Claims for Patent: 10,335,388

Summary for Patent: 10,335,388

Title:	Combination therapy of a HIF-2-alpha inhibitor and an immunotherapeutic agent and uses thereof
Abstract:	The present invention provides methods and pharmaceutical compositions for treating proliferative disorders. The method involves step of administering to said subject a HIF-2alpha inhibitor and an immunotherapeutic agent.
Inventor(s):	John A. Josey, Eli M. Wallace, Guangzhou HAN
Assignee:	Peloton Therapeutics Inc
Application Number:	US15/564,348
Patent Claims:	1. A method of treating cancer in a subject in need thereof, comprising administering to said subject an effective amount of a HIF-2α inhibitor in combination B with an immunotherapeutic agent, wherein the cancer is selected from the group consisting of melanoma, renal cell carcinoma, and colorectal cancer, wherein the immunotherapeutic agent is a PD-1 inhibitor or a CTLA-4 inhibitor, and wherein the HIF-2α inhibitor is a compound of Formula I-C: or a pharmaceutically acceptable salt thereof, wherein: X is CR5 or N; Y is CR6 or N; Z is —O—, —S—, —C(HR7)—, —N(R8)— or absent; R1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; R4 is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R5, R6, R7 and R8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; R11 is hydrogen, halo, hydroxy, alkoxy or amino; R12 is hydrogen, alkyl, alkenyl or alkynyl; or R11 and R12 in combination form oxo or oxime; each of R13 is independently selected from the group consisting of hydrogen, fluoro, chloro, hydroxy, alkyl and heteroalkyl; or two R13s 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 the HIF-2α inhibitor and the immunotherapeutic agent yield a synergistic effect in treating the cancer. 3. The method of claim 1, wherein the HIF-2α inhibitor is administered before, simultaneously with, or after the immunotherapeutic agent. 4. The method of claim 1, wherein the HIF-2α inhibitor inhibits one or more biological effects selected from the group consisting of heterodimerization of HIF-2α to HIF1β, HIF-2α target gene expression, VEGF gene expression, and VEGF protein secretion. 5. The method of claim 4, wherein the HIF-2α inhibitor inhibits heterodimerization of HIF-2α to HIF1β but not heterodimerization of HIF1α to HIF1β. 6. The method of claim 1, wherein the HIF-2α inhibitor binds the PAS-B domain cavity of HIF2α. 7. The method of claim 1, wherein R12 is hydrogen. 8. The method of claim 1, wherein: R4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R11 is hydroxy or amino; and R12 is hydrogen. 9. The method of claim 1, wherein R13 is fluoro and n is 1, 2 or 3. 10. 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. 11. The method of claim 1, wherein R11 is hydroxy or amino. 12. The method of claim 1, wherein R1 is phenyl, monocyclic heteroaryl or bicyclic heteroaryl. 13. The method of claim 12, wherein R1 is phenyl or pyridyl. 14. The method of claim 1, wherein R1 is substituted with at least one substituent selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy and cyano. 15. The method of claim 1, wherein R4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. 16. The method of claim 1, wherein Z is —O—. 17. The method of claim 1, wherein: R4 is fluoroalkyl or sulfonyl; n is 0, 1, 2 or 3; Z is —O—; R11 is hydroxy; and R12 is hydrogen. 18. The method of claim 17, wherein R1 is phenyl, pyridyl, cycloalkyl or heterocycloalkyl. 19. The method of claim 1, wherein X is CR5 and Y is CR6. 20. The method of claim 1, wherein the HIF-2α inhibitor is selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 21. The method of claim 1, wherein the immunotherapeutic agent is selected from nivolumab, pembrolizumab, tremelimumab and ipilimumab.