Smithkline Beecham Corporation

Glaxo Wellcome Inc.

Lee Frederick Kuyper

Karen Elizabeth Lackey

Philip Anthony Harris

James Marvin Veal

Michael Luzzio

Scott Howard Dickerson

Stephen Thomas Davis

Robert Neil Hunter, Iii

Duncan Herrick Walker

Robert Walton McNutt, Jr

Stephen V Frye

Edgar Raymond Wood, Iii

Kimberley Caroline Glennon

Robert N Hunter

Michael Robert Peel

Compounds of formula (I) wherein R1, R2, R3, R4, R5, R6, R7, R8, A, D, X, Y and Z have the meaning as defined in the claims exhibit protein tyrosine kinase and protein serin/threonine kinase inhibitory activity.

Compounds

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.

Substituted oxindole derivatives as protein tyrosine and as protein serine/threonine kinase inhibitors and compositions and methods of treating chemotherapy and radiation therapy side effects

The present invention is related to oxindole derivatives of structure (I), compositions containing the same, and methods of use and manufacture of the same. Such compounds generally are useful pharmacologically as agents in those disease states alleviated by the alteration of mitogen activated signaling pathways in general, and in particular in the inhibition or antagonism of protein kinases, which pathologically involve aberrant cellular proliferation. Such disease states include tumor growth, restenosis, atherosclerosis, pain and thrombosis, In particular, the present invention relates to a series of substituted oxindole compounds, which exhibit Trk family protein tyrosine kinase inhibition, and which are useful in cancer therapy and chronic pain indications.

Substituted oxindole derivatives as tyrosine kinase inhibitors

The present invention is related to oxindole derivatives of structure (I), compositions containing the same, and methods of use and manufacture of the same. Such compounds generally are useful pharmacologically as agents in those disease states alleviated by the alteration of mitogen activated signaling pathways in general, and in particular in the inhibition or antagonism of protein kinases, which pathologically involve aberrant cellular proliferation. Such disease states include tumor growth, restenosis, atherosclerosis, pain and thrombosis. In particular, the present invention relates to a series of substituted oxindole compounds, which exhibit Trk family protein tyrosine kinase inhibition, and which are useful in cancer therapy and chronic pain indications.

Oxindole derivatives

Substituted aza-oxindole derivatives useful as cyclin dependent kinase II inhibitors, for preventing/reducing the severity of epithelial cytotoxicity side-effects (e.g., alopecia, plantar-palmar syndrome, mucositis) induced by chemoptherapy and/or radiation therapy in a patient receiving such therapy.

Substituted aza-oxindole derivatives

Substituted aza-oxindole derivatives useful as cyclin dependent kinase 11 inhibitors, for preventing/reducing the severity of epithelial cytotoxicity side-effects (e.g., alopecia, plantar-palmar syndrome, mucositis) induced by chemoptherapy and/or radiation therapy in a patient receiving such therapy.

Compounds of formula (I): wherein X is N, CH, CCF , or C(C aliphatic); R is sulfonic acid, C aliphatic-sulfonyl, sulfonyl-C aliphatic, C aliphatic-sulfonyl-C aliphatic, C aliphatic-amino, R -sulfonyl, R sulfonyl-C aliphatic, R -aminosulfonyl, R -aminosulfonyl-C aliphatic, R -sulfonylamino, R -sulfonylamino-C aliphatic, aminosulfonylamino, di-C aliphatic amino, di-C aliphatic aminocarbonyl, di-C aliphatic aminosulfonyl, di-C aliphatic amino, di-C aliphatic aminocarbonyl, di-C aliphatic aminosulfonyl-C aliphatic, (R ) -Arylamino, (R ) -Arylsulfonyl, (R ) -Aryl-aminosulfonyl, (R ) -Aryl-sulfonylamino, Het-amino, Het-sulfonyl, Het-aminosulfonyl, aminoiminoamino, or aminoiminoaminosulfonyl, R is hydrogen; and further wherein R and R are 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.

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

The present invention relates generally to novel substituted oxindole compounds and compositions. Such compounds and compositions have utility as pharmacological agents in treating diseases or conditions alleviated by the inhibition or antagonism of protein kinase activated signalling pathways. 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 inhibiting tumor growth via inhibition of such kinases as well as protecting a patient undergoing chemotherapy from chemotherapy induced alopecia.

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

The present invention relates generally to novel amine substituted oxindole compounds and compositions. Such compounds and compositions have utility as pharmacological agents in treating diseases or conditions alleviated by the inhibition or antagonism of protein kinase activated signalling pathways in general, and in particular in the pathological processes which involve aberrant cellular proliferation, such as tumor growth. 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 inhibiting tumor growth via inhibition of tumor-related angiogenesis.

Growing community of inventors

Durham, NC, United States of America

Lee Frederick Kuyper