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 . In certain aspects of the invention, a compound of formula (I) is provided: 
       
         
           
           
               
               
           
         
         or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein 
         ring A is an optionally substituted 4-10 membered cycloalkyl or 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; 
         ring B is a C 6 -C 10  aryl or 5-10 membered heteroaryl having 1-3 nitrogen atoms, preferably 1-2 nitrogen atoms and more preferably 1 nitrogen atom, or oxidized versions thereof, wherein the aryl or heteroaryl is optionally substituted; 
            is a single or a double bond; 
         each Y and Z is independently CR 10 R 11 , O, S, SO, SO 2 , or NR 12 ; each R 10  and R 11  independently is hydrogen or C 1 -C 3  alkyl optionally substituted with halo, OH, or C 1 -C 6  alkoxy, or CR 10 R 11  is C═O; R 12  is hydrogen or C 1 -C 6  alkyl; provided that if one of Y and Z is O, S, SO, SO 2 , then the other is not CO, and provided that Y and Z are both not heteroatoms or oxidized forms thereof; 
         ring C is C 6 -C 10  aryl, optionally substituted; 
         V 1  and V 2  independently are C 1 -C 6  alkoxy; or V 1  and V 2  together with the carbon atom they are attached to form a ring of formula: 
       
       
         
           
           
               
               
           
         
         wherein each V 3  and V 4  are independently O, S, or NH, provided that when one of V 3  and V 4  is S, the other is NH, and provided that V 3  and V 4  are both not NH; q is 1 or 2; each V 5  is independently C 1 -C 6  alkyl or CO 2 R 60 , where each R 60  independently is C 1 -C 6  alkyl or hydrogen; t is 0, 1, 2, or 4; or CV 1 V 2  is C═V, wherein V is O, NOR 80 , or NNR 81 R 82 ; 
         R 80  is optionally substituted C 1 -C 6  alkyl; 
         R 81  and R 82  independently are selected from the group consisting of hydrogen, optionally substituted C 1 -C 6  alkyl, COR 83 , or CO 2 R 84 ; 
         R 83  is hydrogen or optionally substituted C 1 -C 6  alkyl; and 
         R 84  is optionally substituted C 1 -C 6  alkyl. 
       
     
     
         2 . The compound of  claim 1 , wherein V 1  and V 2  independently are C 1 -C 6  alkoxy; or V 1  and V 2  together with the carbon atom they are attached to form a ring of formula: 
       
         
           
           
               
               
           
         
       
       wherein each V 3  and V 4  are independently O, S, or NH, provided that when one of V 3  and V 4  is S the other is NH, and provided that V 3  and V 4  are both not NH; q is 1 or 2; each V 5  is independently C 1 -C 6  alkyl or CO 2 R 60 , where each R 60  independently is C 1 -C 6  alkyl or hydrogen; t is 0, 1, 2, or 4; or CV 1 V 2  is C═V, wherein V is O, and wherein the remaining variables are defined as in  claim 1 . 
     
     
         3 . The compound of  claim 2  of formula (II): 
       
         
           
           
               
               
           
         
         wherein R 5  is hydrogen, C 1 -C 6  alkyl or a prodrug moiety R, wherein the C 1 -C 6  alkyl is optionally substituted with 1-5 halo; 
         R 6  is halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 1 -C 6  S(O)—, C 1 -C 6  S(O) 2 —, wherein the C 1 -C 6  alkyl is optionally substituted with 1-5 halo; or 
         R 6  is 4-10 membered cycloalkyl or heterocycle substituted with an R′R′N— moiety wherein each R′ is independently C 1 -C 6  alkyl or hydrogen; 
         p is 0, 1, 2 or 3; and 
         the remaining variables are defined as in  claim 2 . 
       
     
     
         4 . A compound of  claim 2  or  3  of Formula (IIA): 
       
         
           
           
               
               
           
         
         wherein 
         the variables are defined as in  claims 2  and  3 . 
       
     
     
         5 . The compound of  claim 2 , wherein ring A is optionally substituted with 1-3: halo, C 1 -C 6  alkyl, COR 15  and/or COOR 15 ; wherein R 15  is optionally substituted C 1 -C 6  alkyl, optionally substituted C 6 -C 10  aryl, optionally substituted 5-10 membered heteroaryl containing up to 5 ring heteroatoms, or optionally substituted 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S. 
     
     
         6 . The compound of  claim 4  or  5 , wherein ring B is optionally substituted with 1-3: halo, C 1 -C 6  alkyl COR 15  and/or COOR 15 ; wherein R 15  is optionally substituted C 1 -C 6  alkyl, optionally substituted C 6 -C 10  aryl, optionally substituted 5-10 membered heteroaryl containing up to 5 ring heteroatoms, or optionally substituted 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S. 
     
     
         7 . The compound of  claim 2 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       or an N oxide thereof, wherein
 R 14  is C 1 -C 6  alkyl, C 3 -C 5  cycloalkyl, COR 15  or COOR 5 ; 
 R 15  is optionally substituted C 1 -C 6  alkyl, optionally substituted C 6 -C 10  aryl, optionally substituted 5-10 membered heteroaryl containing up to 5 ring heteroatoms, or optionally substituted 4-10 membered heterocycle containing up to 5 ring heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S; 
 x is 0, 1, or 2; 
 p is 0, 1, and 2; and 
 m is 0, 1 or 2. 
 
     
     
         8 . A compound of  claim 1  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a prodrug thereof, or a pharmaceutically acceptable salt of each thereof. 
     
     
         9 . A composition comprising a compound of any one of  claims 2 - 8  and at least one pharmaceutically acceptable excipient. 
     
     
         10 . 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 any one of  claims 2 - 8  or the composition of  claim 9 . 
     
     
         11 . 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 any one of  claims 2 - 8  or the composition of  claim 9 .