Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 (43), and a backup clinical candidate, . Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.
(S)-N-(8-((2-Amino-2,4-dimethylpentyl)oxy)-5H-chromeno[3,4-c]pyridin-2-yl)acetamide
(1) is a potent adaptor-associated kinase 1 inhibitor,
which may have the potential to treat neuropathic pain and other neurological
disorders including schizophrenia, Parkinson’s disease, bipolar
disorder, and Alzheimer’s disease. For preclinical studies,
a substantial amount of high-quality material was required. The original
discovery route for the preparation of this compound suffered from
scale-up issues that included a very low-yielding C–O coupling
step and the use of expensive and toxic reagents. This paper describes
a rapid scale-up synthesis accomplished in eight steps, which involves
the coupling of phenol 17 with oxathiazolidine 18 as the key transformation.
This paper describes the efficient scale-up synthesis of 1 (BMS-963272) which relies upon a highly selective Mannich-type alkylation strategy to stereospecifically install a quaternary carbon center. An intramolecular cyclization reaction is also used to form the aryl dihydropyridone (ADHP) core. The optimized route has been demonstrated to provide more than 100 g of active pharmaceutical ingredient for preclinical toxicology evaluation. A catalyst screening effort is also discussed as part of a complimentary convergent approach which will facilitate a more expedient assessment of back-up molecules bearing aryl diversity at the C4-position of the ADHP core.
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