Bicyclic heteroaryl inhibitors of PDE4

Abstract

The present invention relates to compounds and methods which may be useful as inhibitors of phosphodiesterase 4 (PDE4) 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 IV 
       
         
           
           
               
               
           
         
       
       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 0-8; 
 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; 
 when s is 0, G 1 , G 2 , and G 3  may not all together be null; 
 R 3  and R 4  are independently selected from the group consisting of alkoxy, lower alkyl, halogen and hydrogen; 
 R 5  is selected from the group consisting of (CH 2 ) p , C(O)NH, N(R 7 ) and S(O) q ; 
 p is 1,2,3 or 4; 
 q is 0, 1 or 2; 
 R 6  is selected from the group consisting of aryl heteroaryl, either of which may be optionally substituted; 
 R 7  selected from the group consisting of hydrogen and optionally substituted lower alkyl; R 17  is selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, hydroxyalkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl and aminoalkoxy. 
 
     
     
       2. The compound as recited in  claim 1 , wherein
 R 17  is selected from the group consisting of hydrogen, halogen, lower alkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl and aminoalkoxy. 
 
     
     
       3. The compound as recited in  claim 2 , wherein R 17  is hydrogen. 
     
     
       4. The compound as recited in  claim 3 , wherein R 6  is selected from the group consisting of phenyl, pyridine, pyrimidine, pyridazine, and pyrazine, any of which may be optionally substituted. 
     
     
       5. The compound as recited in  claim 4 , wherein R 3  and R 4  are both hydrogen. 
     
     
       6. The compound as recited in  claim 5 , wherein:
 R 5  N(R 7 ); and 
 R 7  hydrogen. 
 
     
     
       7. The compound as recited in  claim 6 , wherein R 2  is lower alkyl. 
     
     
       8. The compound as recited in  claim 7 , 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. 
 
     
     
       9. The compound as recited in  claim 8 , wherein R 2  is methyl. 
     
     
       10. The compound as recited in  claim 9 , wherein R 6  has a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         R 19 , R 20 , R  21 , R 22 , and R 23  are independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, amino, and carboxyl. 
       
     
     
       11. 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, acyl, amino, amido, carbonyl, ether, an amino acid, and null; 
 G 2  is selected from the group consisting of alkyl, alkoxy, acyl, 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 19  and R 23  are independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, amino, and carboxyl. 
 
     
     
       12. The compound as recited in  claim 11 , wherein R 19  and R 23  are independently selected from the group consisting of hydrogen, halogen, and lower alkyl. 
     
     
       13. The compound as recited in  claim 12 , wherein R 2  is lower alkyl. 
     
     
       14. The compound as recited in  claim 13 , 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. 
 
     
     
       15. The compound as recited in  claim 14 , wherein R 2  is methyl. 
     
     
       16. A compound of structural Formula VII 
       
         
           
           
               
               
           
         
       
       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, acyl, amino, amido, carbonyl, ether, an amino acid, and null; G 2  is selected from the group consisting of alkyl, alkoxy, acyl, 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 19 , R 21,  and R 23  are independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, amino, and carboxyl. 
 
     
     
       17. The compound as recited in  claim 16 , wherein R 19 , R 21 , and R 23  are independently selected from the group consisting of hydrogen, halogen, and lower alkyl. 
     
     
       18. The compound as recited in  claim 17 , wherein R 2  is lower alkyl. 
     
     
       19. The compound as recited in  claim 18 , wherein:
 R 1  is selected from the group consisting of —(CH 2 ) s G 1 G 2 G 3 , ower 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. 
 
     
     
       20. The compound as recited in  claim 19 , wherein R 2  is methyl. 
     
     
       21. A compound selected from the group consisting of Examples 1 to 105. 
     
     
       22. A pharmaceutical composition comprising a compound as recited in  claim 1  together with a pharmaceutically acceptable carrier.