- Synthesis of Akt inhibitor ipatasertib. part 1. Route scouting and early process development of a challenging cyclopentylpyrimidine intermediate
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Herein, the route scouting and early process development of a key cyclopentylpyrimidine ketone intermediate toward the synthesis of Akt inhibitor Ipatasertib are described. Initial supplies of the intermediate were prepared through a method that commenced with the natural product (R)-(+)-pulegone and relied on the early construction of a methyl-substituted cyclopentyl ring system. The first process chemistry route, detailed herein, enabled the synthesis of the ketone on a hundred-gram scale, but it was not feasible for the requisite production of multikilogram quantities of this compound and necessitated the exploration of alternative strategies. Several new synthetic approaches were investigated towards the preparation of the cyclopentylpyrimidine ketone, in either racemic or chiral form, which resulted in the discovery of a more practical route that hinged on the initial preparation of a highly substituted dihydroxypyrimidine compound. The cyclopentane ring in the target was then constructed through a key carbonylative esterification and subsequent tandem Dieckmann cyclization-decarboxylation sequence that was demonstrated in a racemic synthesis. This proof-of-concept was later developed into an asymmetric synthesis of the cyclopentylpyrimidine ketone, which will be described in a subsequent paper, along with the synthesis of Ipatasertib.
- Lane, Jonathan W.,Spencer, Keith L.,Shakya, Sagar R.,Kallan, Nicholas C.,Stengel, Peter J.,Remarchuk, Travis
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- COMBINATIONS OF AKT INHIBITOR COMPOUNDS AND VEMURAFENIB, AND METHODS OF USE
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The invention provides a combination of a) a compound of Formula Ia: [insert Formula Ia], or a pharmaceutically acceptable salt thereof, and b) vemurafenib or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of a hy
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- COMBINATIONS OF AKT AND MEK INHIBITOR COMPOUNDS, AND METHODS OF USE
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The invention provides combinations comprising a) compound of formula I : (formula I), or a pharmaceutically acceptable salt thereof; and another agent selected from GDC-0973, PD-0325901, or a pharmaceutically acceptable salt thereof. The combinations are
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- Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors
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The discovery and optimization of a series of 6,7-dihydro-5H-cyclopenta[d] pyrimidine compounds that are ATP-competitive, selective inhibitors of protein kinase B/Akt is reported. The initial design and optimization was guided by the use of X-ray structures of inhibitors in complex with Akt1 and the closely related protein kinase A. The resulting compounds demonstrate potent inhibition of all three Akt isoforms in biochemical assays and poor inhibition of other members of the cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family and block the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. Biological studies with one such compound, 28 (GDC-0068), demonstrate good oral exposure resulting in dose-dependent pharmacodynamic effects on downstream biomarkers and a robust antitumor response in xenograft models in which the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway is activated. 28 is currently being evaluated in human clinical trials for the treatment of cancer.
- Blake, James F.,Xu, Rui,Bencsik, Josef R.,Xiao, Dengming,Kallan, Nicholas C.,Schlachter, Stephen,Mitchell, Ian S.,Spencer, Keith L.,Banka, Anna L.,Wallace, Eli M.,Gloor, Susan L.,Martinson, Matthew,Woessner, Richard D.,Vigers, Guy P.A.,Brandhuber, Barbara J.,Liang, Jun,Safina, Brian S.,Li, Jun,Zhang, Birong,Chabot, Christine,Do, Steven,Lee, Leslie,Oeh, Jason,Sampath, Deepak,Lee, Brian B.,Lin, Kui,Liederer, Bianca M.,Skelton, Nicholas J.
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p. 8110 - 8127
(2012/11/13)
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- PYRIMIDYL CYCLOPENTANES AS AKT PROTEIN KINASE INHIBITORS
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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.
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Page/Page column 52
(2009/03/07)
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- HYDROXYLATED PYRIMIDYL CYCLOPENTANE AS AKT PROTEIN KINASE INHIBITOR
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The present invention provides a compound and pharmaceutically acceptable salts thereof, comprising the Formula I. Also provided are methods of using the compound of this invention as an AKT protein kinase inhibitor and for the treatment of hyperprolifera
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Page/Page column 31-32
(2009/09/04)
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- HYDROXYLATED PYRIMIDYL CYCLOPENTANES AS AKT PROTEIN KINASE INHIBITORS
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The present invention provides compounds, including pharmaceutically acceptable salts thereof, comprising the Formula (I): Also provided are methods of using the compounds of this invention as AKT protein kinase inhibitors and for the treatment of hyperpr
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Page/Page column 31
(2009/09/04)
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- HYDROXYLATED AND METHOXYLATED CYCLOPENTA [D] PYRIMIDINES AS AKT PROTEIN KINASE INHIBITORS
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The present invention provides compounds, including resolved enantiomers, resolved diastereomers, solvates and pharmaceutically acceptable salts thereof, comprising the Formula (I). 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.
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- CYCLOPENTA [D] PYRIMIDINES AS AKT PROTEIN KINASE INHIBITORS
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The present invention provides compounds of Formula I, including tautomers, resolved enantiomers, diastereomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs thereof. Formula (I). 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.
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