Heteroaryl estrogen receptor modulators and uses thereof

Abstract

Described herein are heteroaryl compounds with estrogen receptor modulation activity or function having the Formula I, II, and III structures: and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I, II, and III compounds, as well as methods of using such estrogen receptor modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

We claim: 
     
         1 . A compound selected from Formulas I, II, and III: 
       
         
           
           
               
               
           
         
       
       and
 stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein: 
 A, B, C, and D are independently selected from CR 6  and N; 
 Y 1  is CR b  or N; 
 Y 2  is —(CH 2 )—, —(CH 2 CH 2 )—, or NR a ; 
 Y 3  is NR a  or C(R b ) 2 ; 
 where one of Y 1 , Y 2  and Y 3  is N or NR a ; 
 R a  is selected from H, C 1 -C 6  alkyl, C 2 -C 8  alkenyl, propargyl, C 3 -C 6  cycloalkyl, and C 3 -C 6  heterocyclyl, optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, OH, OCH 3 , and SO 2 CH 3 ; 
 R b  is independently selected from H, —O(C 1 -C 3  alkyl), C 1 -C 6  alkyl, C 2 -C 8  alkenyl, propargyl, —(C 1 -C 6  alkyldiyl)-(C 3 -C 6  cycloalkyl), C 3 -C 6  cycloalkyl, and C 3 -C 6  heterocyclyl, optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, OH, OCH 3 , and SO 2 CH 3 , 
 R c  is selected from H, C 1 -C 6  alkyl, allyl, propargyl, optionally substituted with one or more groups independently selected from F, Cl, Br, I, CN, OH, OCH 3 , and SO 2 CH 3 ; 
 Cy is selected from C 6 -C 20  aryldiyl, C 3 -C 12  carbocyclyldiyl, C 2 -C 20  heterocyclyldiyl, and C 1 -C 20  heteroaryldiyl; 
 Z 1  is selected from CR a  and N; 
 Z 2  is selected from O, S, and NR a    
 Z 3  is selected from O, S, NR a  C 1 -C 6  alkyldiyl, C 1 -C 6  fluoroalkyldiyl, O—(C 1 -C 6  alkyldiyl), O—(C 1 -C 6  fluoroalkyldiyl), C(O), and a bond; 
 R 1 , R 2 , R 3 , R 4 , R 8 , and R 9  are independently selected from H, F, Cl, Br, I, —CN, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH(OH)CH(CH 3 ) 2 , —C(CH 3 ) 2 CH 2 OH, —CH 2 CH 2 SO 2 CH 3 , —CH 2 OP(O)(OH) 2 , —CH 2 F, —CHF 2 , —CH 2 NH 2 , —CH 2 NHSO 2 CH 3 , —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CF 3 , —CH 2 CF 3 , CH 2 CHF 2 , —CH(CH 3 )CN, —C(CH 3 ) 2 CN, —CH 2 CN, —CO 2 H, —COCH 3 , —CO 2 CH 3 , —CO 2 C(CH 3 ) 3 , —COCH(OH)CH 3 , —CONH 2 , —CONHCH 3 , —CONHCH 2 CH 3 , —CONHCH(CH 3 ) 2 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , NHCOCH 3 , —N(CH 3 )COCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , —NO 2 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 N(CH 3 ) 2 , —OP(O)(OH) 2 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , —S(O) 3 H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone, and morpholino; or R 3  and R 8  form a 4, 5, 6, or 7-membered carbocylic or heterocyclic ring; 
 R 5  is selected from H, C 1 -C 9  alkyl, C 3 -C 9  cycloalkyl, C 3 -C 9  heterocycle, C 6 -C 9  aryl, C 6 -C 9  heteroaryl, —(C 1 -C 6  alkyldiyl)-(C 3 -C 9  cycloalkyl), —(C 1 -C 6  alkyldiyl)-(C 3 -C 9  heterocycle), C(O)R b , C(O)NR a , SO 2 R a , and SO 2 NR a , optionally substituted with one or more of halogen, CN, OR a , N(R a ) 2 , C 1 -C 9  alkyl, C 3 -C 9  cycloalkyl, C 3 -C 9  heterocycle, C 6 -C 9  aryl, C 6 -C 9  heteroaryl, C(O)R b , C(O)NR a , SO 2 R a , and SO 2 NR a ; or R 3  and R 5  form a 4, 5, 6, or 7-membered heterocyclic ring; or Cy and R 5  form a 4, 5, 6, or 7-membered heterocyclic ring; 
 R 6  is selected from H, F, Cl, Br, I, —CN, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH(OH)CH(CH 3 ) 2 , —C(CH 3 ) 2 CH 2 OH, —CH 2 CH 2 SO 2 CH 3 , —CH 2 OP(O)(OH) 2 , —CH 2 F, —CHF 2 , —CH 2 NH 2 , —CH 2 NHSO 2 CH 3 , —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CH(CH 3 )CN, —C(CH 3 ) 2 CN, —CH 2 CN, —CO 2 H, —COCH 3 , —CO 2 CH 3 , —CO 2 C(CH 3 ) 3 , —COCH(OH)CH 3 , —CONH 2 , —CONHCH 3 , —CONHCH 2 CH 3 , —CONHCH(CH 3 ) 2 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —N(CH 3 )COCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , —NO 2 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 N(CH 3 ) 2 , —OP(O)(OH) 2 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , —S(O) 3 H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone, and morpholino; 
 R 7  is selected from H, C 1 -C 6  alkyl, C 2 -C 8  alkenyl, and propargyl; or R 7  and Cy form a spiro, 4, 5, 6, or 7-membered carbocyclic or heterocyclic ring; and 
 n is selected from 1 and 2; 
 where alkyldiyl, fluoroalkyldiyl, aryldiyl, carbocyclyldiyl, heterocyclyldiyl, and heteroaryldiyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CN, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH(OH)CH(CH 3 ) 2 , —C(CH 3 ) 2 CH 2 OH, —CH 2 CH 2 SO 2 CH 3 , —CH 2 OP(O)(OH) 2 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , CH 2 CH 2 F, —CH(CH 3 )CN, —C(CH 3 ) 2 CN, —CH 2 CN, —CH 2 NH 2 , —CH 2 NHSO 2 CH 3 , —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CO 2 H, —COCH 3 , —CO 2 CH 3 , —CO 2 C(CH 3 ) 3 , —COCH(OH)CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , NHCOCH 3 , —N(CH 3 )COCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , —NO 2 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 N(CH 3 ) 2 , —OP(O)(OH) 2 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , —S(O) 3 H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone, and morpholino; 
 with the proviso that for a Formula I compound when n is 1; A, B, C, and D are each CR 6 ; and Z 2  is N; then R 7  is not H. 
 
     
     
         2 . The compound of  claim 1  wherein A, B, C, and D are each CR 6 . 
     
     
         3 . The compound of  claim 1  wherein one or two of A, B, C, and D are N. 
     
     
         4 . The compound of  claim 1  having Formula I wherein Z 2  is O. 
     
     
         5 . The compound of  claim 1  having Formula I wherein Z 2  is S. 
     
     
         6 . The compound of  claim 1  having Formula I wherein Z 2  is NR a . 
     
     
         7 . The compound of  claim 1  having Formula II wherein Z 1  is CR a . 
     
     
         8 . The compound of  claim 1  having Formula II wherein Z 1  is N. 
     
     
         9 . The compound of  claim 1  having Formula III wherein Z 2  is O. 
     
     
         10 . The compound of  claim 1  having Formula III wherein Z 2  is S. 
     
     
         11 . The compound of  claim 1  having Formula III wherein Z 2  is NR a . 
     
     
         12 . The compound of  claim 1  wherein Cy is phenyldiyl, substituted with one or more F. 
     
     
         13 . The compound of  claim 1  wherein Z 3  is O or NR a . 
     
     
         14 . The compound of  claim 13  wherein Z 3  is NH. 
     
     
         15 . The compound of  claim 1  wherein Z 3  is O—(C 1 -C 6  is N, Y 2  is —(CH 2 )—, and Y 3  is C(R b ) 2 . 
     
     
         16 . The compound of  claim 15  wherein Y 3  is CH(CH 2 F). 
     
     
         17 . The compound of  claim 1  wherein Y 1  is CR b , Y 2  is —(CH 2 )—, and Y 3  is NR a . 
     
     
         18 . The compound of  claim 17  wherein Y 3  is NCH 2 CH 2 CH 2 F. 
     
     
         19 . The compound of  claim 1  wherein R 5  is C 1 -C 9  alkyl, substituted with one or more F. 
     
     
         20 . The compound of  claim 1  selected from Tables 1a and 1b. 
     
     
         21 . A pharmaceutical composition comprised of a compound of  claim 1  and a pharmaceutically acceptable carrier, glidant, diluent, or excipient. 
     
     
         22 . The pharmaceutical composition according to  claim 21 , further comprising a therapeutic agent. 
     
     
         23 . A process for making a pharmaceutical composition which comprises combining a compound of  claim 1  with a pharmaceutically acceptable carrier, glidant, diluent, or excipient. 
     
     
         24 . A method of treating an ER-related disease or disorder in a patient comprising administering a therapeutically effective amount of the pharmaceutical composition of  claim 21  to a patient with an ER-related disease or condition. 
     
     
         25 . The method of  claim 24  wherein the ER-related disease or disorder is cancer selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer. 
     
     
         26 . The method of  claim 25  wherein the cancer is breast cancer. 
     
     
         27 . The method of  claim 24  further comprising administering an additional therapeutic agent selected from an anti-inflammatory agent, an immunomodulatory agent, chemotherapeutic agent, an apoptosis-enhancer, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, and an agent for treating immunodeficiency disorders. 
     
     
         28 . The method of  claim 24  wherein the pharmaceutical composition is administered in combination with a therapeutic agent selected from paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole, palbociclib, gemcitabine, trastuzumab (HERCEPTIN®, Genentech), trastuzumab emtansine (KADCYLA®, Genentech), pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine, and ixabepilone. 
     
     
         29 . The method of  claim 24  wherein the pharmaceutical composition is administered in combination with a CDK 4/6 inhibitor. 
     
     
         30 . The method of  claim 29  wherein the CDK 4/6 inhibitor is selected from palbociclib (PD-0332991), ribociclib (LEE011) and LY283519. 
     
     
         31 . The method of  claim 24  wherein the pharmaceutical composition is administered in combination with a phosphoinositide 3-kinase (PI3K)/mTOR pathway inhibitor selected from everolimus, temsirolimus, BEZ235 (dactolisib), BYL719 (alpelisib), GDC0032 (taselisib), BKM120 (buparlisib), BGT226, GDC0068 (ipatasertib), GDC-0980 (apitolisib), GDC0941 (pictilisib), INK128 (MLN0128), INK1117, OSI-027, CC-223, AZD8055, SAR245408, SAR245409, PF04691502, WYE125132, GSK2126458, GSK-2636771, BAY806946, PF-05212384, SF1126, PX866, AMG319, ZSTK474, Cal101 (idelalisib), PWT33597, CU-906, AZD-2014 and CUDC-907. 
     
     
         32 . A kit for treating a condition mediated by an estrogen receptor, comprising:
 a) a pharmaceutical composition of  claim 21 ; and   b) instructions for use.