Novel spiro compounds useful as inhibitors of stearoyl-coenzyme A delta-9 desaturase and their preparation and use in the treatment of diseases.

Abstract

Heteroarom. compds. of structural formula I are selective inhibitors of stearoyl-CoA delta-9 desaturase (SCD1) relative to other known stearoyl-CoA desaturases. The compds. of the invention are useful for the prevention and treatment of conditions related to abnormal lipid synthesis and metab. Compds. of formula I wherein Z is S, SO, SO2, O, etc.; B is 5-membered heteroaryl; D and E are independently (CH2)0-2; n is 0 to 2; m is 0 to 4; t is 0 to 8; each R1 is independently H, halo, and (un)substituted C1-3 alkyl; each R2 is H, halo, (un)substituted aryl, (un)substituted heteroaryl; each R3 is H, halo, (un)substituted C1-6 alkyl, etc,; R4 is substituted tetrazolyl, substituted thiazolyl, substituted oxazolyl, etc.; and pharmaceutically acceptable salts thereof, are claimed. Example compd. II was prepd. by cross-coupling of tert-Bu -(trifluoromethylsulfonyloxy)-1'H-spiro[chromene-2,4'-piperidine]-1'-carboxylate with 2-chlorophenylboronic acid followed by hydrolysis; the resulting 4-(2-chlorophenyl)spiro[chromene-2,4'-piperidine] hydrochloride underwent N-arylation with tert-Bu [5-(2-bromothiazol-5-yl)-2H-tetrazol-2-yl]acetate followed by hydrolysis to give compd. II. All the invention compds. were evaluated for their SCD1 inhibitory activity. From the assay, it was detd. that compd. II exhibited IC50 value of 0.92 nM. [on SciFinder(R)]