Preparation of amino acid derivatives as inhibitors of protein arginine methyl transferases.

Abstract

The invention relates to compds. I [X is Ph or 5-membered heteroaryl; R1 is H, halogen, CN, alkyl or substituted alkyl, alkoxy, alkylthio, or alkylsulfonyl; R2 is H or alkyl; R3 is H, Me, or Et; R4 is H, Me, Et, iso-Pr, CH2Ph, OH, or OPh; or R3 and R4 may form a 5- or 6-membered heterocycle; R5 is -W-(CH2)0-3-O0-1-R6, where W is CONH, 1,3,4-oxadiazole-2,5-diyl, etc and R6 is (un)substituted cycloalkyl, heterocyclyl, or aryl] or a stereoisomer, tautomer, or pharmaceutically-acceptable salt and their use in the treatment of hyperproliferative, inflammatory, infectious, and immunoregulatory disorders and diseases. Thus, I [R1-R3 = H, R4 = Me, R5-X = 5-(benzylcarbamoyl)-3-(trifluoromethyl)-1-pyrazolyl] was prepd. from 1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid by hydrogenation over Pd/C, followed by amidation reactions with Boc-Ala-OSu and benzylamine. The product was assayed for inhibition of tumor cell proliferation using the 3H thymidine incorporation protocol (IC50 < 10 μM). [on SciFinder(R)]