MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-KB ACTIVITY AND USE THEREOF

摘要

Novel non-steroidal compounds are provided which are useful in treating diseases associated with modulation of the glucocorticoid receptor, AP-1, and/or NF-?B activity, including metabolic and inflammatory or immune associated diseases or disorders having the structure of formula I or an enantiomer, diastereomer, tautomer, or a pharmaceutically-acceptable salt, thereof, wherein: A is a 5-, 6-, or 7-membered heterocyclo or heteroaryl, each containing 1, 2, or 3 heteroatoms selected from N, O, and S and substituted with one to four groups, R₁, R₂, R₃, and/or R₄, provided that (i) A is not tetrazole or (ii) if A is thienyl or furanyl then Z is selected from a group other than succinimido or thalimido; M is selected from alkyl, cycloalkyl, aryl, heterocyclo, and heteroaryl; Ma is a linker between C and M and is selected from a bond and C₁-C₃alkylene; Q is selected from (i) hydrogen, halogen, nitro, cyano, hydroxy, C₁-4alkyl, and substituted C₁-4 alkyl; or (ii) Q is combined with R6 and with the carbon atoms to which they are attached to form a 3- to 6-membered cycloalkyl; or (iii) Q and M are combined with the carbon atom(s) to which they are attached to form a 3- to 7-membered ring containing 1-2 heteroatoms which are independently selected from the group consisting of O, S, SO₂, and N which ring may be optionally substituted with 0-2 R₅ groups or carbonyl; and Z is selected from alkyl, CF₃, OH, cycloalkyl, heterocyclo, aryl, heteroaryl, -C(=O)NR₈R₉, -C(=O)R₈, -C(NCN)NR₈R₉, -C(=O)OR₈, -SO₂R₈, and -SO2NR8R9. M_a, Z_a, R₁, R₂, R₃, R5_a, R₆, R₇, R₈, R₉ and R₂₂ are as defined herein. Also provided are pharmaceutical compositions, combinations and methods of treating metabolic and inflammatory or immune associated diseases or disorders using said compounds.