Methods for treating or preventing an inflammatory or metabolic condition or inhibiting JNK

A method for treating or preventing otitis externa, acute otitis media, hearing loss, pulmonary interstitial fibrosis, liver fibrosis, renal fibrosis, wound-healing, burn-healing, chronic obstructive pulmonary disease, allergy, allergic rhinitis, acute respiratory distress syndrome, systemic lupus erythematosus, nephropathy, pancreatitis, peritonitis, sepsis, alcohol or toxin-induced liver disease, sclerosis, steatosis or ischemia-reperfusion injury, comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound having the structure:

• 545
• or a pharmaceutically acceptable salt thereof,
• wherein:
• R1 is aryl or heteroaryl optionally substituted with one to four substituents independently selected from R7;
• R2 and R3 are the same or different and are independently hydrogen or lower alkyl;
• R4 represents one to four optional substituents, wherein each substituent is the same or different and independently selected from halogen, hydroxy, lower alkyl or lower alkoxy;
• R5 and R6 are the same or different and independently —R8, —(CH2)αC(═O)R9, —(CH2)αC(═O)OR9 , —(CH2)αC(═O)NR9R10, —(CH2)αC(═O)NR9(CH2)bC(═O)R10, —(CH2)αNR9C(═O)R10, —(CH2)αNR11C(═O)NR9R10, —(CH2)αNR9R10, —(CH2)αOR9, —(CH2)αSOcR9, or —(CH2)αSO2NR9R10;
• or R5 and R6 taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle;
• R7 is at each occurrence independently halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylakyl, sulfonylalkyl, hydroxyalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —C(═O)OR8, —OC(═O)R8, —C(═O)NR8R9, —C(═O)NR8OR9, —SOcR8, —SOcNR8R9, —NR8SOcR9, —NR8R9, —NR8C(═O)R9 ,—NR8C(═O)(CH2)bOR9, —NR8C(═O)(CH2)bR9, —O(CH2)bNR8R9, or heterocycle fused to phenyl;
• R8, R9, R10 and R11 are the same or different and at each occurrence independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl;
• or R8 and R9 taken together with the atom or atoms to which they are attached to form a heterocycle or substituted heterocycle;
• a and b are the same or different and at each occurrence independently selected from 0, 1, 2, 3 or 4;
• and
• c is at each occurrence 0, 1 or 2.

A method for treating or preventing a disease responsive to JNK inhibition, comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound having the structure:

• 546
• or a pharmaceutically acceptable salt thereof,
• wherein:
• R1 is aryl or heteroaryl optionally substituted with one to four substituents independently selected from R7;
• R2 and R3 are the same or different and are independently hydrogen or lower alkyl;
• R4 represents one to four optional substituents, wherein each substituent is the same or different and independently selected from halogen, hydroxy, lower alkyl or lower alkoxy;
• R5 and R6 are the same or different and independently —R8, —(CH2)αC(═O)R9, —(CH2)αC(═O)OR9, —(CH2)αC(═O)NR9R10, —(CH2)αC(═O)NR9(CH2)bC(═O)R10, —(CH2)αNR9C(═O)R10, —(CH2)αNR11C(═O)NR9R10, —(CH2)αNR9R10, —(CH2)αOR9, —(CH2)αSOcR9, or —(CH2)αSO2NR9R10;
• or R5 and R6 taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle;
• R7 is at each occurrence independently halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylakyl, sulfonylalkyl, hydroxyalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —C(═O)OR8, —OC(═O)R8, —C(═O)NR8R9, —C(═O)NR8OR9, —SOcR8, —SOcNR8R9, —NR8SOcR9, —NR8R9, —NR8C(═O)R9, —NR8C(═O)(CH2)bOR9, —NR8C(═O)(CH2)bR9, —O(CH2)bNR8R9, or heterocycle fuised to phenyl;
• R8, R9, R10 and R11 are the same or different and at each occurrence independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl;
• or R8 and R9 taken together with the atom or atoms to which they are attached to form a heterocycle or substituted heterocycle;
• a and b are the same or different and at each occurrence independently selected from 0, 1, 2, 3 or 4;
• and
• c is at each occurrence 0, 1 or 2.