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, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt of each thereof, wherein:
X is CH or N;
Y is CH or N;
Z is absent, CH 2 , O, or S; and
R 1 is mono-hydroxy-(C 1-4 alkyl), di-hydroxy-(C 1-4 alkyl), —CH 2 CH 2 OCH 3 , —CH 2 CH 2 CN, or
2 . The compound of claim 1 , wherein X is CH.
3 . The compound of claim 1 , wherein X is N.
4 . The compound of any one of the preceding claims , wherein Y is CH.
5 . The compound of any one of claims 1-3 , wherein Y is N.
6 . The compound of any one of the preceding claims , wherein Z is absent, CH 2 , or O.
7 . The compound of any one of the preceding claims , wherein Z is absent.
8 . The compound of any one of claims 1-5 , wherein Z is CH 2 .
9 . The compound of any one of claims 1-5 , wherein Z is O.
10 . The compound of any one of claims 1-5 , wherein Z is S.
11 . The compound of claim 1 , of formula Ia:
12 . The compound of any one of the preceding claims , wherein R 1 is —CH 2 OH, —CH 2 CH 2 OH, —CH 2 CH 2 CN, or
13 . The compound of any one of the preceding claims , wherein R 1 is —CH 2 OH or —CH 2 CH 2 OH.
14 . The compound of any one of claims 1-11 , wherein R 1 is mono-hydroxy-(C 1-4 alkyl) or di-hydroxy-(C 1-4 alkyl).
15 . The compound of any one of claims 1-11 , wherein R 1 is hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, or 2-hydroxy-2-methylpropyl.
16 . A compound selected from Table 1, or an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt of each thereof.
17 . A compound selected from Table 1.
18 . A compound selected from Table 2, or an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt of each thereof.
19 . A compound of formula:
or an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt of each thereof.
20 . A compound of formula:
or a pharmaceutically acceptable salt of each thereof.
21 . The compound of claim 20 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
22 . The compound of claim 20 , wherein the compound is:
23 . The compound of claim 20 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
24 . The compound of claim 20 , wherein the compound is:
25 . The compound of claim 20 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
26 . The compound of claim 20 , wherein the compound is:
27 . The compound of claim 20 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
28 . The compound of claim 20 , wherein the compound is:
29 . The compound of claim 20 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
30 . The compound of claim 20 , wherein the compound is:
31 . The compound of claim 20 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
32 . The compound of claim 20 , wherein the compound is:
33 . A pharmaceutical composition comprising a compound according to any one of the preceding claims , or an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt of each thereof, and a pharmaceutically acceptable excipient.
34 . A pharmaceutical composition comprising a compound according to claim 17 , and a pharmaceutically acceptable excipient.
35 . A method for increasing oxygen affinity of hemoglobin S in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1-32 , or an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt of each thereof, or a pharmaceutical composition of claim 33 .
36 . 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 17 or a pharmaceutical composition of claim 34 .
37 . A method for treating a disorder mediated by hemoglobin in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1-32 , or an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt of each thereof, or a pharmaceutical composition of claim 33 .
38 . 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 17 or a pharmaceutical composition of claim 34 .
39 . The method of claim 37 or claim 38 , wherein the hemoglobin is sickle hemoglobin.
40 . A method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a compound according to any one of claims 1-32 , or an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt of each thereof, or a pharmaceutical composition of claim 33 .
41 . A method for treating sickle cell disease in a subject in need thereof, comprising administering to the subject a compound according to claim 17 or a pharmaceutical composition of claim 34 .