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. In particular, the 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, are effective Nek9 inhibitors. The active agent, such as meisoindigo, can act as a Nek9 inhibitor. The active agent can be used together with Nek9 inhibitors or agents that inhibit the expression of Nek9.

What is claimed is: 
     
         1 . A method of treating a disease or condition treatable by administration of a Nek9 inhibitor to a subject in need thereof comprising administration of an effective quantity 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 disease or condition is a hyperproliferative disease. 
     
     
         3 . The method of  claim 2  wherein the hyperproliferative disease is cancer. 
     
     
         4 . The method of  claim 1  wherein the therapeutically active agent is selected from the group consisting of meisoindigo and the salts and solvates thereof. 
     
     
         5 . The method of  claim 4  wherein the therapeutically active agent is meisoindigo. 
     
     
         6 . 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) 1H, 1′H-[2,3′] biindolylidene-3,2′-dione; (4) 5-fluoro-1H, 1′H-[2,3′]biindolylidene-3,2′-dione; (5) 1H,1′H-[2,3′] biindolylidene-3,2′-dione-3-oxime; (6) 1-acetyl-1H, 1′H-[2,3′] biindolylidene-3,2′-dione; (7) 5′-nitro-1H,1′H-[2,3′] biindolylidene-3,2′-dione; (8) 5′-nitro-1H,1′H-[2,3′] biindolylidene-3,2′-dione-3-oxime; (9) 5-fluoro-1H,1′H-[2,3′] biindolylidene-3,2′-dione-3-oxime; (10) 5′-methyl-1H,1′H-[2,3′]biindolylidene-3,2′-dione-3-oxime; (11) 5′-chloro-1H,1′H-[2,3′] biindolylidene-3,2′-dione-3-oxime; (12) 5′-iodo-1H,1′H-[2,3′] biindolylidene-3,2′-dione-3-oxime; (13) 5′,7′-dimethyl-1H,1′H-[2,3′] biindolylidene-3,2′-dione-3-oxime; (14) 5′-chloro-7′-methyl-1H,1′H-[2,3′]biindolylidene-3,2′-dione-3-oxime; (15) 5-bromo-1H,1′H-[2,3′] biindolylidene-3,2′-dione-3-oxime; (16) 3,2′-dioxo-1,3,1′,2′-tetrahydro-[2,3′]biindolylidene-5′-sodium sulfonate; (17) 3-hydroxyimino-2′-oxo-,3,1′,2′-tetrahydro-[2,3′]biindolylidene-5′-sodium sulfonate; (18) 5-bromo-1H,1′H-[2,3′]-biindolylidene-3,2′-dione; (19) 5-bromo-5′-nitro-1H, 1′H-[2,3′]-biindolylidene-3,2′-dione-3-oxime; (20) 5′-methyl-1H,1′H-[2,3′]-biindolylidene-3,2′-dione; (21) 5′-chloro-1H,1′H-[2,3′]-biindolylidene-3,2′-dione; (22) 5′-iodo-1H,1′H-[2,3′]-biindolylidene-3,2′-dione; (23) 5′,7′-dimethyl-1H,1′H-[2,3′]-biindolylidene-3,2′-dione; (24) 5′-chloro,7′-methyl-1H,1′H-[2,3′]-biindolylidene-3,2′-dione; (25) 5′-amino-1H,1′H-[2,3′]-biindolylidene-3,2′-dione; (26) 5-NH-trimethylacetyl-indirubin-3-oxime; (27) 5′-amino-1H,1′H-[2,3′]-biindolylidene-3,2′-dione-3-oxime; (28) 6-hydroxy-5-methylindirubin; (29) 6,7′-dihydroxy-5-methylindirubin; (30) 3,4,5-trihydroxy-6-(5-methyl-1H,1′H-[2′,3]bis-indolyliden-2,3′-dion-6-yl)-tetrahydropyran-2-carboxylic acid; (31) 3,4,5-trihydroxy-6-(7′-hydroxy-5-methyl-1H1′H-[2′,3]bisindolyliden-2,3′-dion-6-yl)-tetrahydropyran-2-carboxylic acid; (32) 5-methylindirubin; (33) indirubin-5-sulfonamide; (34) indirubin-5-sulfonic acid (2-hydroxyethyl)-amide; (35) 5-iodoindirubin-3′-monooxime; (36) 5-fluoroindirubin; (37) 5,5′-dibromoindirubin; (38) 5-nitroindirubin; (39) 5-bromoindirubin; (40) (2′Z,3′E)-6-bromoindirubin-3′-oxime (BIO); (41) 5-iodoindirubin; (42) indirubin-5-sulfonic acid-3′-monooxime; (43) 3,4-bis(1-methylindole-3-yl)-1H-pyrrole-2,5-dione; (44) 3-(1-methylindole-3-yl)-4-(1-propylindole-3-yl)-1H-pyrrole-2,5-dione; (45) 3-[1-(3-cyanopropyl)indole-3-yl]-4-(1-methyl-indole-3-yl)-1H-pyrrole-2,5-dione; (46) 3-[1-(3-aminopropyl)-indole-3-yl]-4-(1-methylindole-3-yl)-1H-pyrrole-2,5-dione; (47) 3-[1-(3-carboxypropyl)indole-3-yl]-4-(1-methyl-indole-3-yl)-1H-pyrrole-2,5-dione; (48) 3-[1-(3-carbamoyl-propyl)indole-3-yl]-4-(1-methylindole-3-yl)-1H-pyrrole-2,5-dione; (49) 3-[1-(3-aminopropyl)indole-3-yl]-4-(1-methyl-5-propyloxyindole-3-yl)-1H-pyrrole-2,5-dione; (50) 3-[1-(3-hydroxypropyl)indole-3-yl]-4-(1-methyl-5-phenylindole-3-yl)-1H-pyrrole-2,5-dione; (51) 3-[1-(3-aminopropyl)indole-3-yl]-4-(1-methyl-5-phenylindole-3-yl)-1H-pyrrole-2,5-dione; (52) 3-[1-(3-hydroxypropyl)indole-3-yl]-4-(1-methyl-5-methoxycarbonylindole-3-yl)-1H-pyrrole-2,5-dione; (53) 3-[1-(3-hydroxypropyl)indole-3-yl]-4-(1-methyl-5-nitroindole-3-yl)-1H-pyrrole-2,5-dione; (54) 3-(1-methylindole-3-yl)-4-[1-(3-hydroxypropyl)-5-nitroindole-3-yl]-1H-pyrrole-2,5-dione; (55) 3-(2-chlorophenyl)-4-(1-methylindole-3-yl)-1H-pyrrole-2,5-dione; (56) 3-(2,4-dichlorophenyl)-4-(1-methylindole-3-yl)-1H-pyrrole-2,5-dione; (57) 3-(2-chlorophenyl)-4-[1-(3-hydroxypropyl)indole-3-yl]-1 H-pyrrole-2,5-dione; (58) 4-[1-(3-aminopropyl)indole-3-yl]-3-(2-chlorophenyl)-1H-pyrrole-2,5-dione; (59) 7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (60) 2-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (61) 9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (62) 9-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (63) 11-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (64) 10-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (65) 8-bromo-6,11-dihydro-thieno[3′,2′:2,3]azepino-[4,5-b]indol-5(4H)-one; (66) 9-bromo-7,12-dihydro-4-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (67) 9-bromo-7,12-dihydro-4-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (68) 7,12-dihydro-4-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (69) 9-bromo-7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (70) 9-bromo-7,12-dihydro-2,3-di-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (71) 7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (72) 7,12-dihydro-9-trifluormethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (73) 7,12-dihydro-2,3-dimethoxy-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6-(5H)-one; (74) 2-bromo-7,12-dihydro-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (75) 9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-thione; (76) 9-bromo-5,12-bis-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (77) 9-bromo-12-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6-(5H)-one; (78) 9-bromo-5,7-bis-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (79) 9-bromo-5,7,12-tri-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (80) 9-bromo-7,12-dihydro-5-methyloxycarbonylmethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (81) 9-bromo-7,12-dihydro-12-methyloxycarbonylmethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (82) 9-bromo-7,12-dihydro-12-(2-hydroxyethyl)-indolo[3,2-d][1]benzazepin-6-(5H)-one; (83) 2,9-dibromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (84) 8,10-dichloro-7,12-dihydro-indolo-[3,2-d][1]benzazepin-6(5H)-one; (85) 9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (86) 9-bromo-7,12-dihydro-5-methyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (87) 5-benzyl-9-bromo-7,12-dihydro-5-methyl-indolo[3,2-d][1]-benzazepin-6(5H)-one; (88) 9-bromo-7,12-dihydro-12-methyl-indolo-[3,2-d][1]benzazepin-6(5H)-one; (89) 9-bromo-12-ethyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (90) 9-bromo-7,12-dihydro-12-(2-propenyl)-indolo[3,2-d][1]benzazepin-6(5H)-one; (91) 7,12-dihydro-9-methyl-indolo[3,2-d][1]-benzazepin-6(5H)-one; (92) 7,12-dihydro-9-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (93) 9-fluoro-7,12-dihydro-12-(2-propenyl)-indolo[3,2-d][1]benzazepin-6(5H)-one; (94) 11-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (95) 9-bromo-7,12-dihydro-2-(methyliminoamine)-indolo[3,2-d][1]benzazepin-6(5H)-one; (96) 9-bromo-7,12-dihydro-2-(carboxylic acid)-indolo[3,2-d][1]benzazepin-6(5H)-one; (97) 9-bromo-7,12-dihydro-10-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (98) 9-bromo-7,12-dihydro-11-hydroxymethyl-indolo[3,2-d][1]-benzazepin-6(5H)-one; (99) 7,12-dihydro-4-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (100) 7,12-dihydro-2,3-dihydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (101) 2,3-dimethoxy-9-nitro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (102) 9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (103) 2,3-dimethoxy-9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (104) 9-nitro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (105) 3-(6-oxo-9-trifluoromethyl-5,6,7,12-tetrahydro-indolo[3,2-d][1]benzazepin-2-yl)-propionitrile; (106) 2-bromo-9-nitro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (107) 3-(6-oxo-9-trifluoromethyl-5,6,7,12-tetrahydro-indolo[3,2-d][1]benzazepin-2-yl)acrylonitrile; (108) 2-(3-hydroxy-1-propinyl)-9-trifluoromethyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (109) 2-iodo-9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (110) 2-(3-oxo-1-butenyl)-9-trifluoromethyl-7,12-tetrahydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (111) 8-chloro-6,11-dihydro-thieno[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-one; (112) 2-iodo-9-trifluoromethyl-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (113) 7,12-dihydro-pyrido[3′,2′:4,5]-pyrrolo[3,2-d][1]benzazepin-6(5H)-one; (114) 11-methyl-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (115) 2-[2-(1-hydroxycyclohexyl)-ethinyl]-9-trifluoromethyl-7,12-dihydro-indolo-[3,2-d][1]benzazepin-6(5H)-one; (116) 2-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (117) 2-iodo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (118) 11-ethyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (119) 8-methyl-6,11-dihydro-thieno[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-one; (120) 3-(6-oxo-9-trifluoromethyl-5,6,7,12-tetrahydro-indolo[3,2-d][1]benzazepin-2-yl)acrylic acid methyl ester; (121) 9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (122) 9-bromo-7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (123) 2-bromo-7,12-dihydro-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (124) 7,12-dihydro-2,3-dimethoxy-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (125) 2,9-dibromo-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (126) 7,12-dihydro-9-trifluoromethyl-indolo-[3,2-d][1]benzazepin-6(5H)-one; (127) 9-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (128) 8-bromo-6,11-dihydro-thieno[3′,2′:2,3]azepino[4,5-b]indole-5(4H)-one; (129) 7,12-dihydro-9-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (130) 10-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (131) 11-bromo-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (132) 11-chloro-7,12-dihydro-indolo[3,2-d]-[1]benzazepin-6(5H)-one; (133) 9-fluoro-7,12-dihydro-indolo-[3,2-d][1]benzazepin-6(5H)-one; (134) 9-methyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (135) 9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-thione; (136) 8,10-dichloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (137) 9-bromo-7,12-dihydro-12-(2-hydroxyethyl)-indolo[3,2-d][1]-benzazepin-6(5H)-one; (138) 9-bromo-7,12-dihydro-2,3-dihydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (139) 2-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (140) 7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (141) 9-bromo-7,12-dihydro-12-methyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (142) 9-bromo-7,12-dihydro-5-methyloxycarbonylmethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (143) 7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (144) 9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (145) 9-bromo-7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (146) 2-bromo-7,12-dihydro-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (147) 7,12-dihydro-2,3-dimethoxy-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (148) 2,9-dibromo-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (149) 7,12-dihydro-9-trifluoromethyl-indolo-[3,2-d][1]benzazepin-6(5H)-one; (150) 9-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (151) 8-bromo-6,11-dihydro-thieno[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-one; (152) 7,12-dihydro-9-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (153) 9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (154) 9-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (155) 11-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (156) 10-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (157) 8-bromo-6,11-dihydro-thieno[3′,2′:2,3]azepino-[4,5-b]indol-5(4H)-one; (158) 9-bromo-7,12-dihydro-4-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (159) 9-bromo-7,12-dihydro-4-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (160) 7,12-dihydro-4-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (161) 9-bromo-7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (162) 9-bromo-7,12-dihydro-2,3-di-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (163) 7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (164) 7,12-dihydro-9-trifluormethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (165) 7,12-dihydro-2,3-dimethoxy-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6-(5H)-one; (166) 2-bromo-7,12-dihydro-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (167) 9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-thione; (168) 9-bromo-5,12-bis-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (169) 9-bromo-12-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6-(5H)-one; (170) 9-bromo-5,7-bis-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (171) 9-bromo-5,7,12-tri-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (172) 9-bromo-7,12-dihydro-5-methyloxycarbonylmethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (173) 9-bromo-7,12-dihydro-12-methyloxycarbonylmethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (174) 9-bromo-7,12-dihydro-12-(2-hydroxyethyl)-indolo[3,2-d][1]benzazepin-6-(5H)-one: (175) 2,9-dibromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (176) 8,10-dichloro-7,12-dihydro-indolo-[3,2-d][1]benzazepin-6(5H)-one: (177) 9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one: (178) 9-bromo-7,12-dihydro-5-methyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (179) 5-benzyl-9-bromo-7,12-dihydro-5-methyl-indolo[3,2-d][1]-benzazepin-6(5H)-one; (180) 9-bromo-7,12-dihydro-12-methyl-indolo-[3,2-d][1]benzazepin-6(5H)-one; (181) 9-bromo-12-ethyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (182) 9-bromo-7,12-dihydro-12-(2-propenyl)-indolo[3,2-d][1]benzazepin-6(5H)-one; (183) 7,12-dihydro-9-methyl-indolo[3,2-d][1]-benzazepin-6(5H)-one; (184) 7,12-dihydro-9-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (185) 9-fluoro-7,12-dihydro-12-(2-propenyl)-indolo[3,2-d][1]benzazepin-6(5H)-one; (186) 11-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (187) 9-bromo-7,12-dihydro-2-(methyliminoamine)-indolo[3,2-d][1]benzazepin-6(5H)-one; (188) 9-bromo-7,12-dihydro-2-(carboxylic acid)-indolo[3,2-d][1]benzazepin-6(5H)-one; (189) 9-bromo-7,12-dihydro-10-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one: (190) 9-bromo-7,12-dihydro-11-hydroxymethyl-indolo[3,2-d][1]-benzazepin-6(5H)-one: (191) 7,12-dihydro-4-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (192) 7,12-dihydro-2,3-dihydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (193) 2,3-dimethoxy-9-nitro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (194) 9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (195) 2,3-dimethoxy-9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (196) 9-nitro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (197) 3-(6-oxo-9-trifluoromethyl-5,6,7,12-tetrahydro-indolo[3,2-d][1]benzazepin-2-yl)-propionitrile; (198) 2-bromo-9-nitro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (199) 3-(6-oxo-9-trifluoromethyl-5,6,7,12-tetrahydro-indolo[3,2-d][1]benzazepin-2-yl)acrylonitrile; (200) 2-(3-hydroxy-1-propinyl)-9-trifluoromethyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (201) 2-iodo-9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (202) 2-(3-oxo-1-butenyl)-9-trifluoromethyl-7,12-tetrahydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (203) 8-chloro-6,11-dihydro-thieno[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-one; (204) 2-iodo-9-trifluoromethyl-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (205) 7,12-dihydro-pyrido[3′,2′:4,5]-pyrrolo[3,2-d][1]benzazepin-6(5H)-one; (206) 11-methyl-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (207) 2-[2-(1-hydroxycyclohexyl)-ethinyl]-9-trifluoromethyl-7,12-dihydro-indolo-[3,2-d][1]benzazepin-6(5H)-one; (208) 2-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (209) 2-iodo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (210) 11-ethyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (211) 8-methyl-6,11-dihydro-thieno[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-one; (212) 3-(6-oxo-9-trifluoromethyl-5,6,7,12-tetrahydro-indolo[3,2-d][1]benzazepin-2-yl)acrylic acid methyl ester; (213) 9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (214) 9-bromo-7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (215) 2-bromo-7,12-dihydro-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (216) 7,12-dihydro-2,3-dimethoxy-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (217) 2,9-dibromo-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (218) 7,12-dihydro-9-trifluoromethyl-indolo-[3,2-d][1]benzazepin-6(5H)-one; (219) 9-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (220) 8-bromo-6,11-dihydro-thieno[3′,2′:2,3]azepino[4,5-b]indole-5(4H)-one: (221) 7,12-dihydro-9-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (222) 10-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (223) 11-bromo-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (224) 11-chloro-7,12-dihydro-indolo[3,2-d]-[1]benzazepin-6(5H)-one: (225) 9-fluoro-7,12-dihydro-indolo-[3,2-d][1]benzazepin-6(5H)-one; (226) 9-methyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (227) 9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-thione; (228) 8,10-dichloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (229) 9-bromo-7,12-dihydro-12-(2-hydroxyethyl)-indolo[3,2-d][1]-benzazepin-6(5H)-one; (230) 9-bromo-7,12-dihydro-2,3-dihydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (231) 2-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (232) 7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (233) 9-bromo-7,12-dihydro-12-methyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (234) 9-bromo-7,12-dihydro-5-methyloxycarbonylmethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (235) 7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (236) 9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one; (237) 9-bromo-7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (238) 2-bromo-7,12-dihydro-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (239) 7,12-dihydro-2,3-dimethoxy-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; (240) 2,9-dibromo-7,12-dihydro-indolo[3,2-d][1]-benzazepin-6(5H)-one; (241) 7,12-dihydro-9-trifluormethyl-indolo-[3,2-d][1]benzazepin-6(5H)-one; (242) 9-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one: (243) 8-bromo-6,11-dihydro-thieno[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-one; (244) 7,12-dihydro-9-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one; (245) 9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one (246) 6-bromoindirubin; (247) 6,6′-dibromoindirubin-3-oxime; (248) 6-bromoindirubin-3′-methoxime; (249) 6-bromo-5-methyl-indirubin; (250) 6-bromo-5-aminoindirubin; (251) 6-bromo-5-methyl-indirubin-3′-oxime; (252) 6-bromo-indirubin-3′-acetoxime; (253) 5-amino-indirubin; (254) 5-amino-indirubin-3′-oxime; (255) 1-methylindirubin; (256) N-1-methylisoindigo; (257) indirubin-5-sulfone-(2-hydroxyethyl)amide; (258) 5-ethylindirubin; (259) 5-isopropylindirubin; (260) 5-n-propylindirubin; (261) 5-carboxymethylindirubin; (262) 5-[2-(piperazin-1-yl)-ethan-2-on-1-yl]indirubin; (263) 5-[2-(morpholin-1-yl)-ethan-2-on-1-yl]indirubin; (264) N-(2-aminoethyl)-2-[3-(3′-oxo-(2′H, 3′H)indol-2′-ylidene)-(2H, 3H)indol-2-one-5-yl]acetamide; (265) N-methyl-2-[3-(3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]acetamide; (266) N,N-dimethyl-2-[3-(3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]acetamide; (267) 2-{2-[3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-acetylamino}-acetic acid; (268) methyl-2-{2-[3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-acetylamino}-acetate; (269) [3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-methylphosphonic acid; (270) diethyl-[3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-methylphosphonate; (271) 5-acetylaminoindirubin; (272) [3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-succinamic acid; (273) 2-amino-N-[3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-acetamide; (274) 2-amino-N-[3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-propionamide; (275) 5-(2-aminoethyl)-aminoindirubin; (276) 5-(2-hydroxyethyl)-aminoindirubin; (277) indirubin-5-sulfonic acid-(piperazin-1-yl-amide); (278) indirubin-5-sulfonic acid-(morpholin-1-yl-amide); (279) methyl-2-{[3′-oxo-(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-sulfonamidyl}-acetate; (280) 5-methylindirubin-3′-monooxime; (281) 5-ethylindirubin-3′-monooxime; (282) 5-isopropylindirubin-3′-monooxime; (283) 5-aminoindirubin-3′-monooxime; (284) 5-acetylaminoindirubin-3′-monooxime; (285) 2-amino-N-[3-(3′-hydroxyimino)(2′H,3′H)indol-2′-ylidene)-(2H,3H)indol-2-one-5-yl]-acetamide; (286) 3-[3′-(iminooxy-O-(2-hydroxyethyl)-(2′H,3′H)indol-2′-ylidene]-(2H,3H)indol-2-one; (287) 3-[3′-(iminooxy-O-(3-hydroxypropyl)-(2′H,3′H)indol-2′-ylidene]-(2H,3H)indol-2-one; (288) 3-[3′-(iminooxy-O-(2-(2-hydroxyethoxy)ethyl)-(2′H,3′H)indol-2′-ylidene]-(2H,3H)indol-2-one; (289) 3-[3′-(iminooxy-O-(2-(2-hydroxy-2-methyl)propyl)-(2′H,3′H)indol-2′-ylidene]-(2H,3H)indol-2-one; (290) 2-{O-[2′-(2-oxo-(2H,3H)indol-3-ylidene)-2′H,3′H-indol-3′-ylidene]aminoxy}acetic acid sodium salt; (291) 3-{O-[2′-(2-oxo-(2H,3H)indol-3-ylidene)-2′H,3′H-indol-3′-ylidene]aminoxy}propionic acid sodium salt; (292) 4-{O-[2′-(2-oxo-(2H,3H)indol-3-ylidene)-2′H,3′H-indol-3′-ylidene]aminoxy}butyric acid sodium salt; (293) 5-{O-[2′-(2-oxo-(2H,3H)indol-3-ylidene)-2′H,3′H-indol-3′-ylidene]aminoxy}pentanoic acid sodium salt; (294) 3-[3′-iminooxy-O-carbethoxy)-(2′H,3′H)-indol-2′-ylidene]-(2H,3H)indol-2-one; (295) ethyl-2-{O-2′-(2-oxo-(2H,3H)indol-3-ylidene-(2′H,3′H)-indol-3′-ylidene]-aminooxy}-acetate; (296) 3-[3′-iminooxy-O—(N,N)-dimethylcarbamoyl)]-(2′H,3′H)-indol-2′-ylidene]-(2H,3H)indol-2-one); (297) 3′-oximido-7-azaindirubin; (298) 7-azaindirubin-3′-oxime ether; (299) 1-methyl-5-azaindirubin; (300) 1-benzyl-5′-chloro-5-azaindirubin; (301) 1-butyl-5-azaindirubin-3′-oxime; (302) 1-butyl-5-azaindirubin-3′-oxime O-methyl ether; (303) 1-isopropyl-5-azaisoindigo; (304) 1-methyl-7-azaindirubin; (305) 1-benzyl-5′-bromo-7-azaindirubin; (306) 1-butyl-7-azaindirubin-3′-oxime; (307) 1-butyl-7-azaindirubin-3′-oxime O-methyl ether; (308) 1-isopropyl-7-azaisoindigo; (309) 2-methyl-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid; (310) 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; (311) 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; (312) 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; (313) 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; (314) 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; (315) 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; (316) 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; (317) 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; (318) N-(2-(dimethylamino)ethyl)-2-methyl-7-[1,2-dihydro-5-fluoro-2-oxo-3H-indo-I-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (319) 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; (320) 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; (321) 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; (322) 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; (323) 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; (324) 2-methyl-3-(morpholine-4-carbonyl)-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole; (325) 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; (326) 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; (327) N,N,2-trimethyl-7-[1,2-dihydro-2-oxo-3H-indol-(Z)-3-ylidene]-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; (328) 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; (329) 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; (330) 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; (331) 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; (332) 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; (333) 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; (334) 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; (335) 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; (336) 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; (337) 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; (338) 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; (339) 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; (340) 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; (341) 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; (342) 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; (343) 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; (344) 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; (345) 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; (346) 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; (347) 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; (348) 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; (349) 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; (350) 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; (351) 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; (352) 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; (353) 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); (354) 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; (355) N-(3-(diethylamino)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; (356) 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; (357) 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; (358) 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; (359) 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; (360) 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; (361) 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; (362) 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; (363) 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; (364) 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; (365) 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; (366) 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; (367) 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; (368) 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; (369) 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; (370) 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; (371) 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; (372) 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; (373) 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; (374) 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; (375) 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; (376) 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; (377) 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; (378) 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; (379) 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; (380) 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; (381) 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; (382) 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; (383) 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; (384) 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; (385) 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; (386) 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; (387) 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; (388) 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; (389) 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; (390) 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; (391) 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; (392) 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; (393) 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; (394) 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; (395) 5-bromoindirubin-3′-oxime; (396) 7-bromoindirubin-3′-oxime; (397) 7-chloroindirubin-3′-oxime; (398) 7-iodoindirubin-3′-oxime; (399) 7-fluoroindirubin-3′-oxime; (400) 1-methyl-7-bromoindirubin-3′-oxime; (401) (2′Z)-7-fluoroindirubin; (402) (2′Z)-7-chloroindirubin; (403) (2′Z)-7-bromoindirubin; (404) (2′Z)-7-iodoindirubin; (405) (2′Z)-7-fluoro-1-methylindirubin; (406) (2′Z)-7-chloro-1-methylindirubin; (407) (2′Z)-7-bromo-1-methylindirubin; (408) (2′Z)-7-iodo-1-methylindirubin; (409) (2′Z,3′E)-7-fluoroindirubin-3′-oxime; (410) (2′Z,3′E)-7-chloroindirubin-3′-oxime; (411) (2′Z,3′E)-7-bromoindirubin-3′-oxime; (412) (2′Z,3′E)-7-iodoindirubin-3′-oxime; (413) (2′Z,3′E)-7-fluoro-1-methylindirubin-3′-oxime; (414) (2′Z,3′E)-7-chloro-1-methylindirubin-3′-oxime; (415) (2′Z,3′E)-7-bromo-1-methylindirubin-3′-oxime; (416) (2′Z,3′E)-7-iodo-1-methylindirubin-3′-oxime; (417) (2′Z,3′E)-7-fluoroindirubin-3′-acetoxime; (418) (2′Z,3′E)-7-chloroindirubin-3′-acetoxime; (419) (2′Z,3′E)-7-bromoindirubin-3′-acetoxime; (420) (2′Z,3′E)-7-iodoindirubin-3′-acetoxime; (421) (2′Z,3′E)-7-fluoro-1-methylindirubin-3′-acetoxime; (422) (2′Z,3′E)-7-chloro-1-methylindirubin-3′-acetoxime; (423) (2′Z,3′E)-7-bromo-1-methylindirubin-3′-acetoxime; (424) (2′Z,3′E)-7-iodo-1-methylindirubin-3′-acetoxime; (425) (2′Z,3′E)-7-fluoroindirubin-3′-methoxime; (426) (2′Z,3′E)-7-chloroindirubin-3′-methoxime; (427) (2′Z,3′E)-7-bromoindirubin-3′-methoxime: (428) (2′Z,3′E)-7-iodoindirubin-3′-methoxime; (429) (2′Z,3′E)-7-fluoro-1-methylindirubin-3′-methoxime; (430) (2′Z,3′E)-7-chloro-1-methylindirubin-3′-methoxime; (431) (2′Z,3′E)-7-bromo-1-methylindirubin-3′-methoxime; (432) (2′Z,3′E)-7-iodo-1-methylindirubin-3′-methoxime; (433) (2′Z,3′E)-7-bromoindirubin-3′-[O-(2-bromoethyl)-oxime]; (434) (2′Z,3′E)-1-methyl-7-bromoindirubin-3′-[O-(2-bromoethyl)-oxime]; (435) (2′Z,3′E)-7-bromoindirubin-3′-[O—(N,N-diethylcarbamyl)-oxime]; (436) (2′Z,3′E)-1-methyl-7-bromoindirubin-3′-[O—(N,N-diethylcarbamyl)-oxime]; (437) (2′Z,3′E)-7-bromoindirubin-3′-[O-(2-pyrrolidin-1-yl-ethyl)-oxime]; (438) (2′Z,3′E)-1-methyl-7-bromoindirubin-3′-[O-(2-pyrrolidin-1-yl-ethyl)-oxime]; (439) (2′Z,3′E)-7-bromoindirubin-3′-[O-(2-morpholin-1-yl-ethyl)-oxime]; (440) (2′Z,3′E)-1-methyl-7-bromoindirubin-3′-[O-(2-morpholin-1-yl-ethyl)-oxime]; (441) (2′Z,3′E)-7-bromoindirubin-3′-[O-(2-imidazol-1-yl-ethyl)-oxime]; (442) (2′Z,3′E)-1-methyl-7-bromoindirubin-3′-[O-(2-imidazol-1-yl-ethyl)-oxime]; (443) (2′Z,3′E)-7-bromoindirubin-3′-[O-(2-piperazin-1-yl-ethyl)-oxime]; (444) (2′Z,3′E)-7-bromoindirubin-3′-[O-(2-dimethylaminoethyl)-oxime]; (445) (2′Z,3′E)-1-methyl-7-bromoindirubin-3′-[O-(2-dimethylaminoethyl)-oxime]; (446) (2′Z,3′E)-7-bromoindirubin-3′-[O-(2-diethylaminoethyl)-oxime] (447) (2′Z,3′E)-1-methyl-7-bromoindirubin-3′-[O-(2-diethylaminoethyl)-oxime]; (448) 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; (449) 6-bromoindirubin-3′-oxime; (450) (2′Z,3′E)-6-bromoindirubin-3′-[O-(2-bromoethyl)-oxime]; (451) (2′Z,3′E)-6-bromoindirubin-3′-[O-(2-hydroxyethyl)-oxime]; (452) (2′Z,3′E)-6-bromoindirubin-3′-[O-(2,3-dihydroxypropyl)-oxime]; (453) (2′Z,3′E)-6-bromoindirubin-3-[O—(N,N-diethylcarbamyl)-oxime]; (454) (2′Z,3′E)-6-bromoindirubin-3′-[O-(2-dimethylaminoethyl)-oxime]; (455) (2′Z,3′E)-6-bromoindirubin-3-[O-(2-diethylaminoethyl)-oxime]; (456) (2′Z,3′E)-6-bromoindirubin-3′-[O-(2-pyrrolidin-1-ylethyl)-oxime]; (457) (2′Z,3′E)-6-bromoindirubin-3′-[O-(2-morpholin-1-ylethyl)-oxime]; (458) (2′Z,3′E)-6-bromoindirubin-3′-[O-(2-N,N-(2-hydroxyethyl)aminoethyl)-oxime]; (459) (2′Z,3′E)-6-bromoindirubin-3′-(O-{2-N,N-dimethyl, N-(2,3-dihydroxypropyl)amino]ethyl}oxime; (460) (2′Z,3′E)-6-bromoindirubin-3′-[O-(2-piperazin-1-ylethyl)-oxime]; (461) (2′Z,3′E)-6-bromoindirubin-3′-{O-[2-(4-methyl-piperazin-1-yl)ethyl]oxime; (462) (2′Z,3′E)-6-bromoindirubin-3′-O-{2-[4-(2-hydroxyethyl)piperazin-1-yl]ethyl}oxime; (463) (2′Z,3′E)-6-bromoindirubin-3′-O-{2-[4-(2-methoxyethyl)piperazin-1-yl]ethyl}oxime; (464) (2′Z,3′E)-6-bromoindirubin-3′-O—[O-2-{4-[2-(2-hydroxyethoxy)-ethyl]piperazin-1-yl}ethyl)oxime; (465) isoindigo; (466) 5-nitroindirubin-3′-oxime; (467) 5′-bromo-5-nitroindirubin-3′-oxime; (468) 5′-hydroxy-5-nitroindirubin-3′-oxime; (469) 5′-hydroxy-5-chloroindirubin-3′-oxime; (470) 5′-hydroxy-5-fluoroindirubin-3′-oxime; (471) 5′-chloro-5-nitroindirubin-3′-oxime; (472) 5′-methyl-5-nitroindirubin-3′-oxime; (473) indirubin-5-sulfonic acid (2-hydroxyethyl)-amide; (475) (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)-(475)”). 
     
     
         6 . 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. 
 
     
     
         7 . The method of  claim 1  wherein the therapeutically active agent is an indirubin derivative or analog that is a GSK-3 antagonist. 
     
     
         8 . The method of  claim 1  wherein the therapeutically active agent is an indirubin derivative or analog that is a Wnt agonist. 
     
     
         9 . The method of  claim 1  wherein the therapeutically active agent is an indirubin derivative or analog that is a CDK2 inhibitor. 
     
     
         10 . The method of  claim 1  wherein the method is characterized by an improvement that is a drug combination, and wherein the drug combination is selected from the group consisting of:
 (i) use with an Nek9 inhibitor; 
 (ii) use with an anti-Nek9 antibody; 
 (iii) use with an agent that inhibits Nek9 expression; 
 (iv) use with an inhibitor of at least one of Mad2, BubR1, and Mps1; 
 (v) use with an HDAC inhibitor; 
 (vi) use with an HDAC inhibitor and an Nek9 inhibitor; 
 (vii) use with an HDAC inhibitor and an anti-Nek9 antibody; 
 (viii) use with an HDAC inhibitor and an agent that inhibits Nek9 expression; and 
 (ix) use with an HDAC inhibitor and an inhibitor of at least one of Mad2, BubR1, and Mps1. 
 
     
     
         11 . The method of  claim 10  wherein the drug combination is use with an Nek9 inhibitor, and wherein the NEK inhibitor is selected from the group consisting of:
 (i) pyrazolo[1,5-a]pyrimidines of Formula (N-I); 
 (ii) triterpenes; 
 (iii) substituted imidazopyridazines of Formula (N-II); 
 (iv) nitrogen-containing heterocyclic compounds of Formula (N-III); 
 (v) imidazopyridazinecarbonitriles of Formula (N-IV); 
 (vi) 4,6-disubstituted aminopyridines of Formula (N-V); 
 (vii) 4-(substituted amino)-7H-pyrrolo[2,3-d]pyrimidines of Formula (N-VI); 
 (viii) phosphorus-containing-group-substituted quinolines; 
 (ix) kinase-inhibiting peptides; 
 (x)N-containing heterocyclic compounds including a [3,2-d]pyrimidine moiety; 
 (xi) substituted bicyclic compounds of Formula (N-VII); 
 (xii) substituted pyrrolotriazines of Formula (N-VIII); 
 (xiii) imidazopyridazinecarbonitriles of Formula (N-IX); 
 (xiv) pyrimido-diazepinone compounds of Formula (N-X); 
 (xv) tetrabromobenzimidazole derivatives of Formula (N-XI); 
 (xvi) 6,7-dialkoxyquinazoline derivatives of Formula (N-XII); 
 (xvii) thiopyrimidines of Formula (N-XIII); 
 (xviii) kinase-binding nucleosides and derivatives of Formula (N-XIV); 
 (xix) polycyclic kinase inhibitors of Formula (N-XV); 
 (xx) pyridinylamines; 
 (xxi) purine derivatives and analogs of Formula (N-XVI); 
 (xxii) therapeutic peptides that are analogs or derivatives of SGRPPMIVWFNRPFLIAVSHTHGQTILFMAKVINPVGA (SEQ ID NO: 5); 
 (xxiii) curaxins or derivatives thereof of Formula (N-XVII); 
 (xxiv) pyrimidine, pyrrolopyridine, and pyrazolopyrimidine derivatives of Formula (N-XVIII); 
 (xxv) indazole compounds of Formulas (N-XIX) or (N-XX); 
 (xxvi) electrophilic Nek9 inhibitors of Formulas (N-XXI), (N-XXII), or (N-XXIII); 
 (xxvii) disphosphate mimetics of Formula (N-XXIV); 
 (xxviii) compounds including two phenyl moieties of Formula (N-XXV); 
 (xxix) compounds with a non-cyclic backbone structure of Formula (N-XXVI); 
 (xxx) 1H-pyrrolo-[2,3b] pyridine compounds of Formula (N-XXVII); and 
 (xxxi) bicyclic heterocyclic derivatives of Formula (N-XXVIII). 
 
     
     
         12 . The method of  claim 10  wherein the drug combination is use with an anti-Nek9 antibody. 
     
     
         13 . The method of  claim 12  wherein the anti-Nek antibody is selected from the group consisting of polyclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized antibodies, and fully human antibodies. 
     
     
         14 . The method of  claim 10  wherein the drug combination is use with an agent that inhibits Nek9 expression. 
     
     
         15 . The method of  claim 14  wherein the agent that inhibits Nek9 expression is selected from the group consisting of short interfering RNA (siRNA), microRNA (miRNA), synthetic hairpin RNA (shRNA), antisense nucleic acids, and complementary DNA (cDNA). 
     
     
         16 . The method of  claim 15  wherein the agent that inhibits Nek9 expression is miRNA. 
     
     
         17 . The method of  claim 10  wherein the drug combination is use with an inhibitor of at least one of Mad2, BubR1, and Mps1. 
     
     
         18 . The method of  claim 10  wherein the drug combination is use with an HDAC inhibitor. 
     
     
         19 . The method of  claim 10  wherein the drug combination is use with an HDAC inhibitor and an agent selected from the group consisting of: (i) an Nek9 inhibitor; (ii) an agent that inhibits Nek9 expression; and (iii) an inhibitor of at least one of Mad2, BubR1, and Mps1.