Aryl ethers and uses thereof
The present disclosure relates to HIF-2α inhibitors and methods of making and using them for treating cancer. Certain compounds were potent in HIF-2α scintillation proximity assay, luciferase assay, and VEGF ELISA assay, and led to tumor size reduction and regression in 786-O xenograft bearing mice in vivo.
1. A method of treating cancer, comprising administering to a subject in need thereof a compound of Formula III:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is aryl or heteroaryl;
R 4 is nitro, halo, cyano, alkyl, sulfinyl, sulfonamide, sulfonyl or sulfoximinyl;
R 5 is hydrogen, halo or alkyl;
R 8 is hydrogen, hydroxy, alkylamino, alkoxy or amino;
R 9 is hydrogen, alkyl, alkenyl or alkynyl, or R 8 and R 9 in combination form oxo or oxime;
each of R 10 is independently selected from the group consisting of fluoro, chloro, hydroxy and alkyl, or two R 10 groups and the carbon atom(s) to which they are attached form 3- to 8-membered cycloalkyl or heterocycloalkyl; and
n is 1, 2, 3 or 4;
in conjunction with a radiation therapy.
2. The method of claim 1 , wherein R 1 is phenyl or pyridyl, wherein said phenyl or pyridyl is substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
3. The method of claim 1 , wherein R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamide, sulfonyl or sulfoximinyl.
4. The method of claim 1 , wherein R 5 is hydrogen.
5. The method of claim 1 , wherein R 8 is hydroxy or amino and R 9 is hydrogen.
6. The method of claim 1 , wherein R 10 is fluoro and n is 1, 2 or 3.
7. The method of claim 1 , wherein the compound of Formula III is represented by Formula IVa, IVb, IVc or IVd:
8. The method of claim 1 , wherein the compound of Formula III is represented by Formula Va, Vb, Vc or Vd:
9. The method of claim 8 , wherein R 1 is phenyl or pyridyl, wherein said phenyl or pyridyl is substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and cyano.
10. The method of claim 8 , wherein R 4 is cyano, fluoroalkyl, sulfinyl, sulfonamide, sulfonyl or sulfoximinyl.
11. The method of claim 8 , wherein R 5 is hydrogen and R 8 is hydroxy or amino.
12. The method of claim 8 , wherein the enantiomeric excess of said compound is at least about 80%.
13. The method of claim 8 , wherein the compound of Formula III is:
or a pharmaceutically acceptable salt thereof.
14. The method of claim 8 , wherein the compound of Formula III is:
or a pharmaceutically acceptable salt thereof.
15. The method of claim 8 , wherein the compound of Formula III is:
or a pharmaceutically acceptable salt thereof.
16. The method of claim 1 , wherein the cancer is hemangioblastoma, pheochromocytoma, a pancreatic neuroendocrine tumor, renal cell carcinoma, astrocytoma, breast cancer, cervical cancer, colorectal cancer, glioblastoma, glioma, head and neck cancer, hepatocellular cancer, non-small cell lung cancer, melanoma, neuroblastoma, ovarian cancer or prostate cancer.
17. The method of claim 16 , wherein the cancer is hemangioblastoma, pheochromocytoma, a pancreatic neuroendocrine tumor, or renal cell carcinoma.
18. The method of claim 17 , wherein the cancer is renal cell carcinoma.
19. The method of claim 1 , wherein administering said compound of Formula III improves radiation response of the cancer being treated.
20. The method of claim 1 , wherein administering said compound of Formula III increases sensitivity of the cancer to said radiation therapy.