Pyrimidyl cyclopentanes as Akt protein kinase inhibitors

摘要

The present invention provides compounds of Formula I, including tautomers, resolved enantiomers, 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 hyperproliferative diseases such as cancer.

主权项

1. A method of treating a hyperproliferative disease or disorder in a mammal that is mediated by Akt signaling, said method comprising administering to said mammal an effective amount of a compound of Formula I:or an enantiomer or a pharmaceutically acceptable salt thereof, wherein:
R1 and R1a are independently selected from H, Me, Et, vinyl, CF3, CHF2 or CH2F; R2 is H, OH, OMe or F; R2a is H, Me or F; R3 is H, Me, Et, or CF3; A is G is phenyl optionally substituted by one to four Re groups or a 5-6 membered heteroaryl optionally substituted by a halogen; R5 and R6 are independently H, OCH3, C3-C6-cycloalkyl optionally substituted with F, OH, C1-C3 alkyl or O(C1-C3 alkyl), 4-6 membered heterocycle optionally substituted with F, OH, C1-C3 alkyl, cyclopropylmethyl or C(=O)(C1-C3 alkyl), or C1-C6-alkyl optionally substituted with one or more groups independently selected from OH, oxo, O(C1-C6-alkyl), CN, F, NH2, NH(C1-C6-alkyl), N(C1-C6-alkyl)2, cyclopropyl, phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, oxetanyl or tetrahydropyranyl, or R5 and R6 together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF3, CH2CF3, CH2CH2OH, O(C1-C3 alkyl), C(=O)CH3, NH2, NHMe, N(Me)2, S(O)2CH3, cyclopropylmethyl and C1-C3 alkyl, or Rc is hydrogen and Rd and R6 together with the atoms to which they are attached form a 4 to 6 membered heterocyclic ring having one nitrogen atom; Ra and Rb are H, or Ra is H, and Rb and R6 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring having one or two ring nitrogen atoms; Rc and Rd are H or Me, or Rc and Rd together with the atom to which they are attached from a cyclopropyl ring; each Re is independently halogen, C1-C6-alkyl, C3-C6-cycloalkyl, O—(C1-C6-alkyl), CF3, OCF3, S(C1-C6-alkyl), CN, OCH2-phenyl, NH2, NO2, N—(C1-C6-alkyl)2, piperidine, pyrrolidine, CH2F, CHF2, OCH2F, OCHF2, OH, SO2(C1-C6-alkyl), C(O)NH2, C(O)NH(C1-C6-alkyl), and C(O)N(C1-C6-alkyl)2; m and n are independently 0, 1, 2 or 3 with the proviso that (m+n) must equal 2, 3 or 4; and p is 0 or 1.