Synthesis of [1,2,4]-triazolo[1,5-a]pyrimidines by Dimroth rearrangement of [1,2,4]-triazolo[4,3-a]pyrimidines: A theoretical and NMR study

Novel [1,2,4]-triazolo-[1,5-a]pyrimidine derivatives were prepared by oxidative cyclization of suitable N-benzylidene-N′-pyrimidin-2-yl hydrazine precursors, followed by a Dimroth rearrangement. Reaction of 6-bromo-[1,2,4]-triazolo-[4,3-a]pyrimidines with aliphatic amines under microwave irradiation gave the unexpected 5-amino compounds from an ANRORC-type mechanism. Full NMR and HRMS characterization was done for all the obtained compounds. DFT calculations of absolute shielding permitted to predict 1H, 13C and 15N chemical shifts, which were in good agreement with the experimental ones. Theoretical studies at the B3LYP/6-311++G(d,p) level corroborated that [1,2,4]-triazolo-[1,5-a]pyrimidines were more stable than their [4,3-a] counterparts. © 2010 Elsevier B.V. All rights reserved.Peer Reviewe

Fragment-hopping-based discovery of a novel chemical series of proto-oncogene PIM-1 kinase inhibitors.

A new chemical series, triazolo[4,5-b]pyridines, has been identified as an inhibitor of PIM-1 by a chemotype hopping strategy based on a chemically feasible fragment database. In this case, structure-based virtual screening and in silico chemogenomics provide added value to the previously reported strategy of prioritizing among proposed novel scaffolds. Pairwise comparison between compound 3, recently discontinued from Phase I clinical trials, and molecule 8, bearing the selected novel scaffold, shows that the primary activities are similar (IC(50) in the 20 to 150 nM range). At the same time, some ADME properties (for example, an increase of more than 45% in metabolic stability in human liver microsomes) and the off-target selectivity (for example, an increase of more than 2 log units in IC(50)vs. FLT3) are improved, and the intellectual property (IP) position is enhanced. The discovery of a reliable starting point that fulfills critical criteria for a plausible medicinal chemistry project is demonstrated in this prospective study

Annotated database of chemically feasible fragments.

<p>Annotated database of chemically feasible fragments.</p

Reagents and conditions.

<p>(a) Triethyl Phosphonoacetate, NaEtO and EtOH; (b) TfOH and pyridine; (c) primary amine and dioxane; (d) BBr₃ and DCM.</p

Compound 8, containing a triazolopyridine, showed better selectivity profiling than compound 3.

<p>IC₅₀ values were obtained as described in the Methods Section. The values reported are an average of two independent data points. Inhibitors were used at a final concentration of 10 µM^a (3) and 5 µM^b (8), respectively. ^cThis designation indicates that the improvement in percentage of inhibition was greater than 50%. IC₅₀ values were obtained as described in the Methods Section. Details of assay conditions can be found at <a href="http://www.ProQinase.com" target="_blank">www.ProQinase.com</a>.</p

Identification ofN,1,4,4-Tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a Potent, Orally Available Cyclin Dependent Kinase Inhibitor

The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described. Starting from compound 1, showing good potency as inhibitor of CDKs but being poorly selective against a panel of serine−threonine and tyrosine kinases, new analogues were synthesized. Enhancement in selectivity, antiproliferative activity against A2780 human ovarian carcinoma cells, and optimization of the physical properties and pharmacokinetic profile led to the identification of highly potent and orally available compounds. Compound 28 (PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma model showed good efficacy and was well tolerated upon repeated daily treatments, was identified as a drug candidate for further development. Compound 28 is currently undergoing phase I and phase II clinical trials

The 66 selected fragments, with their substructures shown in magenta, were functionalized according to the compound 2 substitution pattern before performing docking studies.

<p>The chemotype borne by compound 5 was functionalized accordingly and becomes 5′, after which it was docked.</p