Bicyclic heteroaryl inhibitors of PDE4

Abstract

The present invention relates to compounds and methods which may be useful as inhibitors of phosphodiesterase 4 (PD E4) for the treatment or prevention of inflammatory diseases and other diseases involving elevated levels of cytokines and proinflammatory mediators.

1. A compound of structural Formula VI 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein: 
         R 1  and R 2  are independently selected from the group consisting of —(CH 2 ) s G 1 G 2 G 3 , acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, and hydroxyalkyl, any of which may be optionally substituted; 
         s is 1-8; 
         G 1  is selected from the group consisting of alkoxy, amino, amido, carbonyl, hydroxy, ether, an amino acid, and null; 
         G 2  is selected from the group consisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, an amino acid, and null, any of which may be optionally substituted; 
         G 3  is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate, phosphoamide, and null, any of which may be optionally substituted; and 
         R 20  and R 24  are independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, amino, and carboxyl. 
       
     
     
       2. The compound as recited in  claim 1 , wherein R 20  and R 24  are independently selected from the group consisting of hydrogen, halogen, and lower alkyl. 
     
     
       3. The compound as recited in  claim 2 , wherein R 2  is lower alkyl. 
     
     
       4. The compound as recited in  claim 3 , wherein:
 R 1  is selected from the group consisting of —(CH 2 ) s G 1 G 2 G 3 , lower alkyl, cycloalkyl, cycloalkylalkyl, and heterocycloalkyl, any of which may be optionally substituted; 
 s is 1-6; 
 G 1  is selected from the group consisting of amino, amido, and null; 
 G 2  is selected from the group consisting of alkoxy, aryl, halo, heterocycloalkyl, and null, any of which may be optionally substituted; and 
 G 3  is selected from the group consisting of alkyl, carboxyl, and null, any of which may be optionally substituted. 
 
     
     
       5. The compound as recited in  claim 4 , wherein R 2  is methyl. 
     
     
       6. A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       7. A pharmaceutical composition comprising as recited in  claim 1 , together with a pharmaceutically acceptable carrier.