Compositions for use in treating pulmonary arterial hypertension

1. A method of treating pulmonary arterial hypertension (PAH), comprising administering to a subject in need thereof a composition comprising an effective amount of a HIF-2α inhibitor, wherein the HIF-2α inhibitor is a compound of Formula I-C:

or a pharmaceutically acceptable salt thereof, wherein:

X is CR 5 or N;

Y is CR 6 or N;

Z is O, S, CHR 7 , NR 8 or absent;

R 1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano;

R 4 is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl;

R 5 , R 6 , R 7 and R 8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy;

R 11 is hydroxy, alkoxy or amino;

R 12 is hydrogen;

each of R 13 is independently selected from the group consisting of hydrogen, fluoro, chloro, hydroxy, alkyl and heteroalkyl; or two R 13 s and the carbon atom(s) to which they are attached form a 3- to 8-membered cycloalkyl or heterocycloalkyl moiety; and

n is 0, 1, 2, 3 or 4.

2. The method of claim 1 , wherein:

R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl;

R 11 is hydroxy or amino; and

R 12 is hydrogen.

3. The method of claim 1 , wherein R 13 is fluoro and n is 1, 2 or 3.

4. The method of claim 1 , wherein the HIF-2α inhibitor is a compound of Formula I-H, I-I, I-J or I-K:

or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 , wherein R 11 is hydroxy or amino.

6. The method of claim 1 , wherein R 1 is phenyl, monocyclic heteroaryl or bicyclic heteroaryl.

7. The method of claim 6 , wherein R 1 is phenyl or pyridyl.

8. The method of claim 1 , wherein R 1 is substituted with at least one substituent selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.

9. The method of claim 1 , wherein R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl.

10. The method of claim 1 , wherein Z is O.

11. The method of claim 1 , wherein:

R 4 is fluoroalkyl or sulfonyl;

n is 0, 1, 2 or 3;

Z is O;

R 11 is hydroxy; and

R 12 is hydrogen.

12. The method of claim 11 , wherein R 1 is phenyl, pyridyl, cycloalkyl or heterocycloalkyl.

13. The method of claim 1 , wherein X is CR 5 and Y is CR 6 .

14. The method of claim 1 , wherein the HIF-2α inhibitor is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 , wherein a second therapeutic agent is administered simultaneously or sequentially with the HIF-2α inhibitor.

16. The method of claim 1 , further comprising (a) measuring a physiological indicator of PAH before and after the administering, and (b) adjusting dosage or discontinuing use of the HIF-2α inhibitor based on a result of step (a).