COMPOUNDS AND USES THEREOF FOR THE MODULATION OF HEMOGLOBIN

1 . A compound of Formula (I):

or a tautomer thereof, or pharmaceutically acceptable salt of each of 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 with 1-3 halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, oxo, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo, or R 1 and R 2 together with the nitrogen atom they are attached to form an optionally substituted 4-7 membered heterocycle;

L 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 provided that when L is NR 70 , R 70 is hydrogen, R 3 is NR 1 R 2 , and one of R 1 and R 2 is hydrogen, then, the other of R 1 and R 2 is not optionally substituted C 6 -C 10 aryl as defined above;

d is 1, 2, or 3;

ring B is a C 6 -C 10 aryl, 5-10 membered heteroaryl having 1-3 nitrogen atoms or oxidized forms of N, 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, wherein the aryl, heteroaryl, or heterocycle is optionally substituted with 1-3 halo, C 1 -C 6 alkyl optionally substituted with 1-5 halo, C 1 -C 6 alkoxy, hydroxy, oxo COR 15 , and CO 2 R 15 ;

R 15 is C 1 -C 6 alkyl, C 6 -C 10 aryl, 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;

R 17 is C 1 -C 6 alkyl, C 6 -C 10 aryl, 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;

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 CO, and provided that Y and Z are not both heteroatoms or oxidized forms thereof;

wherein Y is α or β substituted relative to the -LCOR 3 ;

ring C is a C 6 -C 10 aryl or 5-10 membered heteroaryl containing 1-3 nitrogen atoms, or an oxidized form of N, wherein the aryl or heteroaryl is further optionally substituted with 1-3 halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo;

wherein Z and —CV 1 V 2 H are joined to adjacent atoms on ring C;

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;

R 84 is optionally substituted C 1 -C 6 alkyl;

R 4 is OH, halo, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkoxy or O—R, where R is a prodrug moiety, wherein the C 1 -C 6 alkoxy is optionally substituted with 1-5 halo; and

R 4 and CV 1 V 2 H are adjacent or ortho to each other.

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 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.

3 . A compound of claim 1 of Formula (II):

wherein Y—Z is —CH 2 O— or —CH 2 CH 2 — and the remaining substituents are defined as in claim 1 .

4 . The compound of claim 3 , wherein and R 4 and —CHO are joined to adjacent atoms on ring C.

5 . The compound of claim 2 , of Formula IIIA:

wherein 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;

R 5 is hydrogen, C 1 -C 6 alkyl or a prodrug moiety R;

R 6 is halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo; and

p is 0, 1, 2, or 3.

6 . The compound of claim 2 , wherein the compound is of Formula IIIB, IIIC, or IIID:

wherein

are optionally substituted 4-10 membered heterocycle as defined in claim 1 ;

R 5 is hydrogen, C 1 -C 6 alkyl or a prodrug moiety;

R 6 is halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo; and

p is 0, 1, 2, or 3.

7 . The compound of claim 2 , wherein ring B is substituted with 1-3: halo, C 1 -C 6 alkyl, COR 15 , or COOR 15 ; and

R 15 is C 1 -C 6 alkyl, C 6 -C 10 aryl, 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 the alkyl, aryl, heteroaryl or heterocyclyl is optionally substituted.

8 . (canceled)

9 . A compound of formula:

or an N oxide thereof, or a pharmaceutically acceptable salt of each thereof.

10 . A composition comprising a compound of claim 2 and at least one pharmaceutically acceptable excipient.

11 . 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 2 .

12 . A method for treating oxygen deficiency associated with sickle cell anemia or acute respiratory distress syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 2 .

13 . A composition comprising a compound of claim 9 and at least one pharmaceutically acceptable excipient.

14 . 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 9 .

15 . A method for treating oxygen deficiency associated with sickle cell anemia or acute respiratory distress syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 9 .

16 . 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 composition of claim 13 .

17 . A method for treating oxygen deficiency associated with sickle cell anemia or acute respiratory distress syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition of claim 13 .