Substituted oxindole derivatives as protein tyrosine kinase and as protein serine/threonine kinase inhibitors

The present invention provides novel compounds, novel compositions, method of their use and methods of their manufacture, such compounds generally useful pharmacologically as agents in those disease states alleviated by the alteration of mitogen activated signalling pathways in general, and in particular in the inhibition or antagonism of protein kinases, which pathologically involve aberrant cellular proliferation, such disease states including tumor growth, restenosis, atherosclerosis, and thrombosis. In particular, the present invention relates to a series of substituted oxindole compounds, which exhibit protein tyrosine kinase and protein serine/threonine kinase inhibition, and which are useful in protecting a patient undergoing chemotherapy from chemotherapy-induced alopecia. Compounds of formula (I): wherein X is N, CH, CCF, or C(Caliphatic); Ris sulfonic acid, Caliphatic-sulfonyl, sulfonyl-Caliphatic, Caliphatic-sulfonyl-Caliphatic, Caliphatic-amino, R-sulfonyl, Rsulfonyl-Caliphatic, R-aminosulfonyl, R-aminosulfonyl-Caliphatic, R-sulfonylamino, R-sulfonylamino-Caliphatic, aminosulfonylamino, di-Caliphatic amino, di-Caliphatic aminocarbonyl, di-Caliphatic aminosulfonyl, di-Caliphatic amino, di-Caliphatic aminocarbonyl, di-Caliphatic aminosulfonyl-Caliphatic, (R)-Arylamino, (R)-Arylsulfonyl, (R)-Aryl-aminosulfonyl, (R)-Aryl-sulfonylamino, Het-amino, Het-sulfonyl, Het-aminosulfonyl, aminoiminoamino, or aminoiminoaminosulfonyl, Ris hydrogen; and further wherein Rand Rare optionally joined to form a fused ring, pharmaceutical formulations comprising them and their use in therapy, especially in the treatment of diseases mediated by CDK2 activity, such as alopecia induced by cancer chemotherapy or radiotherapy.