Glucocorticoid Mimetics, Methods of Making Them, Pharmaceutical Compositions, and Uses Thereof

A compound of Formula (IB)

• wherein:
• R1 is hydrogen or C1-C3 alkyl, each optionally independently substituted with one, two, or three substituent groups selected from hydroxy, halogen, or oxo;
• R2 is aryl optionally independently substituted with one, two, three, four, or five substituent groups,
• wherein each substituent group of R2 is independently C1-C5 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C5 alkoxy, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, halogen, cyano, acylamino, C1-C5 alkoxycarbonylamino, C1-C5 alkylsulfonylamino, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-C5 alkyl;
• or ureido wherein either nitrogen atom is optionally independently substituted with C1-C5 alkyl;
• or C1-C5 alkylthio,
• wherein each substituent group of R2 is optionally independently substituted with C1-C3 alkyl, halogen, hydroxyl, or amino,
• wherein R2 cannot be p-methylphenyl;
• R3 is C1-C8 alkyl independently substituted with one, two, three, four, or five substituent groups,
• wherein each substituent group of R3 is independently C3-C6 cycloalkyl, aryl, halogen, trifluoromethyl, trifluoromethoxy, or trifluoromethylthio,
• wherein R3 cannot be a trifluoromethyl;
• R4 is a hydrogen or C1-C5 alkyl, each optionally independently substituted with one, two, or three substituent groups,
• wherein each substituent group of R4 is independently selected from halogen, hydroxy, oxo, cyano, amino, or trifluoromethyl,
• wherein R4 cannot be a trifluoromethyl;
• R5 and R6 are each independently hydrogen, C1-C5 alkyl or phenyl or R5 and R6together with the carbon atom they are commonly attached to form a C3-C8 spiro cycloalkyl ring, each optionally independently substituted with one, two, or three substituent groups,
• wherein each substituent group of R5 and R6 is independently selected from halogen, hydroxy, oxo, cyano, amino, or trifluoromethyl,
• X is O, S wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, or NR7;
• R7 is H, C1-C5 alkyl, or phenyl,
• wherein each substituent group of R7 is optionally independently substituted with one, two, or three substituent groups selected from C1-C3 alkyl, C1-C3 alkoxy, hydroxy, oxo, cyano, amino, or trifluoromethyl;
• and
• R8 is a heteroaryl group optionally independently substituted with one, two, or three substituent groups,
• wherein each substituent group of R8 is independently C1-C3 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, heterocyclyl, aryl, heteroaryl, C1-C5 alkoxy, acyl, acylamino, aminocarbonyl, C1-C3 alkylamioncarbonyl, C1-C3 dialkylaminocarbonyl halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-C5 alkyl;
• or C1-C5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone,
• wherein each substituent group of R8 is optionally independently substituted with one, two, or three substituent groups selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxy, oxo, cyano, amino, or trifluoromethyl,
• or a tautomer, ester, amide, or salt thereof.