Pyrimidyl cyclopentanes as Akt protein kinase inhibitors

摘要

The present invention provides compounds of Formula I including tautomers, resolved enantiomers, resolved diastereomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs thereof.;;Also provided are methods of using the compounds of this invention as Akt protein kinase inhibitors and for the treatment of Akt-mediated diseases, for example, hyperproliferative diseases such as cancer.

主权项

1. A method of inhibiting Akt-1 protein kinase for treating or lessening the severity of a cancer in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Formula I:and tautomers, resolved enantiomers, resolved diastereomers, metabolites, salts and pharmaceutically acceptable prodrugs thereof, wherein:
R1 is H, CH3, CH2CH3, CH(CH3)2, CH═CH2, CH2OH, CF3, CHF2, CH2F, or C3-C6 cycloalkyl; R2 is H, OH, OCH3 or F; R3 is H, F or CH3; each R4 is independently selected from H, F, Cl, Br, I, CN, (CH2)tNR10R10, (CH2)tOR10, (CH2)tC(O)R10, (CH2)1C(O)OR10, (CH2)tC(O)NR10R10, (CH2)tNR10C(O)R10, (CH2)tNR10C(O)OR10, (CH2)tNR10C(O)NR10R10, C1-C6 alkyl, (CR10R10)tC3-C8 cycloalkyl, (CR10R10)tC3-C6 heterocyclyl, (CR10R10)tC6-C8 aryl, O(CR10R10)tC6-C8 aryl, (CR10R10)tC3- C6 heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more F, Cl, Br, I, CN, C1-C3 alkyl, CF3, OH or O(C1-C3 alkyl); R5 is H, C1-C6 alkyl, (CR10R10)tOR10, (CR10R10)tNR10R10, (CH2)tC3-C8 cycloalkyl, (CH2)tC6-C8 aryl, wherein said aryl is optionally substituted by F, Cl, Br or I; R6, R7, R8 and R9 are independently selected from H, C1-C6 alkyl, (CR10R10)tOR10, (CR10R10)tC6-C8 aryl; wherein said aryl is optionally substituted by F, Cl, Br or I; R10 is independently selected from H, OH, O(C1-C3 alkyl), (CH2)tNR11R11, (CH2)tC(O)NR11R11, (CH2)tS(O)NR11R11, (CH2)3S(O)2NR11R11, C3-C6 alkyl, (CH2)tC3-C8 cycloalkyl, (CH2)tC3-C6 heterocyclyl, (CH2)1C6-C8 aryl and (CH2)1C3-C6 heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more F, Cl, Br, I, CN, C1-C3 alkyl, CF3, OH, O(C1-C3 alkyl); or two R10 are taken together to form oxo or a C3-C6 heterocyclyl; R11 is independently selected from H, C1-C3 alkyl, OH, OC1-C3 alkyl, NH2, N(C1-C3 alkyl)2; or two R11 are taken together to form a C3-C6 heterocyclyl, optionally substituted by methyl or ethyl; m and n are independently 1, 2 or 3, provided that m and n taken together are 3, 4 or 5; p is 0, 1, 2 or 3; and each t is independently 0, 1, 2, 3 or 4.