Contrary to the isothiazole, the thiophene has two feasible positions that may be substituted to optimize for potency and PK. As shown in Schemes , we prepared a series of compounds a i with diverse substitutents on the C position on the thiophene ring. The amide derivatives b d plus the amine analog e have been ready following the sequence presented in Scheme . The amides have been obtained from thiophene carboxylic acid by a 3 step reaction sequence: amide coupling, Boc deprotection, and sulfone displacement. Lithium aluminum hydride reduction within the amide b presented the amine . Removal from the SEM group from amides and amine afforded the wanted analogs b e. Cyclic amines, such as the fluoro substituted piperidine analogs f and g, could also be synthesized by way of the reductive amination route as proven in Scheme . The important thing intermediate aldehyde c was ready by to begin with transforming methyl ester a to primary alcohol b which was then oxidized working with the Dess Martin reagent.
The synthetic route to compound i h is proven in Scheme . Compound h that has a methyl group with the benzylic place was prepared by a Ti mediated reductive amination reaction of ketone followed by acidic deprotection on the SEM group. As proven in Table , substituents at C place on the thiophene ring were far better tolerated, for instance, sulfonamide , amide , amine , and ketone extra resources provided potent Aurora A B inhibitors with selection of modest cellular activities. Converting the amide to your corresponding amine did not deliver a substantial enhancement in potency and that is various in the trend observed within the C series. To be able to decrease the metabolic oxidation within the piperidine ring, fluorine was integrated.
The introduction of 1 F group at the position of piperidine ring B-Raf kinase inhibitor somewhat improved the cell potency. In contrast, two fluorine substituents at the position with the piperidine ring resulted in a loss of cell activity. Benzylic webpage substitution using a methyl group to mitigate oxidation resulted from the reduction of Aurora A and B activity. Together with the individual C and C substituents optimized at the thiophene ring, we directed our next energy toward the preparation of thiophene derivatives with substituents at both C and C place. Scheme outlines the synthesis of C and C di substituted thiophene analogs. As shown in Scheme , amino thiophenes with many different substituent in the C place had been synthesized in accordance with the published method. A modified route was utilized to get a c which had numerous amine group on the C .
Ethyl chloro oxobutanoate was condensed with cyanoacetic acid by a Knoevenagel reaction to afford a as a mixture of and regioisomers. Remedy of the with an excess of various secondary amines followed by sulfur flakes in EtOH presented a c. Another major reaction was the direct conversion of ethyl ester in to the corresponding amide through an iPrMgCl mediated response.