The imidazopyridines and related imidazopyrimidines

The imidazopyridines and related imidazopyrimidines – and – were constructed from the key amine intermediates – ( X=CH and Ar=2-FPh, X=N and Ar=2-FPh, X=CH and Ar=5-pyrimidine, X=CH and Ar=2-methyl-5-pyrimidine, and X=CF and Ar=2-methyl-5-pyrimidine). These were synthesized a modified Horner–Emmons condensation of an α-aminophosphonate ester with an aldehyde followed by hydrolysis of the resultant enamine to give the intermediate ketones –. Simple oxime formation from the ketone followed by reduction with zinc and ammonium acetate gave amines – (). From amines –, test compounds could be synthesized in either two ways. For compound , was reacted with commercially available triazole carboxylic alisertib using water soluble carbodiimide and HOBT to give an intermediate amide which was cyclized with POCl to give the triazole (). The other compounds were made using an alternative procedure () as the substituted triazole carboxylic acids were not commercially available. The route involved some functional group manipulation but the chemistry was very straight forward. The first step involved addition of methyl oxalyl chloride to amines – followed by cyclo-condensation with POCl to give esters –. These esters were converted to the amides by aminolysis and dehydrated to nitriles – using TFAA in pyridine. The nitriles were reacted with hydrazine to give the versatile late stage amidrazone intermediates –, which were then cyclo-condensed with a number of carboxylic acids to give the substituted triazoles –, , and –. Methylsulfone analog was synthesized by addition of 1,1′-thiocarbonyldiimidazole to the amidrazone followed by methylation with methyl iodide and finally oxidation with Oxone™. Amide was synthesized by first reacting amidrazone with ethyl oxalylchloride followed by aminolysis of the resultant ester. The reversed imidazopyridazine (X=N) and imidazopyridine (X=CH) were synthesized according to . Ethyl 2-pyridylacetate and ethyl 3-pyridazinylacetate – were each converted to the amino esters – by nitration followed by hydrogenation of the oxime to the amine in the presence of HCl due to stability of the free base. The amine was reacted with 2-fluorophenylacetic acid and water soluble carbodiimide then cyclo-condensed with POCl to give esters –. The ester was hydrolyzed to the acid, converted to the primary amide, dehydrated to the nitrile and finally converted to the amidazone – in a similar sequence to that shown in . – were then reacted with trifluoroacetic anhydride (TFAA) to give the CF triazoles and . Compounds and were synthesized from late stage nitrile intermediates – previously described in the literature, converted into the amidrazones – through a similar sequence shown in then finally reacted with TFAA to give the CF triazoles (). The primary screen was a cell based enzyme assay and the more active compounds tested in isolated rat aorta ()., The pyrazolopyridine core was changed to an imidazopyridine in the first instance because it was novel, kept the key nitrogen required for activity based on previous SAR and was synthetically accessible. Simple alkyl substituents on the triazoles (compounds –) gave a range of potencies, while the more polar electron withdrawing groups such as the sulfone and primary amide being fairly weak. The CF triazole had the best balance of potency and physicochemical properties, with the p of the NH around 6.5 and good potency in isolated rat aorta. The imidazopyridine core was modified by moving/adding nitrogens to the ring to give compounds –. Potency did improve for compound but not for the other variants. Modification of the 2-fluorophenyl group to the pyrimidine gave an improvement in terms of solubility and ADME properties without having a deleterious effect on potency presumably driven by the lower log. The biggest problem with this compound was its potent CYP1A2 inhibition likely caused by its flat conformation and the accessible unflanked nitrogens on the pyrimidine ring. Sterically hindering the two nitrogens by placement of a methyl group between them (compound ) mitigated the CYP1A2 liability, however, the compound was less potent. Placing a fluorine on the pyridine ring in the 6-position to give compound brought back the potency without greatly affecting the overall properties.