Indole derivatives as estrogen receptor degraders

Abstract

The present disclosure relates to compounds and a pharmaceutically acceptable salt thereof, compositions, combinations and medicaments containing the compounds, and processes for their preparation. The disclosure also relates to the use of the compounds, combinations, compositions and medicaments, for example as inhibitors of the activity of the estrogen receptor, including degrading the estrogen receptor, the treatment of diseases and conditions mediated by the estrogen receptor.

What is claimed is: 
     
         1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is H, —OH, —OC 1-3 alkyl, or a halogen; 
 R 2  is —OH or —OC 1-3 alkyl; 
 R 3  is H or an optionally substituted a lower alkyl, 
 L is one or more covalently connected structural units of -(A) q -, wherein q is an integer greater than or equal to 0; 
 R 4  is a straight chain or branched C 1-6 alkyl, or C 3-6  cycloalkyl; 
 R 5  is H, optionally substituted lower alkyl, 
 R 6  is 4-methylthiazol-5-yl, oxazol-5-yl, optionally substituted imidazole, optionally substituted pyrazole, optionally substituted oxadiazole, optionally substituted triazole, halogen, or cyano group, or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         2 . The compound of  claim 1 , wherein R 6  is 4-methylthiazol-5-yl, oxazol-5-yl, or 4-methyloxazole-5-yl. 
     
     
         3 . The compound of  claim 1 , wherein R 6  is 4-methylthiazol-5-yl. 
     
     
         4 . The compound of  claim 1 , wherein R 6  is chloro. 
     
     
         5 . The compound of  claim 1 , wherein R 6  is —CN. 
     
     
         6 . The compound of  claim 1 , wherein when R6 is 4-methylthiazol-5-yl, the methyl group can be substituted with lower alkyl or hydroxyl group 
     
     
         7 . The compound of  claim 1 , wherein R 1  is H, OH, F, Br, Cl, or OCH 3 . 
     
     
         8 . The compound of  claim 7 , wherein R 1  is OH. 
     
     
         9 . The compound of  claim 1 , wherein R 2  is OH or OCH 3 . 
     
     
         10 . The compound of  claim 9 , wherein R 2  is OH. 
     
     
         11 . The compound of  claim 1 , wherein R 3  is H or an optionally substituted C1-C4 alkyl. 
     
     
         12 . The compound of  claim 11 , wherein R 3  is an optionally substituted methyl or an optionally substituted ethyl. 
     
     
         13 . The compound of  claim 12 , wherein R 3  is methyl. 
     
     
         14 . The compound of  claim 1 , wherein R 4  is iso-propyl or tert-butyl. 
     
     
         15 . The compound of  claim 14 , wherein R 4  is tert-butyl. 
     
     
         16 . The compound of  claim 1 , wherein R 5  is H, an optionally substituted C1-6alkyl, hydroxylaklyl, or alkylamino substituted lower alkyl. 
     
     
         17 . The compound of  claim 16 , wherein R 5  is methyl, ethyl, CH 2 F, or CH 2 NHCH 3 . 
     
     
         18 . The compound of  claim 16 , wherein R 5  is H. 
     
     
         19 . The compound of  claim 17 , wherein R 5  is methyl. 
     
     
         20 . The compound of  claim 1 , wherein q is 1 or more. 
     
     
         21 . The compound of  claim 20 , wherein each -(A)-is selected independently from the group consisting of a bond, CR L1 R L2 , O, SO, SO 2 , NR L3 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , CO, CR L1 ═CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 C(═NCN)NR L4 , NR L3 C(═NCN), NR L3 C(═CNO 2 )NR L4 , C 3-11  cycloalkyl optionally substituted with 0-6 R L1  and/or R L2  groups, C 3-11 heteocyclyl optionally substituted with 0-6 R L1  and/or R L2  groups, aryl optionally substituted with 0-6 R L1  and/or R L2  groups, heteroaryl optionally substituted with 0-6 R L1  and/or R L2  groups, where R L1  or R L2 , each independently, can be linked to other A groups to form cycloalkyl and/or heterocyclyl moeity which can be further substituted with 0-4 R L5  groups,
 wherein R L1 , R L2 , R L3 , R L4 , and R L5  are, each independently, H, halo, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl)2, C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OC 1-8 cycloalkyl, SC 1-8 cycloalkyl, NHC 1-8 cycloalkyl, N(C 1-8 cycloalkyl) 2 , N(C 1-8 cycloalkyl)(C 1-8 alkyl), OH, NH 2 , SH, SO 2 C 1-8 alkyl, P(O)(OC 1-8 alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 , CC—C 1-8 alkyl, CCH, CH═CH(C 1-8 alkyl), C(C 1-8 alkyl)═CH(C 1-8 alkyl), C(C 1-8 alkyl)═C(C 1-8 alkyl) 2 , Si(OH) 3 , Si(C 1-8 alkyl) 3 , Si(OH)(C 1-8 alkyl) 2 , COC 1-8 alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1-8 alkyl, SO 2 N(C 1-8 alkyl) 2 , SONHC 1-8 alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 alkyl, CON(C 1-8 alkyl) 2 , N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 , NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl) 2 , NHCONH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl) SO 2 N(C 1-8 alkyl) 2 , NHSO 2 NH(C 1-8 alkyl), NHSO 2 N(C 1-8 alkyl) 2 , NH SO 2 NH 2 . 
 
     
     
         22 . The compound of  claim 1 , wherein L is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 1 , wherein L is an optionally substituted (poly)ethyleneglycol having between 1 and about 100 ethylene glycol units. 
     
     
         24 . The compound of formula (I) according to  claim 1 , wherein the compound is selected from the group consisting of:
 (2S,4R)-1-[(2S)-2-[1-(4-{[2-(4-fluorophenyl)-5-hydroxy-3-methyl-1H-indol-1-yl]methyl}phenyl)-1,4,7,10-tetraoxadodecan-12-amido]-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide;   (2S,4R)-1-[(2S)-2-[1-(4-{[2-(4-fluorophenyl)-5-hydroxy-3-methyl-1H-indol-1-yl]methyl}phenyl)-1,4,7,10-tetraoxadodecan-12-amido]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide;   (2S,4R)-4-hydroxy-1-[(2S)-2-[1-(4-{[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indol-1-yl]methyl}phenyl)-1,4,7,10-tetraoxadodecan-12-amido]-3,3-dimethylbutanoyl]-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide;   (2S,4R)-4-hydroxy-1-[(2S)-2-[1-(4-{[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indol-1-yl]methyl}phenyl)-1,4,7,10-tetraoxadodecan-12-amido]-3,3-dimethylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide;   (2S,4R)-4-hydroxy-1-[(2S)-2-(1-{4-[(5-hydroxy-3-methyl-2-phenyl-1H-indol-1-yl)methyl]phenyl}-1,4,7,10-tetraoxadodecan-12-amido)-3,3-dimethylbutanoyl]-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide;   (2S,4R)-1-[(2S)-2-{2-[2-({1-[2-(4-{[2-(4-fluorophenyl)-5-hydroxy-3-methyl-1H-indol-1-yl]methyl}phenoxy)ethyl]piperidin-4-yl}oxy)ethoxy]acetamido}-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide;   (2S,4R)-1-[(2S)-2-[1-(4-{[2-(4-chlorophenyl)-5-hydroxy-3-methyl-1H-indol-1-yl]methyl}phenyl)-1,4,7,10-tetraoxadodecan-12-amido]-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide;   (2S,4R)-1-[(2S)-2-[1-(4-{[2-(4-bromophenyl)-5-hydroxy-3-methyl-1H-indol-1-yl]methyl}phenyl)-1,4,7,10-tetraoxadodecan-12-amido]-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide;   (2S,4R)-4-hydroxy-1-[(2S)-2-{2-[2-({1-[2-(4-{[5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indol-1-yl]methyl}phenoxy)ethyl]piperidin-4-yl}oxy)ethoxy]acetamido}-3,3-dimethylbutanoyl]-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide; and   a pharmaceutically acceptable salt thereof.   
     
     
         25 . A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more of a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         26 . The composition of  claim 25 , further comprising at least one additional bioactive or therapeutic agent. 
     
     
         27 . The composition of  claim 26 , wherein the additional bioactive or therapeutic agent is an anti-neoplastic agent. 
     
     
         28 . The composition of  claim 27 , wherein the anti-neoplastic agent is selected from: anti-microtubule agents, such as diterpenoids and  vinca  alkaloids; platinum coordination complexes; alkylating agents, such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents, such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors, such as epipodophyllotoxins; antimetabolites, such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors, such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors. 
     
     
         29 . A method of treating an estrogen receptor-mediated disease or disorder in a subject comprising the steps of providing a subject in need thereof, and administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is effective for treating or ameliorating at least one symptom of an estrogen receptor-mediated disease or disorder. 
     
     
         30 . The method of  claim 29 , wherein the estrogen receptor-mediated disease or disorder is cancer. 
     
     
         31 . The method of  claim 30 , wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, colon cancer, prostate cancer, and endometrial cancer.