Geometrically restricted 2-indolinone derivatives as modulators of protein kinase activity

A 2-indolinone having the chemical structure I, II, or III:

• or a physiologically acceptable salt of the compound, wherein:
• R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, hydroxy, alkoxy, —C(═O)OR″, R″C(═O)O—, C-amido, C-thioamido, acetyl, —S(═O)2R″, and trihalomethylsulfonyl, wherein
• R″ is selected from the group consisting of hydrogen alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon);
• A, B, D and E are independently selected from the group consisting of carbon and nitrogen, with the proviso that at least one of A, B, D, or E is nitrogen;
• wherein when A, B, D or E is nitrogen, R2, R3, R4 or R5, respectively does not exist;
• F, G, J and K are independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur, wherein
• when n is 1 and F, G, J or K is an atom other than carbon, R6, R7, R8 or R9, respectively, does not exist;
• when n is 0 and F, G or K is oxygen or sulfur, R6, R8 or R9, respectively, does not exist;
• R2, R3, R4, R5 R6, R7, R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, —S(═O)R″, —S(═O)2R″, S-sulfonamido, N-sulfonamido, N-trihalomethanesulfonamido, —C(═O)R″, —C(═O)OR″, R″C(═O)O—, cyano, nitro, halo, cyanato, isocyanato, thiocyanato, isothiocyanato, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amino and —NR13R14;
• R2 and R3 or R3 and R4 or R4 and R5 or R6 and R7 or R7 and R8 or R8 and R9 may combine to form a methylenedioxy or an ethylenedioxy group;
• R13 and R14 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, —C(═O)R″, acetyl, —S(O)2R″, trihalomethanesulfonyl and, combined, a five-member or a six-member heteroalicyclic ring;
• R10, R11 and R12 are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, cyano, trihalomethyl, hydroxy, alkoxy, alkylthio, aryloxy, arylthio, R″C(═O)O—, —C(═O)OR″, —C(═O)O−M+, —(CH2)rC(═O)OR″, —(CH2)rC(═O)O−M+, C-amido, N-amido, cyanato, isocyanato, thiocyanato, isothiocyanato, amino, —S(═O)R″, —S(═O)2R″, nitro and —NR13R14;
• R10 and R11 or R12 and R12 may combine to form an endo double bond;
• Z is selected from the group consisting of oxygen and sulfur;
• r is 1, 2, 3, 4, 5 or 6;
• and,
• n is 0 or 1;
• it being understood that when n is 0, there are no more than 2 double bonds within the ring comprising F, G and K.