Estrogen receptor modulators

Abstract

Compounds of Formula (I) are estrogen receptor alpha modulators, where the variables in Formula (I) are described in the disclosure. Such compounds, as well as pharmaceutically acceptable salts and compositions thereof, are useful for treating diseases or conditions that are estrogen receptor alpha dependent and/or estrogen receptor alpha mediated, including conditions characterized by excessive cellular proliferation, such as breast cancer.

1 - 31 . (canceled) 
     
     
         32 . A method of inhibiting the growth of a cell, comprising
 identifying a cell having an estrogen receptor alpha that mediates a growth characteristic of the cell; and   contacting the cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:   
       
         
           
           
               
               
           
         
         wherein: 
         X 1 , Y 1  and Z 1  are each independently C or N;
 with the first proviso that at least one of X 1 , Y 1  and Z 1  is N; 
 with the second proviso that each of X 1 , Y 1  and Z 1  is uncharged; 
 with third proviso that two of the dotted lines indicate double bonds; 
 with the fourth proviso that the valencies of X 1 , Y 1  and Z 1  can be each independently satisfied by attachment to a substituent selected from H and R 12 ; 
 
         X 2  is O, NH or S; 
         A 1  is selected from the group consisting of an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl; 
         R 1  is selected from the group consisting of an optionally substituted C 1-6  alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl(C 1-6  alkyl), an optionally substituted cycloalkenyl(C 1-6  alkyl), an optionally substituted aryl(C 1-6  alkyl), an optionally substituted heteroaryl(C 1-6  alkyl) and an optionally substituted heterocyclyl(C 1-6  alkyl); 
         R 2  and R 3  are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6  alkyl and an optionally substituted C 1-6  haloalkyl; or R 2  and R 3  together with the carbon to which R 2  and R 3  are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl or an optionally substituted heterocyclyl; 
         R 4  and R 5  are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6  alkyl and an optionally substituted C 1-6  haloalkyl; or R 4  and R 5  together with the carbon to which R 4  and R 5  are attached form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl or an optionally substituted heterocyclyl; 
         R 6 , R 7 , R 8  and R 9  are each independently selected from the group consisting of hydrogen, halogen, hydroxy, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted haloalkyl, an optionally substituted mono-substituted amine, and an optionally substituted di-substituted amine; 
         R 10  is hydrogen, deuterium, halogen, an optionally substituted alkyl, or an optionally substituted cycloalkyl; 
         R 11  is hydrogen or an optionally substituted C 1-6  alkyl; and 
         R 12  is hydrogen, halogen, an optionally substituted C 1-3  alkyl, an optionally substituted C 1-3  haloalkyl or an optionally substituted C 1-3  alkoxy; 
         provided that when R 11  is hydrogen or methyl, X 1  is NH, Y 1  and Z 1  are each C, X 2  is O, A 1  is a phenyl, 2-fluorophenyl, or 2,6-difluorophenyl, both R 2  and R 3  are methyl or one of R 2  and R 3  is hydrogen and the other of R 2  and R 3  is methyl, and R 4 , R 5 , R 6 , R 7 , R 8 , R 9  and R 10  are each hydrogen, then R 1  cannot be 2-hydroxyethyl, 2-methylpropyl, 2-fluoro-2-methylpropyl, 3-fluoro-2-methylpropyl, 3-hydroxy-2-methylpropyl or 2-fluoro-3-hydroxy-2-methylpropyl. 
       
     
     
         33 - 49 . (canceled) 
     
     
         50 . The method of  claim 32 , wherein R 11  is hydrogen. 
     
     
         51 . The method of  claim 32 , wherein A 1  is an optionally substituted aryl. 
     
     
         52 . The method of  claim 51 , wherein A 1  is an optionally substituted phenyl. 
     
     
         53 . The method of  claim 51 , wherein A 1  is a substituted phenyl. 
     
     
         54 . The method of  claim 51 , wherein A 1  is an unsubstituted phenyl. 
     
     
         55 . The method of  claim 32 , wherein A 1  is an optionally substituted cycloalkyl. 
     
     
         56 . The method of  claim 55 , wherein A 1  is an optionally substituted bicyclopentyl. 
     
     
         57 . The method of  claim 56 , wherein A 1  is an unsubstituted bicyclopentyl. 
     
     
         58 . The method of  claim 32 , wherein R 1  is selected from the group consisting of an optionally substituted C 1-6  alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(C 1-6  alkyl), an optionally substituted heterocyclyl and an optionally substituted heterocyclyl(C 1-6  alkyl). 
     
     
         59 . The method of  claim 58 , wherein R 1  is a substituted C 1-6  alkyl or a substituted cycloalkyl. 
     
     
         60 . The method of  claim 59 , wherein the substituted cycloalkyl is substituted with one or more substituents selected from the group consisting of halogen, hydroxy, haloalkyl, an optionally substituted alkyl, an optionally substituted cycloalkyl, a substituted alkoxy, a substituted mono-substituted amine and a substituted di-substituted amine. 
     
     
         61 . The method of  claim 59 , wherein the substituted alkyl is a C 1-6  haloalkyl. 
     
     
         62 . The method of  claim 59 , wherein the substituted C 1-6  alkyl is substituted with one or more substituents selected from the group consisting of halogen, hydroxy, haloalkyl, an optionally substituted cycloalkyl, a substituted alkoxy, a substituted mono-substituted amine and a substituted di-substituted amine. 
     
     
         63 . The method of  claim 58 , wherein R 1  is an optionally substituted C 1-6  alkyl selected from the group consisting of C 4  alkyl, fluoro(C 4  alkyl), and trifluoro(C 2  alkyl). 
     
     
         64 . The method of  claim 58 , wherein R 1  is an optionally substituted cycloalkyl selected from the group consisting of unsubstituted cyclobutyl, unsubstituted difluorocyclobutyl, unsubstituted cyclopentyl and unsubstituted bicyclopentyl. 
     
     
         65 . The method of  claim 58 , wherein R 1  is an optionally substituted cycloalkyl(C 1-6  alkyl) selected from the group consisting of unsubstituted cyclopropylmethyl, unsubstituted bicyclopentylmethyl, unsubstituted fluorocyclopropylmethyl, unsubstituted fluorocyclobutylmethyl, unsubstituted methoxycyclopropylmethyl, and unsubstituted trifluoromethylcyclopropylmethyl. 
     
     
         66 . The method of  claim 58 , wherein R 1  is an optionally substituted heterocyclyl selected from the group consisting of unsubstituted tetrahydropyranyl, unsubstituted tetrahydrofuranyl, and unsubstituted oxetanyl. 
     
     
         67 . The method of  claim 58 , wherein R 1  is an optionally substituted heterocyclyl(C 1-6  alkyl) selected from the group consisting of unsubstituted oxetanylmethyl and unsubstituted fluorooxetanylmethyl. 
     
     
         68 . The method of  claim 32 , wherein R 2  is selected from the group consisting of hydrogen, methyl, fluoromethyl and difluoromethyl. 
     
     
         69 . The method of  claim 32 , wherein any one or more of each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9  and R 10  is hydrogen. 
     
     
         70 . The method of  claim 32 , wherein R 6  is hydroxy. 
     
     
         71 . The method of  claim 32 , wherein R 7  is selected from the group consisting of halogen, hydroxy, and unsubstituted alkoxy. 
     
     
         72 . The method of  claim 71 , wherein R 7  is fluoro or methoxy. 
     
     
         73 . The method of  claim 32 , wherein R 8  is hydroxy. 
     
     
         74 . The method of  claim 32 , wherein the compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         75 . The method of  claim 32 , wherein the compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         76 . The method of  claim 32 , wherein the compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         77 . The method of  claim 32 , wherein the compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         78 . The method of  claim 32 , provided that when R 10  is hydrogen, R 11  is hydrogen or methyl, X 1  is NH, Y 1  and Z 1  are each C, A 1  is an optionally substituted phenyl, one of R 2  and R 3  is hydrogen or an optionally substituted C 1-6  alkyl and the other of R 2  and R 3  is an optionally substituted C 1-6  alkyl, then R 1  cannot be a substituted C 1-6  alkyl substituted with one or more substituents selected from the group consisting of halogen and hydroxy. 
     
     
         79 . The method of  claim 32 , wherein the compound of Formula (I) is a compound of the Formula 11A: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.