Thiazole compounds as PPAR modulators, their preparation, pharmaceutical compositions, and use in therapy.

Abstract

The invention relates to thiazole compds. of formula I, which are modulators of peroxisome proliferator-activated receptors (PPAR), particularly PPARδ. In compds. I, p is 0-3; L is selected from -XOX-, -XS(O)mX-, and -XS(O)mXO-, where m is 0-2 and X is a bond or (un)substituted C1-4 alkylene; R1 is selected from halo, C1-6 alkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, (un)substituted C6-10 aryl, (un)substituted C5-10 heteroaryl, (un)substituted C3-12 cycloalkyl, and (un)substituted C3-8 heterocyclyl; R2 is -XOXCO2R5 or -XCO2R5, where X is as defined previously and R5 is H or C1-6 alkyl; and R3 and R4 are independently selected from R6 and R6Y, where R6 is (un)substituted C3-12 cycloalkyl, (un)substituted C3-8 heterocyclyl, (un)substituted C6-10 aryl, and (un)substituted C5-13 heteroaryl, and Y is selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, -C(O)N(R5)-, and -OX-, where X and R5 are as defined previously, or R3 and R4, together with the atoms to which they are attached, form fused bi- or tricyclic C5-14 heteroaryl; including pharmaceutically acceptable salts, hydrates, solvates, isomers, and prodrugs thereof. The invention also relates to the prepn. of I, pharmaceutical compns. comprising a therapeutically effective amt. of compd. I in combination with one or more pharmaceutically acceptable excipients, as well as to the use of the compns. to treat or prevent diseases or disorders assocd. with PPAR activity. Cyclocondensation of 2-bromo-4'-methoxyacetophenone with thioacetamide followed by bromination, demethylation, and alkylation with iso-Pr iodide gave bromothiazole II, which was brominated and substituted with phenol III (prepn. in 3 steps from 4-hydroxy-3-methylacetophenone given) to give thiazole IV. Compd. IV underwent Suzuki coupling with 4-(trifluoromethoxy)phenylboronic acid and ester hydrolysis to give thiazole V. Most preferred compds. of the invention express an EC50 value for PPARδ of less than 100 nM. The compds. of the invention are at least 100-fold selective for PPARδ over PPARγ. [on SciFinder(R)]