JPWO2020106642A5 - - Google Patents

Claims (41)

Formula (I):

(I)
[In the formula,
X is CH or N;
Y is CH or N;
Z is absent, _CH2 , O, or S;
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

is]
or an isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt thereof, respectively. 2. The compound of claim 1, wherein X is CH. 2. The compound of claim 1, wherein X is N. 4. The compound of any one of claims 1-3 , wherein Y is CH. 4. The compound of any one of claims 1-3, wherein Y is N. 6. The compound of any one of claims 1-5 , wherein Z is absent, _CH2 , or O. 6. The compound of any one of claims 1-5 , wherein Z is absent. 6. The compound of any one of claims 1-5, wherein Z is _CH2 . 6. The compound of any one of claims 1-5, wherein Z is O. A compound according to any one of claims 1-5, wherein Z is S. Formula (Ia):

2. The compound of claim 1, represented by: R ¹ _{is -CH2OH} , _-CH2CH2OH , _-CH2CH2CN , _or

A compound according to any one of claims 1 to 11 , which is ^12. The compound of any one of claims 1-11 _, wherein R1 is _-CH2OH or _-CH2CH2OH . A compound according to any one of claims 1 to 11, wherein R ¹ is mono-hydroxy-(C _1-4 alkyl) or di-hydroxy-(C _1-4 alkyl). 12. The compound of any one of claims 1-11, wherein ^R1 is hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, or 2-hydroxy-2-methylpropyl. Table below:

3. A compound of claim 1 selected from or an isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt thereof, respectively. 17. A compound selected from the compounds of claim 16. Table below:

3. A compound of claim 1 selected from or an isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt thereof, respectively. formula:

3. The compound of claim 1, represented by or an isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt thereof, respectively. formula:

2. The compound of claim 1, represented by or a pharmaceutically acceptable salt thereof, respectively. the compound is

or a pharmaceutically acceptable salt thereof. the compound is

22. The compound of claim 21, which is the compound is

or a pharmaceutically acceptable salt thereof. the compound is

21. The compound of claim 20, which is the compound is

or a pharmaceutically acceptable salt thereof. the compound is

21. The compound of claim 20, which is the compound is

or a pharmaceutically acceptable salt thereof. the compound is

21. The compound of claim 20, which is the compound is

or a pharmaceutically acceptable salt thereof. the compound is

21. The compound of claim 20, which is the compound is

or a pharmaceutically acceptable salt thereof. the compound is

21. The compound of claim 20, which is 33. A pharmaceutical composition comprising a compound according to any one of claims 1-32, or an isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt thereof, respectively, and a pharmaceutically acceptable excipient. 18. A pharmaceutical composition comprising a compound of claim 17 and a pharmaceutically acceptable excipient. 33. A pharmaceutical composition for increasing the oxygen affinity of hemoglobin S in a subject in need thereof, comprising a compound according to any one of claims 1-32, or an isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt thereof, respectively. 18. A pharmaceutical composition for increasing the oxygen affinity of hemoglobin S in a subject in need thereof, comprising a compound according to claim 17. 33. A pharmaceutical composition for treating a hemoglobin-mediated disorder in a subject in need thereof comprising a compound according to any one of claims 1-32, or an isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt thereof, respectively. 18. A pharmaceutical composition for treating a hemoglobin-mediated disorder in a subject in need thereof, comprising a compound of claim 17. 39. The pharmaceutical composition of claim 37 or claim 38, wherein the hemoglobin is sickle hemoglobin. 33. A pharmaceutical composition for treating sickle cell disease in a subject in need thereof, comprising a compound according to any one of claims 1-32, or an isotopically enriched analogue, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt thereof, respectively. 18. A pharmaceutical composition for treating sickle cell disease in a subject in need thereof, comprising a compound of claim 17.