Preparation of heteroaryl piperidine derivatives as stearoyl CoA desaturase inhibitors.

Abstract

Title compds. I [A = -CONHR1 or ER2; R1 = alkyl, cycloalkyl or alkoxy (wherein alkyl, cycloalkyl and alkoxy are optionally substituted with halo, hydroxy, cyano, etc.); E = heterocyclyl; R2 = alkyl (optionally substituted with halo, hydroxy, cyano, etc.); R3 = H, halo or alkyl; R4 = H, halo or alkyl; R5 = aryl or heterocyclyl (wherein aryl and heterocyclyl are optionally substituted with halo, alkyl, haloalkyl, etc.); R6 = H or halo; V = :CH- or nitrogen atom; W = :CH- or nitrogen atom; with the proviso that V and W can not be :CH- simultaneously; Y = carbonyl, -C(:CH2)-, -C(:N-OR7)-, etc.; R7 = H or alkyl; m = 0-2; n = 0-2] or their pharmacol. acceptable salts were prepd. For example, oxidn. of 4-[(hydroxy)(o-tolyl)methyl]-piperidine-1-carboxylic acid tert-Bu ester, e.g., prepd. from N-Boc-4-piperidinemethanol in 2 steps, followed by treatment with HCl and reaction with 6-chloropyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl)amide afforded compd. II [X1 = H; X2 = methyl]. In stearoyl CoA desaturase inhibition assays, the IC50 of compd. II [X1 = F; X2 = H] was 0.1 μM. Compds. I are claimed useful for the treatment of obesity, hyperlipidemia, etc. Pharmaceutical compns. comprising I are disclosed. [on SciFinder(R)]