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 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, 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, or SO 2 , then the other is not CO, and provided that Y and Z are not both heteroatoms or oxidized forms thereof, 
         ring C is C 6 -C 10  aryl; 
         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 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 not both 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 5  is hydrogen or C 1 -C 6  alkyl, 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  alkyl-S(O)—, C 1 -C 6  alkyl-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 heterocyclyl substituted with an R′R′N— moiety wherein each R′ is independently C 1 -C 6  alkyl or hydrogen; 
         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; 
         k is 0 or 1; and 
         p is 0, 1, 2 or 3. 
       
     
     
         2 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, 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 V 3  and V 4  are independently O, S, or NH, provided that when one or V 3  and V 4  is S the other is NH, and provided that V 3  and V 4  are not both 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 . The compound of  claim 2 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein the compound is of formula (II): 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 2 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein the compound is of Formula (IIA): 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 2 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring A is optionally substituted with 1-3 members independently selected from the group consisting of halo, C 1 -C 6  alkyl, COR 15  and 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 a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring B is optionally substituted with 1-3 members independently selected from the group consisting of halo, C 1 -C 6  alkyl COR 15  and/er 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 . (canceled) 
     
     
         8 . A composition comprising a compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof; and at least one pharmaceutically acceptable excipient. 
     
     
         9 . 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 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof. 
     
     
         10 . A method for treating a condition associated with oxygen deficiency, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof. 
     
     
         11 . The method of  claim 10 , wherein the condition is selected from sickle cell disease, cancer, a pulmonary disorder, stroke, high altitude sickness, an ulcer, a pressure sore, Alzheimer's disease, acute respiratory disease syndrome, and a wound. 
     
     
         12 . The method of  claim 11 , wherein the condition is sickle cell disease. 
     
     
         13 . The method of  claim 11 , wherein the condition is a pulmonary disorder. 
     
     
         14 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring B is an optionally substituted 5-10 membered heteroaryl having 1-2 nitrogen atoms, or oxidized versions thereof. 
     
     
         15 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring B is optionally substituted 5-10 membered heteroaryl having 1 nitrogen atom. 
     
     
         16 . The compound of  claim 15 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring B is pyridyl. 
     
     
         17 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring A is an 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. 
     
     
         18 . The compound of  claim 17 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring A is substituted with 1-3 members independently selected from the group consisting of halo and C 1 -C 6  alkyl. 
     
     
         19 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is