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 a tautomer thereof, or pharmaceutically acceptable salt of each of thereof, wherein R 3  is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 6  alkoxy, C 3 -C 8  cycloalkoxy, or —NR 1 R 2 ; 
         each R 1  and R 2  independently is hydrogen, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4-10 membered heterocycle or 5-10 membered heteroaryl, each 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, wherein each alkyl, cycloalkyl, heterocycle, aryl or heteroaryl is optionally substituted with 1-3 halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, oxo, wherein the C 1 -C 6  alkyl is optionally substituted with 1-5 halo, or R 1  and R 2  together with the nitrogen atom they are attached to form an optionally substituted 4-7 membered heterocycle; 
         L is a bond or is NR 70 , O, S, or (CR 71 R 72 ) d ; wherein each R 70 , R 71 , and R 72  independently are hydrogen or C 1 -C 6  alkyl provided that when L is NR 70 , R 70  is hydrogen, R 3  is NR 1 R 2 , and one of R 1  and R 2  is hydrogen, then, the other of R 1  and R 2  is not optionally substituted C 6 -C 10  aryl as defined above; 
         d is 1, 2, or 3; 
         ring B is a C 6 -C 10  aryl, 5-10 membered heteroaryl having 1-3 nitrogen atoms or oxidized forms of N, 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, wherein the aryl, heteroaryl, or heterocycle is optionally substituted with 1-3 halo, C 1 -C 6  alkyl optionally substituted with 1-5 halo, C 1 -C 6  alkoxy, hydroxy, oxo COR 15 , and CO 2 R 15 ; 
         R 15  is C 1 -C 6  alkyl, C 6 -C 10  aryl, 5-10 membered heteroaryl or a 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; 
         R 17  is C 1 -C 6  alkyl, C 6 -C 10  aryl, 5-10 membered heteroaryl or a 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; 
         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 1-3 halo, OH, or C 1 -C 6  alkoxy, or CR 10 R 11  is C═O, provided that if one of Y and Z is O, S, SO, or SO 2 , then the other is not CO, and provided that Y and Z are not both heteroatoms or oxidized forms thereof; 
         wherein Y is α or β substituted relative to the -LCOR 3 ; 
         ring C is a C 6 -C 10  aryl or 5-10 membered heteroaryl containing 1-3 nitrogen atoms, or an oxidized form of N, wherein the aryl or heteroaryl is further optionally substituted with 1-3 halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, wherein the C 1 -C 6  alkyl is optionally substituted with 1-5 halo; 
         wherein Z and —CV 1 V 2 H are joined to adjacent atoms on ring C; 
         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  and CO 2 R 84 ; 
         R 83  is hydrogen or optionally substituted C 1 -C 6  alkyl; 
         R 84  is optionally substituted C 1 -C 6  alkyl; 
         R 4  is OH, halo, C 1 -C 6  alkoxy, C 3 -C 6  cycloalkoxy or O—R, where R is a prodrug moiety, wherein the C 1 -C 6  alkoxy is optionally substituted with 1-5 halo; and 
         R 4  and CV 1 V 2 H are adjacent or ortho to each other. 
       
     
     
         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. 
       
     
     
         3 . A compound of  claim 1  of Formula (II): 
       
         
           
           
               
               
           
         
         wherein Y—Z is —CH 2 O— or —CH 2 CH 2 — and the remaining substituents are defined as in  claim 1 . 
       
     
     
         4 . The compound of  claim 3 , wherein and R 4  and —CHO are joined to adjacent atoms on ring C. 
     
     
         5 . The compound of  claim 2 , of Formula IIIA: 
       
         
           
           
               
               
           
         
         wherein ring B is a optionally substituted C 6 -C 10  aryl, optionally substituted 5-10 membered heteroaryl having 1-3 nitrogen atoms or oxidized forms of N; 
         R 5  is hydrogen, C 1 -C 6  alkyl or a prodrug moiety R; 
         R 6  is halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, wherein the C 1 -C 6  alkyl is optionally substituted with 1-5 halo; and 
         p is 0, 1, 2, or 3. 
       
     
     
         6 . The compound of  claim 2 , wherein the compound is of Formula IIIB, IIIC, or IIID: 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
         are optionally substituted 4-10 membered heterocycle as defined in  claim 1 ; 
         R 5  is hydrogen, C 1 -C 6  alkyl or a prodrug moiety; 
         R 6  is halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, wherein the C 1 -C 6  alkyl is optionally substituted with 1-5 halo; and 
         p is 0, 1, 2, or 3. 
       
     
     
         7 . The compound of  claim 2 , wherein ring B is substituted with 1-3: halo, C 1 -C 6  alkyl, COR 15 , or COOR 15 ; and
 R 15  is C 1 -C 6  alkyl, C 6 -C 10  aryl, 5-10 membered heteroaryl or a 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, wherein the alkyl, aryl, heteroaryl or heterocyclyl is optionally substituted.   
     
     
         8 . (canceled) 
     
     
         9 . A compound of formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or an N oxide thereof, or a pharmaceutically acceptable salt of each thereof. 
       
     
     
         10 . A composition comprising a compound of  claim 2  and at least one pharmaceutically acceptable excipient. 
     
     
         11 . 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 2 . 
     
     
         12 . A method for treating oxygen deficiency associated with sickle cell anemia or acute respiratory distress syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 2 . 
     
     
         13 . A composition comprising a compound of  claim 9  and at least one pharmaceutically acceptable excipient. 
     
     
         14 . 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 9 . 
     
     
         15 . A method for treating oxygen deficiency associated with sickle cell anemia or acute respiratory distress syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 9 . 
     
     
         16 . 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 composition of  claim 13 . 
     
     
         17 . A method for treating oxygen deficiency associated with sickle cell anemia or acute respiratory distress syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition of  claim 13 .