The Synthetic Study Of Aminopyrimidines And Thiazoles Nitrogen-containing Heterocylcle Molecules

Recent medicinal chemistry research shows that multi-substituted aminopyrimidineshave a inhibitory activity against JNK3kinase, which induces Parkinson diseases, and atype of bithiazole compounds have the corrector activity on the mutant of cystic fibrosistransmembrane conductance regulator protein (ΔF508CFTR). In this study the synthesisof those two types of new biologically important compounds were achieved using easilyaccessible regents as raw materials via simple synthetic routes, laying solid materialfoundation for the study of structure-activity relationship of these compounds andscreening for lead compounds. This research indicates that:(1) The synthetic route which utilizes halobenzonitriles as starting materials and asequential transformations such as amidine formation, cyclization and substitutionreaction, and Buchwald-Hartwig coupling reaction between the chloropyrimidine andaromatic amines is feasible to give diversified multi-substituted aminopyrimidines. Eachstep of the above transformations is accomplished in good yields. A serial of analogs ofmulti-substituted aminopyrimidine could be obtained from commercially availablematerials, making the subsequent study of structure-activity relationship and screening oflead compounds convenient.It is aslo found that differently substituted arylamines behave very differently inthe Buchwald-Hartwig amination reaction. When an electron-donating group at theortho-position of an arylamine, a double coupling reaction is easy to occur to lead tothe formation N,N’-dipyrimidinyl derivative; when an electron-withdrawing group atthe ortho-position of arylamine, a single coupling reaction more likely to take place,and even trend to be inactive; while there was a special situation where an aromaticamine with an electron-donating group at meta-position and para-position, such as3-methylaniline and4-methylaniline, could react with the pyrimidine chloride to givethe singly coupled products; while the aromatic amine with electron-withdrawinggroup, m-aminoacetylbenzene and methyl4-aminobenzoate, gave doubly coupledproducts.(2) A bithiazole34reported in the work of Yoo et al was utilized as a leadcompound, a series of more hydrophilic thiazole-tethered bisazoles were designed using an atom replacement approach. The synthetic route which starts with commerciallyavailable materials such as thiourea and3-chloroacetylacetone, series of sequentialtransformations such as cyclization, amidation and two substitution reaction wererealized to give intermediate47, and then target compound thiazole-oxdiazole37andthiazole-thiadiazole38were generated with two different reagents such as4-toluenensulfonyl chloride and POCl3respectively. Biological assay results indicate thatthiazole-oxadiazole analog37retained the corrector activity, yet thiazole-thiadiazoles38was not active in correcting the mutant CFTR protein. In comparison with the CFTRcorrector activity of other analogues demonstrate that these thiazole-tethered bisazoleanalogs that are able to adopt an U-shaped with low energy input (within~1kcal/mol)can have the CFTR correction activity. The discovery of the U-shaped activeconformation could provides useful theoretical basis for the design of CFTR correctors inthe future.