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.

What is claimed is: 
     
         1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein 
         L 10  is optionally substituted methylene or, preferably, a bond; 
         ring A is C 6 -C 10  aryl, a C 3 -C 8  cycloalkyl, a 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 each of the aryl, heteroaryl, cycloalkyl, or heterocycle is optionally substituted with 1-4: halo, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, and/or C 3 -C 10  cycloalkyl, wherein the C 1 -C 6  alkyl is optionally substituted with 1-5 halo, C 1 -C 6  alkoxy, and/or C 3 -C 10  cycloalkyl; or 
         ring A is C 6 -C 10  aryl, or a 5-10 membered heteroaryl, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the aryl, or heteroaryl is optionally substituted with 1-4 C 1 -C 6  alkyl and/or C 1 -C 6  alkoxy groups;
 ring B is a 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 each of the heteroaryl and the heterocycle is optionally substituted with 1-4: halo, C 1 -C 6  alkyl and/or —CO—C 1 -C 6  alkyl, or 
 
         ring B is: 
       
       
         
           
           
               
               
           
         
         wherein ring B′ including the —N—CO— moiety is a 5-6 membered heterocycle containing up to 3 heteroatoms selected from nitrogen, oxygen, and sulfur and oxidized forms of N and S, wherein each of the heteroaryl and the heterocycle is optionally substituted with 1-4 C 1 -C 6  alkyl groups; 
            is a single or a double bond; 
         each X and Y is independently (CR 20 R 21 ) e , O, S, SO, SO 2 , or NR 20 ; e is 1 to 4, preferably 1; each R 20  and R 21  independently is hydrogen or C 1 -C 3  alkyl optionally substituted with 1-3 halo, OH, or C 1 -C 6  alkoxy, or CR 20 R 21  is C═O, provided that if one of X and Y is O, S, SO, SO 2 , then the other is not CO, and X and Y are both not heteroatoms or oxidized forms thereof; 
         ring C is C 6 -C 10  aryl or a 5-10 membered heteroaryl 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 of which is optionally substituted with 1-4: halo, oxo, —OR 1 , C 1 -C 6  alkyl, —COOR 1 , and/or C 1 -C 6  alkoxy, wherein the C 1 -C 6  alkyl is optionally substituted with 1-5 halo, C 1 -C 6  alkoxy and/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; or 
         ring C is C 6 -C 10  aryl or a 5-10 membered heteroaryl 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 of which is optionally substituted with 1-4: halo, oxo, —OR 1 , C 1 -C 6  alkyl, —COOR 1 , NR 5 R 6 , 
         R 1  is a hydrogen, C 1 -C 6  alkyl or a prodrug moiety; wherein the alkyl is optionally substituted with a 5-10 membered heteroaryl 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, which is optionally substituted with with a 5-10 membered heteroaryl 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 heteroaryl is optionally substituted with C 1 -C 6  alkyl; 
         R 5  and R 6  are each independently hydrogen, optionally substituted C 1 -C 6  alkyl or —COOR 3 ; 
         R 3  is hydrogen or optionally substituted C 1 -C 6  alkyl; 
         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 optionally substituted with 1-3 OH groups, or V 5  is 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; 
         with the proviso that when ring C is C 6 -C 10  aryl; 
         and ring B is optionally substituted 4-10 membered heterocyclyl; 
         then ring A excludes optionally substituted 5-10 membered heteroaryl; 
         and provided that when ring C is C 6 -C 10  aryl; 
         and ring B is optionally substituted 5-10 membered heteroaryl; 
         then ring A is not optionally substituted 4-10 membered heterocycle. 
       
     
     
         2 . A compound of formula (X-I): 
       
         
           
           
               
               
           
         
         or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein 
         ring A is phenyl optionally substituted with 1-3 halo and/or C 1 -C 6  alkoxy, or is 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, optionally substituted, or is 
       
       
         
           
           
               
               
           
         
         
           wherein R 7  is C 1 -C 6  alkyl, optionally substituted with 3-5 fluoro groups, or is C 3 -C 6  cycloalkyl; 
         
         ring B is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         
           wherein R 8  is C 1 -C 6  alkyl, —CO—C 1 -C 6  alkyl or a prodrug moiety and wherein 
           the pyridyl ring is optionally substituted with a halo or an NR 25 (CH 2 ) 2 N(R 25 ) 2  group where each R 25  is independently hydrogen or C 1 -C 6  alkyl; 
         
         X is O, S, SO, or SO 2 ; 
            is a single or a double bond; 
         ring C is phenyl or a 6 membered nitrogen-containing heteroaryl, each of which is optionally substituted with 1-4: halo, oxo, —OR 1 , C 1 -C 6  alkyl, —COOR 1 , and/or C 1 -C 6  alkoxy, wherein the C 1 -C 6  alkyl is optionally substituted with 1-5 halo, C 1 -C 6  alkoxy and/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; and 
         each R 1  is hydrogen or a prodrug moiety R; 
         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 1, 2, or 4; or CV 1 V 2  is C═V, 
         wherein V is O, NOR 80 , or NNR 81 R 82 ; 
         wherein 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; 
         R 84  is optionally substituted C 1 -C 6  alkyl; 
         provided that when ring C is C 6 -C 10  aryl; 
         and ring B is optionally substituted 4-10 membered heterocyclyl; 
         then ring A excludes optionally substituted 5-10 membered heteroaryl; 
         and provided that when ring C is C 6 -C 10  aryl; 
         and ring B is optionally substituted 5-10 membered heteroaryl; 
         then ring A is not optionally substituted 4-10 membered heterocycle. 
       
     
     
         3 . The compound of  claim 2 , 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 or 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 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. 
       
     
     
         4 . The compound of  claim 3 , of formula: 
       
         
           
           
               
               
           
         
         wherein the remaining variables are defined as in  claim 2 . 
       
     
     
         5 . A compound of  claim 3  or  4  selected from formulas (IIA), (IIB) and (IIC): 
       
         
           
           
               
               
           
         
         wherein 
         R 9  is hydrogen, —OR 1 , C 1 -C 6  alkoxy optionally substituted with 1-3 C 1 -C 6  alkoxy or 4-10 membered heterocycle containing up to 5 ring heteroatoms selected from N, O, S or oxidized forms thereof; 
         R 10  is hydrogen, halo, hydroxy, or C 1 -C 6  alkoxy; 
         R H  is hydrogen or C 1 -C 6  alkyl; and 
         R 12  is —OR 1 ; 
         wherein R 1  is hydrogen or the prodrug moiety R. 
       
     
     
         6 . The compound of  claim 4 , wherein ring A is
 phenyl substituted with 1-3 halo or C 1 -C 6  alkoxy, or   C 3 -C 8  heterocyclyl containing 1-3 heteroatoms, wherein the heterocycle is optionally substituted with 1-3 halo.   
     
     
         7 . The compound of any one of  claims 3 - 6 , wherein 
       
         
           
           
               
               
           
         
         is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of any one of  claims 3 - 6 , wherein 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound of  claim 1  wherein:
 ring A is C 6 -C 10  aryl, or a 5-10 membered heteroaryl, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the aryl, or heteroaryl is optionally substituted with 1-4: C 1 -C 6  alkyl and/or C 1 -C 6  alkoxy; 
 ring B is: 
 
       
         
           
           
               
               
           
         
         wherein ring B′ including the —N—CO— moiety is a 5-6 membered heterocycle containing up to 3 heteroatoms selected from nitrogen, oxygen, and sulfur and oxidized forms of N and S, wherein each of the heteroaryl and the heterocycle is optionally substituted with 1-4 C 1 -C 6  alkyl groups; 
         each X and Y is independently CR 20 R 21 , O, S, SO, SO 2 , or NR 20 ; each R 20  and R 21  independently is hydrogen or C 1 -C 3  alkyl optionally substituted with 1-3 halo, OH, or C 1 -C 6  alkoxy, or CR 20 R 21  is C═O, provided that if one of X and Y is O, S, SO, SO 2 , then the other is not CO, and X and Y are both not heteroatoms or oxidized forms thereof; 
         ring C is C 6 -C 10  aryl or a 5-10 membered heteroaryl 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 of which is optionally substituted with 1-4: halo, oxo, —OR 1 , C 1 -C 6  alkyl, —COOR 5 , NR 5 R 6 , 
         R 1  is a hydrogen, C 1 -C 6  alkyl or a prodrug moiety; wherein the alkyl is optionally substituted with a 5-10 membered heteroaryl 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, which is optionally substituted with with a 5-10 membered heteroaryl 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 heteroaryl is optionally substituted with C 1 -C 6  alkyl; 
         R 5  and R 6  are each independently hydrogen, optionally substituted C 1 -C 6  alkyl or —COOR 3 ; 
         R 3  is hydrogen or optionally substituted C 1 -C 6  alkyl; 
         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 optionally substituted with 1-3 OH groups, or V 5  is 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; 
         with the proviso that when ring C is C 6 -C 10  aryl; 
         and ring B is optionally substituted 4-10 membered heterocyclyl; 
         then ring A excludes optionally substituted 5-10 membered heteroaryl; 
         and provided that when ring C is C 6 -C 10  aryl; 
         and ring B is optionally substituted 5-10 membered heteroaryl; 
         then ring A is not optionally substituted 4-10 membered heterocycle. 
       
     
     
         10 . The compound of  claim 9 , wherein CV 1 V 2  is C═V, wherein V is O, and wherein the remaining variables are defined as in  claim 10 . 
     
     
         11 . The compound of  claim 10 , of formula: 
       
         
           
           
               
               
           
         
         or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein wherein the remaining variables are defined as in  claim 9 . 
       
     
     
         12 . A compound of  claim 10  or  11  of formula (VI) or (VII): 
       
         
           
           
               
               
           
         
         or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein 
         ring A is C 6 -C 10  aryl, or a 5-10 membered heteroaryl, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein each of the aryl, or heteroaryl is optionally substituted with 1-4 C 1 -C 6  alkyl; 
         ring B is C 6 -C 10  aryl, C 3 -C 8  cycloalkyl, a 5-10 membered heteroaryl containing up to ring heteroatoms 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 each of the aryl, heteroaryl, cycloalkyl or heterocycle is optionally substituted with 1-4: halo, C 1 -C 6  alkyl, or C 1 -C 6  alkoxy, wherein the C 1 -C 6  alkyl is optionally substituted with 1-5 halo, C 1 -C 6  alkoxy, and/or C 3 -C 10  cycloalkyl; 
         R 4  is halo, oxo, —OR 18 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, —COOR 5 , and/or NR 5 R 6 ; 
         R 18  is hydrogen, substituted C 1 -C 6  alkyl, or a prodrug moiety R; 
         R 5  and R 6  are each independently hydrogen, optionally substituted C 1 -C 6  alkyl or —COOR 3 ; and 
         R 3  is hydrogen, provided that the COOR 3  is not joined to a nitrogen atom, or optionally substituted C 1 -C 6  alkyl. 
       
     
     
         13 . The compound of  claim 12 , wherein ring B is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         14 . A compound of  claim 1  selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a prodrug thereof, or a pharmaceutically acceptable salt of each thereof. 
       
     
     
         15 . A compound of  claim 1  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or N oxides thereof, or a pharmaceutically acceptable salt of each thereof. 
       
     
     
         16 . A composition comprising a compound of any one of  claims 3 - 8  and  10 - 15 , and at least one pharmaceutically acceptable excipient. 
     
     
         17 . 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 3 - 8  and  10 - 15  or the composition of  claim 16 . 
     
     
         18 . 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 3 - 8  and  10 - 15  or the composition of  claim 16 .