Bicyclic heteroaryl compounds and uses thereof for the modulation of hemoglobin

1. A compound of formula (I):

or an N-oxide thereof, or a tautomer thereof, or a pharmaceutically acceptable salt of each of the preceding, wherein

Q is A-B— wherein B is joined with Y;

A is an optionally substituted 5-10 membered heteroaryl 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;

B is a C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl having up to 5 heteroatoms, or a 4-10 membered heterocycle having up to 5 heteroatoms, wherein the heteroatom is selected from N, S, O and oxidized forms of N and S, and the aryl, heterocycle, or the heteroaryl is optionally substituted;

X is O;

Y is CR 10 R 11 ;

R 10 and R 11 independently are hydrogen or C 1 -C 3 alkyl;

CV 1 V 2 is C═V, wherein V is O;

T 1 is N or CR 25 ;

T 2 is N or CR 26 ;

T 3 is N or CR 27 ;

T 4 is N, NR 55 , or CR 28 ;

R 25 , R 26 , R 27 , and R 28 independently are hydrogen, halo, or N(R 30 ) 2 , wherein each R 30 independently is hydrogen, optionally substituted C 1 -C 6 alkoxy, or optionally substituted C 1 -C 6 alkyl, or two R 30 groups, together with the nitrogen to which they are attached, form a 3-7 membered ring, containing 1-2 heteroatoms, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S;

or R 25 , R 26 , R 27 , and R 28 independently are A 1 (CH 2 ) v N(R 65 ) 2 , wherein A 1 is O or S, v is 1, 2, 3, or 4, and each R 65 independently is C 1 -C 6 alkyl or two R 65 groups, together with the nitrogen to which they are attached, form a 3-7 membered ring; and

R 55 is C 1 -C 6 alkyl.

2. The compound of claim 1 , wherein T 1 is CR 25 and T 2 is CR 26 .

3. The compound of claim 1 , wherein Y is CH 2 .

4. A compound selected from the group consisting of:

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

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 in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

7. A method for treating a condition associated with oxygen deficiency, the method comprising administering to a subject suffering from the condition a therapeutically effective amount of a compound of claim 1 .

8. The compound of claim 1 , wherein the optionally substituted groups are optionally substituted with one, two or three substituents selected from the group consisting of oxo, halo, —CN, NO 2 , —CO 2 R 100 , OR 100 , —SR 100 , —SOR 100 , —SO 2 R 100 , —NR 101 R 102 , —CONR 101 R 102 , —SO 2 NR 101 R 102 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —CR 100 ═C(R 100 ) 2 , —C≡CR 100 , C 3 -C 10 cycloalkyl, C 3 -C 10 heterocyclyl, C 6 -C 12 aryl and C 2 -C 12 heteroaryl;

wherein each R 100 independently is hydrogen, C 1 -C 8 alkyl, C 3 -C 12 cycloalkyl, C 3 -C 10 heterocyclyl, C 6 -C 12 aryl, or C 2 -C 12 heteroaryl; wherein each alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 halo, 1-3 C 1 -C 6 alkyl, 1-3 C 1 -C 6 haloalkyl, or 1-3 C 1 -C 6 alkoxy groups;

wherein each R 100 and R 102 are independently hydrogen, C 1 -C 8 alkyl optionally substituted with —CO 2 H or an ester thereof, C 1 -C 6 alkoxy, oxo, —CR 103 ═C(R 103 ) 2 , C 3 -C 10 cycloalkyl, C 3 -C 10 heterocyclyl, C 6 -C 12 aryl, or C 2 -C 12 heteroaryl;

wherein each R 103 independently is hydrogen, C 1 -C 8 alkyl, C 3 -C 12 cycloalkyl, C 3 -C 10 heterocyclyl, C 6 -C 12 aryl, or C 2 -C 12 heteroaryl; wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 alkyl groups or 1-3 halo groups; or

R 101 and R 102 , together with the nitrogen atom to which they are attached, form a 5-7 membered heterocycle.

9. The compound of claim 1 , wherein the optionally substituted groups are optionally substituted with one, two or three substituents selected from the group consisting of chloro, fluoro, —OCH 3 , methyl, ethyl, iso-propyl, cyclopropyl, vinyl, ethynyl, —CO 2 H, —CO 2 CH 3 , —OCF 3 , —CF 3 and —OCHF 2 .

10. The composition of claim 5 , comprising about 1 mg to about 5 mg of the compound.

11. A composition comprising a compound of claim 4 , and at least one pharmaceutically acceptable excipient.

12. The composition of claim 11 , comprising about 1 mg to about 5 mg of the compound.

13. A method for increasing oxygen affinity of hemoglobin S in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 4 .

14. A method for treating a condition associated with oxygen deficiency, the method comprising administering to a subject suffering from the condition a therapeutically effective amount of a compound of claim 4 .

15. The method of claim 14 , 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.

16. The method of claim 15 , wherein the condition is sickle cell disease.

17. The method of claim 15 , wherein the condition is a pulmonary disorder.

18. The method of claim 7 , 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.

19. The method of claim 18 , wherein the condition is sickle cell disease.

20. The method of claim 18 , wherein the condition is a pulmonary disorder.