3-(Cycloalkanoheteroarylidenyl)-2-Indolinone Protein Tyrosine Kinase Inhibitors

A 3- (cycloalkanoheteroarylidenyl)-2-indolinone compound having the following chemical structure:

• 4
• wherein,
• A and B are independently selected from the groups consisting of carbon, nitrogen, oxygen and sulfur wherein,
• at least one of A or B must be nitrogen, oxygen or sulfur;
• when either A or B is oxygen or sulfur, the other must be either carbon or nitrogen and when the other is nitrogen, R7 does not exist;
• when A and B are both nitrogen, R7 is bonded to whichever of A or B is not participating in one of the heteroaryl ring double bonds;
• Z is selected from the group consisting of oxygen, sulfur and NR12 wherein,
• R12 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, hydroxy, alkoxy, aryloxy, carbonyl, C-carboxyl, O-carboxyl, C-amido, guanyl, sulfonyl and trihalomethanesulfonyl;
• R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, trihalomethanecarbonyl, sulfonyl, trihalomethanesulfonyl, C-carboxyl, O-carboxyl, C-amido, and guanyl.
• R2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and halogen;
• R3, R3′, R4, R4′, R5 , R5′, R6 and R6′ are independently selected from the group consisting of hydrogen, alkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, alkoxy, aryloxy, thioalkoxy, thioaryloxy, heteroaryloxy, heteroalicycloxy, sulfinyl, sulfonyl, S-sulfonamido, N-Sulfonamido, trihalomethanesulfonyl, carbonyl, C-carboxyl, O-carboxyl, C-amido, N-amido, cyano, nitro, halo, O-carbamyl, N-carbamyl, O-thiocarbamyl, phosphonyl, N-thiocarbamyl, guanyl, guanidino, ureido, amino, trihalomethane-sulfonamido, and —NR12R13;
• wherein
• R12 and R13 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, C-carboxy, sulfonyl, trihalomethanesulfonyl and, combined, a five- or six-member heteroalicyclic ring;
• When any of R3, R4, R5 and R6 are hydrogen, R3′, R4′, R5′ and R6′, respectively, in addition to being independently selected from the above group, may be independently selected from the group consisting of hydroxy and thiohydroxy;
• Combined, R3 and R3′, R4 and R4′, R5 and R5′ and R6 and R6′ may be independently selected from the group consisting of keto, five-member spirocycloalkyl, five-member spiroheteroalicyclyl, six-member spirocycloalkyl and six member spiroheteroalicyclyl;
• R7 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, trihalomethanecarbonyl, alkenyl, alkynyl, aryl, heteroaryl, C-carboxy, O-carboxy, c-amido, halo, cyano, hydroxy, alkoxy, sulfonyl and trihalomethanesulfonyl,
• R8, R9, R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, trihaloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, cycloalkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkyoxy, thiocycloalkoxy, thioheteraryloxy, thioheteralicycloxy, halo, nitro, cyano, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, silyl, phosphonyl, C-carboxy, O-carboxy, N-amido, C-amido, sulfinyl, sulfonyl, S-sulfonamido, N-sulfonamido, trihalomethanesulfonyl, guanyl, guanidino, trihalomethanesulfonamido, amino and —NR12R13, wherein,
• R12 and R13 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, C-carboxy, sulfonyl, trihalomethanesulfonyl and, combined, a five- or six-member heteroalicyclic ring;
• and physiologically acceptable salts and prodrugs thereof.