Compounds and uses thereof for the modulation of hemoglobin

1. A compound of formula (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;

X is 0, 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 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;

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.

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 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.

3. The compound of claim 2 , of formula:

wherein the remaining variables are defined as in claim 2 .

4. A compound of claim 2 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 or C 1 -C 6 alkoxy;

R 11 is hydrogen or C 1 -C 6 alkyl; and

R 12 is —OR 1 ;

wherein R 1 is hydrogen or the prodrug moiety.

5. The compound of claim 3 , 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.

6. The compound of claim 3 , wherein

is selected from the group consisting of:

7. The compound of claim 3 , wherein

8. A compound selected from the group consisting of:

or an N oxides thereof, or a pharmaceutically acceptable salt of each thereof, wherein is a single or a double bond.

9. A composition comprising a compound of claim 3 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 claim 3 .

11. A method for treating oxygen deficiency associated with sickle cell anemia or acute respiratory disease syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 3 .

12. The method of claim 11 , wherein oxygen affinity of the subject's hemoglobin S is increased.

13. The compound of claim 1 , wherein ring B is

14. The compound of claim 1 , wherein ring B is

wherein R 8 is C 1 -C 6 alkyl, —CO—C 1 -C 6 alkyl or a prodrug moiety.

15. The compound of claim 1 , wherein ring B is

wherein R 8 is C 1 -C 6 alkyl, —CO—C 1 -C 6 alkyl or a prodrug moiety.

16. The compound of claim 1 , wherein ring B is

17. The compound of claim 13 , wherein ring A is selected from:

wherein R 7 is C 1 -C 6 alkyl, optionally substituted with 3-5 fluoro groups, or is C 3 -C 6 cycloalkyl.

18. The compound of claim 14 , wherein ring A is selected from:

wherein R 7 is C 1 -C 6 alkyl, optionally substituted with 3-5 fluoro groups, or is C 3 -C 6 cycloalkyl.

19. The compound of claim 15 , wherein ring A is selected from:

wherein R 7 is C 1 -C 6 alkyl, optionally substituted with 3-5 fluoro groups, or is C 3 -C 6 cycloalkyl.

20. The compound of claim 16 , wherein ring A is selected from:

wherein R 7 is C 1 -C 6 alkyl, optionally substituted with 3-5 fluoro groups, or is C 3 -C 6 cycloalkyl.

21. The compound of claim 1 of formula:

or a pharmaceutically acceptable salt of each thereof wherein R 8 is C 1 -C 6 alkyl, —CO—C 1 -C 6 alkyl or a prodrug moiety.

22. A composition comprising a compound of claim 8 and at least one pharmaceutically acceptable excipient.

23. A composition comprising a compound of claim 21 and at least one pharmaceutically acceptable excipient.

24. A method for treating oxygen deficiency associated with sickle cell anemia or acute respiratory disease syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 8 .

25. A method for treating oxygen deficiency associated with sickle cell anemia or acute respiratory disease syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 21 .