MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1 AND/OR NF-KAPPAB 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 CSUB1/SUB-CSUB3/SUBalkylene; Q is selected from (i) hydrogen, halogen, nitro, cyano, hydroxy, CSUB1/SUB-4alkyl, and substituted CSUB1/SUB-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, SOSUB2/SUB, and N which ring may be optionally substituted with 0-2 RSUB5/SUB groups or carbonyl; and Z is selected from alkyl, CFSUB3/SUB, OH, cycloalkyl, heterocyclo, aryl, heteroaryl, —C(O)NR8R9, —C(O)R8, —C(NCN)NR8R9, —C(O)OR8, —SO2R8, and —SO2NR8R9. MSUBa/SUB, ZSUBa/SUB, RSUB1/SUB, RSUB2/SUB, RSUB3/SUB, R5SUBa/SUB, RSUB6/SUB, RSUB7/SUB, RSUB8/SUB, RSUB9/SUB and RSUB22/SUB 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.