Preparation of heterocyclic carboxamides as modulators of kinase activity.

Abstract

Title compds. I [X = N, or C-R4; Y = N-R5, O, or absent; R1 = L1-R6, L1-R6-L2-R7; R2 = H, OH, CN, NH2, etc.; R3 = H, CH3, Or C(Hal)3; R4 = H, OH, COOH, NH2, or CN; R5 = H, LA or monocyclic alkyl; L1 and L2 independently = single bond, or (un)branched and (un)substituted alkyl; R6 = Ar or monocyclic alkyl; Ar = mono- or bicyclic arom. homo- or unsubstituted heterocycle, linear or cyclic alkyl; LA = (un)branched alkyl; Hal = F, Cl, Br or I; R7 = (un)substituted phenyl], and their stereoisomers, tautomers, or pharmaceutically acceptable salts, are prepd. and disclosed. Thus, e.g., II was prepd. by reaction of 5-bromoquinazoline-8-carbonitrile with tert-Bu trans-3-amino-4-[4-(trifluoromethoxy)phenyl]pyrrolidine-1-carboxylate to get intermediate tert-Bu trans-3-[(8-cyanoquinazolin-5-yl)amino]-4-[4-(trifluoromethoxy)phenyl]pyrrolidine-1-carboxylate which was treated with NaOH to get tert-Bu trans-3-[(8-carbamoylquinazolin-5-yl)amino]-4-[4-(trifluoromethoxy)phenyl]pyrrolidine-1-carboxylate which was underwent deprotection to provide II. Compds. of the invention were evaluated for their inhibitory activity in P70S6K enzyme assay and AKT enzyme assay, e.g., II showed IC50 value of 23 nM. The invention compds. are useful for the treatment of hyperproliferative diseases, such as cancer. [on SciFinder(R)]