3-heteroarylidenyl-2-indolinone compounds for modulating protein kinase activity and for use in cancer chemotherapy

A method for treating cancer comprising administering to a patient in need of such treatment:

• (a) therapeutically effective amount(s) of at least one agent selected from the group consisting of topoisomerase I inhibitors, chemotherapeutic agents, leucovorin, and combinations thereof;
• and (b) a therapeutically effective amount of a compound comprising the chemical structure:
• 6
• wherein:
• R1 is H or alkyl;
• R2 is O or S;
• R3 is hydrogen;
• R4, R5, R6, and R7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO2NRR′, SO3R, SR, NO2, NRR′, OH, CN, C(O)R, OC(O)R, (CH2)nCO2R, and CONRR′;
• A is a five membered heteroaryl ring selected from the group consisting of thiophene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, and tetrazole, optionally substituted at one or more positions with alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO2NRR′, SO3R, SR, NO2, NRR′, OH, CN, C(O)R, OC(O)R, (CH2)nCO2R, or CONRR′;
• n is 0-3;
• and,
• R and R′ are independently selected from the group consisting of H, alkyl or aryl;
• or,
• a physiologically acceptable salt or prodrug thereof.

A combination useful for the treatment of cancer comprising:

• (a) therapeutically effective amount(s) of at least one agent selected from the group consisting of topoisomerase I inhibitors, chemotherapeutic agents, leucovorin, and combinations thereof;
• and (b) a therapeutically effective amount of a compound having the chemical structure:
• 7
• wherein:
• R1 is H or alkyl;
• R2 is O or S;
• R3 is hydrogen;
• R4, R5, R6, and R7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO2NRR′, SO3R, SR, NO2, NRR′, OH, CN, C(O)R, OC(O)R, (CH2)nCO2R, and CONRR′;
• A is a five membered heteroaryl ring selected from the group consisting of thiophene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, and tetrazole, optionally substituted at one or more positions with alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO2NRR′, SO3R, SR, NO2, NRR′, OH, CN, C(O)R, OC(O)R, (CH2)nCO2R, or CONRR′;
• n is 0-3;
• and,
• R and R′ are independently selected from the group consisting of H, alkyl or aryl;
• or,
• a physiologically acceptable salt or prodrug thereof.