
                   
                 2115 
                 4189 
               
               
                   
               
             
          
         
       
     
         [0035]    Formula V 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                   
                 FORMULA V:                          
 
                   
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R1 
                 ATPase 
                 Ub G76V -GFP turn over 
               
               
                   
               
               
                 V-1 
                 4622 
                 9607 
                 KSC-16-103 
                 S 
                 3-Cl-2-OMe 
                 0.9 ± 0.2 
                 6.3 ± 1.7 
               
               
                   
                 4527 
                 9523 
                   
                   
                   
                   
                   
               
               
                 V-2 
                 4622 
                 9607 
                 KSC-16-104 
                 S 
                 3-F-2-Me 
                 0.9 ± 0.1 
                 3.7 ± 0.8 
               
               
                   
                 4522 
                 9524 
                   
                   
                   
                   
                   
               
               
                 V-3 
                 4622 
                 9607 
                 KSC-16-105 
                 S 
                 3-F-5-Me 
                 0.7 ± 0.05 
                 5.4 ± 0.8 
               
               
                   
                 4524 
                 9525 
                   
                   
                   
                   
                   
               
               
                 V-4 
                 4622 
                 9607 
                 KSC-16-105 
                 S 
                 3-F-2-OMe 
                 1.7 ± 0.5 
                  12 ± 3 
               
               
                   
                 4529 
                 9526 
                   
                   
                   
                   
                   
               
               
                 V-5 
                 4622 
                 9607 
                 KSC-16-107 
                 S 
                 3-Cl-2-Me 
                 0.7 ± 0.1 
                 5.5 ± 1 
               
               
                   
                 4523 
                 9527 
                   
                   
                   
                   
                   
               
               
                 V-6 
                 4622 
                 9607 
                 KSC-16-108 
                 S 
                 3-F-6-Me 
                 0.8 ± 0.1 
                   5 ± 1 
               
               
                   
                 4519 
                 9528 
                   
                   
                   
                   
                   
               
               
                 V-7 
                 4622 
                 9607 
                 KSC-16-109 
                 S 
                 3-F-4-Me 
                 0.9 ± 0.2 
                 5.2 ± 1.2 
               
               
                   
                 4528 
                 9529 
                   
                   
                   
                   
                   
               
               
                 V-8 
                 4622 
                 9607 
                 KSC-16-110 
                 S 
                 3-F-4-OMe 
                 0.9 ± 0.1 
                 4.7 ± 0.8 
               
               
                   
                 4530 
                 9530 
                   
                   
                   
                   
                   
               
               
                 V-9 
                 4622 
                 9607 
                 KSC-16-112 
                 S 
                 3-Cl-6-Me 
                 0.8 ± 0.07 
                   7 ± 1.5 
               
               
                   
                 4526 
                 9531 
                   
                   
                   
                   
                   
               
               
                 V-10 
                 4622 
                 9607 
                 KSC-16-113 
                 S 
                 3-Cl-6-OMe 
                 1.1 ± 0.2 
                  16 ± 6 
               
               
                   
                 4518 
                 9532 
                   
                   
                   
                   
                   
               
               
                 V-11 
                 4682 
                 9920 
                 KSC-16-120 
                 S 
                 3-F-6-OMe 
                 6.7 ± 3 
                 9.3 ± 1 
               
               
                   
                 9342 
                 6553 
               
               
                   
               
             
          
         
       
     
         [0036]    Formula VI 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                   
                 FORMULA VI:                          
 
                   
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R1 
                 ATPase 
                 Ub G76V -GFP turn over 
               
               
                   
               
               
                 VI-1 
                 4622 
                 9607 
                 KSC-16-114 
                 S 
                 5-Cl  
                 2.2 ± 0.7 
                  16 ± 2 
               
               
                   
                 4525 
                 9533 
                   
                   
                   
                   
                   
               
               
                 VI-2 
                 4622 
                 9607 
                 KSC-16-115 
                 S 
                 5-F 
                 1.2 ± 0.3 
                  13 ± 2 
               
               
                   
                 4521 
                 9534 
                   
                   
                   
                   
                   
               
               
                 VI-3 
                 4622 
                 9607 
                 KSC-16-117 
                 S 
                 6-Cl  
                 1.6 ± 0.4 
                 6.6 ± 0.9 
               
               
                   
                 4520 
                 9535 
                   
                   
                   
                   
                   
               
               
                 VI-4 
                 5276 
                 9602 
                 KSC-16-102 
                 S 
                 6,7-di-OMe 
                 4.4 ± 1.8 
                 8.8 ± 1.5 
               
               
                   
                  745 
                 2097 
                   
                   
                   
                   
                   
               
               
                 VI-5 
                 4682 
                 9920 
                 KSC-16-121 
                 S 
                 8-OMe 
                 0.6 ± 0.06 
                  10 ± 2 
               
               
                   
                 9340 
                 6522 
                   
                   
                   
                   
                   
               
               
                 VI-6 
                 4682 
                 9920 
                 KSC-16-118 
                 S 
                 7-Me 
                 2.2 ± 0.4 
                 6.1 ± 1.6 
               
               
                   
                 9333 
                 6552 
                   
                   
                   
                   
                   
               
               
                 VI-7 
                 4685 
                 9923 
                 KSC-16-160 
                 S 
                 7-CF 3   
                 9.1 ± 2 
                  19 ± 1 
               
               
                   
                 0874 
                 9928 
                   
                   
                   
                   
                   
               
               
                 V1-9 
                 4685 
                 9923 
                 KSC-16-153 
                 S 
                 8-Br 
                 3.3 ± 0.9 
                  30 ± 2 
               
               
                   
                 0882 
                 9931 
                   
                   
                   
                   
                   
               
               
                 VI-10 
                 4685 
                 9923 
                 KSC-16-154 
                 S 
                 8-F 
                 3.1 ± 0.5 
                  18 ± 2 
               
               
                   
                 0883 
                 9932 
                   
                   
                   
                   
                   
               
               
                 VI-11 
                 4685 
                 9923 
                 KSC-16-156 
                 S 
                 7-F 
                 2.6 ± 0.5 
                 6.1 ± 0.8 
               
               
                   
                 0884 
                 9934 
                   
                   
                   
                   
                   
               
               
                 VI-12 
                 4685 
                 9923 
                 KSC-16-159 
                 S 
                 7-Cl 
                 5.5 ± 0.9 
                 6.3 ± 0.9 
               
               
                   
                 0880 
                 9935 
                   
                   
                   
                   
                   
               
               
                 VI-13 
                 4685 
                 9923 
                 KSC-16-166 
                 S 
                 7-OMe 
                 5.7 ± 1 
                  42 ± 6 
               
               
                   
                 0885 
                 9938 
                   
                   
                   
                   
                   
               
               
                 VI-14 
                 4685 
                 9923 
                 KSC-16-172 
                 S 
                 6-OMe 
                 7.5 ± 1.1 
                 8.6 ± 1.7 
               
               
                   
                 0877 
                 9939 
                   
                   
                   
                   
                   
               
               
                 VI-15 
                 4685 
                 9923 
                 KSC-16-175 
                 S 
                 6-F 
                 4.7 ± 0.4 
                 8.2 ± 1.5 
               
               
                   
                 0873 
                 9941 
               
               
                   
               
             
          
         
       
     
         [0037]    Formula VII 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                   
                 FORMULA VII:                          
 
                   
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R1 
                 n 
                 X 
                 Y** 
                 ATPase 
                 Ub G76V -GFP turn over 
               
               
                   
               
               
                 VII-1 
                 4682 
                 9923 
                 KSC-16-125 
                 S 
                 H 
                 1 
                 CH 2   
                 H, H 
                  4.4 ± 1.8 
                  10 ± 2 
               
               
                   
                 9336 
                 9922 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 VII-2 
                 4682 
                 9923 
                 KSC-16-144 
                 S 
                 H 
                 0 
                 CH 2   
                 H, H 
                   2 ± 0.5 
                  11 ± 3 
               
               
                   
                 9332 
                 9923 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 VII-3 
                 4617 
                 9602 
                 KSC-16-70 
                 S 
                 H 
                 1 
                 O 
                 H, H 
                  0.6 ± 0.2 
                   7 ± 1.9 
               
               
                   
                 3064 
                 2082 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 VII-4 
                 4682 
                 9920 
                 KSC-16-147 
                 S 
                 H 
                 1 
                 NH 
                 H, H 
                  0.4 ± 0.05 
                 6.3 ± 1 
               
               
                   
                 9338 
                 6557 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 VII-5 
                 4687 
                 9931 
                 KSC-16-182 
                 S 
                 8-OMe 
                 1 
                 NH 
                 H, H 
                  0.9 ± 0.1 
                 3.7 ± 0.2 
               
               
                   
                 3816 
                 3586 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 VII-6 
                 4687 
                 9931 
                 KSC-16-191 
                 S 
                 8-OMe 
                 1 
                 O 
                 H, H 
                  0.2 ± 0.02 
                 3.3 ± 0.4 
               
               
                   
                 3819 
                 3591 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 VII-7 
                 4693 
                 9943 
                 KSC-16-232 
                 S 
                 8-OH 
                 1 
                 O 
                 H, H 
                  1.2 ± 0.3 
                 7.7 ± 1.7 
               
               
                   
                 1212 
                 7738 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 VII-8 
                 4983 
                 1039 
                 KSC-16-255 
                 S 
                 8-Ph 
                 1 
                 O 
                 H, H 
                  3.5 ± 0.6 
                   5 ± 0.9 
               
               
                   
                 0264 
                 0418 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   0 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 VII-9 
                 4983 
                 1039 
                 KSC-16-260 
                 S 
                 8-OCH 2 CH 2 OH 
                 1 
                 O 
                 H, H 
                 0.17 ± 0.05 
                 3.8 ± 0.8 
               
               
                   
                 0253 
                 0418 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   1 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 VII-10 
                 4983 
                 1039 
                 KSC-16-265 
                 S 
                 8OCH 2 CH 2 NEt 2   
                 1 
                 O 
                 H, H 
                  0.4 ± 0.08 
                 5.3 ± 0.6 
               
               
                   
                 0265 
                 0418 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   3 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 VII-11 
                 4983 
                 1039 
                 KSC-16-268 
                 S 
                 8-p-OMePh 
                 1 
                 O 
                 H, H 
                  1.1 ± 0.1 
                   9 ± 1 
               
               
                   
                 0267 
                 0418 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   4 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 VII-12 
                 4985 
                 1042 
                 KSC-25-17 
                 S 
                 8-OMe 
                 1 
                 NMe 
                 H, H 
                  3.1 ± 0.5 
                 7.8 ± 0.7 
               
               
                   
                 2177 
                 2195 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   2 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 VII-13 
                 4985 
                 1042 
                 KSC-25-15c1 
                 S 
                 8-OMe 
                 1 
                 NCOMe 
                 H, H 
                  2.7 ± 0.6 
                   8 ± 1 
               
               
                   
                 2173 
                 2195 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   3 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 VII-14 
                 4985 
                 1042 
                 KSC-25-29 
                 S 
                 8-OCH 2 CH 2 OMe 
                 1 
                 O 
                 H, H 
                  0.6 ± 0.03 
                 6.5 ± 0.7 
               
               
                   
                 2181 
                 2195 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   7 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 VII-16 
                 4983 
                 1039 
                 KSC-16-270 
                 S 
                 8-OMe 
                 0 
                 NH 
                 NH 
                 0.11 ± 0.03 
                 0.9 ± 0.1 
               
               
                   
                 0258 
                 0416 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   9 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 VII-17 
                 4983 
                 1039 
                 KSC-16-262cc 
                 S 
                 8-OMe 
                 0 
                 O 
                 O 
                 0.11 ± 0.03 
                   5 ± 1 
               
               
                   
                 0270 
                 0417 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   2 
               
               
                   
               
             
          
         
       
     
         [0038]    Formulas VIII to X 
         [0000]    
       
         
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                 Cpd 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                   
                 ATPase 
                 Ub G76V -GFP turn over 
               
               
                   
               
               
                 VIII 
                 4983 0260 
                 1039 0418   5 
                 KSC-16-290 
                 S 
                                           
 Formula VIII 
                 0.11 ± 0.03 
                 3.5 ± 0.4 
               
               
                   
               
               
                 IX 
                 4985 2184 
                 1042 2195   0 
                 KSC-25-14 
                 S 
                                           
 Formula IX 
                  0.4 ± 0.1 
                 6.4 ± 1 
               
               
                   
               
               
                 X 
                 4985 2172 
                 1042 2195   5 
                 KSC-25-24 
                 S 
                                           
 Formula X 
                  1.1 ± 0.2 
                  10 ± 1 
               
               
                   
               
             
          
         
       
     
         [0039]    Formula XI 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 9 
               
             
             
               
                   
               
               
                   
                 FORMULA XI:                          
 
                   
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R2 
                 ATPase 
                 Ub G76V -GFP turn over 
               
               
                   
               
               
                 XI-5 
                 4985 2185 
                 10422  1947 
                 KSC-25-22 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  0.5 ± 0.2 
                  14 ± 2 
               
               
                   
               
               
                 XI-6 
                 4985 2183 
                 10422  1949 
                 KSC-25-21 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  0.3 ± 0.07 
                 7.8 ± 1.2 
               
               
                   
               
               
                 XI-8 
                 2514 4452 
                 99313  587 
                 KSC-16-187 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   15 ± 3 
                   7 ± 1.3 
               
               
                   
               
               
                 XI-10 
                 4693 1213 
                 99437  735 
                 KSC-16-203 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  2.6 ± 0.4 
                 2.8 ± 0.5 
               
               
                   
               
               
                 XI-11 
                 4983 0269 
                 10390  4171 
                 KSC-16-273 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   12 ± 5 
                 2.1 ± 0.7 
               
               
                   
               
               
                 XI-13 
                 4983 0255 
                 10390  4174 
                 KSC-16-278 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  5.4 ± 0.9 
                 4.2 ± 1 
               
               
                   
               
               
                 XI-14 
                 4983 0257 
                 10390  4175 
                 KSC-16-282 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  1.7 ± 0.4 
                 1.8 ± 0.3 
               
               
                   
               
               
                 XI-15 
                 4983 0266 
                 10390  4176 
                 KSC-16-283 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   11 ± 1 
                  10 ± 3 
               
               
                   
               
               
                 XI-16 
                 4687 3815 
                 99313  592 
                 KSC-16-193 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  0.5 ± 0.1 
                 5.4 ± 1 
               
               
                   
               
               
                 XI-17 
                 4687 3818 
                 99313  593 
                 KSC-16-194 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 0.52 ± 0.04 
                 4.8 ± 0.7 
               
               
                   
               
               
                 XI-18 
                 4687 3813 
                 99313  594 
                 KSC-16-196 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  1.5 ± 0.2 
                 7.1 ± 0.5 
               
               
                   
               
             
          
         
       
     
         [0040]    Formula XII 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 10 
               
             
             
               
                   
               
               
                   
                 FORMULA XII:                          
 
                   
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R4 
                 ATPase 
                 Ub G76V -GFP turn over 
               
               
                   
               
               
                 XII-4 
                 49830  256 
                 10390  4182 
                 KSC-16-261 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.9 ± 0.4 
                 3.7 ± 0.6 
               
               
                   
               
               
                 XII-5 
                 49830  261 
                 10390  4186 
                 KSC-16-295 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.2 ± 0.2 
                   3 ± 0.6 
               
               
                   
               
               
                 XII-6 
                 49830  262 
                 10390  4187 
                 KSC-16-299 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 7.4 ± 0.9 
                 8.2 ± 1 
               
               
                   
               
               
                 XII-7 
                 46931  214 
                 99437  736 
                 KSC-16-219 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  19 ± 5 
                  15 ± 4 
               
               
                   
               
               
                 XII-8 
                 46931  210 
                 99437  737 
                 KSC-16-222 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 4.6 ± 1 
                   6 ± 0.6 
               
               
                   
               
               
                 XII-10   
                 46931  211 
                 99437  740 
                 KSC-16-235c2 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2.4 ± 0.5 
                 7.3 ± 1 
               
               
                   
               
             
          
         
       
     
         [0041]    Formulas XIII-XIX 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 11 
               
             
             
               
                   
               
               
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                 Cpd # 
                 KU SCC # 
                 * 
                   
                 ATPase 
                 Ub G76V -GFP turn over 
               
               
                   
               
             
          
           
               
                 XIII 
                 KSC-16-13 
                 P 
                                           
 Formula XIII 
                 13 ± 5 
                  10 ± 2 
               
               
                   
               
               
                 XIV 
                 KSC-16-16 
                 P 
                                           
 Formula XIV 
                 15 ± 5 
                  14 ± 2.4 
               
               
                   
               
               
                 XV 
                 KSC-16-22 
                 P 
                                           
 Formula XV 
                 14 ± 5 
                 3.7 ± 0.6 
               
               
                   
               
               
                 XVI 
                 KSC-16-23 
                 P 
                                           
 Formula XVI 
                 18 ± 8 
                 5.9 ± 1 
               
               
                   
               
               
                 XVII 
                 KSC-16-24 
                 P 
                                           
 Formula XVII 
                 15 ± 4 
                 5.7 ± 0.8 
               
               
                   
               
               
                 XVIII 
                 KSC-16-55 
                 P 
                                           
 Formula XVIII 
                 10 ± 4 
                 6.3 ± 0.6 
               
               
                   
               
               
                 XIX 
                 KSC-16-56 
                 P 
                                           
 Formula XIX 
                 14 ± 6 
                 7.2 ± 1.1 
               
               
                   
               
             
          
         
       
     
         [0042]    Inhibitors of p97 
         [0043]    Tables 12-17 disclosed the compounds having an IC 50  of 20 μM or less in the p97 ATPase assay (Example 7), but did not decrease the p97-dependent Ub G76V -GFP degradation turn-over assay to 20 μM or less (Example 8). 
         [0044]    Formula I 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 12 
               
               
                   
               
             
             
               
                   
                 FORMULA I:                          
 
                   
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R1 
                 R2 
                 R3 
                 R4 
                 R5 
                 ATPase 
                 Ub G76V -GFP turn over 
               
               
                   
               
               
                 I-11 
                 18190 
                 8779 
                 KSC-1-200 
                 P 
                 H 
                 3,4-di-Cl 
                 H 
                 H 
                 H 
                 7.1 ± 0.4 
                 37 ± 6 
               
               
                   
                   25 
                 6240 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 I-28 
                 15661 
                 8779 
                 KSC-1-235 
                 P 
                 H 
                 4-NO 2   
                 Me 
                 H 
                 H 
                 8.4 ± 4 
                 28 ± 4 
               
               
                   
                   44 
                 6272 
               
               
                   
               
             
          
         
       
     
         [0045]    Formula II 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 13 
               
               
                   
               
             
             
               
                   
                 FORMULA II:                         
 
                   
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                 Cpd 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R1 
                 ATPase 
                 Ub G76V -GFP turn over 
               
               
                   
               
               
                 II-21 
                 4685 
                 9923 
                 KSC-16-152 
                 S 
                 3-I 
                 5.2 ± 1.9 
                 36 ± 4 
               
               
                   
                 0881 
                 9930 
               
               
                   
               
             
          
         
       
     
         [0046]    Formula VII 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 14 
               
               
                   
               
             
             
               
                   
                 FORMULA VII:                          
 
                   
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R1 
                 n 
                 X 
                 Y 
                 ATPase 
                 Ub G76V -GFP turn over 
               
               
                   
               
               
                 VII-15 
                 4985 
                 1042 
                 KSC-25-30 
                 S 
                 8-nButyl 
                 1 
                 O 
                 H, H 
                 2.63 ± 0.7 
                 28 ± 3 
               
               
                   
                 2171 
                 2195 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                   
                   8 
               
               
                   
               
             
          
         
       
     
         [0047]    Formula XI 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 15 
               
               
                   
               
             
             
               
                   
                 FORMULA XI:                          
 
                   
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                 Cpd 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R2 
                 ATPase 
                 Ub G76V -GFP turn over 
               
               
                   
               
               
                 XI-1 
                 49852  176 
                 10422  1943 
                 KSC-25-3 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 3.3 ± 1.1 
                     78 ± 45 
               
               
                   
               
               
                 XI-12 
                 49830  259 
                 10390  4173 
                 KSC-16-277 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                   7 ± 3 
                 &gt;&gt;20 
               
               
                   
               
             
          
         
       
     
         [0048]    Formula XX 
         [0000]    
       
         
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 16 
               
             
             
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                   
                 ATPase 
                 Ub G76V -GFP turn over 
               
               
                   
               
               
                 XX 
                 4985 2180 
                 10422  1956 
                 KSC-25-28 
                 S 
                                           
 Formula XX 
                 2.9 ± 0.2 
                 27 ± 3 
               
               
                   
               
             
          
         
       
     
         [0049]    Formula XXI 
         [0000]    
       
         
               
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 17 
               
               
                   
               
             
             
               
                   
                 FORMULA XXI                          
 
                   
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 IC50 (μM) 
               
             
          
           
               
                 Cpd 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R1 
                 ATPase 
                 Ub G76V -GFP turn over 
               
               
                   
               
               
                 XXI-1 
                 4985 
                 10422 
                 KSC-25-23 
                 S 
                 5,6-di-Me 
                 2 ± 0.4 
                 89 ± 39 
               
               
                   
                 2182 
                  1948 
               
               
                   
               
             
          
         
       
     
         [0050]    Inhibitors of p97-Dependent UPS Substrate Ub G76V -GFP 
         [0051]    Tables 18-26 disclosed the compounds having an IC 50  of 20 μM or less in the p97-dependent Ub G76V GFP degradation turn-over assay (Example 7), but did not decrease p97 to less than 20 uM. 
         [0052]    Formula I 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 18 
               
             
             
               
                   
               
               
                 FORMULA I: 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Ub G76V -GFP 
               
               
                 Cpd 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R1 
                 R2 
                 R3 
                 R4 
                 R5 
                 ATPase 
                 turn over 
               
               
                   
               
               
                 I-12 
                  2452792 
                 87796250 
                 KSC-1-211 
                 P 
                 H 
                 H 
                 H 
                 H 
                 3-Cl 
                 28 ± 9  
                 17 ± 4 
               
               
                 I-14 
                  2465033 
                 87796253 
                 KSC-1-214 
                 P 
                 H 
                 H 
                 H 
                 H 
                 2-Cl 
                 30 ± 10 
                 11 ± 3 
               
               
                 I-15 
                  2456309 
                 87796254 
                 KSC-1-215 
                 P 
                 H 
                 H 
                 H 
                 H 
                 4-Cl 
                 &gt;30 
                 15 ± 3 
               
               
                 I-16 
                 15993188 
                 87796256 
                 KSC-1-217 
                 P 
                 H 
                 2-F 
                 H 
                 H 
                 2-Cl 
                 26 ± 12 
                 15 ± 3 
               
               
                 I-25 
                  1553819 
                 87796289 
                 KSC-1-258 
                 P 
                 H 
                 H 
                 Me 
                 H 
                 H 
                 49 ± 17 
                 17 ± 5 
               
               
                 I-26 
                 15995431 
                 87796257 
                 KSC-1-218 
                 P 
                 H 
                 2-F 
                 Me 
                 H 
                 H 
                 25 ± 4  
                  6.0 ± 2.0 
               
               
                 I-27 
                  2178012 
                 87796229 
                 KSC-1-148 
                 P 
                 H 
                 2-NO 2   
                 Me 
                 H 
                 H 
                 25 ± 11 
                 11 ± 6 
               
               
                 I-29 
                  5051334 
                 87796275 
                 KSC-1-238 
                 P 
                 H 
                 H 
                 H 
                 Me 
                 H 
                 27 ± 14 
                 13 ± 1 
               
               
                 I-31 
                 15992808 
                 87796255 
                 KSC-1-216 
                 P 
                 H 
                 2-F 
                 H 
                 Me 
                 H 
                 &gt;30 
                 15 ± 4 
               
               
                 I-32 
                  8074678 
                 87796236 
                 KSC-1-193 
                 P 
                 7-Cl 
                 H 
                 H 
                 H 
                 H 
                 70 ± 24 
                 12 ± 4 
               
               
                 I-35 
                  2454628 
                 87796252 
                 KSC-1-213 
                 P 
                 H 
                 H 
                 CH2-* 
                 H 
                 2-CH2-* 
                 &gt;30 
                 19 ± 5 
               
               
                   
               
               
                 *R 3  and R 5  are connected 
               
             
          
         
       
     
         [0053]    Formula II 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 19 
               
             
             
               
                   
               
               
                 FORMULA II: 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Ub G76V - 
               
               
                   
                   
                   
                   
                   
                   
                   
                 GFP 
               
               
                 Cpd 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R1 
                 ATPase 
                 turn over 
               
               
                   
               
               
                 II-8  
                  2384230 
                 92252641 
                 KSC-1-289 
                 S 
                 2-Cl 
                 69 ± 25 
                 13 ± 2 
               
               
                 II-10 
                 45108363 
                 92252640 
                 KSC-1-288 
                 S 
                 2-Br 
                 64 ± 24 
                 13 ± 2 
               
               
                   
               
             
          
         
       
     
         [0054]    Formula VI 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 20 
               
             
             
               
                   
               
               
                 FORMULA VI: 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Ub G76V - 
               
               
                   
                   
                   
                   
                   
                   
                   
                 GFP 
               
               
                   
                   
                   
                   
                   
                   
                   
                 turn 
               
               
                 Cpd 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R2 
                 ATPase 
                 over 
               
               
                   
               
               
                 VI-16 
                 46850876 
                 99239943 
                 KSC-16-122 
                 S 
                 7-Br 
                 22 ± 4 
                 10 ± 2 
               
               
                   
               
             
          
         
       
     
         [0055]    Formula XI 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 21 
               
             
             
               
                   
               
               
                 FORMULA XI: 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Ub G76V -GFP 
               
               
                 Cpd 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R2 
                 ATPase 
                 turn over 
               
               
                   
               
               
                 XI-9 
                 46873821 
                 99313588 
                 KSC-16-188 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;30 
                 9.2 ± 1.2 
               
               
                   
               
             
          
         
       
     
         [0056]    Formula XII 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 22 
               
             
             
               
                   
               
               
                 FORMULA XII: 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Ub G76V -GFP 
               
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R4 
                 ATPase 
                 turn over 
               
               
                   
               
               
                 XII-1  
                 49852170 
                 104221951 
                 KSC-25-6  
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 38 ± 7  
                 20 ± 3  
               
               
                   
               
               
                 XII-2  
                 49830271 
                 103904178 
                 KSC-16-243 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 52 ± 10 
                 19 ± 4  
               
               
                   
               
               
                 XII-9  
                 46931215 
                  99437739 
                 KSC-16-227 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 47 ± 22 
                 4.5 ± 0.5 
               
               
                   
               
               
                 XII-11 
                 46873814 
                  99313590 
                 KSC-16-190 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;30 
                 8.1 ± 1.8 
               
               
                   
               
             
          
         
       
     
         [0057]    Formulas XXII-XXIV 
         [0000]    
       
         
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 23 
               
             
             
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Ub G76V -GFP 
               
               
                 Cpd 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                   
                 ATPase 
                 turn over 
               
               
                   
               
               
                 XXII 
                  696840 
                 87796233 
                 KSC-1-152  
                 P 
                                           
 Formula XXII 
                 26 ± 4 
                 7.3 ± 2 
               
               
                   
               
               
                 XXIII 
                  1337599 
                 92093137 
                 KSC-1-203  
                 P 
                                           
 Formula XXIII 
                 33 ± 8 
                  12 ± 1 
               
               
                   
               
               
                 XXIV 
                 46873817 
                 99313595 
                 KSC-16-197 
                 S 
                                           
 Formula XXIV 
                 &gt;30 
                   11 ± 0.8 
               
               
                   
               
             
          
         
       
     
         [0058]    Formula XXV 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 24 
               
             
             
               
                   
               
               
                 Formula XXV 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                   
                 Ub G76V -GFP 
               
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R1 
                 R2 
                 ATPase 
                 turn over 
               
               
                   
               
               
                 XXV-2 
                 46850879 
                 99239936 
                 KSC-16-163 
                 S 
                 3-Cl 
                 H 
                 34 ± 16 
                 12 ± 2 
               
               
                 XXV-3 
                 46850870 
                 99239937 
                 KSC-16-164 
                 S 
                 3-Cl 
                 4-OMe 
                 34 ± 14 
                 13 ± 1 
               
               
                   
               
             
          
         
       
     
         [0059]    Formula XXVI-XLI 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 25 
               
             
             
               
                   
               
               
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                   
                   
                 Ub G76V -GFP 
               
               
                 Cpd # 
                 KU SCC # 
                 * 
                   
                 ATPase 
                 turn over 
               
               
                   
               
               
                 XXVI 
                 KSC-16-16 
                 P 
                                           
 Formula XXVI 
                 ND (no data) 
                 10.4 ± 1.5  
               
               
                   
               
               
                 XXVII 
                 KSC-16-22 
                 P 
                                           
 Formula XXVII 
                 ND 
                 13 ± 3  
               
               
                   
               
               
                 XXVIII 
                 KSC-16-11 
                 P 
                                           
 Formula XXVIII 
                 ND 
                 17 ± 3  
               
               
                   
               
               
                 XXIX 
                 KSC-16-14 
                 P 
                                           
 Formula XXIX 
                 ND 
                 18 ± 3  
               
               
                   
               
               
                 XXX 
                 KSC-16-18 
                 P 
                                           
 Formula XXX 
                 ND 
                 14 ± 3  
               
               
                   
               
               
                 XXXI 
                 KSC-16-45 
                 P 
                                           
 Formula XXXI 
                 ND 
                 8 ± 2 
               
               
                   
               
               
                 XXXII 
                 KSC-16-46 
                 P 
                                           
 Formula XXXII 
                 ND 
                 2.6 ± 0.2 
               
               
                   
               
               
                 XXXIII 
                 KSC-16-47 
                 P 
                                           
 Formula XXXIII 
                 ND 
                 3.4 ± 0.6 
               
               
                   
               
               
                 XXXIV 
                 KSC-16-48 
                 P 
                                           
 Formula XXXIV 
                 ND 
                 5.9 ± 0.8 
               
               
                   
               
               
                 XXXV 
                 KSC-16-49 
                 P 
                                           
 Formula XXXV 
                 ND 
                 6.1 ± 0.6 
               
               
                   
               
               
                 XXXVI 
                 KSC-16-50 
                 P 
                                           
 Formula XXXVI 
                 ND 
                 15 ± 2  
               
               
                   
               
               
                 XXXVII 
                 KSC-16-51 
                 P 
                                           
 Formula XXXVII 
                 ND 
                  13 ± 1.4 
               
               
                   
               
               
                 XXXVIII 
                 KSC-16-53 
                 P 
                                           
 Formula XXXVIII 
                 ND 
                  16 ± 1.4 
               
               
                   
               
               
                 XXXIX 
                 KSC-16-55 
                 P 
                                           
 Formula XXXIX 
                 ND 
                 6.3 ± 0.6 
               
               
                   
               
               
                 XL 
                 KSC-16-57 
                 P 
                                           
 Formula XL 
                 ND 
                  10 ± 1.4 
               
               
                   
               
               
                 XLI 
                 KSC-16-59 
                 P 
                                           
 Formula XLI 
                 ND 
                 6.5 ± 0.8 
               
               
                   
               
             
          
         
       
     
         [0060]    Formulas XLII and XLIII 
         [0000]    
       
         
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 26 
               
             
             
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Ub G76V -GFP 
               
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                   
                 ATPase 
                 turn over 
               
               
                   
               
               
                 XLII 
                 46873820 
                  99313589 
                 KSC-16-189 
                 S 
                                           
 Formula XLII 
                 &gt;30 
                 11 ± 2 
               
               
                   
               
               
                 XLIII 
                 49830263 
                 103904177 
                 KSC-16-241 
                 S 
                                           
 Formula XLIII 
                 30 ± 6 
                 16 ± 2 
               
               
                   
               
             
          
         
       
     
       COMPARATIVE EXAMPLES 
       [0061]    In the following Tables 27-33, compounds are shown that did not decrease either p97 or Ub G76V -GFP to 20 μM or less. 
         [0062]    Formula I 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 27 
               
             
             
               
                   
               
               
                 Formula I: 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 Ub G76V -GFP 
               
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R1 
                 R2 
                 R3 
                 R4 
                 R5 
                 ATPase 
                 turn over 
               
               
                   
               
               
                 I-7  
                 2047240 
                 87796235 
                 KSC-1-147 
                 P 
                 H 
                 4-Br 
                 H 
                 H 
                 H 
                 72 ± 14 
                 25 ± 10 
               
               
                 I-33 
                 8080035 
                 87796237 
                 KSC-1-194 
                 P 
                 7-Cl 
                 4-Me 
                 H 
                 H 
                 H 
                 39 ± 13 
                 24 ± 5  
               
               
                 I-34 
                 8080040 
                 87796238 
                 KSC-1-195 
                 P 
                 7-Cl 
                 4-OMe 
                 H 
                 H 
                 H 
                 25 ± 11 
                 70 ± 30 
               
               
                   
               
             
          
         
       
     
         [0063]    Formula II 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 28 
               
             
             
               
                   
               
               
                 FORMULA II: 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Ub G76V - 
               
               
                   
                   
                   
                   
                   
                   
                   
                 GFP 
               
               
                   
                   
                   
                   
                   
                   
                   
                 turn 
               
               
                 Cpd # 
                 CID 
                 SID 
                 KU SSC # 
                 * 
                 R1 
                 ATPase 
                 over 
               
               
                   
               
               
                 II-20 
                 46829335 
                 99239925 
                 KSC-16-150 
                 S 
                 3-CF3 
                 50 ± 16 
                 21 ± 1 
               
               
                   
               
             
          
         
       
     
         [0064]    Formula VI 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 29 
               
             
             
               
                   
               
               
                 Formula VI: 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Ub G76V - 
               
               
                   
                   
                   
                   
                   
                   
                   
                 GFP 
               
               
                   
                   
                   
                   
                   
                   
                   
                 turn 
               
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R2 
                 ATPase 
                 over 
               
               
                   
               
               
                 VI-8 
                 46850869 
                 99239929 
                 KSC-16-167 
                 S 
                 7-CN 
                 25 ± 10 
                 21 ± 3 
               
               
                   
               
             
          
         
       
     
         [0065]    Formula XI 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 30 
               
             
             
               
                   
               
               
                 Formula XI: 
               
               
                                           
 Formula XI 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Ub G76V -GFP 
               
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R2 
                 ATPase 
                 turn over 
               
               
                   
               
               
                 XI-2  
                 49852179 
                 104221944 
                 KSC-25-10  
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 31 ± 7  
                 47 ± 9  
               
               
                   
               
               
                 XI-3  
                 49852174 
                 104221945 
                 KSC-25-12  
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 49 ± 10 
                 108 ± 31  
               
               
                   
               
               
                 XI-4  
                 49852178 
                 104221946 
                 KSC-25-16  
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;&gt;30 
                 45 ± 18 
               
               
                   
               
               
                 XI-7  
                 49852175 
                 104221954 
                 KSC-25-10  
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 60 ± 23 
                 37 ± 7  
               
               
                   
               
               
                 XI-19 
                 49830268 
                 103904170 
                 KSC-16-272 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  &gt;30 
                 &gt;&gt;20 
               
               
                   
               
             
          
         
       
     
         [0066]    Formula XII 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 31 
               
             
             
               
                   
               
               
                 FORMULA XII: 
               
             
          
           
               
                   
                   
                   
                   
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                                 IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Ub G76V -GFP 
               
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R4 
                 ATPase 
                 turn over 
               
               
                   
               
               
                 XII-3 
                 4983 0254 
                 10390  4179 
                 KSC-16-251 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 33 ± 7 
                 23 ± 2 
               
               
                   
               
             
          
         
       
     
         [0067]    Formula XXV 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 32 
               
             
             
               
                   
               
               
                 Formula XXV 
               
             
          
           
               
                   
                 
                   
                             
                     
                         
                         
                     
                   
                 
                                     IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                   
                 Ub G76V -GFP 
               
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                 R1 
                 R2 
                 ATPase 
                 turn over 
               
               
                   
               
             
          
           
               
                 XXV-1 
                 1732 
                 9923 
                 KSC-16- 
                 S 
                 4-OMe 
                 4-OMe 
                 22 ± 4  
                 23 ± 3 
               
               
                   
                 4423 
                 9924 
                 149 
                   
                   
                   
                   
                   
               
               
                 XXV-4 
                 4685 
                 9923 
                 KSC-16- 
                 S 
                 3-Cl 
                 4-Me 
                  49 ± 19  
                 30 ± 4 
               
               
                   
                 0872 
                 9940 
                 174 
                   
                   
                   
                   
                   
               
               
                 XXV-5 
                 4685 
                 9923 
                 KSC-16- 
                 S 
                 3-Cl 
                 4-Cl 
                 117 ± 5.8 
                 21 ± 2 
               
               
                   
                 0878 
                 9942 
                 176 
                   
                   
                   
                   
                   
               
               
                 XXV-6 
                 4685 
                 9923 
                 KSC-16- 
                 S 
                 4-Me 
                 4-Me 
                  54 ± 19  
                 21 ± 4 
               
               
                   
                 0875 
                 9944 
                 151 
               
               
                   
               
             
          
         
       
     
         [0068]    Formulas XLIV-XLXI 
         [0000]    
       
         
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 33 
               
             
             
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 IC 50  (μM) 
               
             
          
           
               
                   
                   
                   
                   
                   
                   
                   
                 Ub G76V -GFP 
               
               
                 Cpd # 
                 CID 
                 SID 
                 KU SCC # 
                 * 
                   
                 ATPase 
                 turn over 
               
               
                   
               
               
                 XLIV 
                  832282 
                 87796232 
                 KSC-1-151 
                 P 
                                           
 Formula XLIV 
                 23 ± 6  
                 36 ± 9  
               
               
                   
               
               
                 XLV 
                  832283 
                 92093143 
                 KSC-1-260 
                 P 
                                           
 Formula XLV 
                 53 ± 18 
                 31 ± 6  
               
               
                   
               
               
                 XLVI 
                 2950240 
                 87796276 
                 KSC-1-240 
                 P 
                                           
 Formula XLVI 
                 34 ± 10 
                  36 ± 0.3 
               
               
                   
               
               
                 XLVII 
                 1330669 
                 87796248 
                 KSC-1-208 
                 P 
                                           
 Formula XLVII 
                 34 ± 11 
                 35 ± 5  
               
               
                   
               
               
                 XLVIII 
                 2955641 
                 87796277 
                 KSC-1-241 
                 P 
                                           
 Formula XLVIII 
                 22 ± 12 
                 39 ± 18 
               
               
                   
               
               
                 XLIX 
                 3419814 
                 92093139 
                 KSC-1-239 
                 P 
                                           
 Formula XLIX 
                 43 ± 13 
                 70 ± 16 
               
               
                   
               
               
                 LI 
                 1091839 
                 92093140 
                 KSC-1-242 
                 P 
                                           
 Formula L 
                 57 ± 15 
                 56 ± 10 
               
               
                   
               
               
                 LI 
                 2932797 
                 92093142 
                 KSC-1-254 
                 P 
                                           
 Formula LI 
                 30 ± 6  
                 34 ± 6  
               
               
                   
               
             
          
         
       
     
         [0069]    Compound Derivatives 
         [0070]    In one embodiment, a compound of the present invention is a derivative of one of the compounds disclosed herein. In another embodiment of the present invention, an inhibitor of p97 ATPase is identified by assaying any of the compound derivatives of Formulas LII through LXVI in the ATPase assay as described in Example 7. 
         [0071]    For example, a compound derivative is represented by Formula LII: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0072]    For Formula LII above, n is 0, 1 or 2. A compound of Formula LII can be synthesized as detailed in Example 3. 
         [0073]    In another example, a compound derivative is represented by Formula LIII: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0074]    For Formula LIII above, R 1  and R 2  can vary independently. R 1  and R 2  are independently selected from hydrogen (H), methyl, ethyl, propyl, or butyl. A compound of Formula LIII can be synthesized as detailed in Example 3. 
         [0075]    In another example, a compound derivative is represented by Formula LIV: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0076]    For Formula LIV above, R 1  is selected from H, methyl, F, Cl, Br, and OMe on any position in the ring. R 2  is selected from hydrogen (H), methyl, ethyl, propyl and butyl. A compound of Formula LIV can be synthesized as detailed in Example 3. 
         [0077]    In another example, a compound derivative is represented by Formula LV: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0078]    For Formula LV above, R 1  is selected from H, methyl, F, Cl, Br, and OMe on any position in the ring. A compound of Formula LV can be synthesized as detailed in Example 3. 
         [0079]    In another example, a compound derivative is represented by Formula LVI: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0080]    For Formula LVI above, R 1  and R 2  vary independently. R 1  and R 2  are selected from H, methyl, F, Cl, Br, and OMe on any position in the ring. A compound of Formula LVI can be synthesized as detailed in Example 3. 
         [0081]    In another example, a compound derivative is represented by Formula LVII: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0082]    For Formula LVII above, X is selected from O, NMe (nitrogen-methyl), NEt (nitrogen-ethyl), and NPh (nitrogen-phenyl) at any position in the ring; n is −1, 0, 1, or 2; and m is 1, 2, 3, or 4. R 1  and R 2  can vary independently. R 1  and R 2  are independently selected from H, Me, F, Cl, Br, and OMe at any position on the ring. A compound of Formula LVII can be synthesized as detailed in Example 4. 
         [0083]    In another example, a compound derivative is represented by Formula LVIII: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0084]    For Formula LVIII above, X is selected from 0, NMe (nitrogen-methyl), NEt (nitrogen-ethyl), and NPh (nitrogen-phenyl) at any position in the ring; n is −1, 0, 1, or 2; and m is 1, 2, 3, or 4. R 1  is selected from H, Me, F, Cl, Br, and OMe on any position on the ring. A compound of Formula LVIII can be synthesized as detailed in Example 4. 
         [0085]    In another example, a compound derivative is represented by Formula LIX: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0086]    For Formula LIX above, R 1 , R 2  and R 3  can vary independently and are each independently selected from H, A(CH 2 ) n CH 3 , and A(CH 2 ) n X, where n is 0, 1, 2, 3, 4 or 5, A=O, S or NH and X is heteroaryl, O(alkyl), S(alkyl), (O-alkyl) 2 , or (S-alkyl) 2 . A compound of Formula LIX can be synthesized as detailed in Example 5. 
         [0087]    In another example, a compound derivative is represented by Formula LX: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0088]    For Formula LX above, R 1  is selected from H, A(CH 2 ) n CH 3 , and A(CH 2 ) n X, wherein n is 0, 1, 2, 3, 4, or 5, A is O, S or NH and X is selected from heteroaryl, O(alkyl), S(alkyl), (O-alkyl) 2 , and (S-alkyl) 2 . A 1  is selected from O, S, Se, N, NH, CH, CH 2 , CHalkyl, and Calkyl; and A 2  is selected from N, NH, CH, and Calkyl. A compound of Formula LVX can be synthesized as detailed in Example 5. 
         [0089]    In another example, a compound derivative is represented by Formula LXI: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0090]    For Formula LXI above, R 1 , R 2  and R 3  can vary independently. R 1 , R 2  and R 3  are independently selected from alkyl, alkoxyalkyl, and aminoalkyl. R 4  is selected from H, halogen, alkyl, and alkyoxy. X is selected from CH 2 , O NH, NMe, NEt, NCOMe, and NPh. Y is selected from NH, O, S, [H, H], and n is 0 or 1. A compound of Formula LXI can be synthesized as detailed in Example 6. 
         [0091]    In another example, a compound derivative is represented by Formula LXII: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0092]    For Formula LXII above, n is −1, 0, 1, or 2; m is 0, 1, or 2, and X is selected from CH 2 , O, NMe, NEt, and NPh at any position in the ring. A compound of Formula LXII can be synthesized following a scheme as shown in Example 4. 
         [0093]    In another example, a compound derivative is represented by Formula LXIII: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0094]    For Formula LXIII above, R 1  and R 2  vary independently. R 1  and R 2  independently selected from H, Me, Et, Pr, and Bu. n is −1, 0, 1, or 2. X is selected from CH 2 , O, NMe, NEt, NPh at any position in the ring. A compound of Formula LXIII can be synthesized following a scheme as shown in Example 4. 
         [0095]    In another example, a compound derivative is represented by Formula LXIV: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0096]    For Formula LXIV, R 1  is selected from H, Me, F, Cl, Br, and OMe at any position on the ring. R 2  is selected from H, Me, Et, Pr, and Bu. X is selected from CH 2 , O, NMe, NEt, and NPh at any position on the ring. n is −1, 0, 1, or 2. A compound of Formula LXIV can be synthesized following a scheme as shown in Example 4. 
         [0097]    In another example, a compound derivative is represented by Formula LXV: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0098]    For Formula LXV, R 1  is selected from H, Me, F, Cl, Br, and OMe at any position on the ring. R 2  is selected from H, Me, Et, Pr, and Bu. X is selected from CH 2 , O, NMe, NEt, and NPh at any position on the ring. n is −1, 0, 1, or 2. A compound of Formula LXV can be synthesized following a scheme as shown in Example 4. 
         [0099]    In another example, a compound derivative is represented by Formula LXVI: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0100]    For Formula LXVI, R 1  and R 2  can vary independently. R 1  and R 2  are independently selected from H, Me, F, Cl, Br, and OMe at any position on the ring. X is selected from CH 2 , O, NMe, NEt, and NPh at any position on the ring. n is −1, 0, 1, or 2. A compound of Formula LXVI can be synthesized following a scheme as shown in Example 4. 
         [0101]    Isomers 
         [0102]    Compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms “R” and “S” are as defined in  Pure Appl. Chem.  (1976) 45, 11-30. Compounds having asymmetrically substituted carbon atoms with equal amounts of R and S configurations are racemic at those atoms. Atoms having excess of one configuration over the other are assigned the configuration in excess, preferably an excess of about 85%-90%, more preferably an excess of about 95%-99%, and still more preferably an excess greater than about 99%. Accordingly, this invention is meant to embrace racemic mixtures and relative and absolute diastereoisomers of the compounds thereof. 
         [0103]    Compounds of this invention may also contain carbon-carbon double bonds or carbon-nitrogen double bonds in the Z or E configuration, in which the term “Z” represents the larger two substituents on the same side of a carbon-carbon or carbon-nitrogen double bond and the term “E” represents the larger two substituents on opposite sides of a carbon-carbon or carbon-nitrogen double bond. The compounds of this invention may also exist as a mixture of “Z” and “E” isomers. 
         [0104]    Compounds of this invention may also exist as tautomers or equilibrium mixtures thereof wherein a proton of a compound shifts from one atom to another. Examples of tautomers include, but are not limited to, keto-enol, phenol-keto, oxime-nitroso, nitro-aci, imine-enamine and the like. 
         [0105]    In one embodiment, isomers of the disclosed compounds are regioisomers or stereoisomers. 
         [0106]    Compound Analogs 
         [0107]    The compounds disclosed herein may be further modified to enhance solubility, detection and/or delivery in the body. The following modifications are not necessarily exclusive to another and can be combined. For example, a PEGylated and fluorescently labeled compound is disclosed. 
         [0108]    In one embodiment, a compound of the present invention is fluorescently labeled. Suitable fluorescent labels are well known. A fluorescent label to be added to an inhibitor compound includes, but is not limited to, NBD-Cl (4-Chloro-7-nitro-2,1,3-benzoxadiazole), R—NCO (isocyanate), R—NCS (FITC). 
         [0109]    In one embodiment, a compound of the present invention is biotinylated. Biotinylation is carried out using a biotin derivative. Examples of biotin derivatives include ester-biotin, amine-biotin, amide-biotin, and OH-biotin. 
         [0110]    In one embodiment, a compound of the present invention is PEGylated with at least one PEG moiety. It is well known in the art that polyalkylene glycols, such as polyethylene glycol (PEG), may be attached to a therapeutic agent. Polyalkylene glycolated (PAGylated) therapeutic agents, and in particular, PEGylated therapeutic agents, have been reported to increase solubility, circulating life, safety, decrease renal excretion, and decrease immunogenicity thus potentially providing a method of improved drug delivery. A PEGylated therapeutic agent may exhibit (a) increased plasma circulatory half lives in vivo compared to the corresponding non-PEGylated compound, (b) enhanced therapeutic indices compared to the corresponding non-PEGylated compounds and (c) increased solubility compared to the corresponding non-PEGylated compounds, effecting possible improved drug delivery. Examples in which PEGylation has been used to effect drug delivery are disclosed, for example, in U.S. Pat. No. 6,623,729, U.S. Pat. No. 6,517,824, U.S. Pat. No. 6,515,017, U.S. Pat. No. 6,217,869, U.S. Pat. No. 6,191,105, U.S. Pat. No. 5,681,811, U.S. Pat. No. 5,455,027, U S Published Patent Application No 20040018960, U S Published Patent Application No 20030229010, U S Published Patent Application No 20030229006, U S Published Patent Application No 20030186869, U S Published Patent Application No 20030026764, and U S Published Patent Application No 20030017131 U.S. Pat. No. 6,214,966, U S Published Patent Application No 2003000447, and U S Published Patent Application No. 2001021763 describe soluble, degradable poly(ethylene glycol) derivatives for controlled release of bound molecules into solution. Recent reviews on PEGylation are provided in, for example, Greenwald R. B., Choe Y. H., McGuire J., Conover C D. Adv. Drug Del. Rev. 2003, 55, 217, Molineux G. Pharmacotherapy 2003, (8 Pt 2), 3S-8S, Roberts M. J., Bentley, M. D., Harris J. M. Adv. Drug Deliv. Rev. 2002, 54, 459, Bhadra D., Bhadra S., Jain P., Jain N. K. Pharmazie 2002, 57, 5, Greenwald R B. J. Controlled Release 2001, 74, 159, Veronese F. M., Morpurgo M. Farmaco. 1999, 54, 497 and Zalipsky S. Adv. Drug Deliv. Rev. 1995, 76, 157. In particular, the compounds of formulas I through LXVI as described herein, may be PEGylated. 
         [0111]    Pharmaceutical Salts 
         [0112]    The phrase “pharmaceutically acceptable” is used herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of the medical arts, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. 
         [0113]    Compounds of the present invention, including all analogs and isomers of the compounds may exist as acid addition salts, basic addition salts or zwitterions. Salts of compounds disclosed herein are prepared during their isolation or following their purification. Acid addition salts are those derived from the reaction of a compound of the present invention with acid. Accordingly, salts including the acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, para-toluenesulfonate and undecanoate salts of the compounds having any of formulas I through LXVI are meant to be embraced by this invention. Basic addition salts of compounds are those derived from the reaction of the compounds with the bicarbonate, carbonate, hydroxide or phosphate of cations such as lithium, sodium, potassium, calcium and magnesium. Lists of suitable salts are found in Remington&#39;s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and in the Journal of Pharmaceutical Science, 66, 2 (1977), the disclosures of each of which are hereby incorporated by reference. 
         [0114]    Pharmaceutical Formulations and Dosage Forms 
         [0115]    When employed as pharmaceuticals, the compounds of any of Formulas (I-LXVI) can be administered in the form of pharmaceutical compositions. These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal, and can be prepared in a manner well known in the pharmaceutical art. 
         [0116]    This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of Formulas I-LXVI (including analogs and isomers thereof) above in combination with one or more pharmaceutically acceptable carriers. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. 
         [0117]    In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh. 
         [0118]    Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. 
         [0119]    The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient&#39;s symptoms, and the like. 
         [0120]    Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner. 
         [0121]    The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. An amount adequate to accomplish this is referred to as “therapeutically effective amount.” Effective doses will depend on the disease condition being treated as well as by the judgement of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like. 
         [0122]    The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts. 
         [0123]    Compounds disclosed herein may be administered, for example, bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperintoneally intrasternally, intravenously, subcutaneously), rectally, topically, transdermally, vaginally and intraarterially as well as by intraarticular injection, infusion, and placement in the body, such as, for example, the vasculature by means of, for example, a stent. 
         [0124]    The present invention also includes pharmaceutical kits useful, for example, in the treatment of cancers, which comprise one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I-LXVI). Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit. 
       EXAMPLES 
     Example 1 
     Purchased Compounds 
       [0125]    Compounds shown in Tables 1-33 were either synthesized or purchased as indicated in the Tables, wherein S indicates synthesized and P indicates purchased. Table 34 below provides company information for purchased compounds. 
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 34 
               
               
                   
               
               
                 Cpd # 
                 KU SCC # 
                 Company 
               
               
                   
               
             
             
               
                 I-1 
                 KSC-1-150 
                 Chembridge 
               
               
                 I-2 
                 KSC-1-145 
                 Aldrich 
               
               
                 I-3 
                 KSC-1-146 
                 Chembridge 
               
               
                 I-4 
                 KSC-1-149 
                 Chembridge 
               
               
                 I-5 
                 KSC-1-226 
                 Chemdiv 
               
               
                 I-6 
                 KSC-1-236 
                 Princeton Biomecular Research, Inc 
               
               
                 I-7 
                 KSC-1-147 
                 Chembridge 
               
               
                 I-8 
                 KSC-1-234 
                 Princeton Biomecular Research, Inc 
               
               
                 I-9 
                 KSC-1-227 
                 Chemdiv 
               
               
                 I-10 
                 KSC-1-224 
                 Chemdiv 
               
               
                 I-11 
                 KSC-1-200 
                 Ryan Scientific, Inc. 
               
               
                 I-12 
                 KSC-1-211 
                 Ryan Scientific 
               
               
                 I-13 
                 KSC-1-212 
                 Ryan Scientific 
               
               
                 I-14 
                 KSC-1-214 
                 Ryan Scientific 
               
               
                 I-15 
                 KSC-1-215 
                 Ryan Scientific 
               
               
                 I-16 
                 KSC-1-217 
                 Chemdiv 
               
               
                 I-17 
                 KSC-1-219 
                 Chemdiv 
               
               
                 I-20  
                 KSC-1-220 
                 Chemdiv 
               
               
                 I-21 
                 KSC-1-221 
                 Chemdiv 
               
               
                 I-22 
                 KSC-1-222 
                 Chemdiv 
               
               
                 I-23  
                 KSC-1-223 
                 Chemdiv 
               
               
                 I-24 
                 KSC-1-225 
                 Chemdiv 
               
               
                 I-25  
                 KSC-1-258 
                 Interchim 
               
               
                 I-26  
                 KSC-1-218 
                 Chemdiv 
               
               
                 I-27  
                 KSC-1-148 
                 Chembridge 
               
               
                 I-28  
                 KSC-1-235 
                 Princeton Biomecular Research, Inc 
               
               
                 I-29  
                 KSC-1-238 
                 Princeton Biomecular Research, Inc 
               
               
                 I-30  
                 KSC-1-237 
                 Princeton Biomecular Research, Inc 
               
               
                 I-31  
                 KSC-1-216 
                 Chemdiv 
               
               
                 I-32  
                 KSC-1-193 
                 Albany Molecular Research, Inc. 
               
               
                 I-33  
                 KSC-1-194 
                 Albany Molecular Research 
               
               
                 I-34  
                 KSC-1-195 
                 Albany Molecular Research 
               
               
                 I-35  
                 KSC-1-213 
                 Ryan Scientific 
               
               
                 XXII  
                 KSC-1-152 
                 Chembridge 
               
               
                 XLIV  
                 KSC-1-151 
                 Chembridge 
               
               
                 XLV 
                 KSC-1-260 
                 interchim 
               
               
                 XLVI  
                 KSC-1-240 
                 Princeton Biomecular Research, Inc 
               
               
                 XLVII 
                 KSC-1-208 
                 Ryan Scientific 
               
               
                 XLVIII 
                 KSC-1-241 
                 Princeton Biomecular Research, Inc 
               
               
                 XXIII 
                 KSC-1-203 
                 Ryan Scientific 
               
               
                 XLIX  
                 KSC-1-239 
                 Princeton Biomecular Research 
               
               
                 L 
                 KSC-1-242 
                 Princeton Biomecular Research 
               
               
                 LI 
                 KSC-1-254 
                 Princeton Biomecular Research, Inc 
               
               
                 II-1  
                 KSC-1-153 
                 Chembridge 
               
               
                 II-2  
                 KSC-1-251 
                 Princeton Biomecular Research 
               
               
                 II-3  
                 KSC-1-246 
                 Princeton Biomecular Research 
               
               
                 II-4 
                 KSC-1-249 
                 Princeton Biomecular Research 
               
               
                 II-5  
                 KSC-1-245 
                 Princeton Biomecular Research 
               
               
                 II-6  
                 KSC-1-250 
                 Princeton Biomecular Research 
               
               
                 II-7  
                 KSC-1-252 
                 Princeton Biomecular Research 
               
               
                 II-9  
                 KSC-1-247 
                 Princeton Biomecular Research 
               
               
                 II-11 
                 KSC-1-248 
                 Princeton Biomecular Research 
               
               
                 II-12 
                 KSC-1-253 
                 Princeton Biomecular Research 
               
               
                 II-13 
                 KSC-1-244 
                 Princeton Biomecular Research 
               
               
                 II-17 
                 KSC-1-259 
                 interchim 
               
               
                   
               
             
          
         
       
     
       Example 2 
     Compound Synthesis 
       [0126]    In general, compounds of the invention, including salts and solvates thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which can range from the solvent&#39;s freezing temperature to the solvent&#39;s boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected. 
         [0127]    Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley &amp; Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety. 
         [0128]    Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or  13 C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography. 
         [0129]    Synthesized compounds were synthesized using one of the following three synthesis schemes. Synthesis scheme I was carried out with reference to Gavish et al. WO 2008/023357A1. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0130]    Synthesis scheme II was carried out with reference to Gahman et al. US 2009/0209536 A1. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0131]    Representative compound synthesis: N2,N4-dibenzyl-8-methoxyquinazoline-2,4-diamine. (Compound #VI-5). To a suspension of 2,4-dichloro-8-methoxyquinazoline (50 mg, 0.22 mmol) in acetonitrile (1 mL) was added benzylamine (0.12 mL, 1.09 mmol, 5 equiv.). The mixture was heated to 180° C. for 1 h under microwave irradiation. The concentrated residue was purified by silica gel chromatography (Ethyl acetate) to give a white solid.  1 H NMR (400 MHz, CDCl 3 ) δ 7.44-7.18 (m, 11H), 7.11 (dd, J=1.6, 7.9 Hz, 1H), 7.07-6.93 (m, 2H), 5.86 (s, br. 1H), 5.49 (s, br. 1H), 4.78 (d, J=5.7 Hz, 2H), 4.75 (d, J=5.7 Hz, 2H), 3.99 (s, 3H).  13 C NMR (101 MHz, CDCl 3 ) δ 160.1, 159.3, 153.2, 144.2, 140.2, 138.7, 128.7, 128.4, 128.0, 127.5, 126.8, 120.4, 112.5, 111.2, 110.9, 55.9, 45.7, 45.2. HRMS (m/z): calcd for C 23 H 23 N 4 O (M+H) 371.1872; found 371.1871. 
         [0132]    Some specific examples of synthesis schemes are shown as follows. 
         [0133]    Specifically, for XXIV, the synthesis scheme is as shown below: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0134]    A synthesis scheme for Formula II is shown below: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0135]    A synthesis scheme for Formula III is shown below: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0136]    A synthesis scheme for Formula IV is shown below: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0137]    A synthesis scheme for Formula V is shown below: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0138]    A synthesis scheme for Formula VI is shown below: 
         [0000]    
       
                 
         
             
             
         
       
     
       Example 3 
     Synthesis of Compound Derivatives LII, LIII, LIV, LV and LVI 
       [0139]    Synthesis Schemes with reference to Kohn et al., 1983,  J. Am. Chem. Soc,  105, 4106-4108. 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
       Example 4 
     Synthesis of Compound Derivatives LVII, LVIII, LXII, LXIII, LXIV, LXV, and LXVI 
       [0140]    Synthesis scheme for LVII. For LVIII and LXII-LXVI, reference is made to the scheme below, with reference to schemes disclosed herein and Zaugg, 1984,  Synthesis,  86-110. 
         [0000]    
       
                 
         
             
             
         
       
     
       Example 5 
     Synthesis of Compound Derivatives LIX and LXI 
       [0141]    Synthesis scheme for LIX with reference to Tikad et al., 2006,  Synlett,  1938-1942. 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0142]    Synthesis scheme for LX with reference to above reaction and reference for LIX. 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
       Example 6 
     Synthesis of Compound Derivative LXI 
       [0143]    Synthesis scheme for LXI with reference to Zaugg, 1984,  Synthesis,  86-110. 
         [0000]    
       
                 
         
             
             
         
       
     
       Example 7 
     ATPase Assay 
       [0144]    Assay Buffer (20 μL of 2.5× concentration, where 1×=50 mM Tris pH 7.4, 20 mM MgCl 2 , 1 mM EDTA, 0.5 mM TCEP) was dispensed into each well of a 96 well plate. Purified p97 (25 μL of 50 μM) was diluted in 975 μL, of 1× Assay Buffer and 10 μL was dispensed in each well. Test compound (10 μL) or 5% DMSO (10 μL) was then added to each well and the plate was incubated at room temperature for 10 min. The ATPase assay was carried out by adding to each well 10 μL of 500 μM ATP (pH 7.5), incubating at room temperature for 60 min, and then adding 50 μL Kinase Glo Plus reagent (Promega) followed by a final 10 min incubation at room temperature in the dark. Luminescence was read on an Analyst AD (Molecular Devices). Compounds were assayed at a range of concentrations (0, 0.048, 0.24, 1.2, 6, 30 μM) in triplicate. The percent of remaining activity for each reaction was calculated using the following mathematical expression: ((Test Compound-High Control)/(Low Control-High Control))*100. Test_Compound is defined as wells containing test compound, Low_Control is defined as wells containing DMSO, High_Control is defined as wells containing no p97 protein. IC 50  values were calculated from fitting the percentage of remaining activity (% RA) with various concentrations of compounds to a Langmuir equation [% RA=100/(1+[Compound]/IC 50 )] by non-linear regression analysis using the JUMP IN program. The result was expressed as mean +/− standard error. For assays with Myriad 12 and 19, 100 μL of biomol green reagent (Enzo Life Sciences) was added to each well instead of kinase Glo Plus (Promega) and absorbance at 630 nm was measured. This was done because these compounds interfered with luciferase activity. For assays with compounds that interfered with luciferase activity, 100 μL of biomol green reagent (Enzo Life Sciences) was added to each well instead of kinase Glo Plus (Promega) and absorbance at 630 nm was measured. 
       Example 8 
     Ub G76V -GFP Degradation Assay 
       [0145]    Two GFP images with 100 ms exposure time per well were acquired and the average GFP intensity per area of a HeLa cell was determined by using MetaXpress software. Mean GFP intensity of 300-500 cells was calculated using Excel. Normalized GFP intensity was calculated using the following formula: (Test compound−Background)/(Basal GFP intensity—Background). Where: Test compound is defined as Mean GFP intensity of Ub G76V -GFP-expressing cells treated with the test compound. Background is defined as background GFP intensity of HeLa cells. Basal GFP intensity is defined as mean GFP intensity of Ub G76V -GFP-expressing cells treated with DMSO. The degradation rate constant (k) was obtained from the slope of the linear range of plotting Ln (Normalized GFP intensity) versus time ranging from 90 to 180 min. The percent of remaining k for each compound is calculated using the following formula: (Test compound/DMSO control)*100. Where: Test_compound is defined as k determined from wells containing test compound, DMSO control is defined as k determined from wells containing DMSO. IC 50  values were calculated from fitting the percentage of remaining k (% k) with various concentrations of compounds to a Langmuir equation [% k=100/(1+[Compound]/IC 50 )] by non-linear regression analysis using the JUMP IN program. The result was expressed as mean +/− standard error. 
       Example 9 
     NMR Analysis of Compounds 
       [0146]    NMR data for all compounds in attached in the Appendix. 
         [0147]      1 H and  13 C spectra were recorded on a Bruker Avance 400 or 500 MHz spectrometer. Chemical shifts are reported in parts per million and were referenced to residual proton solvent signals.