Compositions and methods to improve the therapeutic benefit of indirubin and analogs thereof, including meisoindigo

Abstract

The present invention describes methods and compositions for improving the therapeutic efficacy of therapeutically active agents previously limited by suboptimal therapeutic performance by either improving efficacy as monotherapy or reducing side effects. Such methods and compositions are particularly applicable to therapeutically active agents selected from the group consisting of: (i) indirubin; (ii) an analog of indirubin; (iii) a derivative of indirubin or of an analog of indirubin; and (iv) a pharmaceutical composition comprising indirubin, an analog of indirubin, or a derivative of indirubin or of an analog of indirubin, especially meisoindigo.

1 . A method to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy comprising the steps of:
 (a) identifying at least one factor or parameter associated with the efficacy and/or occurrence of side effects of the drug therapy; and   (b) modifying the factor or parameter to improve the efficacy and/or reduce the side effects of the drug therapy, wherein the suboptimally administered drug therapy comprises administration of a therapeutically active agent selected from the group consisting of: (i) indirubin; (ii) an analog of indirubin; (iii) a derivative of indirubin or of an analog of indirubin; and (iv) a pharmaceutical composition comprising indirubin, an analog of indirubin, or a derivative of indirubin or of an analog of indirubin.   
     
     
         2 . The method of  claim 1  wherein the factor or parameter is selected from the group consisting of:
 (a) dose modification; 
 (b) route of administration; 
 (c) schedule of administration; 
 (d) indications for use; 
 (e) selection of disease stage; 
 (f) other indications; 
 (g) patient selection; 
 (h) patient/disease phenotype; 
 (i) patient/disease genotype; 
 (j) pre/post-treatment preparation 
 (k) toxicity management; 
 (l) pharmacokinetic/pharmacodynamic monitoring; 
 (m) drug combinations; 
 (n) chemosensitization; 
 (o) chemopotentiation; 
 (p) post-treatment patient management; 
 (q) alternative medicine/therapeutic support; 
 (r) bulk drug product improvements; 
 (s) diluent systems; 
 (t) solvent systems; 
 (u) excipients; 
 (v) dosage forms; 
 (w) dosage kits and packaging; 
 (x) drug delivery systems; 
 (y) drug conjugate forms; 
 (z) compound analogs; 
 (aa) prodrugs; 
 (ab) multiple drug systems; 
 (ac) biotherapeutic enhancement; 
 (ad) biotherapeutic resistance modulation; 
 (ae) radiation therapy enhancement; 
 (af) novel mechanisms of action; and 
 (ag) selective target cell population therapeutics. 
 
     
     
         3 . The method of  claim 1  wherein the drug therapy is administered to treat a hyperproliferative disease wherein the hyperproliferative disease is cancer. 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 3  wherein the cancer is a cancer selected from the group consisting of acute myelogenous leukemia, chronic myelogenous leukemia, and colorectal cancer. 
     
     
         6 . The method of  claim 1  wherein the therapeutically active agent is selected from the group consisting of meisoindigo and the salts, solvates, analogues, congeners, bioisosteres, hydrolysis products, metabolites, precursors, and prodrugs thereof. 
     
     
         7 . The method of  claim 6  wherein the therapeutically active agent is meisoindigo. 
     
     
         8 .- 24 . (canceled) 
     
     
         25 . The method of  claim 1  wherein the therapeutically active agent is selected from the group consisting of: (1) indirubin 3′-monooxime; (2) indirubin 5-sulfonic acid; (3); (4) 1H, 1′H-[2,3′]biindolylidene-3,2′-dione; (5) 5-fluoro-1H,1′H-[2,3′]biindolylidene-3,2′-dione; (6) 1H,1′H-[2,3′]biindolylidene-3,2′-dione-3-oxime; (7) 1-acetyl-1H,1′H-[2,3′]biindolylidene-3,2′-dione; (8) 5′-nitro-1H,1′H-[2,3′]biindolylidene-3,2′-dione; (9) 5′-nitro-1H,1′H-[2,3′]biindolylidene-3,2′-dione-3-oxime; (10) 5-fluoro-1H,1′H-[2,3′]biindolylidene-3,2′-dione-3-oxime; (11) 5′-methyl-1H,1′H-[2,3′]biindolylidene-3,2′-dione-3-oxime; (12) 5′-chloro-1H,1′H-[2,3′]biindolylidene-3,2′-dione-3-oxime; (13) 5′-iodo-1H,1′H-[2,3′]biindolylidene-3,2′-dione-3-oxime; (14) 5′,7′-dimethyl-1H,1′H-[2,3′]biindolylidene-3,2′-dione-3-oxime; (15) 5′-chloro-7′-methyl-1H,1′H-[2,3′]biindolylidene-3,2′-dione-3-oxime; (16) 5-bromo-1H,1′H-[2,3′]biindolylidene-3,2′-dione-3-oxime; (17) 3,2′-dioxo-1,3,1′,2′-tetrahydro-[2,3]biindolylidene-5′-sodium sulfonate; (18) 3-hydroxyimino-2′-oxo-3,1′,2′-tetrahydro-[2,3]biindolylidene-5′-sodium sulfonate; (19) 5-bromo-1H,1′H-[2,3′]-biindolylidene-3,2′-dione; (20) 5-bromo-5′-nitro-1H,1′H-[2,3′]-biindolylidene-3,2′-dione-3-oxime; (21) 5′-methyl-1H,1′H-[2,3′]-biindolylidene-3,2′-dione; (22) 5′-chloro-1H,1′H-[2,3′]-biindolylidene-3,2′-dione; (23) 5′-iodo-1H,1′H-[2,3′]-biindolylidene-3,2′-dione; (24) 5′,7′-dimethyl-1H,1′H-[2,3′]-biindolylidene-3,2′-dione; (25) 5′-chloro,7′-methyl-1H,1′H-[2,3′]-biindolylidene-3,2′-dione; (26) 5′-amino-1H,1′H-[2,3′]-biindolylidene-3,2′-dione; (27) 5-NH-trimethylacetyl-indirubin-3-oxime; (28) 5′-amino-1H,1′H-[2,3′]-biindolylidene-3,2′-dione-3-oxime; (29) 6-hydroxy-5-methylindirubin; (30) 6,7′-dihydroxy-5-methylindirubin; (31) 3,4,5-trihydroxy-6-(5-methyl-1H,1′H-[2′,3]bis-indolyliden-2,3′-dion-6-yl)-tetrahydropyran-2-carboxylic acid; (32) 3,4,5-trihydroxy-6-(7′-hydroxy-5-methyl-1H1′H-[2′,3]bisindolyliden-2,3′-dion-6-yl)-tetrahydropyran-2-carboxylic acid; (33) 5-methylindirubin; (34) indirubin-5-sulfonamide; (35) indirubin-5-sulfonic acid (2-hydroxyethyl)-amide; (36) 5-iodoindirubin-3′-monooxime; (37) 5-fluoroindirubin; (38) 5,5′-dibromoindirubin; (39) 5-nitroindirubin; (40) 5-bromoindirubin; (41) (2′Z,3′E)-6-bromoindirubin-3′-oxime (BIO); (42) 5-iodoindirubin; (43) indirubin-5-sulfonic acid-3′-monooxime; (44) 3,4-bis(1-methylindole-3-yl)-1H-pyrrole-2,5-dione; (45) 3-(1-methylindole-3-yl)-4-(1-propylindole-3-yl)-1H-pyrrole-2,5-dione; (46) 3-[1-(3-cyanopropyl)indole-3-yl]-4-(1-methyl-indole-3-yl)-1H-pyrrole-2,5-dione; (47) 3-[1-(3-aminopropyl)-indole-3-yl]-4-(1-methylindole-3-yl)-1H-pyrrole-2,5-dione; (48) 3-[1-(3-carboxypropyl)indole-3-yl]-4-(1-methyl-indole-3-yl)-1H-pyrrole-2,5-dione; (49) 3-[1-(3-carbamoyl-propyl)indole-3-yl]-4-(1-methylindole-3-yl)-1H-pyrrole-2,5-dione; (50) 3-[1-(3-aminopropyl)indole-3-yl]-4-(1-methyl-5-propyloxyindole-3-yl)-1H-pyrrole-2,5-dione; (51) 3-[1-(3-hydroxypropyl)indole-3-yl]-4-(1-methyl-5-phenylindole-3-yl)-1H-pyrrole-2,5-dione; (52) 3-[1-(3-aminopropyl)indole-3-yl]-4-(1-methyl-5-phenylindole-3-yl)-1H-pyrrole-2,5-dione; (53) 3-[1-(3-hydroxypropyl)indole-3-yl]-4-(1-methyl-5-methoxycarbonylindole-3-yl)-1H-pyrrole-2,5-dione; (54) 3-[1-(3-hydroxypropyl)indole-3-yl]-4-(1-methyl-5-nitroindole-3-yl)-1H-pyrrole-2,5-dione; (55) 3-(1-methylindole-3-yl)-4-[1-(3-hydroxypropyl)-5-nitroindole-3-yl]-1H-pyrrole-2,5-dione; (56) 3-(2-chlorophenyl)-4-(1-methylindole-3-yl)-1H-pyrrole-2,5-dione; (57) 3-(2,4-dichlorophenyl)-4-(1-methylindole-3-yl)-1H-pyrrole-2,5-dione; (58) 3-(2-chlorophenyl)-4-[1-(3-hydroxypropyl)indole-3-yl]-1H-pyrrole-2,5-dione; (59) 4-[1-(3-aminopropyl)indole-3-yl]-3-(2-chlorophenyl)-1H-pyrrole-2,5-dione; (60) 7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (61) 2-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (62) 9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (63) 9-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (64) 11-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (65) 10-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (66) 8-bromo-6,11-dihydro-thieno[3′,2′:2,3]azepino-[4,5-b]indol-5(4H)-one; (67) 9-bromo-7,12-dihydro-4-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (68) 9-bromo-7,12-dihydro-4-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (69) 7,12-dihydro-4-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (70) 9-bromo-7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (71) 9-bromo-7,12-dihydro-2,3-di-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (72) 7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (73) 7,12-dihydro-9-trifluormethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (74) 7,12-dihydro-2,3-dimethoxy-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6-(5H)-one; (75) 2-bromo-7,12-dihydro-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (76) 9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-thione; (77) 9-bromo-5,12-bis-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (78) 9-bromo-12-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6-(5H)-one; (79) 9-bromo-5,7-bis-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (80) 9-bromo-5,7,12-tri-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (81) 9-bromo-7,12-dihydro-5-methyloxycarbonylmethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (82) 9-bromo-7,12-dihydro-12-methyloxycarbonylmethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (83) 9-bromo-7,12-dihydro-12-(2-hydroxyethyl)-indolo[3,2-d][1]benzazepin-6-(5H)-one; (84) 2,9-dibromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (85) 8,10-dichloro-7,12-dihydro-indolo-[3,2-d][1]benzazepin-6(5H)-one; (86) 9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (87) 9-bromo-7,12-dihydro-5-methyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (88) 5-benzyl-9-bromo-7,12-dihydro-5-methyl-indolo[3,2-d][1]-benzazepin-6(5H)-one; (89) 9-bromo-7,12-dihydro-12-methyl-indolo-[3,2-d][1]benzazepin-6(5H)-one; (90) 9-bromo-12-ethyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (91) 9-bromo-7,12-dihydro-12-(2-propenyl)-indolo[3,2-d][1]benzazepin-6(5H)-one; (92) 7,12-dihydro-9-methyl-indolo[3,2-d][1]-benzazepin-6(5H)-one; (93) 7,12-dihydro-9-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (94) 9-fluoro-7,12-dihydro-12-(2-propenyl)-indolo[3,2-d][1]benzazepin-6(5H)-one; (95) 11-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (96) 9-bromo-7,12-dihydro-2-(methyliminoamine)-indolo[3,2-d][1]benzazepin-6(5H)-one; (97) 9-bromo-7,12-dihydro-2-(carboxylic acid)-indolo[3,2-d][1]benzazepin-6(5H)-one; (98) 9-bromo-7,12-dihydro-10-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (99) 9-bromo-7,12-dihydro-11-hydroxymethyl-indolo[3,2-d][1]-benzazepin-6(5H)-one; (100) 7,12-dihydro-4-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (101) 7,12-dihydro-2,3-dihydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (102) 2,3-dimethoxy-9-nitro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (103) 9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (104) 2,3-dimethoxy-9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (105) 9-nitro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (106) 3-(6-oxo-9-trifluoromethyl-5,6,7,12-tetrahydro-indolo[3,2-d][1]benzazepin-2-yl)-propionitrile; (107) 2-bromo-9-nitro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (108) 3-(6-oxo-9-trifluoromethyl-5,6,7,12-tetrahydro-indolo[3,2-d][1]benzazepin-2-yl)acrylonitrile; (109) 2-(3-hydroxy-1-propinyl)-9-trifluoromethyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (110) 2-iodo-9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (111) 2-(3-oxo-1-butenyl)-9-trifluoromethyl-7,12-tetrahydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (112) 8-chloro-6,11-dihydro-thieno[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-one; (113) 2-iodo-9-trifluoromethyl-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (114) 7,12-dihydro-pyrido[3′,2′:4,5]-pyrrolo[3,2-d][1]benzazepin-6(5H)-one; (115) 11-methyl-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (116) 2-[2-(1-hydroxycyclohexyl)-ethinyl]-9-trifluoromethyl-7,12-dihydro-indolo-[3,2-d][1]benzazepin-6(5H)-one; (117) 2-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (118) 2-iodo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (119) 11-ethyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (120) 8-methyl-6,11-dihydro-thieno[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-one; (121) 3-(6-oxo-9-trifluoromethyl-5,6,7,12-tetrahydro-indolo[3,2-d][1]benzazepin-2-yl)acrylic acid methyl ester; (122) 9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (123) 9-bromo-7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (124) 2-bromo-7,12-dihydro-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (125) 7,12-dihydro-2,3-dimethoxy-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (126) 2,9-dibromo-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (127) 7,12-dihydro-9-trifluoromethyl-indolo-[3,2-d][1]benzazepin-6(5H)-one; (128) 9-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (129) 8-bromo-6,11-dihydro-thieno[3′,2′:2,3]azepino[4,5-b]indole-5(4H)-one; (130) 7,12-dihydro-9-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (131) 10-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (132) 11-bromo-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (133) 11-chloro-7,12-dihydro-indolo[3,2-d]-[1]benzazepin-6(5H)-one; (134) 9-fluoro-7,12-dihydro-indolo-[3,2-d][1]benzazepin-6(5H)-one; (135) 9-methyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (136) 9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-thione; (137) 8,10-dichloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (138) 9-bromo-7,12-dihydro-12-(2-hydroxyethyl)-indolo[3,2-d][1]-benzazepin-6(5H)-one; (139) 9-bromo-7,12-dihydro-2,3-dihydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (140) 2-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (141) 7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (142) 9-bromo-7,12-dihydro-12-methyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (143) 9-bromo-7,12-dihydro-5-methyloxycarbonylmethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (144) 7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (145) 9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (146) 9-bromo-7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (147) 2-bromo-7,12-dihydro-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (148) 7,12-dihydro-2,3-dimethoxy-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (149) 2,9-dibromo-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (150) 7,12-dihydro-9-trifluoromethyl-indolo-[3,2-d][1]benzazepin-6(5H)-one; (151) 9-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (152) 8-bromo-6,11-dihydro-thieno[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-one; (153) 7,12-dihydro-9-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (154) 9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (155) 9-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (156) 11-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (157) 10-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (158) 8-bromo-6,11-dihydro-thieno[3′,2′:2,3]azepino-[4,5-b]indol-5(4H)-one; (159) 9-bromo-7,12-dihydro-4-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (160) 9-bromo-7,12-dihydro-4-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (161) 7,12-dihydro-4-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (162) 9-bromo-7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (163) 9-bromo-7,12-dihydro-2,3-di-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (164) 7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (165) 7,12-dihydro-9-trifluormethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (166) 7,12-dihydro-2,3-dimethoxy-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6-(5H)-one; (167) 2-bromo-7,12-dihydro-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (168) 9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-thione; (169) 9-bromo-5,12-bis-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (170) 9-bromo-12-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6-(5H)-one: (171) 9-bromo-5,7-bis-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (172) 9-bromo-5,7,12-tri-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (173) 9-bromo-7,12-dihydro-5-methyloxycarbonylmethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (174) 9-bromo-7,12-dihydro-12-methyloxycarbonylmethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (175) 9-bromo-7,12-dihydro-12-(2-hydroxyethyl)-indolo[3,2-d][1]benzazepin-6-(5H)-one: (176) 2,9-dibromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (177) 8,10-dichloro-7,12-dihydro-indolo-[3,2-d][1]benzazepin-6(5H)-one: (178) 9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one: (179) 9-bromo-7,12-dihydro-5-methyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (180) 5-benzyl-9-bromo-7,12-dihydro-5-methyl-indolo[3,2-d][1]-benzazepin-6(5H)-one; (181) 9-bromo-7,12-dihydro-12-methyl-indolo-[3,2-d][1]benzazepin-6(5H)-one; (182) 9-bromo-12-ethyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (183) 9-bromo-7,12-dihydro-12-(2-propenyl)-indolo[3,2-d][1]benzazepin-6(5H)-one; (184) 7,12-dihydro-9-methyl-indolo[3,2-d][1]-benzazepin-6(5H)-one; (185) 7,12-dihydro-9-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (186) 9-fluoro-7,12-dihydro-12-(2-propenyl)-indolo[3,2-d][1]benzazepin-6(5H)-one; (187) 11-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (188) 9-bromo-7,12-dihydro-2-(methyliminoamine)-indolo[3,2-d][1]benzazepin-6(5H)-one; (189) 9-bromo-7,12-dihydro-2-(carboxylic acid)-indolo[3,2-d][1]benzazepin-6(5H)-one; (190) 9-bromo-7,12-dihydro-10-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one: (191) 9-bromo-7,12-dihydro-11-hydroxymethyl-indolo[3,2-d][1]-benzazepin-6(5H)-one: (192) 7,12-dihydro-4-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (193) 7,12-dihydro-2,3-dihydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (194) 2,3-dimethoxy-9-nitro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (195) 9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (196) 2,3-dimethoxy-9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (197) 9-nitro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (198) 3-(6-oxo-9-trifluoromethyl-5,6,7,12-tetrahydro-indolo[3,2-d][1]benzazepin-2-yl)-propionitrile; (199) 2-bromo-9-nitro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (200) 3-(6-oxo-9-trifluoromethyl-5,6,7,12-tetrahydro-indolo[3,2-d][1]benzazepin-2-yl)acrylonitrile; (201) 2-(3-hydroxy-1-propinyl)-9-trifluoromethyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (202) 2-iodo-9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (203) 2-(3-oxo-1-butenyl)-9-trifluoromethyl-7,12-tetrahydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (204) 8-chloro-6,11-dihydro-thieno[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-one; (205) 2-iodo-9-trifluoromethyl-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (206) 7,12-dihydro-pyrido[3′,2′:4,5]-pyrrolo[3,2-d][1]benzazepin-6(5H)-one; (207) 11-methyl-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (208) 2-[2-(1-hydroxycyclohexyl)-ethinyl]-9-trifluoromethyl-7,12-dihydro-indolo-[3,2-d][1]benzazepin-6(5H)-one; (209) 2-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (210) 2-iodo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (211) 11-ethyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (212) 8-methyl-6,11-dihydro-thieno[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-one; (213) 3-(6-oxo-9-trifluoromethyl-5,6,7,12-tetrahydro-indolo[3,2-d][1]benzazepin-2-yl)acrylic acid methyl ester; (214) 9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (215) 9-bromo-7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (216) 2-bromo-7,12-dihydro-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (217) 7,12-dihydro-2,3-dimethoxy-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (218) 2,9-dibromo-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (219) 7,12-dihydro-9-trifluoromethyl-indolo-[3,2-d][1]benzazepin-6(5H)-one; (220) 9-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (221) 8-bromo-6,11-dihydro-thieno[3′,2′:2,3]azepino[4,5-b]indole-5(4H)-one: (222) 7,12-dihydro-9-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (223) 10-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (224) 11-bromo-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (225) 11-chloro-7,12-dihydro-indolo[3,2-d]-[1]benzazepin-6(5H)-one: (226) 9-fluoro-7,12-dihydro-indolo-[3,2-d][1]benzazepin-6(5H)-one; (227) 9-methyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (228) 9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-thione; (229) 8,10-dichloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one: (230) 9-bromo-7,12-dihydro-12-(2-hydroxyethyl)-indolo[3,2-d][1]-benzazepin-6(5H)-one; (231) 9-bromo-7,12-dihydro-2,3-dihydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (232) 2-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (233) 7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (234) 9-bromo-7,12-dihydro-12-methyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (235) 9-bromo-7,12-dihydro-5-methyloxycarbonylmethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (236) 7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (237) 9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (238) 9-bromo-7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (239) 2-bromo-7,12-dihydro-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (240) 7,12-dihydro-2,3-dimethoxy-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (241) 2,9-dibromo-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (242) 7,12-dihydro-9-trifluormethyl-indolo-[3,2-d][1]benzazepin-6(5H)-one; (243) 9-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one: (244) 8-bromo-6,11-dihydro-thieno[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-one; (245) 7,12-dihydro-9-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (246) 9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one (247) 6-bromoindirubin; (248) 6,6′-dibromoindirubin-3-oxime; (249) 6-bromoindirubin-3′-methoxime; (250) 6-bromo-5-methyl-indirubin; (251) 6-bromo-5-aminoindirubin; (252) 6-bromo-5-methyl-indirubin-3′-oxime; (253) 6-bromo-indirubin-3′-acetoxime; (254) 5-amino-indirubin; (255) 5-amino-indirubin-3′-oxime; (256) 1-methylindirubin; (257) N-1-methylisoindigo; (258) indirubin-5-sulfone-(2-hydroxyethyl)amide; (259) 5-ethylindirubin; (260) 5-isopropylindirubin; (261) 5-n-propylindirubin; (262) 5-carboxymethylindirubin; (263) 5-[2-(piperazin-1-yl)-ethan-2-on-1-yl]indirubin; (264) 5-[2-(morpholin-1-yl)-ethan-2-on-1-yl]indirubin; (265) N-(2-aminoethyl)-2-[3-(3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]acetamide; (266) N-methyl-2-[3-(3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]acetamide; (267) N,N-dimethyl-2-[3-(3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]acetamide; (268) 2-{2-[3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-acetylamino}-acetic acid; (269) methyl-2-{2-[3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-acetylamino}-acetate; (270) [3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-methylphosphonic acid; (271) diethyl-[3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-methylphosphonate; (272) 5-acetylaminoindirubin; (274) [3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-succinamic acid; (275) 2-amino-N-[3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-acetamide; (276) 2-amino-N-[3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-propionamide; (277) 5-(2-aminoethyl)-aminoindirubin; (278) 5-(2-hydroxyethyl)-aminoindirubin; (279) indirubin-5-sulfonic acid-(piperazin-1-yl-amide); (280) indirubin-5-sulfonic acid-(morpholin-1-yl-amide); (281) methyl-2-{[3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-sulfonamidyl}-acetate; (282) 5-methylindirubin-3′-monooxime; (283) 5-ethylindirubin-3′-monooxime; (284) 5-isopropylindirubin-3′-monooxime; (285) 5-aminoindirubin-3′-monooxime; (286) 5-acetylaminoindirubin-3′-monooxime; (287) 2-amino-N-[3-(3′-hydroxyimino)(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-acetamide; (288) 3-[3′-(iminooxy-O-(2-hydroxyethyl)-(2′H,3′H)indol-2′-ylidene]-(2H,3H)indol-2-one; (289) 3-[3′-(iminooxy-O-(3-hydroxypropyl)-(2′H,3′H)indol-2′-ylidene]-(2H,3H)indol-2-one; (290) 3-[3′-(iminooxy-O-(2-(2-hydroxyethoxy)ethyl)-(2′H,3′H)indol-2′-ylidene]-(2H,3H)indol-2-one; (291) 3-[3′-(iminooxy-O-(2-(2-hydroxy-2-methyl)propyl)-(2′H,3′H)indol-2′-ylidene]-(2H,3H)indol-2-one; (292) 2-{O-[2′-(2-oxo-(2H,3H)indol-3-ylidene)-2′H,3′H-indol-3′-ylidene]aminoxy}acetic acid sodium salt; (293) 3-{O-[2′-(2-oxo-(2H,3H)indol-3-ylidene)-2′H,3′H-indol-3′-ylidene]aminoxy}propionic acid sodium salt; (294) 4-{O-[2′-(2-oxo-(2H,3H)indol-3-ylidene)-2′H,3′H-indol-3′-ylidene]aminoxy}butyric acid sodium salt; (295) 5-{O-[2′-(2-oxo-(2H,3H)indol-3-ylidene)-2′H,3′H-indol-3′-ylidene]aminoxy}pentanoic acid sodium salt; (296) 3-[3′-iminooxy-O-carbethoxy)-(2′H,3′H)-indol-2′-ylidene]-(2H,3H)indol-2-one; (297) ethyl-2-{O-2′-(2-oxo-(2H,3H)indol-3-ylidene-(2′H,3′H)-indol-3′-ylidene]-aminooxy}-acetate; (298) 3-[3′-iminooxy-O—(N,N)-dimethylcarbamoyl)]-(2′H,3′H)-indol-2′-ylidene](2H,3H)indol-2-one); (299) 3′-oximido-7-azaindirubin; (300) 7-azaindirubin-3′-oxime ether; (301) 1-methyl-5-azaindirubin; (302) 1-benzyl-5′-chloro-5-azaindirubin; (303) 1-butyl-5-azaindirubin-3′-oxime; (304) 1-butyl-5-azaindirubin-3′-oxime O-methyl ether; (305) 1-isopropyl-5-azaisoindigo; (306) 1-methyl-7-azaindirubin; (307) 1-benzyl-5′-bromo-7-azaindirubin; (308) 1-butyl-7-azaindirubin-3′-oxime; (309) 1-butyl-7-azaindirubin-3′-oxime O-methyl ether; (310) 1-isopropyl-7-azaisoindigo; (311) 2-methyl-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid; (312) 2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid; (313) 2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid; (314) 2-methyl-7-[1,2-dihydro-5-methyl-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid; (315) ethyl 2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxylate; (316) N-(2-(diethylamino)ethyl)-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (317) N-(2-(diethylamino)ethyl)-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (318) N-(2-(diethylamino)ethyl)-2-methyl-7-[1,2-dihydro-5-methyl-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (319) N-(2-(diethylamino)ethyl)-2-methyl-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (320) N-(2-(dimethylamino)ethyl)-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indo-1-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (321) N-(3-(dimethylamino)propyl)-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3H-ind-ol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (322) N-(2-hydroxyethyl)-2-methyl-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (323) N-(2-hydroxyethyl)-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (324); (325) 2-methyl-3-(morpholine-4-carbonyl)-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole; (326) 2-methyl-3-(morpholine-4-carbonyl)-7-[1,2-dihydro-5-chloro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole; (327) 2-methyl-3-(morpholine-4-carbonyl)-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole; (328) 2-methyl-3-(4-methylpiperazine-1-carbonyl)-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole; (329) 2-methyl-3-(4-methylpiperazine-1-carbonyl)-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole; (330) N,N,2-trimethyl-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (331) N-(2-morpholinoethyl)-2-methyl-7-[1,2-dihydro-5-methyl-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (332) N-(2-morpholinoethyl)-2-methyl-7-[1,2-dihydro-5-methyl-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (333) N-(2-morpholinoethyl)-2-methyl-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (334) N-(2-morpholinoethyl)-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (345) N-(2-morpholinoethyl)-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (346) N-(3-morpholinopropyl)-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (347) N-(3-morpholinopropyl)-2-methyl-7-[1,2-dihydro-5-bromo-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (348) N-(2-morpholinoethyl)-2-methyl-7-[1,2-dihydro-7-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (349) N-(2-(pyrrolidin-1-yl)ethyl)-2-methyl-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (350) N-(2-(piperidin-1-yl)ethyl)-2-methyl-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (351) N-(2-(piperidin-1-yl)ethyl)-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (352) N-(2-(pyrrolidin-1-yl)ethyl)-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (353) N-(3-(pyrrolidin-1-yl)propyl)-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (354) N-(3-(4-methylpiperazin-1-yl)propyl)-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (355) N-(3-(pyrrolidin-1-yl)propyl)-2-methyl-7-[1,2-dihydro-5-bromo-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (356) N-(2-(piperidin-1-yl)ethyl)-2-methyl-7-[1,2-dihydro-6-chloro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (357) N-(3-(pyrrolidin-1-yl)propyl)-2-methyl-7-[1,2-dihydro-4-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (358) N-(3-(pyrrolidin-1-yl)propyl)-2-methyl-7-[1,2-dihydro-7-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (359) N-(2-(diethylamino)ethyl)-2-methyl-7-[1,2-dihydro-5,7-dimethyl-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (360) N-(2-(diethylamino)ethyl)-2-methyl-7-[N-isopropyl-1,2-dihydro-2-oxo-3H-indol-5-sulfonamide-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (361) N-(2-(diethylamino)ethyl)-2-methyl-7-[1,2-dihydro-5-bromo-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (362) N-(2-(diethylamino)ethyl)-2-methyl-7-[1,2-dihydro-5-nitro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (363) N-(3-(dimethylamino)propyl)-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (364) N-(2-(diethylamino)ethyl)-2-methyl-7-[1,2-dihydro-5-methoxy carbonyl-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (365) N-(2-(diethylamino)ethyl)-2-methyl-7-[1,2-dihydro-7-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (366) N-(2-(diethylamino)ethyl)-2-methyl-7-[N-(4-fluorophenyl)-1,2-dihydro-2-oxo-3H-indol-5-sulfonamide-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide); (367) N-(2-(diethylamino)ethyl)-2-methyl-7-[5-(piperidin-1-ylsulfonyl)-1,2-dihydro-2-oxo-3H-indol-5-sulfonamide-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (368) N-(3-(diethylamino)propyl)-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indo-1-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (369) N-(2-(diethylamino)ethyl)-2-methyl-7-[1,2-dihydro-5-carboxyl-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (370) N-(2-(diethylamino)ethyl)-2-methyl-7-[1,2-dihydro-5-carboxyl-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (371) N-(2-(diethylamino)ethyl)-2-methyl-7-[1,2-dihydro-6-chloro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; 372) N-(3-(diethylamino)propyl)-2-methyl-7-[1,2-dihydro-6-chloro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (373) N-(3-(diethylamino)propyl)-2-methyl-7-[1,2-dihydro-5-bromo-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (374) N-(2-(diethylamino)ethyl)-2-methyl-7-[1,2-dihydro-4-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (375) N-(2-(diethylamino)ethyl)-2-methyl-7-[5-(pyrrolidine-1-carbonyl)-1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (376) N-(2-(diethylamino)ethyl)-2-methyl-7-[N-(4-fluorophenyl)-5-carboxamide-1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (377) N-(3-(diethylamino)propyl)-2-methyl-7-[1,2-dihydro-7-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (378) N-(2-(diethylamino)ethyl)-2-methyl-7-[1,2-dihydro-5-methoxy-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (379) N-(2-(diethylamino)ethyl)-2-methyl-7-[1,2-dihydro-5-trifluoromethoxy-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (380) N-(2-(diethylamino)ethyl)-2-methyl-7-[N-methyl-1,2-dihydro-2-oxo-3H-indol-5-sulfonamide-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (381) N-(2-(pyridin-2-yl)ethyl)-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (382) N-(2-(dimethylamino)ethyl)-N,2-dimethyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (383) N-(2-(dimethylamino)ethyl)-N,2-dimethyl-7-[1,2-dihydro-6-chloro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (384) N-benzyl-N,2-dimethyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (385) 2-methyl-3-[(S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-carbonyl)]-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole; (386) 2-methyl-3-[4-(2-hydroxyethyl)-piperazin-1-carbonyl]-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole; (387) 2-methyl-3-(1,4′-bipiperidin-1′-carbonyl)-7-[1,2-dihydro-5-fluoro-2-oxo-3-H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole; (388) N-(3-(diethylamino)-2-hydroxypropyl)-2-methyl-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (389) N-(3-(diethylamino)-2-hydroxypropyl)-2-methyl-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (390) N-(3-(diethylamino)-2-hydroxypropyl)-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (391) N-(3-(dimethylamino)-2-hydroxypropyl)-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (392) N-(2-hydroxy-3-morpholinopropyl)-2-methyl-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (393) N-(2-hydroxy-3-morpholinopropyl)-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3-H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (394) N-(2-hydroxy-3-morpholinopropyl)-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3-H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (395) N-(2-hydroxy-3-(pyrrolidin-1-yl)propyl)-2-methyl-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (396) N-(2-hydroxy-3-(pyrrolidin-1-yl)propyl)-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (397) N-(2-hydroxy-3-(pyrrolidin-1-yl)propyl)-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (398) N-(2-hydroxy-3-(piperidin-1-yl)propyl)-2-methyl-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (399) N-(2-hydroxy-3-(piperidin-1-yl)propyl)-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (400) N-(2-hydroxy-3-(piperidin-1-yl)propyl)-2-methyl-7-[1,2-dihydro-5-chloro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (401) N-[2-hydroxy-3-(4-methylpiperazin-1-yl)propyl]-2-methyl-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (402) N-[2-hydroxy-3-(4-methylpiperazin-1-yl)propyl]-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (403) N-[2-hydroxy-3-(4-methylpiperazin-1-yl)propyl]-2-methyl-7-[1,2-dihydro-5 chloro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (404) N-[3-(cyclohexyl(methyl)amino)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-5-methyl-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (405) N-(3-(diethylamino)-2-hydroxypropyl)-2-methyl-7-[1,2-dihydro-5-bromo-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (406) N-(2-hydroxy-3-morpholinopropyl)-2-methyl-7-[1,2-dihydro-6-chloro-2-oxo-3-H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (407) N-[3-(cyclohexyl(methyl)amino)-2-hydroxypropyl]-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (408) 5-bromoindirubin-3′-oxime; (409) 7-bromoindirubin-3′-oxime; (410) 7-chloroindirubin-3′-oxime; (411) 7-iodoindirubin-3′-oxime; (412) 7-fluoroindirubin-3′-oxime; (413) 1-methyl-7-bromoindirubin-3′-oxime; (414) (2′Z)-7-fluoroindirubin; (415) (2′Z)-7-chloroindirubin; (416) (2′Z)-7-bromoindirubin; (417) (2′Z)-7-iodoindirubin; (418) (2′Z)-7-fluoro-1-methylindirubin; (419) (2′Z)-7-chloro-1-methylindirubin; (420) (2′Z)-7-bromo-1-methylindirubin; (421) (2′Z)-7-iodo-1-methylindirubin; (422 (2′Z,3′E)-7-fluoroindirubin-3′-oxime; (423) (2′Z,3′E)-7-chloroindirubin-3′-oxime; (424) (2′Z,3′E)-7-bromoindirubin-3′-oxime; (425) (2′Z,3′E)-7-iodoindirubin-3′-oxime; (426) (2′Z,3′E)-7-fluoro-1-methylindirubin-3′-oxime; (427) (2′Z,3′E)-7-chloro-1-methylindirubin-3′-oxime; (428) (2′Z,3′E)-7-bromo-1-methylindirubin-3′-oxime; (429) (2′Z,3′E)-7-iodo-1-methylindirubin-3′-oxime; (430) (2′Z,3′E)-7-fluoroindirubin-3′-acetoxime; (431) (2′Z,3′E)-7-chloroindirubin-3′-acetoxime; (432) (2′Z,3′E)-7-bromoindirubin-3′-acetoxime; (433) (2′Z,3′E)-7-iodoindirubin-3′-acetoxime; (434) (2′Z,3′E)-7-fluoro-1-methylindirubin-3′-acetoxime; (435) (2′Z,3′E)-7-chloro-1-methylindirubin-3′-acetoxime; (436) (2′Z,3′E)-7-bromo-1-methylindirubin-3′-acetoxime; (437) (2′Z,3′E)-7-iodo-1-methylindirubin-3′-acetoxime; (438) (2′Z,3′E)-7-fluoroindirubin-3′-methoxime; (439) (2′Z,3′E)-7-chloroindirubin-3′-methoxime; (440) (2′Z,3′E)-7-bromoindirubin-3′-methoxime: (441) (2′Z,3′E)-7-iodoindirubin-3′-methoxime; (442) (2′Z,3′E)-7-fluoro-1-methylindirubin-3′-methoxime; (443) (2′Z,3′E)-7-chloro-1-methylindirubin-3′-methoxime; (444) (2′Z,3′E)-7-bromo-1-methylindirubin-3′-methoxime, (2′Z,3′E)-7-iodo-1-methylindirubin-3′-methoxime; (445) (2′Z,3′E)-7-bromoindirubin-3′-[O-(2-bromoethyl)-oxime]; (446) (2′Z,3′E)-1-methyl-7-bromoindirubin-3′-[O-(2-bromoethyl)-oxime]; (447) (2′Z,3′E)-7-bromoindirubin-3′-[O—(N,N-diethylcarbamyl)-oxime]; (448) 2′Z,3′E)-1-methyl-7-bromoindirubin-3′-[O—(N,N-diethylcarbamyl)-oxime]; (449) (2′Z,3′E)-7-bromoindirubin-3′-[O-(2-pyrrolidin-1-yl-ethyl)-oxime]; (450) (2′Z,3′E)-1-methyl-7-bromoindirubin-3′-[O-(2-pyrrolidin-1-yl-ethyl)-oxime], (451) (2′Z,3′E)-7-bromoindirubin-3′-[O-(2-morpholin-1-yl-ethyl)-oxime], (452) (2′Z,3′E)-1-methyl-7-bromoindirubin-3′-[O-(2-morpholin-1-yl-ethyl)-oxime]; (453) (2′Z,3′E)-7-bromoindirubin-3′-[O-(2-imidazol-1-yl-ethyl)-oxime]; (454) (2′Z,3′E)-1-methyl-7-bromoindirubin-3′-[O-(2-imidazol-1-yl-ethyl)-oxime]; (455) (2′Z,3′E)-7-bromoindirubin-3′-[O-(2-piperazin-1-yl-ethyl)-oxime]; (456) (2′Z,3′E)-7-bromoindirubin-3′-[O-(2-dimethylaminoethyl)-oxime]; (457) (2′Z,3′E)-1-methyl-7-bromoindirubin-3′-[O-(2-dimethylaminoethyl)-oxime]; (458) (2′Z,3′E)-7-bromoindirubin-3′[O-(2-diethylaminoethyl)-oxime] (459) (2′Z,3′E)-1-methyl-7-bromoindirubin-3′-[O-(2-diethylaminoethyl)-oxime]; (460) N-(2-hydroxy-3-morpholinopropyl)-2-methyl-7-[1,2-dihydro-5-bromo-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (461) 6-bromoindirubin-3′-oxime; (462) (2′Z,3′E)-6-bromoindirubin-3′-[O-(2-bromoethyl)-oxime]; (463) (2′Z,3′E)-6-bromoindirubin-3′-[O-(2-hydroxyethyl)-oxime]; (464) (2′Z,3′E)-6-bromoindirubin-3′-[O-(2,3-dihydroxypropyl)-oxime]; (465) (2′Z,3′E)-6-bromoindirubin-3-[O—(N,N-diethylcarbamyl)-oxime]; (466) (2′Z,3′E)-6-bromoindirubin-3′-[O-(2-dimethylaminoethyl)-oxime]; (467) (2′Z,3′E)-6-bromoindirubin-340-(2-diethylaminoethyl)-oxime]; (468) (2′Z,3′E)-6-bromoindirubin-3′-[O-(2-pyrrolidin-1-ylethyl)-oxime]; (469) (2′Z,3′E)-6-bromoindirubin-3′-[O-(2-morpholin-1-ylethyl)-oxime]; (470) (2′Z,3′E)-6-bromoindirubin-3′-[O-(2-N,N-(2-hydroxyethyl)aminoethyl)-oxime]; (471) (2′Z,3′E)-6-bromoindirubin-3′-(O-{2-N,N-dimethyl, N-(2,3-dihydroxypropyl)amino]ethyl}oxime; (472) (2′Z,3′E)-6-bromoindirubin-3′-[O-(2-piperazin-1-ylethyl)-oxime]; (473) (2′Z,3′E)-6-bromoindirubin-3′-{O-[2-(4-methyl-piperazin-1-yl)ethyl]oxime; (474) (2′Z,3′E)-6-bromoindirubin-3′-O-{2-[4-(2-hydroxyethyl)piperazin-1-yl]ethyl}oxime; (475) (2′Z,3′E)-6-bromoindirubin-3′-O-{2-[4-(2-methoxyethyl)piperazin-1-yl]ethyl}oxime; (476) (2′Z,3′E)-6-bromoindirubin-3′-O—[O-2-{-4-[2-(2-hydroxyethoxy)-ethyl]piperazin-1-yl}ethyl)oxime; (477) isoindigo; (478) 5-nitroindirubin-3′-oxime; (479) 5′-bromo-5-nitroindirubin-3′-oxime; (480) 5′-hydroxy-5-nitroindirubin-3′-oxime; (481) 5′-hydroxy-5-chloroindirubin-3′-oxime; (482) 5′-hydroxy-5-fluoroindirubin-3′-oxime; (483) 5′-chloro-5-nitroindirubin-3′-oxime; (484) 5′-methyl-5-nitroindirubin-3′-oxime; (485) indirubin-5-sulfonic acid (2-hydroxyethyl)-amide; (486) (3-[3-(3,4-dihydroxybutoxyamino)-1H-indol-2-yl]indol-2-one); and the salts, solvates, analogues, congeners, bioisosteres, hydrolysis products, metabolites, precursors, and prodrugs thereof (hereinafter “Alternatives 1-486)”). 
     
     
         26 . The method of  claim 1  wherein the therapeutically active agent is a pharmaceutically acceptable salt of (i) indirubin; (ii) an analog of indirubin; (iii) a derivative of indirubin or of an analog of indirubin; or (iv) a pharmaceutical composition comprising indirubin, an analog of indirubin, or a derivative of indirubin or of an analog of indirubin, wherein the pharmaceutically acceptable salt is selected from the group consisting of:
 (a) a salt with a positively-charged ion selected from the group consisting of sodium, potassium, aluminum, lithium, calcium, magnesium, zinc, ammonium, caffeine, arginine, diethylamine, N-ethylpiperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N-ethylmorpholine, piperazine, piperidine, triethylamine, trimethylamine, ethanolamine, diethanolamine, N-methylglucamine, and tris(hydroxymethyl)aminomethane; and 
 (b) a salt with a negatively-charged ion selected from the group consisting of chloride, bromide, iodide, carbonate, nitrate, sulfate, bisulfate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, formate, acetate, adipate, butyrate, propionate, succinate, glycolate, gluconate, lactate, malate, tartrate, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilate, mesylate, 4′-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, ethanedisulfonate, benzenesulfonate, pantothenate, 2-hydroxyethanesulfonate, p-toluenesulfonate, sulfanilate, cyclohexylaminosulfonate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfonate, glucoheptanoate, glycerophosphonate, heptanoate, hexanoate, 2-hydroxyethanesulfonate, nicotinate, isonicotinate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfurate, 2-phenylpropionate, picrate, pivalate, thiocyanate, mesylate, undecanoate, stearate, algenate, β-hydroxybutyrate, salicylate, galactarate, galacturonate, caprylate, isobutyrate, malonate, suberate, sebacate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, phenylacetate, isethionate, lactobionate, p-aminobenzoate, sulfamate, diethylacetate, pimelate, aminosulfonate, acrylate, γ-hydroxybutyrate, and methoxybenzoate. 
 
     
     
         27 . The method of  claim 1  wherein the therapeutically active agent is an indirubin derivative or analog that is a GSK-3 antagonist, a Wnt agonist, or a CDK2 inhibitor. 
     
     
         28 .- 29 . (canceled) 
     
     
         30 . The method of  claim 2  wherein the improvement is made by dose modification and wherein the dose modification is a modification selected from the group consisting of:
 (i) continuous i.v. infusion for hours to days; 
 (ii) biweekly administration; 
 (iii) doses greater than 5 mg/m 2 /day; 
 (iv) progressive escalation of dosing from 1 mg/m 2 /day based on patient tolerance; 
 (v) use of caffeine to modulate metabolism; 
 (vi) use of isonazid to modulate metabolism; 
 (vii) selected and intermittent boosting of dosage administration; 
 (viii) administration of single and multiple doses escalating from 5 mg/m 2 /day via bolus; 
 (ix) oral dosages of below 30 mg/m 2 ; 
 (x) oral dosages of above 130 mg/m 2 ; 
 (xi) chronic low dose administration of from about 10 mg/day to about 25 mg/day; 
 (xii) intermittent administration of from about 50 mg to about 150 mg twice weekly or three times weekly; 
 (xiii) administration of from about 50 mg/day to about 150 mg/day for 10-14 days per month; and 
 (xiv) chronic daily dosing at a dose of equal to or greater than 100 mg/day. 
 
     
     
         31 .- 32 . (canceled) 
     
     
         33 . The method of  claim 2  wherein the improvement is made by the route of administration and wherein the route of administration is selected from the group consisting of:
 (i) topical administration; 
 (ii) intravesicular administration for bladder cancer; 
 (iii) oral administration; 
 (iv) slow release oral delivery; 
 (v) intrathecal administration; 
 (vi) intraarterial administration; 
 (vii) continuous infusion; and 
 (ix) intermittent infusion. 
 
     
     
         34 .- 35 . (canceled) 
     
     
         36 . The method of  claim 2  wherein the improvement is made by the schedule of administration and wherein the schedule of administration is selected from the group consisting of:
 (i) daily administration; 
 (ii) weekly administration; 
 (iii) weekly administration for three weeks; 
 (iv) biweekly administration; 
 (v) biweekly administration for three weeks with a 1-2 week rest period; 
 (vi) intermittent boost dose administration; and 
 (vii) daily administration for one week for multiple weeks. 
 
     
     
         37 .- 38 . (canceled) 
     
     
         39 . The method of  claim 2  wherein the improvement is made by the indication for use and wherein the indication for use is selected from the group consisting of:
 (i) use for treatment of leukemias; 
 (ii) use for treatment of myelodysplastic syndrome; 
 (iii) use for treatment of T-cell lymphomas; 
 (iv) use for treatment of B-cell lymphomas; 
 (v) use for treatment of mantle cell lymphoma; 
 (vi) use for suppression of proliferation of cancer stem cells; 
 (vii) use for treatment of ovarian carcinoma; 
 (viii) use for treatment of carcinoma of the lung; 
 (ix) use for treatment of angiogenic diseases; 
 (x) use for treatment of benign prostatic hyperplasia; 
 (xi) use for treatment of psoriasis; 
 (xii) use for treatment of gout; 
 (xiii) use for treatment of autoimmune conditions; 
 (xiv) use for treatment of treatment of insulin-resistant diabetes; 
 (xv) use for treatment of transplantation rejection; 
 (xvi) use for prevention of restenosis in cardiovascular disease; 
 (xvii) use for treatment of mycosis fungoides; 
 (xviii) use in bone marrow transplantation; 
 (xix) use as an anti-infective agent; 
 (xx) use for treatment of AIDS; and 
 (xxi) use for treatment of Alzheimer's disease. 
 
     
     
         40 . (canceled) 
     
     
         41 . The method of  claim 39  wherein the indication for use is use for treatment of leukemia, and the leukemia is selected from the group consisting of acute myelocytic leukemia (AML), chronic myelocytic leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and acute promyelocytic leukemia (APL). 
     
     
         42 .- 54 . (canceled) 
     
     
         55 . The method of  claim 2  wherein the improvement is made by selection of disease stage and wherein the selection of disease stage is selected from the group consisting of:
 (i) use for the treatment of localized polyp stage colon cancer; 
 (ii) use for leukoplakia in the oral cavity; 
 (iii) use for angio genesis inhibition to prevent or limit metastatic spread of a malignancy; and 
 (iv) use for treatment of HIV with a therapy selected from the group consisting of azidothymidine (AZT), dideoxyadenosine (DDI), and reverse transcriptase inhibitors. 
 
     
     
         56 .- 57 . (canceled) 
     
     
         58 . The method of  claim 2  wherein the improvement is made by other indications and wherein the other indication is selected from the group consisting of:
 (i) use as an anti-infective agent; 
 (ii) use as an antiviral agent; 
 (iii) use as an antibacterial agent; 
 (iv) use as an agent to treat pleural effusion; 
 (v) use as an antifungal agent; 
 (vi) use as an anti-parasitic agent; 
 (vii) use as an agent to treat eczema; 
 (viii) use as an agent to treat herpes zoster (shingles); 
 (ix) use as an agent to treat condylomata; 
 (x) use as an agent to treat HPV; and 
 (xi) use as an agent to treat HSV. 
 
     
     
         59 .- 60 . (canceled) 
     
     
         61 . The method of  claim 2  wherein the improvement is made by patient selection and wherein the patient selection is carried out by a criterion selected from the group consisting of:
 (i) selecting patients with a disease condition characterized by a high level of a metabolic enzyme selected from the group consisting of histone deacetylase and ornithine decarboxylase; 
 (ii) selecting patients with a low or high susceptibility to a condition selected from the group consisting of thrombocytopenia and neutropenia; 
 (iii) selecting patients intolerant of GI toxicities; and 
 (iv) selecting patients characterized by over- or under-expression of a gene selected from the group consisting of c-Jun, a GPCR, a signal transduction protein, VEGF, a prostate-specific gene, and a protein kinase. 
 
     
     
         62 .- 63 . (canceled) 
     
     
         64 . The method of  claim 2  wherein the improvement is made by analysis of patient or disease phenotype and wherein the analysis of patient or disease phenotype is carried out by a method selected from the group consisting of:
 (i) use of a diagnostic tool, a diagnostic technique, a diagnostic kit, or a diagnostic assay to confirm a patient's particular phenotype; 
 (ii) use of a method for measurement of a marker selected from the group consisting of histone deacetylase, ornithine decarboxylase, VEGF, a protein that is a gene product of a prostate specific gene, a protein that is a gene product of jun, and a protein kinase; 
 (iii) surrogate compound dosing; and 
 (iv) low dose pre-testing for enzymatic status. 
 
     
     
         65 .- 66 . (canceled) 
     
     
         67 . The method of  claim 2  wherein the improvement is made by analysis of patient or disease genotype and wherein the analysis of patient or disease genotype is carried out by a method selected from the group consisting of:
 (i) use of a diagnostic tool, a diagnostic technique, a diagnostic kit, or a diagnostic assay to confirm a patient's particular genotype; 
 (ii) use of a gene chip; 
 (iii) use of gene expression analysis; 
 (iv) use of single nucleotide polymorphism (SNP) analysis; and 
 (v) measurement of the level of a metabolite or a metabolic enzyme. 
 
     
     
         68 .- 70 . (canceled) 
     
     
         71 . The method of  claim 2  wherein the improvement is made by pre/post treatment preparation and wherein the pre/post treatment preparation is selected from the group consisting of:
 (i) the use of colchicine or an analog thereof; 
 (ii) the use of a uricosuric; 
 (iii) the use of uricase; 
 (iv) the non-oral use of nicotinamide; 
 (v) the use of a sustained-release form of nicotinamide; 
 (vi) the use of an inhibitor of poly-ADP ribose polymerase; 
 (vii) the use of caffeine; 
 (viii) the use of leucovorin rescue; 
 (ix) infection control; and 
 (x) the use of an anti-hypertensive agent. 
 
     
     
         72 .- 74 . (canceled) 
     
     
         75 . The method of  claim 2  wherein the improvement is made by toxicity management and wherein the toxicity management is selected from the group consisting of:
 (i) the use of colchicine or an analog thereof; 
 (ii) the use of a uricosuric; 
 (iii) the use of uricase; 
 (iv) the non-oral use of nicotinamide; 
 (v) the use of a sustained-release form of nicotinamide; 
 (vi) the use of an inhibitor of poly-ADP ribose polymerase; 
 (vii) the use of caffeine; 
 (viii) the use of leucovorin rescue; 
 (ix) the use of sustained-release allopurinol; 
 (x) the non-oral use of allopurinol; 
 (xi) the use of bone marrow transplants; 
 (xii) the use of a blood cell stimulant; 
 (xiii) the use of blood or platelet infusions; 
 (xiv) the administration of an agent selected from the group consisting of filgrastim, G-CSF, and GM-CSF; 
 (xv) the application of a pain management technique; 
 (xvi) the administration of an anti-inflammatory agent; 
 (xvii) the administration of fluids; 
 (xviii) the administration of a corticosteroid; 
 (xix) the administration of an insulin control medication; 
 (xx) the administration of an antipyretic; 
 (xxi) the administration of an anti-nausea treatment; 
 (xxii) the administration of an anti-diarrheal treatment; 
 (xxiii) the administration of N-acetylcysteine; and 
 (xxiv) the administration of an antihistamine. 
 
     
     
         76 .- 77 . (canceled) 
     
     
         78 . The method of  claim 2  wherein the improvement is made by pharmacokinetic/pharmacodynamic monitoring and wherein the pharmacokinetic/pharmacodynamic monitoring is performed by a method selected from the group consisting of:
 (i) multiple determinations of blood plasma levels; and 
 (ii) multiple determinations of at least one metabolite in blood or urine. 
 
     
     
         79 .- 80 . (canceled) 
     
     
         81 . The method of  claim 2  wherein the improvement is made by drug combination and wherein the drug combination is selected from the group consisting of:
 (i) use with topoisomerase inhibitors; 
 (ii) use with fraudulent nucleosides; 
 (iii) use with fraudulent nucleotides; 
 (iv) use with thymidylate synthetase inhibitors; 
 (v) use with signal transduction inhibitors; 
 (vi) use with cisplatin or platinum analogs; 
 (vii) use with alkylating agents; 
 (viii) use with anti-tubulin agents; 
 (ix) use with antimetabolites; 
 (x) use with berberine; 
 (xi) use with apigenin; 
 (xii) use with amonafide; 
 (xiii) use with colchicine or an analog thereof; 
 (xiv) use with genistein; 
 (xv) use with etoposide; 
 (xvi) use with cytarabine; 
 (xvii) use with a camptothecin; 
 (xviii) use with a vinca alkaloid; 
 (xix) use with 5-fluorouracil; 
 (xx) use with curcumin; 
 (xxi) use with an NF-κB inhibitor; 
 (xxii) use with rosmarinic acid; 
 (xxiii) use with mitoguazone; 
 (xxiv) use with tetandrine; 
 (xxv) use with an antineoplastic agent not metabolized by cytochrome P450 CYP 1A2 or CYP 2C19; 
 (xxvi) use with a biological therapy; 
 (xxvii) use with a tyrosine kinase inhibitor; 
 (xxviii) use with all-trans-retinoic acid; 
 (xxix) use with an arsenical; 
 (xxx) use with hydroxyurea; 
 (xxxi) use with thioguanine; 
 (xxxii) use with mercaptopurine; 
 (xxxiii) use with homoharringtonine; 
 (xxxiv) use with oridonin; 
 (xxxv) use with uracil mustard; 
 (xxxvi) use with nilotinib; 
 (xxxvii) use with dasatinib; 
 (xxxviii) use with lonidamine; 
 (xxxix) use with 5-azacytidine; 
 (xl) use with thalidomide or an analog thereof; 
 (xli) use with an EGFR inhibitor; 
 (xlii) use with a gold salt; 
 (xliii) use with dibromodulcitol; 
 (xliv) use with dianhydrogalactitol; 
 (xlv) use with decitabine; and 
 (xlvi) use with a proteasome inhibitor. 
 
     
     
         82 - 87 . (canceled) 
     
     
         88 . The method of  claim 2  wherein the improvement is made by chemosensitization or chemopotentiation and wherein the chemosensitization comprises the use of the therapeutically active agent as a chemosensitizer or chemopotentiator in combination with an agent selected from the group consisting of:
 (i) topoisomerase inhibitors; 
 (ii) fraudulent nucleosides; 
 (iii) fraudulent nucleotides; 
 (iv) thymidylate synthetase inhibitors; 
 (v) signal transduction inhibitors; 
 (vi) cisplatin or platinum analogs; 
 (vii) alkylating agents; 
 (viii) anti-tubulin agents; 
 (ix) antimetabolites; 
 (x) berberine; 
 (xi) apigenin; 
 (xii) amonafide; 
 (xiii) vinca alkaloids; 
 (xiv) 5-fluorouracil; 
 (xv) curcumin; 
 (xvi) NF-κB inhibitors; 
 (xvii) rosmarinic acid; 
 (xviii) mitoguazone; 
 (xix) tetrandrine; and 
 (xx) proteasome inhibitors. 
 
     
     
         89 .- 94 . (canceled) 
     
     
         95 . The method of  claim 2  wherein the improvement is made by post-treatment management and wherein the post-treatment management is selected from the group consisting of:
 (i) a therapy associated with pain management; 
 (ii) administration of an anti-emetic; 
 (iii) an anti-nausea therapy; 
 (iv) administration of an anti-inflammatory agent; 
 (v) administration of an anti-pyretic agent; and 
 (vi) administration of an immune stimulant. 
 
     
     
         96 .- 106 . (canceled) 
     
     
         107 . The method of  claim 2  wherein the improvement is made by a bulk drug product improvement and wherein the bulk drug product improvement is selected from the group consisting of:
 (i) salt formation; 
 (ii) preparation as a homogeneous crystal structure; 
 (iii) preparation as a pure isomer; 
 (iv) increased purity; 
 (v) preparation with lower residual solvent content; and 
 (vi) preparation with lower residual heavy metal content. 
 
     
     
         108 .- 109 . (canceled) 
     
     
         110 . The method of  claim 2  wherein the improvement is made by use of a diluent or a solvent system and wherein the diluent or solvent system is selected from the group consisting of:
 (i) an emulsion; 
 (ii) dimethylsulfoxide (DMSO); 
 (iii) N-methylformamide (NMF); 
 (iv) dimethylformamide (DMF); 
 (v) ethanol; 
 (vi) benzyl alcohol; 
 (vii) dextrose-containing water for injection; 
 (viii) Cremophor; 
 (ix) cyclodextrin; and 
 (x) PEG. 
 
     
     
         111 .- 115 . (canceled) 
     
     
         116 . The method of  claim 2  wherein the improvement is made by use of an excipient and wherein the excipient is selected from the group consisting of:
 (i) mannitol; 
 (ii) albumin; 
 (iii) EDTA; 
 (iv) sodium bisulfate; 
 (v) benzyl alcohol; 
 (vi) a carbonate buffer; 
 (vii) a phosphate buffer; and 
 (viii) methylcellulose. 
 
     
     
         117 .- 118 . (canceled) 
     
     
         119 . The method of  claim 2  wherein the improvement is made by use of a dosage form and wherein the dosage form is selected from the group consisting of:
 (i) tablets; 
 (ii) capsules; 
 (iii) topical gels; 
 (iv) topical creams; 
 (v) patches; 
 (vi) suppositories; and 
 (vii) lyophilized dosage fills. 
 
     
     
         120 .- 124 . (canceled) 
     
     
         125 . The method of  claim 2  wherein the improvement is made by use of a drug delivery system and wherein the drug delivery system is selected from the group consisting of:
 (i) nanocrystals; 
 (ii) bioerodible polymers; 
 (iii) liposomes; 
 (iv) slow release injectable gels; 
 (v) microspheres; 
 (vi) vascular disrupting agents; and 
 (vii) polymer-coated stents. 
 
     
     
         126 .- 127 . (canceled) 
     
     
         128 . The method of  claim 2  wherein the improvement is made by use of a drug conjugate form and wherein the drug conjugate form is selected from the group consisting of:
 (i) a polymer system; 
 (ii) polylactides; 
 (iii) polyglycolides; 
 (iv) amino acids; 
 (v) peptides; and 
 (vi) multivalent linkers. 
 
     
     
         129 .- 131 . (canceled) 
     
     
         132 . The method of  claim 2  wherein the improvement is made by use of a compound analog and wherein the compound analog is selected from the group consisting of:
 (i) alteration of side chains to increase or decrease lipophilicity; 
 (ii) addition of an additional chemical functionality to alter a property selected from the group consisting of reactivity, electron affinity, and binding capacity; and 
 (iii) alteration of salt form. 
 
     
     
         133 . (canceled) 
     
     
         134 . The method of  claim 132  wherein the compound analog is an addition of an additional chemical functionality and wherein the addition of an additional chemical functionality is selected from the group consisting of addition of a moiety that acts as an alkylating agent and a moiety that acts as a colchicine binding site. 
     
     
         135 . (canceled) 
     
     
         136 . The method of  claim 2  wherein the improvement is made by use of a prodrug system and wherein the prodrug system is selected from the group consisting of:
 (i) the use of enzyme sensitive esters; 
 (ii) the use of dimers; 
 (iii) the use of Schiff bases; 
 (iv) the use of pyridoxal complexes; 
 (v) the use of caffeine complexes; 
 (vi) the use of N-substituted carbohydrate derivatives; 
 (vii) the use of Mannich N-oxides; 
 (viii) the use of products of reaction with an acylating or carbamylating agent; 
 (ix) the use of hexanoate conjugates; 
 (x) the use of polymer-agent conjugates; and 
 (xi) the use of prodrugs that are activated by bioreduction in hypoxic cells. 
 
     
     
         137 . (canceled) 
     
     
         138 . The method of  claim 2  wherein the improvement is made by use of a multiple drug system and wherein the multiple drug system employs a mechanism selected from:
 (i) use of multi-drug resistance inhibitors; 
 (ii) use of specific drug resistance inhibitors; 
 (iii) use of specific inhibitors of selective enzymes; 
 (iv) use of signal transduction inhibitors; 
 (v) use of repair inhibition; and 
 (vi) use of topoisomerase inhibitors with non-overlapping side effects. 
 
     
     
         139 .- 140 . (canceled) 
     
     
         141 . The method of  claim 2  wherein the improvement is made by use of biotherapeutic enhancement and wherein the biotherapeutic enhancement is performed by use in combination as sensitizers/potentiators with a therapeutic agent or technique selected from the group consisting of:
 (i) cytokines; 
 (ii) lymphokines; 
 (iii) therapeutic antibodies; 
 (iv) antisense therapies; 
 (v) gene therapies; 
 (vi) ribozymes; and 
 (vii) RNA interference. 
 
     
     
         142 .- 144 . (canceled) 
     
     
         145 . The method of  claim 2  wherein the improvement is made by use of biotherapeutic resistance modulation and wherein the biotherapeutic resistance modulation comprises use against tumors resistant to a therapeutic agent or technique selected from the group consisting of:
 (i) biological response modifiers; 
 (ii) cytokines; 
 (iii) lymphokines; 
 (iv) therapeutic antibodies; 
 (v) antisense therapies; 
 (vi) gene therapies; 
 (vii) ribozymes; and 
 (viii) RNA interference. 
 
     
     
         146 .- 148 . (canceled) 
     
     
         149 . The method of  claim 2  wherein the improvement is made by use of radiation therapy enhancement and wherein the radiation therapy enhancement is performed by use of an agent or technique selected from the group consisting of:
 (i) hypoxic cell sensitizers; 
 (ii) radiation sensitizers/protectors; 
 (iii) photosensitizers; 
 (iv) radiation repair inhibitors; 
 (v) thiol depleters; 
 (vi) vaso-targeted agents; 
 (vii) DNA repair inhibitors; 
 (viii) radioactive seeds; 
 (ix) radionuclides; 
 (x) radiolabeled antibodies; and 
 (xi) brachytherapy. 
 
     
     
         150 .- 151 . (canceled) 
     
     
         152 . The method of  claim 2  wherein the improvement is made by use of novel mechanisms of action and wherein the novel mechanism of action is a therapeutic interaction with a target or mechanism selected from the group consisting of:
 (i) inhibitors of poly-ADP ribose polymerase; 
 (ii) agents that affect vasculature or vasodilation; 
 (iii) oncogenic targeted agents; 
 (iv) signal transduction inhibitors; 
 (v) EGFR inhibition; 
 (vi) protein kinase C inhibition; 
 (vii) phospholipase C downregulation; 
 (viii) Jun downregulation; 
 (ix) histone genes; 
 (x) VEGF; 
 (xi) ornithine decarboxylase; 
 (xii) ubiquitin C; 
 (xiii) jun D; 
 (xiv) v-jun; 
 (xv) GPCRs; 
 (xvi) protein kinase A; 
 (xvii) protein kinases other than protein kinase A; 
 (xviii) prostate specific genes; 
 (xix) telomerase; and 
 (xx) histone deacetylase. 
 
     
     
         153 .- 154 . (canceled) 
     
     
         155 . The method of  claim 2  wherein the improvement is made by use of selective target cell population therapeutics and wherein the use of selective target cell population therapeutics is a use selected from the group consisting of:
 (i) use against radiation sensitive cells; 
 (ii) use against radiation resistant cells; 
 (iii) use against energy depleted cells; and 
 (iv) use against endothelial cells. 
 
     
     
         156 .- 157 . (canceled) 
     
     
         158 . A composition to improve the efficacy and/or reduce the side effects of suboptimally administered drug therapy comprising an alternative selected from the group consisting of:
 (a) a therapeutically effective quantity of a modified therapeutic agent or a derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent, wherein the modified therapeutic agent or the derivative, analog or prodrug of the therapeutic agent or modified therapeutic agent possesses increased therapeutic efficacy or reduced side effects as compared with an unmodified therapeutic agent;   (b) a composition comprising:
 (i) a therapeutically effective quantity of a therapeutic agent, a modified therapeutic agent or a derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent; and 
 (ii) at least one additional therapeutic agent, therapeutic agent subject to chemosensitization, therapeutic agent subject to chemopotentiation, diluent, excipient, solvent system, or drug delivery system, wherein the composition possesses increased therapeutic efficacy or reduced side effects as compared with an unmodified therapeutic agent; 
   (c) a therapeutically effective quantity of a therapeutic agent, a modified therapeutic agent, or a derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent that is incorporated into a dosage form, wherein the therapeutic agent, the modified therapeutic agent, or the derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent incorporated into the dosage form possesses increased therapeutic efficacy or reduced side effects as compared with an unmodified therapeutic agent;   (d) a therapeutically effective quantity of a therapeutic agent, a modified therapeutic agent, or a derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent that is incorporated into a dosage kit and packaging, wherein the therapeutic agent, the modified therapeutic agent, or the derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent incorporated into the dosage kit and packaging possesses increased therapeutic efficacy or reduced side effects as compared with an unmodified therapeutic agent; and   (e) a therapeutically effective quantity of a therapeutic agent, a modified therapeutic agent, or a derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent that is subjected to a bulk drug product improvement, wherein the therapeutic agent, the modified therapeutic agent, or the derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent subject to the bulk drug product improvement possesses increased therapeutic efficacy or reduced side effects as compared with an unmodified therapeutic agent;   
       wherein the therapeutic agent, the modified therapeutic agent or the derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent is selected from the group consisting of: (i) indirubin; (ii) an analog of indirubin; and (iii) a derivative of indirubin or of an analog of indirubin. 
     
     
         159 . The composition of  claim 158  wherein the therapeutically active agent, modified therapeutic agent, or the derivative, analog, or prodrug of a therapeutic agent or modified therapeutic agent is selected from the group consisting of meisoindigo and the salts, solvates, analogues, congeners, bioisosteres, hydrolysis products, metabolites, precursors, and prodrugs thereof. 
     
     
         160 . The composition of  claim 158  wherein the composition comprises a therapeutically active agent, and the therapeutically active agent is meisoindigo. 
     
     
         161 . The composition of  claim 158  wherein the composition possesses increased efficacy or reduced side effects for cancer therapy. 
     
     
         162 . The composition of  claim 158  wherein the therapeutically active agent is an agent selected from the group consisting of Alternatives (1)-(486), the modified therapeutic agent is a modification of an agent selected from the group consisting of Alternatives (1)-(486), and the derivative, analog, or prodrug is a derivative, analog, or prodrug of an agent selected from the group consisting of Alternatives (1)-(486) or of a modification of an agent selected from the group consisting of Alternatives (1)-(486). 
     
     
         163 . (canceled) 
     
     
         164 . The composition of  claim 158  wherein the composition comprises a drug combination comprising:
 (a) a therapeutically active agent selected from the group consisting of Alternatives (1)-(486); and 
 (b) an additional therapeutic agent selected from the group consisting of:
 (i) topoisomerase inhibitors; 
 (ii) fraudulent nucleosides; 
 (iii) fraudulent nucleotides; 
 (iv) thymidylate synthetase inhibitors; 
 (v) signal transduction inhibitors; 
 (vi) cisplatin or platinum analogs; 
 (vii) alkylating agents; 
 (viii) anti-tubulin agents; 
 (ix) antimetabolites; 
 (x) berberine; 
 (xi) apigenin; 
 (xii) amonafide; 
 (xiii) colchicine or an analog thereof; 
 (xiv) genistein; 
 (xv) etoposide; 
 (xvi) cytarabine; 
 (xvii) a camptothecin; 
 (xviii) a vinca alkaloid; 
 (xix) 5-fluorouracil; 
 (xx) curcumin; 
 (xxi) an NF-κB inhibitor; 
 (xxii) rosmarinic acid; 
 (xxiii) mitoguazone; 
 (xxiv) tetandrine; 
 (xxv) an antineoplastic agent not metabolized by cytochrome P450 CYP 1A2 or CYP 2C19; 
 (xxvi) a biological therapy; 
 (xxvii) a tyrosine kinase inhibitor; 
 (xxviii) all-trans-retinoic acid; 
 (xxix) an arsenical; 
 (xxx) hydroxyurea; 
 (xxxi) thioguanine; 
 (xxxii) mercaptopurine; 
 (xxxiii) homoharringtonine; 
 (xxxiv) oridonin; 
 (xxxv) uracil mustard; 
 (xxxvi) nilotinib; 
 (xxxvii) dasatinib; 
 (xxxviii) lonidamine; 
 (xxxix) 5-azacytidine; 
 (xl) thalidomide or an analog thereof; 
 (xli) an EGFR inhibitor; 
 (xlii) a gold salt; 
 (xliii) dibromodulcitol; 
 (xliv) dianhydrogalactitol; 
 (xlv) decitabine; and 
 (xlvi) a proteasome inhibitor. 
 
 
     
     
         165 .- 166 . (canceled) 
     
     
         167 . The composition of  claim 158  wherein the composition comprises:
 (a) a therapeutically active agent selected from the group consisting of Alternatives (1)-(486); and 
 (b) a therapeutic agent subject to chemosensitization or chemopotentiation selected from the group consisting of:
 (i) topoisomerase inhibitors; 
 (ii) fraudulent nucleosides; 
 (iii) fraudulent nucleotides; 
 (iv) thymidylate synthetase inhibitors; 
 (v) signal transduction inhibitors; 
 (vi) cisplatin or platinum analogs; 
 (vii) alkylating agents; 
 (viii) anti-tubulin agents; 
 (ix) antimetabolites; 
 (x) berberine; 
 (xi) apigenin; 
 (xii) amonafide; 
 (xiii) vinca alkaloids; 
 (xiv) 5-fluorouracil; 
 (xv) curcumin; 
 (xvi) NF-κB inhibitors; 
 (xvii) rosmarinic acid; 
 (xviii) mitoguazone; 
 (xix) tetrandrine; and 
 (xx) a proteasome inhibitor; 
 
 
       wherein the therapeutically active agent selected from the group consisting of Alternatives (1)-(486) acts as a chemosensitizer or chemopotentiator. 
     
     
         168 .- 171 . (canceled) 
     
     
         172 . The composition of  claim 158  wherein the therapeutic agent is a therapeutically active agent selected from the group consisting of Alternatives (1)-(486) and the therapeutically active agent selected from the group consisting of Alternatives (1)-(486) is subjected to a bulk drug product improvement, wherein the bulk drug product improvement is selected from the group consisting of:
 (i) salt formation; 
 (ii) preparation as a homogeneous crystal structure; 
 (iii) preparation as a pure isomer; 
 (iv) increased purity; 
 (v) preparation with lower residual solvent content; and 
 (vi) preparation with lower residual heavy metal content. 
 
     
     
         173 . (canceled) 
     
     
         174 . The composition of  claim 158  wherein the therapeutic agent is a therapeutically active agent selected from the group consisting of Alternatives (1)-(486) and the composition comprises a diluent or a solvent system, wherein the diluent or the solvent system is selected from the group consisting of:
 (i) an emulsion; 
 (ii) dimethylsulfoxide (DMSO); 
 (iii) N-methylformamide (NMF) 
 (iv) DMF; 
 (v) ethanol; 
 (vi) benzyl alcohol; 
 (vii) dextrose-containing water for injection; 
 (viii) Cremophor; 
 (ix) cyclodextrin; and 
 (x) PEG. 
 
     
     
         175 .- 177 . (canceled) 
     
     
         178 . The composition of  claim 158  wherein the therapeutic agent is a therapeutically active agent selected from the group consisting of Alternatives (1)-(486) and the composition comprises an excipient, wherein the excipient is selected from the group consisting of:
 (i) mannitol; 
 (ii) albumin; 
 (iii) EDTA; 
 (iv) sodium bisulfite; 
 (v) benzyl alcohol; 
 (vi) a carbonate buffer; 
 (vii) a phosphate buffer; and 
 (viii) methylcellulose. 
 
     
     
         179 . (canceled) 
     
     
         180 . The composition of  claim 158  wherein the therapeutic agent is a therapeutically active agent selected from the group consisting of Alternatives (1)-(486) and the therapeutically active agent selected from the group consisting of Alternatives (1)-(486) is incorporated into a dosage form selected from the group consisting of:
 (i) tablets; 
 (ii) capsules; 
 (iii) topical gels; 
 (iv) topical creams; 
 (v) patches; 
 (vi) suppositories; and 
 (vii) lyophilized dosage fills. 
 
     
     
         181 .- 183 . (canceled) 
     
     
         184 . The composition of  claim 158  wherein the therapeutic agent is a therapeutically active agent selected from the group consisting of Alternatives (1)-(486) and the composition comprises a drug delivery system selected from the group consisting of:
 (i) nanocrystals; 
 (ii) bioerodible polymers; 
 (iii) liposomes; 
 (iv) slow release injectable gels; 
 (v) microspheres; 
 (vi) vascular disrupting agents; and 
 (vii) polymer-coated stents. 
 
     
     
         185 . (canceled) 
     
     
         186 . The composition of  claim 158  wherein the therapeutic agent is a therapeutically active agent selected from the group consisting of Alternatives (1)-(486) and the therapeutically active agent selected from the group consisting of Alternatives (1)-(486) is present in the composition in a drug conjugate form selected from the group consisting of:
 (i) a polymer system; 
 (ii) polylactides; 
 (iii) polyglycolides; 
 (iv) amino acids; 
 (v) peptides; and 
 (vi) multivalent linkers. 
 
     
     
         187 . (canceled) 
     
     
         188 . The composition of  claim 158  wherein the therapeutic agent is a modified therapeutically active agent selected from the group consisting of Alternatives (1)-(486) and the modification is selected from the group consisting of:
 (i) alteration of side chains to increase or decrease lipophilicity; 
 (ii) addition of an additional chemical functionality to alter a property selected from the group consisting of reactivity, electron affinity, and binding capacity; and 
 (iii) alteration of salt form. 
 
     
     
         189 . (canceled) 
     
     
         190 . The composition of  claim 158  wherein the therapeutic agent is a therapeutically active agent selected from the group consisting of Alternatives (1)-(486) and the therapeutically active agent selected from the group consisting of Alternatives (1)-(486) is in the form of a prodrug system, wherein the prodrug system is selected from the group consisting of:
 (i) the use of enzyme sensitive esters; 
 (ii) the use of dimers; 
 (iii) the use of Schiff bases; 
 (iv) the use of pyridoxal complexes; 
 (v) the use of caffeine complexes; 
 (vi) the use of N-substituted carbohydrate derivatives; 
 (vii) the use of Mannich N-oxides; 
 (viii) the use of products of reaction with an acylating or carbamylating agent; 
 (ix) the use of hexanoate conjugates; 
 (x) the use of polymer-agent conjugates; and 
 (xi) the use of prodrugs subject to redox activation. 
 
     
     
         191 . (canceled) 
     
     
         192 . The composition of  claim 158  wherein the therapeutic agent is a therapeutically active agent selected from the group consisting of Alternatives (1)-(486) and the composition further comprises at least one additional therapeutic agent to form a multiple drug system, wherein the at least one additional therapeutic agent is selected from the group consisting of:
 (i) an inhibitor of multi-drug resistance; 
 (ii) a specific drug resistance inhibitor; 
 (iii) a specific inhibitor of a selective enzyme; 
 (iv) a signal transduction inhibitor; 
 (v) an inhibitor of a repair enzyme; and 
 (vi) a topoisomerase inhibitor with non-overlapping side effects. 
 
     
     
         193 . (canceled)