US2022125769A1PendingUtilityA1

Estrogen receptor modulators for treating mutants

Assignee: RECURIUM IP HOLDINGS LLCPriority: Aug 6, 2019Filed: Jan 5, 2022Published: Apr 28, 2022

Est. expiryAug 6, 2039(~13.1 yrs left)· nominal 20-yr term from priority

Inventors:Ahmed Abdi Samatar Jiali Li Jianhui Ma Sayee Gajanan Hegde Peter Qinhua Huang Kevin Duane Bunker Fernando Donate

A61P 35/00A61K 31/437A61P 35/04

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Claims

Abstract

Uses and methods that include an effective amount of Compound (A), or a pharmaceutically acceptable salt thereof, are described herein for treating breast cancer in a subject in need thereof, wherein the breast cancer has at least one point mutation within the Estrogen Receptor 1 (ESR1) that encodes Estrogen receptor alpha (ERα).

Claims

exact text as granted — not AI-modified

What is claimed is: 
     
         1 . A method for treating breast cancer in a subject having breast cancer comprising administering to the subject having breast cancer an effective amount of a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is Compound (A), or a pharmaceutically acceptable salt thereof, having the structure: 
       
         
           
           
               
               
           
         
       
       and
 wherein the breast cancer has at least one point mutation within the Estrogen Receptor 1 (ESR1) that encodes Estrogen receptor alpha (ERα), wherein the mutation is selected from the group consisting of: K303R, D538G, Y537S, E380Q, Y537C, Y537N, A283V, A546D, A546T, A58T, A593D, A65V, C530L, D411H, E279V, E471D, E471V, E523Q, E542G, F461V, F97L, G145D, G160D, G274R, G344D, G420D, G442R, G557R, H524L, K252N, K481N, K531E, L370F, L453F, L466Q, L497R, L536H, L536P, L536Q, L536R, L540Q, L549P, M388L, M396V, M421V, M437I, M522I, N156T, N532K, N69K, P147Q, P222S, P535H, R233G, R477Q, R503W, R555H, S282C, S329Y, S338G, S432L, S463P, S47T, S576L, V392I, V418E, V478L, V533M, V534E, Y537D and Y537H. 
 
     
     
         2 . The method of  claim 1 , wherein the breast cancer is ER positive breast cancer. 
     
     
         3 . The method of  claim 1 , wherein the breast cancer is ER positive/HER2-negative breast cancer. 
     
     
         4 . The method of  claim 1 , wherein the breast cancer is selected from the group consisting of local breast cancer, metastatic breast cancer and recurrent breast cancer. 
     
     
         5 . The method of  claim 1 , wherein the subject has been previously treated with an endocrine therapy. 
     
     
         6 . The method of  claim 5 , wherein the treatment was with a selective ER modulator (SERM). 
     
     
         7 . The method of  claim 6 , wherein the selective ER modulator is selected from the group consisting of tamoxifen, raloxifene, ospemifene, bazedoxifene, toremifene and lasofoxifene. 
     
     
         8 . The method of  claim 5 , wherein the treatment was with a selective ER degrader (SERD). 
     
     
         9 . The method of  claim 8 , wherein the selective ER degrader is selected from the group consisting of fulvestrant, elacestrant, (E)-3-[3,5-Difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid, (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid, (E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid, (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid and 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol. 
     
     
         10 . The method of  claim 5 , wherein the treatment was with an aromatase inhibitor. 
     
     
         11 . The method of  claim 10 , wherein the aromatase inhibitor is a steroidal aromatase inhibitor. 
     
     
         12 . The method of  claim 10 , wherein the aromatase inhibitor is a non-steroidal aromatase inhibitor. 
     
     
         13 . The method of  claim 10 , wherein the aromatase inhibitor is selected from the group consisting of exemestane, testolactone, anastazole and letrazole. 
     
     
         14 . The method of  claim 1 , wherein the subject is a woman. 
     
     
         15 . The method of  claim 14 , wherein the subject is a premenopausal woman. 
     
     
         16 . The method of  claim 14 , wherein the subject is a perimenopausal woman. 
     
     
         17 . The method of  claim 14 , wherein the subject is a menopausal woman. 
     
     
         18 . The method of  claim 14 , wherein the subject is a postmenopausal woman. 
     
     
         19 . The method of  claim 1 , wherein the subject is a man. 
     
     
         20 . The method of  claim 1 , wherein the subject has a serum estradiol level in the range of &gt;15 pg/mL to 350 pg/mL.

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