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 inhibiting the activity of AKT in a mammal, said method comprising administering to said mammal an effective amount of a compound of the Formula: and enantiomers and salts thereof, wherein: R1 and R1a are independently selected from H, Me, Et, CH═CH2, CH2OH, CF3, CHF2 or CH2F; R2 and R2a are independently selected from H or F; R5 is H, Me, Et, or CF3; A is  wherein G is phenyl optionally substituted with one to four R9 groups or a 5-6 membered monocyclic or 9 member bicyclic heteroaryl optionally substituted by a halogen; R6 and R7 are independently H, (C3-C6 cycloalkyl)-(CH2), (C3-C6 cycloalkyl)-(CH2CH2), V—(CH2)0-1 wherein V is a 5-6 membered heteroaryl, W—(CH2)1-2 wherein W is phenyl optionally substituted with F, Cl, Br, I, OMe, CF3or Me, C3-C6-cycloalkyl, hydroxy-(C3-C6-cycloalkyl), fluoro-(C3-C6-cycloalkyl), CH(CH3)CH(OH)phenyl, 4-6 membered heterocycle optionally substituted with F, OH, cyclopropylmethyl, C1-C3alkyl or C(═O)(C1-C3alkyl), 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, tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, oxetanyl, piperidinyl, and pyrrolidinyl, or R6 and R7 together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring optionally substituted with one or more groups independently selected from OH, halogen, oxo, CF3, CH2CF3, CH2CH2OH, C(═O)CH3, and (C1-C3)alkyl; 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 form a cyclopropyl ring; R8 is H, Me, or OH, or R8 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; each R9 is independently halogen, C1-C6-alkyl, C3-C6-cycloalkyl, O—(C1-C6-alkyl), CF3, OCF3, S(C1-C6-alkyl), CN, OCH2-phenyl, CH2O-phenyl, NH2, NO2, NH—(C1-C6-alkyl), 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; and m, n and p are independently 0 or 1.