N-BENZYLBENZIMIDAZOLE MODULATORS OF PPARG

摘要

The invention provides molecular entities that bind with high affinity to PPARG (PPARγ), inhibit cdk5-mediated phosphorylation of PPARG, but do not exert an agonistic effect on PPARG. Compounds of the invention can be used for treatment of conditions in patients wherein PPARG plays a role, such as diabetes or obesity. Methods of preparation of the compounds, bioassay methods for evaluating compounds of the invention as non-agonistic PPARG binding compounds, and pharmaceutical compositions are also provided.

主权项

1. A non-agonist PPARG modulatory compound of formula (IA) or (IB) or a pharmaceutically acceptable salt thereof:wherein:
R2 is H or (C1-C4)alkyl; R3 is optionally mono- or multi-substituted (C1-C8)alkyl, (C1-C8)alkenyl, (C1-C8)alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, or heterocyclylalkyl; wherein if present each substituent on R3 is independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl, (C3-C9)cycloalkyl, halo, nitro, cyano, CO2R′, methylenedioxy, OR′, N(R′)2, (C1-C4)alkyl-S(O)q, SO2NR′2, and (C1-C6)alkoxyl, wherein R′ is independently H, (C1-C6)alkyl, (C1-C6)haloalkyl, or (C3-C9)cycloalkyl, or wherein two R′ bonded to an atom together with the atom form a 3-8 membered ring optionally further comprising a heteroatom selected from the group consisting of O, NR′, and S(O)q, and wherein alkyl, alkenyl, alkynyl, aryl, arylalkyl, or cycloalkyl is optionally mono- or independently multi-substituted with (C1-C6) alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halo, OR′, N(R′)2, aryl, or aroyl; and wherein an alkyl or an alkyl group of a cycloalkylalkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl can be substituted with oxo; the ring bearing R4 is optionally a pyridine, optionally fused with a phenyl optionally substituted with n instances of R4, or both; each R4 is independently halo, nitro, CO2R′, CN, OR′, N(R′)2, (C1-C4)alkyl optionally substituted with OR′ or N(R′)2, C-bonded tetrazolyl, (C1-C4)alkyl-S(O)q, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl; or R4 is—(C(R′)2)mCO2R′ or —O(C(R′)2)mCO2R′ wherein m is 1, 2, or 3;
R is independently H or (C1-C6)alkyl optionally substituted with halo; n is 0, 1, or 2; q is 0, 1, or 2; Y is (C1-C2)alkyl, or sulfur; when Y is (C1-C2)alkyl, R5 and R6 are independently H or (C1-C4)alkyl or independently each R5 and R6 together with the carbon atom to which they are bonded form a carbonyl; and, when Y is sulfur, R5 and R6 are both oxygen.