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

A compound according to formula I,

• its enantiomers, diastereomers, tautomers, a prodrug ester thereof, or a pharmaceutically-acceptable salt, or hydrate, thereof, wherein:
• the side chain group
• is attached to the bicyclic ring
• at the 5- or 6-position;
• is heterocyclo or heteroaryl;
• E is selected from —N—, —NR1—, —O—, C(═O)—, —S—, —SO2—, and —CR2—;
• F is selected from —N—, —NR1a—, —O—, —C(═O)—, —S—, SO2—, and —CR2a—;
• G is selected from N, —NR1b—, —O—, —C(═O)—, —S—, SO2—, and —CR2b—, provided that the E-F-G containing heterocyclic ring formed does not contain a S—S or S—O bond, and at least one of E, F and G is a heteroatom;
• J is C or N;
• Ja is C or N, provided that only one of J and Ja can be N, and each of J and Ja can be C;
• and that when E is CR2, F is N and G is NR1b, then Ja is C;
• M is selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclo other than piperidinyl;
• Ma is a linker between C and M and is selected from a bond;
• C1-C5 alkylene;
• C1-C5 alkylene which includes at any position in the chain a) a nitrogen which is substituted with alkyl, b) an oxygen, c) a sulfur, or d) an SO2 group;
• —C(Rm1)(Rm2)C(═O)N(Rm3)—;
• —C(Rm1)(Rm2)S(═O)2N(Rm3)—;
• Oalkyl;
• —N(Rm3)C(═O)C(Rm1)(Rm2)—;
• —S(═O)2N(Rm1)C(Rm2)(Rm3)—;
• and —N(Rm1)C(═O)N(Rm2)—;
• where Rm1, Rm2 and Rm3 are the same or different and at each occurrence independently selected from H and C1-C4 alkyl, or Rm1 and Rm2 combine to form a C3-6 carbocyclic or heterocyclo ring;
• Q is selected from
• (i) hydrogen, halogen, nitro, cyano, hydroxy, and C1-C4 alkyl;
• or
• (ii) Q and R6 are combined with the carbons to which they are attached to form a 3- to 6-membered cycloalkyl;
• or
• (iii) Q and -Ma-M are combined with the carbons to which they are attached to form a 3- to 7-membered ring containing 0, 1 or 2 heteroatoms which are the same or different and are independently selected from the group consisting of O, S, SO2, and
• which ring may be optionally substituted with 0-2 R3 groups or carbonyl;
• Z is selected from alkyl, cycloalkyl, heterocyclo, aryl, alkylsulfonyl, and heteroaryl other than substituted or unsubstituted 4-pyridyl;
• Za is a linker between N and Z and is selected from a bond;
• C1-C5 alkylene;
• C1-C5 alkylene which includes at any position in the chain a nitrogen which is substituted with alkyl or an SO2 group;
• —C(Rz1)(Rz2)C(═O)N(Rz3)—;
• —C(═O)N(Rz1)C(Rz2)(Rz3)—;
• —C(Rz1)(Rz2)S(═O)2N(Rz3)—;
• or —S(═O)2N(Rz1)C(Rz2)(Rz3)—;
• where Rz1, Rz2 and Rz3 at each occurrence are independently selected from H and C1-C4 alkyl;
• R1, R1a and R1b are the same or different and at each occurrence are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclo;
• R2, R2a and R2b are the same or different and at each occurrence are independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, —OR10, —NR10R11, —C(═O)R10, —CO2R10, —C(═O)NR10R11, —O—C(═O)R10, —NR10C(═O)R11, —NR10C(═O)OR11, —NR10C(S)OR11, —S(═O)pR12, —NR10SO2R12, —SO2NR10R11, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclo, aryl, and heteroaryl;
• R3 at each occurrence is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, —OR13, —NR13R14, —C(═O)R13, —CO2R13, —C(═O)NR13R14, —O—C(═O)R13, —NR13C(═O)R14, —NR13C(═O)OR14, —NR13C(S)OR14, —S(═O)pR15, —NR13SO2R15, —SO2NR13R14, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclo, aryl, and heteroaryl;
• R4 is selected from hydrogen, alkyl, halogen, and C1-C4 alkoxy;
• R6 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, —OR16, —NR16R17, —C(═O)R17, —CO2R17, —C(═O)NR16R17, —O—C(═O)R16, —NR16C(═O)R17, —NR16C(═O)OR17, —NR16C(═S)OR17, —S(═O)pR18, —NR16SO2R18, —SO2NR16R17, cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl;
• R7 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, nitro, cyano, —OR19, —NR19R20, —C(═O)R19, —CO2R19, —C(═O)NR19R20, —O—C(═O)R19, —NR19C(═O)R20, —NR19C(═O)OR20, —NR19C(═S)OR20, —S(═O)pR21, —NR18SO2R21, —SO2NR19R20, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclo, aryl, and heteroaryl;
• or R6 and R7 are taken together with the carbon to which they are attached to form a cycloalkyl, cycloalkenyl, or heterocyclo group;
• R5, R10, R11, R13, R14, R16, R17, R19 and R20 are the same or different and at each occurrence are independently selected from
• (i) hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclo;
• or
• (ii) with respect to R3, R13 is taken together with R10;
• and/or with respect to R6, R16 is taken together with R17;
• and/or with respect to R7, R19 is taken together with R20 to form a 4- to 6-membered heteroaryl or heterocyclo ring;
• R12, R15, R18, and R21 are the same or different and are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclo;
• and
• p is 0, 1 or 2,
• provided that
• 1) at least one of Q, Ma-M, R6 and R7 must be other than hydrogen;
• or
• 2) when Q and R6 (and the carbons to which they are attached) combine to form a 3- to 7-membered carbocyclic ring, then —Za—Z cannot be C1-C5 alkyl;
• or
• 3) when Q and Ma-M combine to form a 3- to 7-membered carbocyclic ring, then —Za—Z cannot be C1-C5 alkyl;
• or
• 4) when Za is a bond, then Z is other than