NON-HORMONAL STEROID MODULATORS OF NF-kB FOR TREATMENT OF DISEASE

A method of reducing the symptoms of arthritis comprising the administration, to a patient in need thereof, of a therapeutically effective amount of a compound having structural Formula I:

• or a salt thereof, wherein:
• said dashed line indicates an optional double bond;
• R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, unsubstituted lower alkyl, lower haloalkyl, and halogen;
• R5 is selected from the group consisting of hydrogen, lower alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl, said lower alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of acyl, alkenyl, alkoxy, alkyl, alkynyl, amido, amino, aryl, aryloxy, cycloalkyl, haloalkoxy, haloalkyl, heteroalkyl, heteroaryl, hydroxy, perhaloalkoxy, and thiol;
• R6 is selected from the group consisting of hydrogen, hydroxyl, and lower alkyl, said lower alkyl being optionally substituted with one or more substituents selected from the group consisting of alkenyl, alkoxy, alkyl, alkynyl, aryl, aryloxy, haloalkoxy, haloalkyl, heteroalkyl, hydroxy, and thiol;
• R7 and R8 are independently selected from the groups consisting of hydrogen, unsubstituted C1-3 alkyl, or R7 and R8 can be taken together to form oxo or C3-6 saturated cycloalkyl;
• and
• R9 is selected from the group consisting of hydrogen, acyl, and alkyl, said acyl and alkyl being optionally substituted with one or more substituents selected from the group consisting of acyl, alkenyl, alkoxy, alkyl, alkylamino, alkylthio, alkynyl, amido, amino, aryl, aryloxy, aroyl, carbamate, carboxyl, cyano, cycloalkyl, halogen, haloalkoxy, haloalkyl, heteroalkyl, heterocycloalkyl, heteroaryl, hydrazinyl, hydroxy, mercaptyl, nitro, oxo, perhaloalkoxy, alkylsulfonyl, N-sulfonamido, S-sulfonamido, and thiol;
• if R1, R2, R3, R4, R7, and R8 are each hydrogen, R5 is methyl, and R6 is hydroxyl, then R9 is not —C(O)CH2CH2CO2H;
• if said dashed line does not indicate a double bond, R1, R2, R3, R4, R5, R7, and R8 are each hydrogen, and R6 is hydroxyl, then R9 is not —C(O)CH2CH2CO2H;
• if said dashed line indicates a double bond, R1 is methyl, R2, R3, R4, R5, R7, and R8 are each hydrogen, and R6 is hydroxyl, then R9 is not —C(O)CH2CH2CO2H;
• if R1, R2, R3, R4, R5, R7, and R8 are each hydrogen and R6 is hydroxyl, then R9 is not hydrogen or acetyl;
• if said dashed line does not indicate a double bond, R1 is fluorine, R2, R3, R4, R7, and R8 are each hydrogen, R5 is methyl, and R6 is hydroxyl, then R9 is not hydrogen or acetyl;
• and
• if said dashed line does not indicate a double bond, R1 is methyl, R2, R3, R4, R5, R7, and R8 are each hydrogen, and R6 is hydroxyl, then R9 is not acetyl.

A method of reducing the symptoms of a NF-κB-mediated disease, comprising the administration, to a patient in need thereof, of a therapeutically effective amount of a compound having structural Formula I:

• or a salt thereof, wherein:
• said dashed line indicates an optional double bond;
• R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, unsubstituted lower alkyl, lower haloalkyl, and halogen;
• R5 is selected from the group consisting of hydrogen, lower alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl, said lower alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of acyl, alkenyl, alkoxy, alkyl, alkynyl, amido, amino, aryl, aryloxy, cycloalkyl, haloalkoxy, haloalkyl, heteroalkyl, heteroaryl, hydroxy, perhaloalkoxy, and thiol;
• R6 is selected from the group consisting of hydrogen, hydroxyl, and lower alkyl, said lower alkyl being optionally substituted with one or more substituents selected from the group consisting of alkenyl, alkoxy, alkyl, alkynyl, aryl, aryloxy, haloalkoxy, haloalkyl, heteroalkyl, hydroxy, and thiol;
• R7 and R8 are independently selected from the groups consisting of hydrogen, unsubstituted C2-C3 alkyl, or R7 and R8 can be taken together to form C3-6 saturated cycloalkyl;
• R9 is selected from the group consisting of hydrogen, acyl, and alkyl, said acyl and alkyl being optionally substituted with one or more substituents selected from the group consisting of acyl, alkenyl, alkoxy, alkyl, alkylamino, alkylthio, alkynyl, amino, aryl, aryloxy, aroyl, carbamate, cyano, cycloalkyl, halogen, haloalkoxy, haloalkyl, heteroalkyl, heterocycloalkyl, heteroaryl, hydrazinyl, hydroxy, mercaptyl, perhaloalkoxy, sulfonate, alkyl sulfonyl, N-sulfonamido, S-sulfonamido, and thiol;
• if R1 is hydrogen, methyl, —CH2F, or fluoro, R2, R3, R4, R5, R7, and R8 are each hydrogen, and R6 is hydroxyl, then R9 is not hydrogen, formyl, unsubstituted C1-C5 alkylacyl, or benzoyl;
• if R1 is hydrogen, methyl, —CH2F, or fluoro, R2, R3, R4, R7, and R8 are each hydrogen, R5 is methyl, and R6 is hydroxyl, then R9 is not hydrogen, formyl, unsubstituted C1-C5 alkylacyl, trifluoroacetyl, —C(O)-adamantyl, or benzoyl;
• if R1 is hydrogen, methyl, fluoro, or chloro, R2, R3, R4, R6, R7, and R8 are each hydrogen, and R5 is methyl, then R9 is not hydrogen, unsubstituted C1-C5 alkylacyl, or benzoyl;
• if said dashed line indicates a double bond, R1, R2, R3, R4, R7, and R8 are each hydrogen, and R5 and R6 are each methyl, then R9 is not hydrogen, acetyl, or benzoyl;
• if said dashed line indicates a double bond, R1, R2, R3, R4, R5, R7, and R8 are each hydrogen, and R6 is ethyl, then R9 is not acetyl;
• if said dashed line does not indicate a double bond, R1 is hydrogen or fluoro, and R2, R3, R4, R5, R6, R7, and R8 are each hydrogen, then R9 is not hydrogen or acetyl;
• if R1, R2, R4, R5, R7, and R8 are each hydrogen, R3 is methyl, and R6 is hydroxyl, then R9 is not hydrogen, formyl, unsubstituted C1-C5 alkylacyl, or benzoyl;
• and
• if R1 and R2 are each fluoro, R3, R4, R7, and R8 are each hydrogen, R5 is methyl, and R6 is hydroxyl, then R9 is not acetyl.

A method of reducing the symptoms of a NF-κB-mediated disease comprising the administration, to a patient in need thereof, of a therapeutically effective amount of a compound having structural Formula I:

• or a salt thereof, wherein:
• said dashed line indicates an optional double bond;
• R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, unsubstituted lower alkyl, lower haloalkyl, and halogen;
• R5 is selected from the group consisting of C2-C8 alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl, said C2-C8 alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of acyl, alkenyl, alkoxy, alkyl, alkynyl, amido, amino, aryl, aryloxy, cycloalkyl, haloalkoxy, haloalkyl, heteroalkyl, heteroaryl, hydroxy, perhaloalkoxy, and thiol;
• R6 is selected from the group consisting of hydrogen, hydroxyl, and lower alkyl, said lower alkyl being optionally substituted with one or more substituents selected from the group consisting of alkenyl, alkoxy, alkyl, alkynyl, aryl, aryloxy, haloalkoxy, haloalkyl, heteroalkyl, hydroxy, and thiol;
• R7 and R8 are independently selected from the groups consisting of hydrogen, unsubstituted C1-3 alkyl, or R7 and R8 can be taken together to form oxo or C3-6 saturated cycloalkyl;
• and
• R9 is selected from the group consisting of hydrogen, acyl, and alkyl, said acyl and alkyl being optionally substituted with one or more substituents selected from the group consisting of acyl, alkenyl, alkoxy, alkyl, alkylamino, alkylthio, alkynyl, amido, amino, aryl, aryloxy, aroyl, carbamate, carboxyl, cyano, cycloalkyl, halogen, haloalkoxy, haloalkyl, heteroalkyl, heterocycloalkyl, heteroaryl, hydrazinyl, hydroxy, mercaptyl, nitro, oxo, perhaloalkoxy, sulfonate, alkylsulfonyl, N-sulfonamido, S-sulfonamido, and thiol.

A compound of structural Formula I:

• or a salt thereof, wherein:
• said dashed line indicates an optional double bond;
• R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, unsubstituted lower alkyl, lower haloalkyl, and halogen;
• R5 is selected from the group consisting of hydrogen, lower alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl, said lower alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of acyl, alkenyl, alkoxy, alkyl, alkynyl, amido, amino, aryl, aryloxy, cycloalkyl, haloalkoxy, haloalkyl, heteroalkyl, heteroaryl, hydroxy, perhaloalkoxy, and thiol;
• R6 is selected from the group consisting of hydrogen, hydroxyl, and lower alkyl, said lower alkyl being optionally substituted with one or more substituents selected from the group consisting of alkenyl, alkoxy, alkyl, alkynyl, aryl, aryloxy, haloalkoxy, haloalkyl, heteroalkyl, hydroxy, and thiol;
• R7 and R8 are independently selected from the groups consisting of hydrogen, unsubstituted C2-C3 alkyl, or R7 and R8 can be taken together to form C3-6 saturated cycloalkyl;
• and
• R9 is selected from the group consisting of hydrogen, acyl, and alkyl, said acyl and alkyl being optionally substituted with one or more substituents selected from the group consisting of acyl, alkenyl, alkoxy, alkyl, alkylamino, alkylthio, alkynyl, amino, aryl, aryloxy, aroyl, carbamate, cyano, cycloalkyl, halogen, haloalkoxy, haloalkyl, heteroalkyl, heterocycloalkyl, heteroaryl, hydrazinyl, hydroxy, mercaptyl, perhaloalkoxy, sulfonate, alkyl sulfonyl, N-sulfonamido, S-sulfonamido, and thiol.
• if R1 is hydrogen, methyl, —CH2F, or fluoro, R2, R3, R4, R5, R7, and R8 are each hydrogen, and R6 is hydroxyl, then R9 is not hydrogen, formyl, unsubstituted C1-C5 alkylacyl, or benzoyl;
• if R1 is hydrogen, methyl, —CH2F, or fluoro, R2, R3, R4, R7, and R8 are each hydrogen, R5 is methyl, and R6 is hydroxyl, then R9 is not hydrogen, formyl, unsubstituted C1-C5 alkylacyl, trifluoroacetyl, —C(O)-adamantyl, or benzoyl;
• if R1 is hydrogen, methyl, fluoro, or chloro, R2, R3, R4, R6, R7, and R8 are each hydrogen, and R5 is methyl, then R9 is not hydrogen, unsubstituted C1-C5 alkylacyl, or benzoyl;
• if said dashed line indicates a double bond, R1, R2, R3, R4, R7, and R8 are each hydrogen, and R5 and R6 are each methyl, then R9 is not hydrogen, acetyl, or benzoyl;
• if said dashed line indicates a double bond, R1, R2, R3, R4, R5, R7, and R8 are each hydrogen, and R6 is ethyl, then R9 is not acetyl;
• if said dashed line does not indicate a double bond, R1 is hydrogen or fluoro, and R2, R3, R4, R5, R6, R7, and R8 are each hydrogen, then R9 is not hydrogen or acetyl;
• if R1, R2, R4, R5, R7, and R8 are each hydrogen, R3 is methyl, and R6 is hydroxyl, then R9 is not hydrogen, formyl, unsubstituted C1-C5 alkylacyl, or benzoyl;
• and
• if R1 and R2 are each fluoro, R3, R4, R7, and R8 are each hydrogen, R5 is methyl, and R6 is hydroxyl, then R9 is not acetyl.

A compound having structural Formula I:

• or a salt thereof, wherein:
• said dashed line indicates an optional double bond;
• R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, unsubstituted lower alkyl, lower haloalkyl, and halogen;
• R5 is selected from the group consisting of C2-C8 alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl, said C2-C8 alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of acyl, alkenyl, alkoxy, alkyl, alkynyl, amido, amino, aryl, aryloxy, cycloalkyl, haloalkoxy, haloalkyl, heteroalkyl, heteroaryl, hydroxy, perhaloalkoxy, and thiol;
• R6 is selected from the group consisting of hydrogen, hydroxyl, and lower alkyl, said lower alkyl being optionally substituted with one or more substituents selected from the group consisting of alkenyl, alkoxy, alkyl, alkynyl, aryl, aryloxy, haloalkoxy, haloalkyl, heteroalkyl, hydroxy, and thiol;
• R7 and R8 are independently selected from the groups consisting of hydrogen, unsubstituted C1-3 alkyl, or R7 and R8 can be taken together to form oxo or C3-6 saturated cycloalkyl;
• and
• R9 is selected from the group consisting of hydrogen, acyl, and alkyl, said acyl and alkyl being optionally substituted with one or more substituents selected from the group consisting of acyl, alkenyl, alkoxy, alkyl, alkylamino, alkylthio, alkynyl, amido, amino, aryl, aryloxy, aroyl, carbamate, carboxyl, cyano, cycloalkyl, halogen, haloalkoxy, haloalkyl, heteroalkyl, heterocycloalkyl, heteroaryl, hydrazinyl, hydroxy, mercaptyl, nitro, oxo, perhaloalkoxy, sulfonate, alkylsulfonyl, N-sulfonamido, S-sulfonamido, and thiol.