Compounds and uses thereof for the modulation of hemoglobin

A compound of Formula (I) is provided:

• or a tautomer thereof, or pharmaceutically acceptable salt of each of thereof, wherein
• R3 is C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, or —NR1R2;
• each R1 and R2 independently is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 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 R1 and R2 together with the nitrogen atom they are attached to form an optionally substituted 4-7 membered heterocycle;
• L is a bond or is NR70, O, S, or(CR71R72)d;
• wherein each R70, R71, and R72 independently are hydrogen or C1-C6 alkyl;
• d is 1, 2, or 3;
• ring B is a optionally substituted C6-C10 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;
• each Y and Z is independently CR10R11, O, S, SO, SO2, or NR12;
• each R10 and R11 independently is hydrogen or C1-C3 alkyl optionally substituted with 1-3 halo, OH, or C1-C6 alkoxy, or CR10R11 is C═O, provided that if one of Y and Z is O, S, SO, SO2, 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 -LCOR3;
• ring C is a optionally substituted C6-C10 aryl or optionally substituted 5-10 membered heteroaryl containing 1-3 nitrogen atoms, or an oxidized form of N;
• wherein Z and —CV1V2H are joined to adjacent atoms on ring C;
• V1 and V2 independently are C1-C6 alkoxy;
• or V1 and V2 together with the carbon atom they are attached to form a ring of formula:
• wherein each V3 and V4 are independently O, S, or NH, provided that when one of V3 and V4 is S, the other is NH, and provided that V3 and V4 are both not NH;
• q is 1 or 2;
• each V5 is independently C1-C6 alkyl or CO2R60, where each R60 independently is C1-C6 alkyl or hydrogen;
• t is 0, 1, 2, or 4;
• or CV1V2 is C═V, wherein V is O, NOR80, or NNR81R82;
• R80 is optionally substituted C1-C6 alkyl;
• R81 and R82 independently are selected from the group consisting of hydrogen;
• optionally substituted C1-C6 alkyl, COR83 and CO2R84;
• R83 is hydrogen or optionally substituted C1-C6 alkyl;
• and
• R84 is optionally substituted C1-C6 alkyl;
• R4 is OH, halo, C1-C6 alkoxy, C3-C6 cycloalkoxy or O—R, where R is a prodrug moiety, wherein the C1-C6 alkoxy is optionally substituted with 1-5 halo.