Heteroarylalkoxy-substituted quinolone 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.

What is claimed is: 
     
       1. A compound of structural Formula VI 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein: 
         R 1  is —(CH 2 ) s G 1 G 2 G 3 ; 
         R 2  is methyl; 
         s is 6; 
         G 1  is null; 
         G 2  is heterocycloalkyl, which may be optionally substituted; 
         G 3  is null; and 
         R 20  and R 24  are halogen. 
       
     
     
       2. The compound as recited in  claim 1 , wherein said heterocycloalkyl is selected from the group consisting of a five-, six-, and seven-membered ring containing one or two nitrogens. 
     
     
       3. The compound as recited in  claim 2 , wherein G 2  has a formula selected from the group consisting of 
       
         
           
           
               
               
           
         
         t is 1 or 2; 
         w is 0 or 1; and 
         R 27  is selected from the group consisting of hydrogen, methyl. 
       
     
     
       4. The compound as recited in  claim 3 , wherein G 2  has a formula selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
       5. The compound as recited in  claim 4 , wherein R 20  and R 24  are each chlorine. 
     
     
       6. The compound as recited in  claim 5 , wherein G 2  is 
       
         
           
           
               
               
           
         
       
     
     
       7. The compound as recited in  claim 6 , wherein R 27  is methyl. 
     
     
       8. The compound as recited in  claim 7 , wherein t is 1. 
     
     
       9. The compound as recited in  claim 5 , wherein G 2  is 
       
         
           
           
               
               
           
         
       
     
     
       10. A compound selected from the group consisting of:
 4-(3,5-Dichloropyridin-4-ylamino)-7-methoxy-8-(6-(4-methylpiperazin-1-yl) hexyloxy)quinolin-2(1H)-one, 
 4-(3,5-Dichloropyridin-4-ylamino)-7-methoxy-8-(6-morpholinohexyloxy)quinolin-2(1H) -one, 
 4-(3,5-Dichloropyridin-4-ylamino)-7-methoxy-8-(6-(piperazin-1-yl)hexyloxy)quinolin -2(1H)-one, 
 4-(3,5-dichloropyridin-4-ylamino)-8-(6-(4-ethylpiperazin- 1-yl)hexyloxy)-7-methoxyquinolin -2(1H)-one, 
 8-(6-(1,4-Diazepan-1-yl)hexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one 
 4-(3,5-Dichloropyridin-4-ylamino)-7-methoxy-8-(6-(4-methyl-1,4-diazepan-1-yl)hexyloxy)quinolin-2(1H)-one, 
 8-(6-(2H-tetrazol-5-yl)hexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one, 
 8-(6-(1H-imidazol-1-yl)hexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one, and 
 8-(6-(2H-tetrazol-5-yl)hexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one. 
 
     
     
       11. A pharmaceutical composition comprising a compound as recited in  claim 1  together with a pharmaceutically acceptable carrier. 
     
     
       12. A method of treatment of a allergic conjunctivitis and dry eye comprising the administration of a therapeutically effective amount of a compound as recited in  claim 1  to a patient in need thereof. 
     
     
       13. A method of treatment of allergic conjunctivitis to a patient in need thereof comprising the administration of a compound as recited in  claim 10 . 
     
     
       14. 4-(3,5-Dichloropyridin-4-ylamino)-7-methoxy-8-(6-(4-methylpiperazin- l -yl)hexyloxy)quinolin-2(1H)-one, or a salt thereof. 
     
     
       15. A pharmaceutical composition comprising a compound as recited in  claim 14  together with a pharmaceutically acceptable carrier. 
     
     
       16. A method of treatment of allergic conjunctivitis to a patient in need thereof comprising the administration of a compound as recited in  claim 14 . 
     
     
       17. 4-(3,5-Dichloropyridin-4-ylamino)-7-methoxy-8-(6-morpholinohexyloxy)quinolin-2(1H)-one, or a salt thereof. 
     
     
       18. A pharmaceutical composition comprising a compound as recited in  claim 17  together with a pharmaceutically acceptable carrier. 
     
     
       19. A method of treatment of allergic conjunctivitis to a patient in need thereof comprising the administration of a compound as recited in  claim 17 .