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

1. A method for treating Type I diabetes, diabetes insipidus, diabetes mellitus, maturity-onset diabetes, juvenile diabetes, insulin-dependant diabetes, non-insulin dependant diabetes, malnutrition-related diabetes, ketosis-prone diabetes, or ketosis-resistant diabetes, comprising administering to a patient in need thereof an effective amount of a compound having the structure:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is aryl optionally substituted with one to four substituents independently selected from R 7 or heteroaryl substituted with one to four substituents independently selected from R 7 ;

R 2 and R 3 are the same or different and are independently hydrogen or lower alkyl;

R 4 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;

R 5 and R 6 are the same or different and independently —R 8 , —(CH 2 ) a C(═O)R 9, —(CH 2 ) a C(═O)OR 9 , —(CH 2 ) a C(═O)NR 9 R 10 , —(CH 2 ) a C(═O)NR 9 (CH 2 ) b C(═O)R 10 , —(CH 2 ) a NR 9 C(═O)R 10 , —(CH 2 ) a NR 11 C(═O)NR 9 R 10 , —(CH 2 ) a NR 9 R 10 , —(CH 2 ) a OR 9 , —(CH 2 ) a SO c R 9 , or —(CH 2 ) a SO 2 NR 9 R 10 ;

or R 5 and R 6 taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle;

R 7 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)OR 8 , —OC(═O)R 8 , —C(═O)NR 8 R 9 , —C(═O)NR 8 OR 9 , —SO c R 8 , —SO c NR 8 R 9 , —NR 8 SO c R 9 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)(CH 2 ) b OR 9 , —NR 8 C(═O)(CH 2 ) b R 9 , —O(CH 2 ) b NR 8 R 9 , or heterocycle fused to phenyl;

R 8 , R 9 , R 10 and R 11 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 R 8 and R 9 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.

2. The method of claim 1 , wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is aryl optionally substituted with one to four substituents independently selected from R 7 or heteroaryl substituted with one to four substituents independently selected from R 7 ;

R 5 and R 6 are the same or different and independently R 8 , —(CH 2 ) a C(═O)R 9 , —(CH 2 ) a C(═O)OR 9 , —(CH 2 ) a C(═O)NR 9 R 10 , —(CH 2 ) a C(═O)NR 9 (CH 2 ) b C(═O)R 10 , (CH 2 ) a NR 9 C(═O)R 10 , —(CH 2 ) a NR 11 C(═O)NR 9 R 10 , —(CH 2 ) a NR 9 R 10 , —(CH 2 ) a OR 9 , —(CH 2 ) a SO c R 9 , or —(CH 2 ) a SO 2 NR 9 R 10 ;

or R 5 and R 6 taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle;

R 7 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)O 8 , —OC(═O)R 8 , —C(═O)NR 8 R 9 , —C(═O)NR 8 OR 9 , —SO c R 8 , —SO c NR 8 R 9 , —NR 8 SO c R 9 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)(CH 2 ) b OR 9 , —NR 8 C(═O)(CH 2 ) b R 9 , —O(CH 2 ) b NR 8 R 9 , or heterocycle fused to phenyl;

R 8 , R 9 , R 10 and R 11 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 R 8 and R 9 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.

3. The method of claim 1 , wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof,

wherein:

R 5 and R 6 are the same or different and independently —R 8 , —(CH 2 ) a C(═O)R 9 , —(CH 2 ) a C(═O)OR 9 , —(CH 2 ) a C(═O)NR 9 R 10 , —(CH 2 ) a C(═O)NR 9 (CH 2 ) b C(═O)R 10 , —(CH 2 ) a NR 9 C(═O)R 10 , —(CH 2 ) a NR 11 C(═O)NR 9 R 10 , —(CH 2 ) a NR 9 R 10 , (CH 2 ) a OR 9 , —(CH 2 ) a SO c R 9 , or —(CH 2 ) a SO 2 NR 9 R 10 ;

or R 5 and R 6 taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle;

R 7 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)OR 8 , —OC(═O)R 8 , —C(═O)NR 8 R 9 , —C(═O)NR 8 OR 9 , —SO c R 8 , —SO c NR 8 R 9 , —NR 8 SO c R 9 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)(CH 2 ) b OR 9 , —NR 8 C(═O)(CH 2 ) b R 9 , —O(CH 2 ) b NR 8 R 9 , or heterocycle fused to phenyl;

R 8 , R 9 , R 10 and R 11 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 R 8 and R 9 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.

4. The method of claim 3 , wherein the compound has the structure:

or a pharmaceutically acceptable salt thereof,

wherein:

R 5 and R 6 are the same or different and independently —R 8 , —(CH 2 ) a C(═O)R 9 , —(CH 2 ) a C(═O)OR 9 , —(CH 2 ) a C(═O)NR 9 R 10 , —(CH 2 ) a C(═O)NR 9 (CH 2 ) b C(═O)R 10 , —(CH 2 ) a NR 9 C(═O)R 10 , —(CH 2 ) a NR 11 C(═O)NR 9 R 10 , —(CH 2 ) a NR 9 R 10 , —(CH 2 ) a OR 9 , —(CH 2 ) a SO c R 9 , or —(CH 2 ) a SO 2 NR 9 R 10 ;

or R 5 and R 6 taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle;

R 7 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)OR 8 , —OC(═O)R 8 , —C(═O)NR 8 R 9 , —C(═O)NR 8 OR 9 , —SO c NR 8 , —SO c NR 8 R 9 , —NR 8 SO c R 9 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)(CH 2 ) b OR 9 , —NR 8 C(═O)(CH 2 ) b R 9 , —O(CH 2 ) b NR 8 R 9 , or heterocycle fused to phenyl;

R 8 , R 9 , R 10 and R 11 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 R 8 and R 9 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.