Compounds and uses thereof for the modulation of hemoglobin

1. A compound of Formula (II):

or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein

R 3 is C 1 -C 6 alkoxy;

ring B is an optionally substituted 5-10 membered heteroaryl having 1-3 nitrogen atoms or oxidized forms of N;

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 C═O, and Y and Z are not both heteroatoms or oxidized forms thereof;

wherein Y is α or β substituted relative to the —COR 3 ;

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;

wherein Z and —CHO are joined to adjacent atoms on ring C;

R 4 is OH, halo, C 1 -C 6 alkoxy, or C 3 -C 6 cycloalkoxy, wherein the C 1 -C 6 alkoxy is optionally substituted with 1-5 halo; and

wherein R 4 and —CHO are joined to adjacent atoms on ring C.

2. The compound of claim 1 , wherein Y—Z is —CH 2 O— or —CH 2 CH 2 —.

3. The compound of claim 2 , wherein R 3 is C 1 -C 3 alkoxy.

4. The compound of claim 1 , of Formula IIIA:

wherein ring B is optionally substituted 5-6 membered heteroaryl having 1-2 nitrogen atoms;

R 5 is hydrogen or C 1 -C 6 alkyl;

each R 6 is independently halo, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, wherein the C 1 -C 6 alkyl is optionally substituted with 1-3 halo; and

p is 0, 1, 2, or 3.

5. A composition comprising a compound of claim 1 and at least one pharmaceutically acceptable excipient.

6. A method for increasing oxygen affinity of hemoglobin S in a subject, the method comprising administering to a subject in need thereof a compound of claim 1 .

7. A method for treating sickle cell disease, the method comprising administering to a subject in need thereof a compound of claim 1 .