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 or a pharmaceutically acceptable salt 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, or R 1  and R 2  together with the nitrogen atom they are attached to form an optionally substituted 4-7 membered heterocycle; or 
 R 3  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; 
 L 1  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; 
 d is 1, 2, or 3; 
 L 2  is C═O or SO 2 ; 
 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, 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; or 
 ring B is a 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; 
 each Y and Z is independently CR 10 R 11 , O, S, SO, SO 2 , or NR 10 ; 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, SO 2 , then the other is not CO, and Y and Z are both not heteroatoms or oxidized forms thereof; 
 wherein Y is α or β substituted relative to the -L 1 L 2 R 3 ; 
 wherein Z and —CV 1 V 2 H are joined to adjacent atoms on ring C; 
 ring C is a optionally substituted C 6 -C 10  aryl or optionally substituted 5-10 membered heteroaryl containing 1-3 nitrogen atoms, or an oxidized form of N; 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 19 , C 1 -C 6  alkyl, 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; and 
 R 19  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 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; and 
         R 84  is optionally substituted C 1 -C 6  alkyl. 
       
     
     
         2 - 19 . (canceled)