1295516-49-2

Upstream product

• 65844-74-8 2-methylpropan-1,1,3-tricarboxylic acid trimethyl ester 
• 623-43-8 crotonic acid methyl ester 
• 1092460-40-6 methyl 3-(4,6-dihydroxypyrimidin-5-yl)butanoate 
• 623-43-8 methyl crotonate 

Downstream Products

• 1177447-31-2 4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one 
• 1001180-45-5 tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]-pyrimidin-4-yl)piperazine-1-carboxylate 
• 1001180-21-7 (R)-tert-butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]-pyrimidin-4-yl)piperazine-1-carboxylate 

Relevant academic research and scientific papers

AKT INHIBITOR

The present invention discloses an AKT inhibitor, and specifically relates to a compound represented by formula I or a pharmaceutically acceptable salt thereof. The present invention further provides a preparation method thereof, and the use thereof in prevention and/or treatment of a disease mediated by AKT protein kinase.

Discovery of chiral dihydropyridopyrimidinones as potent, selective and orally bioavailable inhibitors of AKT

During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK2. A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design and physical properties-based design resulted in replacement of a highly hydrophobic poly fluorinated aryl ring by a simple trifluoromethyl that led to identification of compound 6 with much improved physicochemical properties. Subsequent SAR studies led to the synthesis of new pyran analog 7 with improved cell potency. Further optimization of pharmacokintetics properties by increasing permeability with appropriate fluorinated alkyl led to compound 8 as a potent, selective AKT inhibitors that blocks the phosphorylation of GSK3β in vivo and had robust, dose and concentration dependent efficacy in the U87MG tumor xenograft model.

Synthesis of Akt inhibitor ipatasertib. part 1. Route scouting and early process development of a challenging cyclopentylpyrimidine intermediate

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.

AKT INHIBITORS

The present invention provides AKT inhibitors of the formula: Formula I The present invention also provides pharmaceutical compositions comprising compounds of Formula I, uses of compounds of Formula I and method of using compounds of Formula I.