US 20190040000A1 ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 / 0040000 A1 Narayanan et al. (43 ) Pub . Date : Feb . 7 , 2019 ( 54 ) SELECTIVE ANDROGEN RECEPTOR (60 ) Provisional application No .62 / 220 ,094 , filed on Sep . DEGRADER (SARD ) LIGANDS AND 17 , 2015 , provisional application No . 62 /150 , 768 , METHODS OF USE THEREOF filed on Apr. 21 , 2015 . ( 71 ) Applicants :GTx , Inc ., Memphis , TN (US ) ; University of Tennessee Research Publication Classification Foundation , Knoxville , TN (US ) (51 ) Int. Cl. C07C 237 / 20 ( 2006 .01 ) ( 72 ) Inventors : Ramesh Narayanan , Cordova , TN A61P 25 / 00 ( 2006 .01 ) ( US ) ; Duane D . MILLER , Collierville , A61P 5 / 28 TN (US ) ; Thamarai PONNUSAMY , (2006 .01 ) Memphis , TN (US ) ; Dong - Jin A61P 35 / 00 ( 2006 .01 ) HWANG , Arlington , TN (US ) ; Charles (52 ) U . S . CI. B . DUKE , Memphis , TN (US ) ; CPC .. C07C 237/ 20 ( 2013 .01 ) ; A61P 25 /00 Christopher C . COSS , Upper ( 2018 .01 ) ; A61P 35 / 00 ( 2018 .01 ) ; A61P 5 /28 Arlington , OH (US ) ; Amanda JONES , ( 2018 .01 ) Silver Spring , MI (US ) ; James T . DALTON , Ann Arbor , MI (US ) ( 57 ) ABSTRACT (21 ) Appl. No. : 16 /153 , 193 This invention provides novel 3 - amino propanamide selec tive androgen receptor degrader (SARD ) compounds , phar ( 22 ) Filed : Oct . 5 , 2018 maceutical compositions and uses thereof in treating pros tate cancer , advanced prostate cancer, castration resistant Related U . S . Application Data prostate cancer , androgenic alopecia or other 5 hyperandro (63 ) Continuation of application No . 15 / 830 , 688, filed on genic dermal diseases, Kennedy ' s disease , amyotrophic lat Dec . 4 , 2017 , now Pat. No . 10 , 093 ,613 , which is a eral sclerosis ( ALS ) , and uterine fibroids , and to methods for continuation - in - part of application No . 15 /331 , 751 , reducing the levels of androgen receptor- full length (AR filed on Oct. 21 , 2016 , now Pat . No. 9 , 834 ,507 , which FL ) including pathogenic or resistance mutations, AR - splice is a continuation - in -part of application No . 15/ 135 , variants (AR -SV ) , and pathogenic polyglutamine (polyQ ) 151, filed on Apr. 21, 2016 , now Pat. No . 9 ,815 ,776 . polymorphisms of AR in a subject . 0) , in It 36 pix CMH 37 . Coronad 1 AS RU * 10 300 301x } 10 .000 ACT Compoudd 17 4- 0 . 1 011 83981 OM 1418 1010 10 , 000 + + + + + + + + + + + + + + + + + + + Cxoplonost 17 var 791 let Actia 1 . Car ws Betis WOMMV: 00 AR itx Buzdo TOM Corsyon sa Lesio AR coix Patent Application Publication Feb . 7 , 2019 Sheet 1 of 16 US 2019 /0040000 A1 0 . 3 WX3881 1933 . Crond 37 . * * * * ! ! ! ! ! ! ! ! ! Compound! ! ! ! ! ! ! ! 17! . - . - . 12WXUA Compound 1 ? . .. cececececs Compound 17 Vet Activ List OMMOV3300 { has{ ttis TOM Csapjunkl. 14 AR Figure 1 Patent Application Publication Feb . 7 , 2019 Sheet 2 of 16 US 2019 /0040000 A1 0 . 1 RW R1881 0 . 1 W R1881 M . 1 10 100 1000 10000 Copa 17 Figure 2A 0 .35 0 . 3 0 .25 $ 0 . 2 50 .15 0 .13 0 .05 100010000 1001000 10000 1001000 10000 Enzalutamide ARN - 509 Compound 17 Figure 28 Patent Application Publication Feb . 7 , 2019 Sheet 3 of 16 US 2019 /0040000 A1 ter *777777 w tiettttt 1 w pt on ** 292 st*** * * * MEDTA14 100100010000 -110102103104. 0.1MR18811AM TE WWW wwwWE metai0.1mmR1881 10 . 1 . AND . - MASC-19 ARIActin Cmpd-17 ASC-J9 ARN-509 Figure3 th th stitih htpotwih !home WWWIN 100100010000 0.1OMR18810.1OMR1881 aMcmpd17-110102103104. in0.10MR1881 FUL 110 nik pe . 0.50 00.0 Actin/ AR AM AR-FL. AR-V7 ARFL AR-FL V7-AR Patent Application Publication Feb . 7 , 2019 Sheet 4 of 16 US 2019 /0040000 A1 B ( continued ) 24 country MA*** 4440+AHH 14*** AR/Actin tott * * L skatteretter **** * Westershid444Ah 444 MARA with VA . DM ARN 500 1 10 104 104 104 . - 1 10 102 103 104 Cmpd 14 MDV - 3100 AR AR- - 5V SV -- - - - - - - Actin - Figure 3 ( continued ) Patent Application Publication Feb . 7 , 2019 Sheet 5 of 16 US 2019 /0040000 A1 #{R}AB CITU Cuss BRS 17 : 31 WWW * * * * * K3887 No cross - reactivity to ER No cross- reactivity to PR 3 : Cusd 17 Cud 17 hirsill 12 24 48 72 ERO Quia Figure 4 Patent Application Publication Feb . 7 , 2019 Sheet 6 of 16 US 2019 /0040000 A1 Prostate Compound 17 Compound 14 Prostate(mg/gb.wt) 20 mgs BID 20 mgs BID 13 UM * hr 320M * hr SV Compound 17 Compound 14 20 mys BID 20 mgs BID (IM*q7/8u)A'S 13 Mihr 320M * hr Figure 5 Patent Application Publication Feb . 7 , 2019 Sheet 7 of 16 US 2019 /0040000 A1 3. 09 2. 8 RLU 2. 446 GRS * 1. 4 * 1 . 2 Compound 17 + 0 . 1 nM Dex 10 - 5 18 - 4 le - 3 10 - 2 10 - 1 10 - 0 10 + 1 10 + 2 14 + 3 10 + 4 1e + 5 nM (Dexamethasone ) RLU CMR om Compound 17 + 0 . 1 nM Ald 0 . 8mm 1e - 5 18 - 4 1e - 3 10 - 2 1 - 1 1e + 0 1e + 1 1e + 2 1e + 3 le + 4 18 + 5 NM (Aldesterone ) PR . 0. 2 . 1e - 5 10 -4 10 - 3 10 -2 10 - 1 10 + 0 10 + 1 18 + 2 1e + 3 14 + 4 10 + 5 nM (Progesterone ) Figure 6 Patent Application Publication Feb . 7 , 2019 Sheet 8 of 16 US 2019 /0040000 A1 RNA Poll (PSA Esku. KNA PII (PSA Pr033 . } . DIA Pestras C . KNA Poil (FKBP ARE ) RNA Polli ( IMPRSS ? ARE ) . POMPIR . RIN1051 C . 17 Bic · Cmd 1 . Bie M YYYYYYYYYYYYYYYYYYYYYYY R1881 RI881 01RM 11881 M1881 - 4. Comund 17 UUUUUUUUUUUUUUUUUUUUUUUUUU Lower magnificatios .TR Fligbes magnification : Beus Figure 7 Patent Application Publication Feb . 7 , 2019 Sheet 9 of 16 US 2019 /0040000 A1 ve inimiiiiiiiiiiiiiiiiiiiiiiiiiiiii Melalui SSSSSSSSS leteleleelteleteleletelteleletele log{ Cmpd 17 ) Figure 8 Patent Application Publication Feb . 7 , 2019 Sheet 10 of 16 US 2019 /0040000 A1 R1881 Comp 49 OM . 100 1000 10000 AR Actin Figure 9 AR Comp 49 AR - V7 ActinoNO Figure 10 Patent Application Publication Feb . 7 , 2019 Sheet 11 of 16 US 2019 /0040000 A1 Figure 11A Enobosarm Cmpd 17 AFI+ TMAO + E mummaande * * AELF AFI + TMAO + 17 **** * Relativefluorescence singumandaimme memandanganmaahanmuudanten ** ** * na kriminiminimimininingninimiminiminiminigaminiminiminiminingin wwwind AFI AF1 AFI AF1 + TMAO Figure 11B AR AF - 1 AR AF - 1 + 1 M 17 nommaitmomentumuntammentmomenttradumandangenun ARAF - 1 + 10 UM 17 FluorescenceIntensity AR AF- 1 + 15 UM 17 mantannnnnnnnnnnnnnnndengan 2x (307nm) Wavelength (nm ) AFluorescence Concentration Cpd (UM ) Patent Application Publication Feb . 7 , 2019 Sheet 12 of 16 US 2019 /0040000 A1 Sefa AFTAF1 loaded biosesors COMPOUND 17 wwambwandownloadinandorondombombomman ERD14 reference biosensors within Biocytin reference biosensors momentan 1700 1800 1900 2000 2100 2200 Time (sec ) Figure 12 Patent Application Publication Feb . 7 , 2019 Sheet 13 of 16 US 2019 /0040000 A1 150 . 100 RLU - 17 (48 , 44 nM ) 50 - A Enza ( 464 .82 nM ) - 14 12 10 8 6 M ( log ) Figure 13A Patent Application Publication Feb . 7 , 2019 Sheet 14 of 16 US 2019 /0040000 A1 1504 100 RLU + AR - - W741L - AR * T877A -AR - 14 - 12 - 10 - 8 M (log ) 17 Figure 13B RLU(%) AR - - GR * MR - 12 - 10 - - 6 -50 M ( log ) 17 Figure 13C FKBPS/GAPDH(Fold) Enza Figure 13D Patent Application Publication Feb . 7 , 2019 Sheet 15 of 16 US 2019 /0040000 A1 Figure 14A 0 . 1 nM R1881 W Figure 148 Gene/GAPDH(Fold) FKBP5 . AR 0 .0 + - 14 - 12 - 10 - 8 - 6 - 4 M ( log ) 17 Figure 15 Patent Application Publication Feb . 7 , 2019 Sheet 16 of 16 US 2019 /0040000 A1 AR (PSA Enhancer ) AR/Input Vehicle R1881 17+R1881 Bical+R1881 Figure 16A RNA Pol II ( PSA Promoter ) PolIl/Input Vehicle R1881 17+R1881 Bical+R1881 Figure 16B US 2019 /0040000 A1 Feb . 7 , 2019 SELECTIVE ANDROGEN RECEPTOR [0006 ] A critical barrier to progress in treating CRPC is DEGRADER (SARD ) LIGANDS AND that AR signaling inhibitors such as enzalutamide, bicalu METHODS OF USE THEREOF tamide , and abiraterone , acting through the LBD , fail to inhibit growth driven by the N - terminal domain (NTD ) CROSS REFERENCE TO RELATED dependent constitutively active AR - SV such as AR - V7, the APPLICATIONS most prominent AR - SV . Recent high - impact clinical trials with enzalutamide and abiraterone in CRPC patients dem [ 0001 ] This Application is a Continuation -in - Part applica onstrated that just 13 . 9 % of AR - V7 - positive patients among tion of U . S . patent application Ser . No . 15 /830 ,688 , filed on 202 patients starting treatment with enzalutamide (Xtandi ) Dec . 4 , 2017 , which is a Continuation - in - Part application of or abiraterone acetate ( Zytiga ) had PSA responses to either U . S . patent application Ser. No . 15 /331 , 751, filed on Oct. 21 , of the treatments ( Antonarakis E S , Lu C , Luber E , et al. J . 2016 , now U . S . Pat . No. 9 ,834 , 507, which is a Continuation Clin . Oncol . 2017 April 6 . doi: 25 10 . 1200 /X0 . 2016 . 70 . in -Part application of U . S . patent application Ser. No . 1961) , indicating the requirement for next generation AR 15 / 135 , 151 , filed on Apr. 21 , 2016 , now U . S . Pat . No. antagonists that target AR - SVs. In addition , a significant 9 , 815 , 776 , which claims the benefit of U . S . Provisional number of CRPC patients are becoming refractory to abi Application Ser. No . 62 /220 , 094 , filed on Sep . 17 , 2015 , and raterone or enzalutamide , emphasizing the need for next U . S . Provisional Application Ser . No . 62 / 150 , 768 , filed on generation AR antagonists . Apr. 21 , 2015 , which are incorporated in their entirety herein [0007 ] Current evidences demonstrate that CRPC growth by reference . is dependent on constitutively active AR including AR -SV ' s that lack the LBD such as AR - V7 and therefore cannot be FIELD OF THE INVENTION inhibited by conventional antagonists . AR inhibition and [0002 ] This invention is directed to 3 - amino -propanamide degradation through binding to a domain that is distinct from selective androgen receptor degrader (SARD ) compounds, the AR LBD provides alternate strategies to manage CRPC .