Modulators of hemoglobin
The present disclosure relates generally to compounds and pharmaceutical compositions suitable as modulators of hemoglobin, and methods for their use in treating disorders mediated by hemoglobin.
1. A compound of formula (I):
or an isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof,
wherein:
ring A is aryl or heteroaryl, wherein ring A is optionally substituted with 1-3 R 3 ;
ring B is aryl, nitrogen-containing heteroaryl, or nitrogen-containing heterocyclyl, wherein ring B is optionally substituted with 1-3 R 4 ;
L is absent, —C(O)—, —C(O)O—, or —CH 2 —;
R 1 is —C(O)H;
R 2 is H or OH;
each R 3 is independently halo, hydroxy, C 1-3 alkyl, C 2-3 alkenyl, C 1-3 alkoxy, C 1-3 haloalkyl, or C 1-3 haloalkoxy; and
each R 4 is independently oxo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, or C 3-5 cycloalkyl.
2. The compound of claim 1 , wherein L is absent, and ring B is aryl or nitrogen-containing heteroaryl, wherein ring B is optionally substituted with 1-3 R 4 .
3. The compound of claim 1 , wherein L is absent, and ring B is C 6 or C 10 aryl optionally substituted with 1-3 R 4 .
4. The compound of claim 3 , wherein ring B is phenyl optionally substituted with 1-3 R 4 .
5. The compound of claim 4 , wherein ring B is phenyl.
6. The compound of claim 1 , wherein L is absent, and ring B is a 5-membered or 6-membered nitrogen-containing heteroaryl optionally substituted with 1-3 R 4 .
7. The compound of claim 6 , wherein ring B is a pyridyl ring or pyrazinyl ring, each of which is optionally substituted with 1-3 R 4 .
8. The compound of claim 7 , wherein
9. The compound of claim 8 , wherein
10. The compound of claim 1 , wherein L is —C(O)—, and ring B is a nitrogen-containing heterocyclyl optionally substituted with 1-3 R 4 .
11. The compound of claim 10 , wherein ring B is a 5-membered or 6-membered nitrogen-containing heterocyclyl optionally substituted with 1-3 R 4 .
12. The compound of claim 11 , wherein ring B is a 5-membered or 6-membered nitrogen-containing heterocyclyl.
13. The compound of claim 10 , wherein ring B is
and X is absent, —CH 2 —, —N(R 5 )—, —O—, —S(O) 0-2 —, —CH 2 CH 2 —, —CH 2 —O—, or —O—CH 2 —; wherein R 5 is H, C 1-3 alkyl, or C 3-5 cycloalkyl.
14. The compound of claim 13 , wherein ring B is
15. The compound of claim 13 , wherein ring B is
16. The compound of claim 11 , wherein ring B is a 5-membered or 6-membered nitrogen-containing heterocyclyl substituted with one R 4 , wherein R 4 is C 1-3 alkyl.
17. The compound of claim 10 , wherein ring B is
and X is absent, —CH 2 —, —N(R 5 )—, —O—, —S(O) 0-2 —, —CH 2 CH 2 —, —CH 2 —O—, or —O—CH 2 —; wherein R 5 is H, C 1-3 alkyl, or C 3-5 cycloalkyl.
18. The compound of claim 17 , wherein ring B is
wherein R 4 is C 1-3 alkyl.
19. The compound of claim 1 , wherein
are attached in a 1,2-position relative to each other on ring B.
20. The compound of claim 1 , wherein
are attached in a 1,3-position relative to each other on ring B.
21. The compound of claim 1 , wherein
are attached in a 1,4-position relative to each other on ring B.
22. The compound of claim 1 , wherein ring A is a C 6 or C 10 aryl optionally substituted with 1-3 R 3 .
23. The compound of claim 22 , wherein ring A is a phenyl optionally substituted with 1-3 R 3 .
24. The compound of claim 23 , wherein ring A is a phenyl substituted with 1-3 R 3 .
25. The compound of claim 1 , wherein ring A is a 5-membered or 6-membered heteroaryl optionally substituted with 1-3 R 3 .
26. The compound of claim 25 , wherein ring A is a 5-membered heteroaryl substituted with 1-3 R 3 .
27. The compound of claim 25 , wherein ring A is a 6-membered heteroaryl substituted with 1-3 R 3 .
28. The compound of claim 25 , wherein ring A is a pyridinyl, pyrimidinyl, pyrazolyl, furanyl, oxazolyl, or thiazolyl, each of which is substituted with 1-3 R 3 .
29. The compound of claim 1 , wherein R 1 and L are attached in a 1,3-position relative to each other on ring A.
30. The compound of claim 1 , wherein R 1 and L are attached in a 1,2-position relative to each other on ring A.
31. The compound of claim 1 , wherein R 1 and L are attached in a 1,4-position relative to each other on ring A.
32. The compound of claim 1 , wherein each R 3 is independently halo, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy.
33. The compound of claim 1 , of formula (IIa):
wherein:
ring B is aryl or nitrogen-containing heteroaryl, wherein ring B is optionally substituted with 1-3 R 4 ; and
R 1 and ring B are attached in a 1,3-position relative to each other on ring A.
34. The compound of claim 1 , of formula (IIIa):
wherein:
ring B is phenyl or 6-membered nitrogen-containing heteroaryl; and ring A and
are attached on adjacent ring carbon atoms of ring B.
35. The compound of claim 34 , of formula (IIIa(i)):
36. The compound of claim 35 , wherein R 1 and
are attached in a 1,3-position relative to each other on ring A.
37. The compound of claim 34 , wherein ring A is phenyl, 5-membered heteroaryl, or 6-membered heteroaryl, each of which is optionally substituted with 1-3 R 3 ;
wherein each R 3 is independently halo, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy.
38. The compound of claim 1 , of formula (IVa):
wherein:
ring B is a nitrogen-containing heterocyclyl optionally substituted with 1-3 R 4 ; and
R 1 and —C(O)— of the moiety
are attached on adjacent ring atoms of ring A.
39. The compound of claim 1 , of formula (IVb):
wherein:
ring B is a nitrogen-containing heterocyclyl optionally substituted with 1-3 R 4 ; and
R 1 and —C(O)— of the moiety
are attached in a 1,3-position relative to each other on ring A.
40. The compound of claim 1 , of formula (IVc):
wherein:
ring B is a nitrogen-containing heterocyclyl optionally substituted with 1-3 R 4 ; and
R 1 and —C(O)— of the moiety
are attached in a 1,4-position relative to each other on ring A.
41. The compound of claim 1 , of formula (Va(1)):
wherein X is absent, —CH 2 —, —CH 2 CH 2 —, —O—, or —S—.
42. The compound of claim 41 , wherein R 1 and —C(O)— of the moiety
are attached on adjacent ring atoms of ring A.
43. The compound of claim 41 , wherein ring A is phenyl or pyridinyl, each of which is optionally substituted with 1-3 R 3 ; wherein each R 3 is independently halo, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy.
44. The compound of claim 1 , of formula (Vb):
wherein X is absent, —CH 2 —, —N(R 5 )—, —O—, —S(O) 0-2 —, —CH 2 CH 2 —, —CH 2 —O—, or —O—CH 2 —; and
R 5 is H, C 1-3 alkyl, or C 3-5 cycloalkyl.
45. The compound of claim 44 , wherein R 1 and —C(O)— of the moiety
are attached on adjacent ring atoms of ring A.
46. The compound of claim 44 , wherein ring A is phenyl or pyridinyl, each of which is optionally substituted with 1-3 R 3 ; wherein each R 3 is independently halo, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy.
47. The compound of claim 44 , wherein ring A is phenyl optionally substituted with 1-3 R 3 ; wherein each R 3 is independently halo, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy.
48. The compound of claim 44 , wherein R 4 is C 1-3 alkyl.
49. The compound of claim 1 , of formula (VIa):
wherein X is absent, —CH 2 —, —CH 2 CH 2 —, —O—, or —S—.
50. The compound of claim 49 , wherein R 1 and —C(O)— of the moiety
are attached in a 1,2-position or a 1,3-position relative to each other on ring A.
51. The compound of claim 49 , wherein ring A is phenyl optionally substituted with 1-3 R 3 ; wherein each R 3 is independently halo, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy.
52. The compound of claim 1 , wherein R 2 is OH.
53. The compound of claim 1 , wherein R 2 is H.
54. A compound of formula:
or a pharmaceutically acceptable salt thereof.
55. A compound of formula:
or a pharmaceutically acceptable salt thereof.
56. A pharmaceutical composition comprising a compound according to claim 1 , or an isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof, and a pharmaceutically acceptable excipient.
57. A method for increasing oxygen affinity of hemoglobin S in a subject in need thereof, comprising administering to the subject a compound according to claim 1 , or an isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.
58. A method for treating a disorder mediated by hemoglobin in a subject in need thereof, comprising administering to the subject a compound according to claim 1 , or an isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.
59. The method of claim 58 , wherein the hemoglobin is sickle hemoglobin.
60. A method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a compound according to claim 1 , or an isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.