COMPOUNDS AND USES THEREOF FOR THE MODULATION OF HEMOGLOBIN
Provide herein are compounds and pharmaceutical compositions suitable as modulators of hemoglobin, methods and intermediates for their preparation, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation.
1 . A compound of formula (I):
or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein
K is
or K is:
ring B is C 6 -C 10 aryl, C 3 -C 8 cycloalkyl, a 5-10 membered heteroaryl containing up to 5 ring heteroatoms 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 each of the aryl, heteroaryl, cycloalkyl or heterocycle is optionally substituted with 1-4: halo, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo, C 1 -C 6 alkoxy, and/or C 3 -C 10 cycloalkyl;
ring B 1 is a 5-10 membered heteroaryl containing up to 5 ring heteroatoms 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 at least one of the heteroatoms or oxidized forms thereof is gamma (γ) to the position where Y is attached to B, each of the heteroaryl or heterocycle is optionally substituted with 1-4: halo, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo, C 1 -C 6 alkoxy, and/or C 3 -C 10 cycloalkyl;
each X and Y is independently CR 10 R 11 , O, S, SO, SO 2 , or NR 10 ; 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, SO 2 , then the other is not CO, and Y and Z are both not heteroatoms or oxidized forms thereof;
ring C is C 6 -C 10 aryl or a 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, each of which is optionally substituted with 1-4: halo, oxo, —OR 2 , C 1 -C 6 alkyl, and/or C 1 -C 6 alkoxy, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo, C 1 -C 6 alkoxy and/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 1 is optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, or is C 6 -C 10 aryl, a 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, C 3 -C 8 cycloalkyl 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; and
R 2 is hydrogen or a prodrug moiety R;
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 optionally substituted with 1-3 OH groups, or V 5 is 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 , or CO 2 R 84 ;
R 83 is hydrogen or optionally substituted C 1 -C 6 alkyl; and
R 84 is optionally substituted C 1 -C 6 alkyl.
2 . A compound of formula (II) of claim 1 :
or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein
ring B is C 6 -C 10 aryl, C 3 -C 8 cycloalkyl, a 5-10 membered heteroaryl containing up to 5 ring heteroatoms 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 each of the aryl, heteroaryl, cycloalkyl or heterocycle is optionally substituted with 1-4: halo, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo, C 1 -C 6 alkoxy, and/or C 3 -C 10 cycloalkyl;
each X and Y is independently CR 10 R 11 , O, S, SO, SO 2 , or NR 10 ; 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, SO 2 , then the other is not CO, and Y and Z are both not heteroatoms or oxidized forms thereof;
ring C is C 6 -C 10 aryl or a 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, each of which is optionally substituted with 1-4: halo, oxo, —OR 2 , C 1 -C 6 alkyl, and/or C 1 -C 6 alkoxy, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo, C 1 -C 6 alkoxy and/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 1 is optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, or is C 6 -C 10 aryl, a 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, C 3 -C 8 cycloalkyl 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; and
R 2 is hydrogen or a prodrug moiety R;
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 0, 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 optionally substituted with 1-3 OH groups, or V 5 is 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 , or CO 2 R 84 ;
R 83 is hydrogen or optionally substituted C 1 -C 6 alkyl; and
R 84 is optionally substituted C 1 -C 6 alkyl.
3 . The compound of claim 2 , wherein CV 1 V 2 is C═V, wherein V is O, and wherein the remaining variables are defined as in claim 2 .
4 . The compound of claim 3 , of formula (III):
wherein the remaining variables are defined as in claim 3 .
5 . A compound of claim 3 of formula (IV):
wherein
R 1 is optionally substituted C 1 -C 6 alkyl 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;
R 3 is halo, oxo, C 1 -C 6 alkyl and/or C 1 -C 6 alkoxy; and
R 4 is hydrogen or a prodrug moiety R.
6 . The compound of claim 5 , wherein ring B is
C 3 -C 8 heteroaryl containing 1-3 heteroatoms, wherein the heteroaryl is optionally substituted with C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
phenyl substituted with 1-3 halo, or
C 3 -C 8 heterocyclyl containing 1-3 heteroatoms.
7 . A compound of claim 1 selected from the group consisting of:
or N oxides thereof, or a pharmaceutically acceptable salt of each thereof.
8 . A compound of formula (V) of claim 1 :
or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein
ring B 1 is a 5-10 membered heteroaryl containing up to 5 ring heteroatoms 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 at least one of the heteroatoms or oxidized forms thereof is γ to the position where Y is attached to B 1 , each of the heteroaryl or heterocycle is optionally substituted with 1-4: halo, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo, C 1 -C 6 alkoxy, and/or C 3 -C 10 cycloalkyl;
each X and Y is independently CR 10 R 11 , O, S, SO, SO 2 , or NR 10 ; 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, SO 2 , then the other is not CO, and Y and Z are both not heteroatoms or oxidized forms thereof;
ring C is C 6 -C 10 aryl or a 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, each of which is optionally substituted with 1-4: halo, oxo, —OR 2 , C 1 -C 6 alkyl, and/or C 1 -C 6 alkoxy, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo, C 1 -C 6 alkoxy and/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 2 is hydrogen or a prodrug moiety R;
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 optionally substituted with 1-3 OH groups or V 5 is 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 11 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 , or CO 2 R 84 ;
R 83 is hydrogen or optionally substituted C 1 -C 6 alkyl; and
R 84 is optionally substituted C 1 -C 6 alkyl.
9 . The compound of claim 8 , wherein CV 1 V 2 is C═V, wherein V is O, and wherein the remaining variables are defined as in claim 8 .
10 . The compound of claim 9 , of formula:
or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein
ring B is a 5-10 membered heteroaryl containing up to 5 ring heteroatoms 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 each of the heterocycle is optionally substituted with 1-4: halo, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo, C 1 -C 6 alkoxy, and/or C 3 -C 10 cycloalkyl;
X is O, S, SO or SO 2 ;
ring C is C 6 -C 10 aryl or a 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, each of which is optionally substituted with 1-4: halo, oxo, —OR 2 , C 1 -C 6 alkyl, and/or C 1 -C 6 alkoxy, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo, C 1 -C 6 alkoxy and/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; and
R 2 is hydrogen or a prodrug moiety R.
11 . The compound of claim 9 of formula:
or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein
ring B 1 is a 5-10 membered heteroaryl containing up to 5 ring heteroatoms 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 each of the aryl, heteroaryl, cycloalkyl or heterocycle is optionally substituted with 1-4: halo, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo, C 1 -C 6 alkoxy, and/or C 3 -C 10 cycloalkyl;
R 3 is halo, oxo, C 1 -C 6 alkyl and/or C 1 -C 6 alkoxy; and
R 4 is hydrogen or a prodrug moiety R.
12 . The compound of claim 11 , wherein ring B 1 is selected from the group consisting of
wherein Z is O or NR 10 ; and
R 10 is hydrogen or optionally substituted C 1 -C 6 alkyl.
13 . A compound of claim 1 selected from the group consisting of:
or N oxides thereof, or a pharmaceutically acceptable salt of each thereof.
14 . A compound of formula (VIII):
or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein
ring A is a 5-10 membered heteroaryl, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the heteroaryl is optionally substituted with 1-4: C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo, C 1 -C 6 alkoxy, and/or C 3 -C 10 cycloalkyl;
ring B 2 is a 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, wherein the heteroaryl is optionally substituted with with 1-4: C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo, C 1 -C 6 alkoxy, and/or C 3 -C 10 cycloalkyl;
each X and Y is independently CR 10 R 11 , O, S, SO, SO 2 , or NR 10 ; 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, SO 2 , 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 ring B;
L is joined with X and is a bond or is C 1 -C 6 alkylene; and
R 150 is hydrogen, optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkynyl, or C 2 -C 6 alkynyl, or is C 6 -C 10 aryl, a 5-10 membered heteroaryl, containing up to 5 ring heteroatoms wherein the heteroatom is selected from the group consisting of O, N, S, C 3 -C 8 cycloalkyl 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.
15 . The compound of claim 14 of formula:
or a tautomer thereof, or a pharmaceutically acceptable salt of each thereof, wherein
ring A is a 5-10 membered heteroaryl, wherein the heteroatom is selected from the group consisting of O, N, S, and oxidized forms of N and S, wherein the heteroaryl is optionally substituted with 1-4: C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo, C 1 -C 6 alkoxy, and/or C 3 -C 10 cycloalkyl;
ring B 2 is a 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, wherein the heteroaryl is optionally substituted with with 1-4: C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1-5 halo, C 1 -C 6 alkoxy, and/or C 3 -C 10 cycloalkyl;
X is O, S, SO or SO 2 ;
L is joined with X and is a bond or is C 1 -C 6 alkylene; and
R 150 is hydrogen or optionally substituted C 1 -C 6 alkyl.
16 . The compound of claim 15 , wherein L is methylene or ethylene.
17 . A compound of claim 14 selected from:
18 . A composition comprising a compound of claim 2 and at least one pharmaceutically acceptable excipient.
19 . 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 .
20 . A method for treating oxygen deficiency associated with sickle cell anemia, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 2 .