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 an optionally substituted 4-10 membered cycloalkyl 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;

ring B is a C 6 -C 10 aryl or 5-10 membered heteroaryl having 1-3 nitrogen atoms, or oxidized versions thereof, wherein the aryl or heteroaryl is optionally substituted;

is a single or a double bond;

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 halo, OH, or C 1 -C 6 alkoxy, or CR 10 R 11 is C═O; R 12 is hydrogen or C 1 -C 6 alkyl; 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,

ring C is C 6 -C 10 aryl;

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 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 not both 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 5 is hydrogen or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo;

R 6 is halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkyl-S(O)—, C 1 -C 6 alkyl-S(O) 2 —, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo; or

R 6 is 4-10 membered cycloalkyl or heterocyclyl substituted with an R′R′N— moiety wherein each R′ is independently C 1 -C 6 alkyl or hydrogen;

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;

k is 0 or 1; and

p is 0, 1, 2 or 3.

2 . The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, 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 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 not both 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 . The compound of claim 2 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein the compound is of formula (II):

4 . The compound of claim 2 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein the compound is of Formula (IIA):

5 . The compound of claim 2 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring A is optionally substituted with 1-3 members independently selected from the group consisting of halo, C 1 -C 6 alkyl, COR 15 and COOR 15 ; wherein R 15 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5-10 membered heteroaryl containing up to 5 ring heteroatoms, 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.

6 . The compound of claim 4 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring B is optionally substituted with 1-3 members independently selected from the group consisting of halo, C 1 -C 6 alkyl COR 15 and/er COOR 15 ; wherein R 15 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5-10 membered heteroaryl containing up to 5 ring heteroatoms, 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.

7 . (canceled)

8 . A composition comprising a compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof; and at least one pharmaceutically acceptable excipient.

9 . 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 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof.

10 . A method for treating a condition associated with oxygen deficiency, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof.

11 . The method of claim 10 , wherein the condition is selected from sickle cell disease, cancer, a pulmonary disorder, stroke, high altitude sickness, an ulcer, a pressure sore, Alzheimer's disease, acute respiratory disease syndrome, and a wound.

12 . The method of claim 11 , wherein the condition is sickle cell disease.

13 . The method of claim 11 , wherein the condition is a pulmonary disorder.

14 . The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring B is an optionally substituted 5-10 membered heteroaryl having 1-2 nitrogen atoms, or oxidized versions thereof.

15 . The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring B is optionally substituted 5-10 membered heteroaryl having 1 nitrogen atom.

16 . The compound of claim 15 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring B is pyridyl.

17 . The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring A is an 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.

18 . The compound of claim 17 , or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein ring A is substituted with 1-3 members independently selected from the group consisting of halo and C 1 -C 6 alkyl.

19 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is