High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identifying compounds with improved cellular potency, improved aqueous solubility, and good stability in human hepatocyte incubations. Knowledge from empirical SAR investigations was combined with an understanding of the molecular interactions in the crystal lattice to improve both cellular potency and solubility, and the composite parameters of LLE and pIC50-pSolubility were used to assess compound quality and progress. Predictive models were employed to efficiently mine the attractive chemical space identified resulting in the discovery of 42 (AZD3147), an extremely potent and selective dual inhibitor of mTORC1 and mTORC2 with physicochemical and pharmacokinetic properties suitable for development as a potential clinical candidate.

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A scalable route to histone deacetylase inhibitors containing an unusual 2-aryl-3-cyano-5-aminomethylpyridine core has been developed which has the flexibility to deliver a range of compounds on at least a multigram scale. The key step involves a novel Mannich reaction using 3-dimethylaminoacrolein, formaldehyde, and a secondary amine to yield a 2-(alkylaminomethyl)-3-dimethylaminoacrolein. Tuning of this reaction in process development was fundamental to the success of the approach in terms of flexibility and operability on scale-up. This new methodology will also enable access an underutilised family of 3,5-disubstituted pyrid-2-ones and 2,3,5-trisubstituted pyridines.