3-methylidenyl-2-indolinone modulators of protein kinase

A compound having the chemical structure:

• 253
• wherein:
• A is selected from the group consisting of carbon and nitrogen;
• Q is selected from the group consisting of
• 254
• bonds a and b may be either single or double bonds as indicated by the dotted lines with the proviso that a and b are both single bonds or both double bonds in any one compound of this invention;
• r is 1 when a and b are double bonds;
• r is 2 when a and b are single bonds;
• R0 is selected from the group consisting of hydrogen, alkyl, —C(O)R19 and —C(O)OR19;
• R1 is selected from the group consisting of hydrogen, alkyl, alkoxy, halo, aryl, —(CH2)nOC(O)R19;
• —C(O)NR19;
• —C(O)OR19 and —(CH2)nR20, wherein:
• R19 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl and aryl;
• n is 1, 2, 3 or 4;
• R20 is selected from the group consisting of hydroxy, halo, —C(O)OR19, —OC(O)NR21R22;
• —OC(S)NR21R22, —OC(O)NHS2R21R22;
• —NR21R22and a heteroalicylic group containing at least one nitrogen atom in the ring, the ring being bonded to the adjacent CH2 group through the nitrogen atom;
• R2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, trihalomethyl, alkoxy, halo, —(CH2)nR20, —SO2NR21R22, —C(O)OR19, —C(O)R19, —NHC(O)OR19, —NR21R22and —N═CR23 wherein
• R21 and R22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic;
• R23 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl;
• R3 is selected from the group consisting of hydrogen, alkyl, trihalomethyl, alkoxy, aryl, aryloxy, heteraryl, heteroalicyclic, hydroxy, halo, —SO2NR21R22, —NHSO2R19, —C(O)OR19, —NR21R22 and —NHC(O)R24, wherein
• R24 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heteroalicyclic;
• R4 is selected from the group consisting of hydrogen, alkyl, alkoxy and halo;
• R5 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, halo, aryl and heteroaryl;
• R6 is selected from the group consisting of hydrogen, alkyl, alkoxy, halo, cycloalkyl, aryl and, combined with R18, a heteroalicyclic group having the structure
• 255
• wherein
• y and y′ are independently selected from the group consisting of hydrogen, alkyl and aryl;
• R7 is OR8, wherein R18 is selected from the group consisting of alkyl, —(CH)nR20 and, combined with R6 or R8, a heteroalicyclic group having the structure
• 256
• R8 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxy, halo, aryl, heteroaryl and, combined with R18, a heteroalicyclic ring having the structure
• 257
• R9 is selected from the group consisting of hydrogen, alkyl, alkoxy, halo and —NR21R22;
• R10 is selected from the group consisting of alkyl and —C(O)OR19;
• R11 is selected from the group consisting of hydrogen, alkyl and —C(O)OR19;
• R12 is —(CH2)nR20;
• R13 is either a bond through which Q is bonded to the rest of the molecule or a group selected from the group consisting of hydrogen and alkyl;
• R14 is either a bond through which Q is bonded to the rest of the molecule or a group selected from the group consisting of hydrogen, alkyl and —(CH2)nR20;
• R15is either a bond through which Q is bonded to the rest of the molecule or hydrogen;
• with the proviso that only one of R13, R14 or R15 is the bond linking Q to the rest of the molecule in any one compound herein;
• R16 and R17, when a and b are single bonds, are independently selected from the group consisting of hydrogen, alkyl and aryl and, when a and b are double bonds, R16 is hydrogen and R17 does not exist;
• and,
• physiologically acceptable salts thereof.