The synthesis of substituted pyrimidinone carboxamides

The synthesis of 2-substituted pyrimidinone carboxamides – is outlined in , . Treatment of readily accessible nitriles with N-methylhydroxylamine hydrochloride in the presence of Sennoside D provided the adducts , which were subsequently reacted with diethyl acetylenedicarboxylate to afford inseparable mixtures of and with nitrile or 2,5-dihydro-1,2,4-oxadiazole intermediates with nitriles . Heating a xylenes solution of or at reflux provided the desired pyrimidinone esters . Treatment of and with benzoic anhydride in pyridine furnished benzoate esters and . Oxidation of intermediate with mCPBA yielded the sulfone , which was subsequently converted into cyclopentyl derivative by reacting with 1,4-diiodobutane in the presence of CsCO. Finally, heating with 4-fluorobenzylamine and triethylamine provided the final compound , the methylsulfonyl moiety was expelled by -ene reaction under thermal condition. The C2-cyclopentyl compound was prepared by heating intermediate with 4-fluorobenzylamine. Treatment of methylthiofuranyl intermediate with -butyl carbonazidate (Boc-N) in the presence of anhydrous ferrous chloride furnished the 2,5-dihydrofuranyl derivative . Reaction of Boc-N with generates a transient sulfanylidene intermediate which instantaneously undergoes -ene reaction to afford . Heating with 4-fluorobenzylamine and triethylamine yielded final compound , which was subsequently converted to C2-tetrahydrofuran-3-yl derivative by reducing the double bond under hydrogenation condition. Methylthiotetrahydrofuranyl analog was obtained by heating with excess 4-fluorobenzylamine and triethylamine in DMF. The spirocyclic pyrimidinone carboxamides were prepared following the synthesis sequence shown in . Alkylation of cyclopentylcarbonitrile with 3-chloro-4-iodopropane led to the intermediate . Heating with hydroxylamine hydrochloride in the presence of base gave spirocyclic intermediate , which when treated with diethyl acetylenedicarboxylate yielded the tricyclic spirocycle . Upon heating the solution of in refluxing 2,4-dichlorotoluene afforded the desired pyrimidinone ester . The final spirocyclic pyrimidinone carboxamides were prepared by heating with appropriate benzylamine in the presence of triethylamine. Finally, the bicyclic pyrimidinone carboxamides were prepared in five steps starting from simple starting materials as illustrated in . The nitrile was prepared from acetone cyanohydrin and 2-chloroethanol by following the procedure reported in the literature. Treatment of with 50% aqueous hydroxylamine in the presence of sodium iodide provided intermediate , which upon exposure to diethyl acetylenedicarboxylate yielded intermediate . Pyrolysis of in boiling 1,2,4-trimethylbenzene furnished the pyrimidinone ester , which was converted into the desired carboxamides by reacting with appropriate benzylamine and triethylamine at 90 °C. Observations of differences in the biological activities between the unsaturated and saturated C2-substituted pyrimidinone carboxamides led to the hypothesis that the geometric arrangement between the C2-substituent and the pyrimidinone core was an important factor. This led to the concept of a spirocycle-based pyrimidinone chemotype designed to mimic what was hypothesized to be the bound conformation of . The synthesis and evaluation of the spirocyclic carboxamides validated the design proposal, but these molecules suffered from poor physicochemical and pharmacokinetic properties. This was addressed by truncating the spirocyclic ring and introducing a heteroatom into the fused saturated ring of to provide compounds with reduced lipophilicity. The antiviral activity, preclinical pharmacokinetics and safety profile of BMS-707035 () supported continued development into phase I clinical trials conducted in normal healthy human volunteers. Single oral doses of 200, 600, 800 and 1200 mg of were well tolerated with no clinically significant adverse events noted. The mean C following the 600 mg QD dose was 340 ng/mL which is approximately 1.9-fold the protein binding-adjusted-EC value of 180 ng/mL, lending support to a 600 mg QD dose being sufficient to significantly inhibit viral replication in HIV-1-infected subjects. Unfortunately, further development of was halted due to the occurrence of convulsions in two dogs with high Cmax exposure (≥67 μg/mL) in a 12 month toxicological study.