Modulators of TNF-alpha signaling

A compound of Formula II,

• 391
• and physiological salts thereof, wherein,
• R5 is substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkylalkyl;
• R6 is —H or —NR13R14;
• R7 is substituted or unsubstituted phenyl;
• and
• R13 and R14 are each, independently, —H, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl;
• or
• R13 and R14 together with the nitrogen to which they are attached are a heterocycloalkyl.

A compound of Formula III,

• 392
• and physiological salts thereof, wherein:
• R8 and R12 are each, independently, —H, a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, substituted or unsubstituted aralkyl or a substituted or unsubstituted heteroaralkyl;
• R9 is —H, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heteroaralkyl;
• R10 is substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaralkyl, or a substituted or unsubstituted heterocycloalkylalkyl;
• and
• R11 is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted cycloalkylalkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted benzophenone, or a substituted or unsubstituted cycloalkylalkyl.

A method of treating a TNF-α mediated condition in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula I,

• 396
• and physiological salts thereof, wherein:
• n is 0, or 2;
• X is O, CH2, S or SO2;
• R1 is H or NH2;
• R2 and R3 are each, independently, —H, —OH, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkoxy;
• R4 is, —H or a substituted or unsubstituted alkyl;
• V, W and Z are each, independently, N or CH;
• and
• Y is selected from the group consisting of substituted and unsubstituted phenyl, and substituted and unsubstituted heterocyclyl.

A method of treating a TNF-α mediated condition in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula II,

• 399
• and physiological salts thereof, wherein,
• R5 is substituted or unsubstituted aralkyl, susbstituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkylalkyl;
• R6 is —H or —NR13R14;
• R7 is substituted or unsubstituted phenyl;
• and
• R13 and R14 are each, independently, —H, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl;
• or
• R13 and R14 together with the nitrogen to which they are attached are a heterocycloalkyl.

A method of treating a TNF-α mediated condition in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula III,

• 400
• and physiological salts thereof, wherein:
• R8 and R12 are each, independently, —H, a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, substituted or unsubstituted aralkyl or a substituted or unsubstituted heteroaralkyl;
• R9 is —H, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heteroaralkyl;
• R10 is substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaralkyl, or a substituted or unsubstituted heterocycloalkylalkyl;
• and
• R11 is a substituted or unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted cycloalkylalkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heteroaralkyl, a substituted or unsubstituted benzophenonyl, or a substituted or unsubstituted cycloalkylalkyl.

A compound of Formula I,

• 403
• and physiological salts thereof, wherein:
• n is 0, 1 or 2;
• X is O, CH2, S or SO2;
• R1 is H or NH2;
• R2 and R3 are each, independently, —H, —OH, a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkoxy;
• R4 is, —H or a substituted or unsubstituted alkyl;
• V, W and Z are each, independently, N or CH;
• and
• Y is represented by the following structural formula:
• 404
• wherein R50 and R51 are independently an alkyl group, a substituted alkyl group, an aryl group a substituted aryl group, or, taken together with the nitrogen atom to which they are bonded, are a substituted heterocycloalkyl, an unsubstituted heterocycloalkyl, a substituted heteroaryl group or an unsubstituted heteroaryl. group.