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 process for preparing 3-[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile, comprising:
(i) fluorinating a compound of Formula A:
to provide a compound of Formula B:
and
(ii) deprotecting the compound of Formula B to provide 3-[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile, represented by the formula:
wherein P is a protecting group.
2. The process of claim 1 , wherein P is selected from acyl and methoxymethyl ether.
3. The process of claim 2 , wherein P is C(═O)R, wherein R is C 1 -C 4 alkyl.
4. The process of claim 3 , wherein P is C(═O)CH 3 .
5. The process of claim 1 , wherein the fluorinating comprises adding (diethylamino)sulfur trifluoride to the compound of Formula A.
6. The process of claim 1 , further comprising, prior to step (i):
(i-a) hydrolyzing a compound of Formula C:
to provide the compound of Formula A.
7. The process of claim 6 , wherein the hydrolyzing comprises a silver salt.
8. The process of claim 7 , wherein the silver salt is selected from Ag 2 CO 3 , AgClO 4 and AgBF 4 .
9. The process of claim 6 , further comprising, prior to step (i-a):
(i-b) brominating a compound of Formula D:
to provide the compound of Formula C.
10. The process of claim 9 , further comprising, prior to step (i-b):
(i-c) protecting the hydroxy group of 3-fluoro-5-(((1S,2R)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile, represented by the formula:
with protecting group P to provide the compound of Formula D.
11. A process for preparing 3-fluoro-5-(((1S,2R)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile, comprising:
(i) fluorinating 3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile, represented by the formula:
to provide 3-fluoro-5-((2-fluoro-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile, represented by the formula:
and
(ii) reducing the 3-fluoro-5-((2-fluoro-7-(methylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile to provide the 3-fluoro-5-(((1S,2R)-2-fluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile, represented by the formula:
12. The process of claim 11 , wherein the fluorinating comprises adding N-fluoro-o-benzendisulfonamide, acetyl hypofluorite, 1fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), 1-fluoro-4-methyl-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), or N-fluorobenzenesulfonamide to the 3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile.
13. The process of claim 11 , wherein the reducing is an asymmetric reduction.
14. The process of claim 13 , wherein the reducing provides the 3-fluoro-5-(((1S,2R)-2-fluoro-1-hydroxy-7-(methyl sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)benzonitrile with greater than 90% enantioselectivity.
15. The process of claim 13 , wherein the asymmetric reduction is selected from Corey-Bakshi-Shibata reduction, asymmetric hydrogenation, and asymmetric transfer hydrogenation.
16. The process of claim 13 , further comprising a ruthenium catalyst.
17. The process of claim 11 , further comprising, prior to step (i):
(i-a) oxidizing 3-fluoro-5-(7-methylsulfanyl-1-oxo-indan-4-yl)oxy-benzonitrile, represented by the formula:
to provide the 3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile.
18. The process of claim 17 , further comprising, prior to step (i-a):
(i-b) converting 3-(2-hydroxy-5-methylsulfanyl-phenyl)propanoic acid, represented by the formula:
to 3-[2-(3-cyano-5-fluoro-phenoxy)-5-methylsulfanyl-phenyl]propanoic acid, represented by the formula:
and
(i-c) cyclizing the 3-[2-(3-cyano-5-fluoro-phenoxy)-5-methylsulfanyl-phenyl]propanoic acid to provide the 3-fluoro-5-(7-methylsulfanyl-1-oxo-indan-4-yl)oxy-benzonitrile.