Compounds and uses thereof for the modulation of hemoglobin

Abstract

Provide herein are compounds and pharmaceutical compositions suitable as modulators of hemoglobin, methods and intermediates for their preparation, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or an N oxide thereof, or a pharmaceutically acceptable salt of each thereof, wherein 
         A is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         wherein R 1  is C 1 -C 6  alkyl optionally substituted with 3-6 fluoro atoms; 
         R 2  is hydrogen or C 1 -C 6  alkyl; 
         R 3  is C 1 -C 6  alkyl; 
         each R 4  independently is hydrogen or C 1 -C 6  alkyl; 
         ring B is 
       
       
         
           
           
               
               
           
         
         or ring B together with A is: 
       
       
         
           
           
               
               
           
         
         X is oxygen, S, SO, or SO 2 ; 
         ring C is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         wherein R 5  is selected from the group consisting of hydrogen; C 1 -C 6  alkoxy, optionally substituted with a C 1 -C 6  alkoxy group or with up to 3 fluoro atoms; C 1 -C 6  alkyl; and halo; 
         R 6  is hydrogen or halo; 
         R is hydrogen, a phosphate, a diphosphate, a phosphonate or a phosphoramidate containing moiety, or another promoiety; 
         provided that the compound of formula (I) comprises at least 1 OR group where R is not hydrogen. 
       
     
     
         2 . The compound of  claim 1 , of formula (II): 
       
         
           
           
               
               
           
         
         wherein R and R 1  are defined as in  claim 1 . 
       
     
     
         3 . The compound of  claim 1 , wherein R is —C(O)R 31 , C(O)OR 31 , or CONR 13 R 14  wherein each R 31  is independently a C 1 -C 6  alkyl; C 3 -C 8  cycloalkyl, 4-9 membered heterocycle, or a 5-10 membered heteroaryl, containing at least 1 basic nitrogen moiety; and
 R 13  and R 14  independently are C 1 -C 6  alkyl; C 3 -C 8  cycloalkyl, 4-9 membered heterocycle, or a 5-10 membered heteroaryl, containing at least 1 basic nitrogen moiety; or R 13  and R 14  together with the nitrogen atom they are bonded to for a 4-9 member heterocycle substituted with at least 1 amino, C 1 -C 6  alkyl amino, or di C 1 -C 6  alkylamino group. 
 
     
     
         4 . The compound of  claim 1 , wherein R 1  is isopropyl. 
     
     
         5 . A compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein R is phosphate, C(O)(CH 2 ) m NR 34 R 35 , or C(O)O(CH 2 ) m NR 34 R 35 ; and 
         wherein m, R 1 , R 34  and R 35  are defined as tabulated below: 
       
       
         
           
                 
                 
                 
                 
                 
                 
               
                     
                 
                   R 
                   R 1   
                   m 
                   R 34   
                   R 35   
                   NR 34 R 35   
                 
                     
                 
                   C(O)(CH 2 ) m NR 34 R 35   
                   iso- 
                   2 
                   Me 
                   Me 
                     
                 
                     
                   propyl 
                     
                     
                     
                     
                 
                   C(O)(CH 2 ) m NR 34 R 35   
                   iso- 
                   3 
                   Me 
                   Me 
                     
                 
                     
                   propyl 
                     
                     
                     
                     
                 
                   C(O)(CH 2 ) m NR 34 R 35   
                   iso- 
                   4 
                   Me 
                   Me 
                     
                 
                     
                   propyl 
                     
                     
                     
                     
                 
                     
                 
                   C(O)(CH 2 ) m NR 34 R 35   
                   iso- propyl 
                   2 
                     
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   C(O)(CH 2 ) m NR 34 R 35   
                   iso- propyl 
                   3 
                     
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   C(O)(CH 2 ) m NR 34 R 35   
                   iso- propyl 
                   4 
                     
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   C(O)O(CH 2 ) m NR 34 R 35   
                   iso- 
                   2 
                   Me 
                   Me 
                     
                 
                     
                   propyl 
                     
                     
                     
                     
                 
                   C(O)O(CH 2 ) m NR 34 R 35   
                   iso- 
                   3 
                   Me 
                   Me 
                     
                 
                     
                   propyl 
                     
                     
                     
                     
                 
                   C(O)O(CH 2 ) m NR 34 R 35   
                   iso- 
                   4 
                   Me 
                   Me 
                     
                 
                     
                   propyl 
                     
                     
                     
                     
                 
                     
                 
                   C(O)O(CH 2 ) m NR 34 R 35   
                   iso- propyl 
                   2 
                     
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   C(O)O(CH 2 ) m NR 34 R 35   
                   iso- propyl 
                   3 
                     
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   C(O)O(CH 2 ) m NR 34 R 35   
                   iso- propyl 
                   4 
                     
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   P(O)(OH) 2   
                   iso- propyl 
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         an N oxide thereof, or a pharmaceutically acceptable salt of each thereof. 
       
     
     
         6 . A composition comprising a compound of  claim 1  and at least one pharmaceutically acceptable excipient. 
     
     
         7 . A method for increasing oxygen affinity of hemoglobin S in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 . 
     
     
         8 . A method for treating oxygen deficiency associated with sickle cell anemia, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 .