HUMUUUUUUUUUUUS009744149B2 (12 ) United States Patent (10 ) Patent No

HUMUUUUUUUUUUUS009744149B2 (12 ) United States Patent (10 ) Patent No. : US 9 , 744 , 149 B2 Dalton et al. (45 ) Date of Patent: * Aug. 29 , 2017

(54 ) METHOD OF TREATING ANDROGEN 4 , 211 , 781 A 7 / 1980 Chapman et al . RECEPTOR (AR ) - POSITIVE BREAST 4 ,239 , 776 A 12 / 1980 Glen et al. 4 , 282 , 218 A 8 / 1981 Glen et al . CANCERS WITH SELECTIVE ANDROGEN 4 , 386 ,080 A 5 / 1983 Crossley et al . RECEPTOR MODULATOR (SARMS ) 4 ,411 , 890 A 10 / 1983 Momany et al . 4 ,447 ,421 A 5 / 1984 Klothen et al . (71 ) Applicant : GTx , Inc. , Memphis , TN (US ) 4 , 465 , 507 A 8 / 1984 Konno et al . 4 ,636 , 505 A 1 / 1987 Tucker 4 ,670 , 249 A 6 / 1987 Ivy et al. ( 72 ) Inventors : James T . Dalton , Ann Arbor, MI (US ) ; 4 ,753 , 932 A 6 / 1988 Teutsch et al. Mitchell S . Steiner , Germantown , TN 4 , 837 , 004 A 6 / 1989 Wu et al . (US ); Ramesh Narayanan , Cordova , 4 , 849 ,447 A 7 / 1989 Jacobs et al. TN (US ) ; Sunjoo Ahn , Daejeon (KR ) 4 , 880 , 839 A 11/ 1989 Tucker 4 , 904 ,473 A 2 / 1990 Schricker et al . 4 , 977 , 288 A 12 / 1990 Kassis et al . (73 ) Assignee : GTX , INC ., Memphis, TN (US ) 5 ,030 ,657 A 7 / 1991 Burtle et al . 5 , 162 , 504 A 11/ 1992 Horoszewicz ( * ) Notice : Subject to any disclaimer, the term of this 5 , 179 ,080 A 1 / 1993 Rothkopf et al . patent is extended or adjusted under 35 5 , 288 ,496 A 2 / 1994 Lewis et al. U . S . C . 154 ( b ) by 0 days. 5 ,441 , 868 A 8 / 1995 Lin et al . This patent is subject to a terminal dis 5 ,547 , 933 A 8 / 1996 Lin et al. claimer. (Continued ) ( 21) Appl. No. : 14 /798 , 208 FOREIGN PATENT DOCUMENTS AU 2002364949 6 / 2003 (22 ) Filed : Jul. 13 , 2015 AU 2003216174 9 /2003 ?? 1305665 7 / 1992 Prior Publication Data CA 2149240 5 / 1994 (65 ) CA 2247946 10 / 1997 US 2016 /0128968 A1 May 12 , 2016 2281570 9 / 1998 2313089 6 / 1999 2344316 3 / 2000 Related U . S . Application Data 2420279 2 / 2002 (63 ) Continuation - in -part of application No . 14 /293 , 632 , 2458452 A1 2 /2003 filed on Jun . 2 , 2014 , which is a continuation -in -part (Continued ) of application No . 13 / 953 ,492 , filed on Jul. 29 , 2013 , which is a continuation - in -part of application No . OTHER PUBLICATIONS 13 /789 ,005 , filed on Mar. 7 , 2013 . Abuchowski et al. , “ Immunosuppresive properties and circulating (60 ) Provisional application No . 61 /671 , 366 , filed on Jul . life of achromobacter glutaminase -asparaginase covalently attached 13 , 2012 , provisional application No. 61 /726 ,274 , to polyethylene glycol in man ” Cancert Treat. Rep . 65 : 1077 - 1081 , filed on Nov . 14 , 2012 . 1981 . (51 ) Int. Ci. (Continued ) A61K 31/ 167 ( 2006 .01 ) A61K 31/ 277 (2006 .01 ) Primary Examiner — Samira Jean - Louis A61K 9 /48 ( 2006 .01 ) (74 ) Attorney , Agent, or Firm — Mark S . Cohen ; Pearl A61K 9 /50 ( 2006 .01 ) Cohen Zedek Latzer Baratz LLP (52 ) U .S . Cl. CPC ...... A61K 31 /277 (2013 . 01 ) ; A61K 9 /4808 ( 2013 .01 ) ; A61K 9 /50 ( 2013 .01 ) ; A61K 31/ 167 (57 ) ABSTRACT ( 2013 .01 ) This invention relates to the treatment of breast cancer in a ( 58 ) Field of Classification Search subject , for example a female subject. Including methods of: CPC ...... A61K 31/ 167 treating metastatic breast cancer ; refractory breast cancer ; See application file for complete search history. AR - positive breast cancer ; AR -positive refractory breast cancer ; AR -positive metastatic breast cancer ; AR -positive ( 56 ) References Cited and ER -positive breast cancer ; triple negative breast cancer ; advanced breast cancer ; breast cancer that has failed SERM U . S . PATENT DOCUMENTS ( tamoxifen , toremifene ) , aromatase inhibitor , trastuzumab 3 , 239 , 345 A 3 / 1966 Hodge et al . (Herceptin , ado - trastuzumab emtansine ) , pertuzumab (Per 3 , 256 ,096 A 6 / 1966 Tucker et al. jeta ), lapatinib , exemestane ( Aromasin ) , bevacizumab 3 , 865, 801 A 2 / 1975 Chiba et al . ( Avastin ), and /or fulvestrant treatments ; metastasis in a 3 , 875 , 229 A 4 / 1975 Gold subject suffering from breast cancer ; comprising adminis 3 , 946 , 109 A 3 / 1976 Kolb et al. 3 , 949 ,085 A 4 / 1976 Feuer et al . tering to the subject a therapeutically effective amount of a 3 , 991, 750 A 11/ 1976 Vickery et al. selective androgen receptor modulator (SARM ) compound . 4 ,036 ,979 A 7 / 1977 Asato et al . 4 , 139 ,638 A 2 / 1979 Neri et al. 4 ,191 , 775 A 3 / 1980 Glen 12 Claims, 36 Drawing Sheets US 9 , 744 , 149 B2 Page 2

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FIGURE 1A FIGURE 1B iCs in AR positive 200MLARvirus 500ULARvirus cells lacZvirus Virus IC50 (UL ) (nM ) AR DHT 200 0 . 8 500 0 .7 actin Fomula IX 200 32 500 14 FIGURE 1C FIGURE 1D DHT DHT

DHT --

. o . . . . . : • . . . !- Cellsurvival% %lennns180 Oo oo

20 - . - 0 . 0 1. 0 100 .0 10000 . 0 0. 0 1. 0 100. 0 10000. 0 M

FIGURE 1E FIGURE 1F Formula IX 8. Formula IX

- CellSurvival% § 0 CellSurvival% 8 O

& -- - - 8 ------0. 0 1. 0 1000 . 0000. 0. 0 1. 0 100. 0 10000. 0 nim nim FIGURE 1G FIGURE 1H Bicalutamide Bicalutamide 120 ;

- - 120 - 00

CellSurvival% 13 - Cellsurvival%

------0. 0 0. 3 1. 0 20 .0 100. 0 10000 10010 . . 0 . 0 10 100. 0 10000 . 0 ? ! om U . S . Patent Aug . 29, 2017 Sheet 2 of 36 US 9 ,744 , 149 B2

FIGURE 1 (cont . ) FIGURE 11 FIG . 1J R - isomer of Formula IX R - isomer of Formula IX 1202 120 - on @ @ 8 Cellsurvival% 70 CellSurvival% ö

20 ...... , 0 .0 1. 0 100. 0 10000 .0 201 0001 1000 100000.

FIGURE 2A FIGURE B IC5, in AR positive cells 200ULARvirus 500ALARvirus Virus IC50 laczvirus (UL ) (NM ) DHT Hotels200 0 . 9 e AR ? YYYYYYYYYYYYYYYYY 500 1 . 3 Formula 637 actin ? FormulaIX 200 637 YYYYYYYYYYYYYYYY 500 34 FIGURE 2C FIGURE 2D DHT DHT O - oo - OO - Cellsurvival% A A A A Cellsurvival% 20 : Oo oo

20 . . 0. 0 1. 0 100. 0 10000. 0 0 .0 1 . 0 100 .0 10000 .0 OM OM U . S . Patent Aug. 29 , 2017 Sheet 3 of 36 US 9 ,744 , 149 B2

FIGURE 2 ( cont. ) FIGURE 2E FIGURE 2F Formula IX Formula IX 120 cm

o : o A A A A CellSurvival% CellSurvival% Anoo 170 . A 20 ...... 0 .0 1. 0 100 .0 10000 . 0 .0 1 . 0 100. 0 10000 .0 12113 mm CO 10 100 000

FIGURE 2G FIGURE 2H Bicalutamide Bicalutamide 160. 120 . 000 . . 0 . ! . . oo CellSurvival% CellSurvival% ?a

20 : 20 0. 0 1. 0 100 .0 10000. 0 0. 0 1. 0 100. 0 10000. 0 mm mm U . S . Patent Aug . 29, 2017 Sheet 4 of 36 US 9 ,744 , 149 B2

FIGURE 3A FIGURE 3B DHT DHT 120 - -

Od 0 : o. 0 ? - om ? * Cellsurvival% Cellsurvival% A A o A A A 0 .0 1. 0 100 .0 10000. 0 0 . 0 1. 0 100. 0 10000 .0 nM nM

FIGURE 3C Formula IX L ' 20 ,

CellSurvival% 2 O - Oo A A A med AD

20 - - - 0 .0 1. 0 100. 0 10000 . 0 0 . 0 10 100 . 0 10000. 0 nM

FIGURE 3D FIGURE 3E Formula IX

. IC . , in AR positive cells

- # O Compound Pretreatment IC50 (NM ) - CellSurvival% DHT 10 UM Bical 9 07 : 2 Formula IX 10 UM Bical 213 20 - 0 .0 0 3. 0 0. 0 10000. 0 40 OM U . S . Patent Aug . 29, 2017 Sheet 5 of 36 US 9 ,744 , 149 B2

FIGURE 4A FIGURE 4B 150 DHT 150 ; DHT

1000 %les . . . . . 100 AAAAAA A A . Cellsurvival% 1 0 13 A A Oo oo A

O ------0. 0 1. 0 100. 0 10000 .0 0 .0 1. 0 M 100. 0 10000. C nM FIGURE 4C FIGURE 4D 150 150 Bicalutamide Bicalutamide 1000 100 À Cellsurvival% Cellsurvival% 50

0 ------0 .0 1 . 0 100. 0 10000. 0 0 .0 1. 0 M 100 .0 10000. 0 TIM FIGURE 4E FIGURE 4F

150 Formula X 150 Formula X o 100 0 o 100 A A A : 0 Cellsurvival% À A Cellsurvival% 0 0 0

om 0. 0 1. 0 100 .0 10000 .0 0. 0 1. 0 100 .0 10000 .C OM AM FIGURE 4G FIGURE 4H 150 150 - Formula IX Formula IX hedo 1001000 0 O0 8 m 100 Cellsurvival% Ceisurvival% Oo

O 0 .0 1 . 0 100. 0 10000 . 0 0 .0 1 .0 100 .0 10000. 0 JUVILIWV1L . ) OM " . U . S . Patent Aug . 29, 2017 Sheet 6 of 36 US 9 ,744 , 149 B2

FIGURE 41 FIGURE 43 150 R - Isomer of Formula IX 150 R - Isomer of Formula IX A 100 Cellsurvival% 1000 08 : º Cellsurvival% A À A

0 -- - 0 ,- - - 0 .0 1. 0 100 .0 10000. 1 n 0. 0 1. 0 OM- 100. 0 10000 .0 FIGURE 4K FIGURE 4L 150 150 Formula XIV Formula XIV 1000 O . 100 A À A A I Ceilsurvival% OO Cellsurvival% Oo A

o 0 . 0 1 .0 100 . 0 10000 . 0 0 .0 1 .0 100 . 0 10000 . C OM OM FIGURE 4M FIGURE 4N Formula XIII 150 Formula XIII 100 @ @ 100 Celsurvival% Oo Cellsurvival% A A A A A sa Ooo 8

o - -- o - - - 0. 0 1. 0 100 .0 10000 .0 0 . 0 1 .0 100 .0 10000 . OM FIGURE 40 FIGURE 4P 150 Formula VIII 150 Formula VIII 31000 O . . Cetsurvival% . o 100 AAAAAA 3501000 . OOOOO Cellsurvival

O -- - - 0. 0 1. 0 100. 0 10000. 0 0. 0 1. 0 1000 10000. ! nM nM U . S . Patent Aug . 29, 2017 Sheet 7 of 36 US 9 , 744, 149 B2

FIGURE 4Q IC50 values (nM ) Activity Cell growth ECO 1050 Trial 1 Trial 2 Mean SD DHT 0 . 2 1 . 2 1 .0 1 10 . 1 Formula x 566 407 486 + 113 Formula IX 88 65 77 + 16 Formula XIV Formula XIV on 134 + 70 Formula XIII 77 + 23 Formula VIII 81 + 6 Bicalutamide N 22 . 4 U . S . Patent Aug . 29, 2017 Sheet 8 of 36 US 9 , 744, 149 B2

FIGURE 5

0 .41

N 0 . 3

o DHT Dame 40. Formula X Formula IX Formula XIV Formula X1 RLU VID Form ula V 111 A - IX

0 . 0

164 163 18- 2 test 1eto 10 + 1 1e + 2 12 + 3 12 14 1e45 OM U . S . Patent Aug . 29, 2017 Sheet 9 of 36 US 9 ,744 ,149 B2

FIGURE 6A FIGURE 6B

ERa50UL ERa100UL ERb200L lacz ERB100UL ERb300UL Era lacz Actin ERO Actin FIGURE 6C E2 in MDA -MB - 231 IQ in MDA -MB - 231 150

# lacz 100 6 O de 1000 O CellSurvival% Celsurvival% O ERa- Ady 10 ul petseu 8 A ERa- Adv 50 L

o 0 : 0 . 0 1. 0 1000 10000. 0 0 . 0 1 . 0 100. 0 10000 . 0 OM

FIGURE 6D 52 in MDA - VB - X la In MDA -MB -231 150 - 150 o lacz 100 8O 1000 O ERa - Adv 10 UL Cellsurvival% Cosurvival% . : : . : s A ERa -Adv 50 UL

O 0. 0 1 .0 1000 10000. 0 nu 0. 0 1. 0 100. 0 10000. 0

FIGURE 6E E2 in MDA -MB - 231 Ict in MDA -MB - 231 150 : # lacz O ERb - Adv 50 UL QRRead Cellsurvival% Cellsurvival% De 8 A ERb- Adv 100 L . 50 AERb - Adv 300 UL

OM o 0 .0 1 . 0 100 . 0 10000 .0 0 . 0 10 1000 10000 .0 nu U . S . Patent Aug . 29, 2017 Sheet 10 of 36 US 9 ,744 , 149 B2

FIGURE 7 Vehicle Bicalutamide DHT 10 AM

100 nM

1000 nM

FIGURE 8

0 --/ PR

RLU/Ren(foldchange) ------A

ER - beta ? ER - alpha - MR GR o 0 104- 11 104 - 10 10 ^ - 9 10 ^ - 8 10 ^ - 7 10 ^ - 6 10 ^ - 5 U . S . Patent Aug . 29, 2017 Sheet 11 of 36 US 9 ,744 , 149 B2

FIGURE 9

0 . 12

0 . 10

0 .08 -

RLUR} 0 . 044

AA *** * * * * 0 .02 -

0 . 00

12- 18 - 3 18 - 2 1e- 16 0 12 + 1 12 + 2 + 3 124 12 + 5 M U . S . Patent Aug 29, 2017 Sheet 12 of 36 US 9 , 744 ,149 B2

????? *

??? ??????

( FIGURE10

2 * ?????? ?? ???????? ? *%

??? { ?eo { }{ ??? ???

*% ?? ??

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{ { { { U . S . Patent Aug . 29, 2017 Sheet 13 of 36 US 9 ,744 , 149 B2

# # # # # # # Tumorweight(mg) 04.0=p vehicleForniulaVIT

La * * * * * * * * * * * * * ** * * * * * * * * ** ** * * * * * * * * ** ** * * * * * * * * * * ** ** * * * * * * * * ** * ** * * * * * * * * * * * ** * * * * * * * ** * ** * * FIGURE11C 1200 3 0

- FormulaVIII Tumorsize(%change) 0005.0=p IIIIIIIIIIIIIIIIIIIIIIII vehicle ...... 002 009 WS 400 200 001 100- -200 FIGURE11B FormulaVIII Tumorsize(mm) 002.0=p

» , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , - , vehicle

. 1400 1200 0001 800 29 7 200 FIGURE11A U . S . Patent Aug. 29 , 2017 Sheet 14 of 36 US 9 ,744 , 149 B2

Bicalutamide100nM CompoundVIII100nM

CompoundIXRisomer DHT10nM 100nM

CompoundIX100nM FIGURE12 Vehicle U . S . Patent Aug. 29 , 2017 Sheet 15 of 36 US 9 ,744 , 149 B2

FIGURE 13A

cs ? ------is I pone come in an inte d 0 ? ehave 0 0 so wetimeemerswan ne RLU menowww DHT momama-- -nowo w - - - Compound IX - - - Compound VIII o we ** * * *------Inactive isomer en met medwerden ic

www 10 - 4 1 - 3 1 - 2 1 - 1 te + 0 1e + 1 12 + 2 14 + 3 1814 1e + 5 IM FIGURE 13B

0 .44 DHT Compound IX Compound VIII najl A Compound IX R - isomer

RLURLU

pot ama mwenendomA S -

10- 4 10 -3 10 - 2 1 - 1 1 + 0 10 + 1 1 + 2 14 + 3 +8 + 4 12 + 5 na U . S . Patent Aug . 29, 2017 Sheet 16 of 36 US 9 ,744 , 149 B2

FIGURE 13C

ekatebejeö Bicalutamide + DHT RLU

1e - 4 1e - 3 1 - 2 1 - 1 1e + 0 1e + 1 12 + 2 1e3 + 14 + 4 1e + 5 OM U . S . Patent Aug . 29, 2017 Sheet 17 of 36 US 9 ,744 , 149 B2

TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT

------

Bicstutamide1.2018,WW2 1933you'01D110111Kubit*

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ER FIGURE14 Mchon 200 199 20 90, 29 SIKITISSUES count U . S . Patent Aug . 29, 2017 Sheet 18 of 36 US 9 ,744 , 149 B2

*P<0.001betweenthetwogroups

1:.

:1 .

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H :1 Affymetrixmicroarrayresults * .DVOUCOULOMMI: N=1092

FIGURE15 expression gene in change ) 2 ( Log . . . . . 1

U . S . Patent Aug . 29, 2017 Sheet 19 of 36 US 9 ,744 , 149 B2

M.BUDIMOog ISDA

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*:FKBPS che fo?ci :: : : :: : :: : :: : :: :: : :: : : :: : :: : :: : : : : : : : :: : :: :: ...... CYCKA

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FIGURE16 ...... Kild U . S . Patent Aug . 29, 2017 Sheet 20 of 36 US 9 ,744 , 149 B2

cccc

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...... ,? ...... ?? ...... : : : : : ? : : ?: : ? : ? : : ? : : ? : ? : : ? : : ? : ? : : ? : :: ? : ? : ? : : . ?:,????.;??????????? nua1 ? , ? : : .: . .:???????????? ......

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: ...... : ...... ? asI punodwo IIIA

PuE %

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Unov U . S . Patent Aug . 29, 2017 Sheet 22 of 36 US 9 ,744 , 149 B2

PSA NKx3.1NCOATFKBPSISNAI2MUCIALCAM ------800000 400000 200000 000009Change Fold

. .. le ? es óLLLLL o 30mpkCompoundVIII Change Fold Vehicle

: : : : : : 11 22 ...... Hi SREBP1 It PRGFRAIADAMTS19 12 11 : : : : 1 : 1 : 2 : 37 : 2 CCND1

: : : : : : 1 : 1 2 : 20NCOR2 PS2 : : 21 ------.- .-. - . - . - wü önü ün FIGURE20 Change Fold Change Fold U . S . Patent Aug . 29, 2017 Sheet 23 of 36 US 9 ,744 , 149 B2

FIGURE 21

Vehicle Formula VIII

PINK Figure 22

www Vehicle . . . , 5 mpk V8 * * * ** * ** 10 mpk VII - 5 mpk iX - 10 mpk X %changeintumorvolume - - 30 mpk IX > 85 %

w w wwwwwwwww 2HHHH 3

eeks MDA - MB - 231 -AR xenograft (n = 7 -8 )/ group U . S . Patent Aug . 29, 2017 Sheet 24 of 36 US 9 ,744 , 149 B2

FIGURE 23

11133

Tumorwt(mg)/bodyg ounoache?so

: 1 . . : : : : : : :. : : : : : : : : : . : : : : ...... : : . . : : : : : : 33 : . : . : . : . o NIT949491 * * * * * mg/ kg 0 5 10 5 10 30 WA XI U . S . Patent Aug. 29, 2017 Sheet 25 of 36 US 9 , 744 ,149 B2

| ???

1 manmaan

H iii.

| #1

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5mpk{; {d?QT ?? allde30mpk{X *030mgk{X ????exice *5mpkXX

. H

. FIGURE24 }wt tumor- ( .wt Body in Dif? 0 U . S . Patent Aug . 29, 2017 Sheet 26 of 36 US 9 ,744 , 149 B2

VI E21UM 10M

VIA 1000M + E2 TIM VIN UM + ES M 11 . 0 VIX 100111 + InME2. 0 MCF-7FARGeneExpressionofPR.1913 VI 1UM

VIX 1000M Figure25B EZ InM

2 10M . 0

Vehicla

+ 19 S 4 N Fcdcaçe

VI 1UM E2 IAM VIR 1001M + E2 IOM

VIH TUM + 62 10M . 0

VIR 100nM + E2 17M . 0 MCF-7+GFPGeneExpressionofPR1713 VHS TUM

!VI 1000M 22 WUL Figure25A E2 11M. 0

Vehicle

JE sto ------to Change Fold

25Figure Sin' ju?zd ny& · 67‘ LIOT v??YS LT JO 9€ SN 6* IDL' tl 78

VN TUM + E2 InM VIN 1000M + E2 10M VIN TUM * €2 11M . 0 VH 1000M + E2 11M. 0 MCF-7+ARGeneExpressionofPS21913 VI IUM Figure25D VIH 1000M

E2 InM

:Vft 110 .E24 ????? Figure25C VIII 1000M + €2 IM

VIN TUM + E2 17M . 0

VIN 10011M + E2 17M . 0

MCF-7+GFPGeneExpressionofPS271913 VIII 1UM VIR M 100 E2 ?

EZ 10M. 0

Volicie

v . . . N o Change Fold Figure25(cont.) U . S . Patent Aug . 29, 2017 Sheet 28 of 36 US 9 ,744 , 149 B2

VIII 1uM + E2 inM

VIII 1000M + E2 InM VIII TUM + E2 16M. 0

VILL 1000M + E2 10M . 0 MCF-7+ARGeneExpressionofFKBP511913 HUAWNL VIII 1000M Figure25E

HOME2

E2 1nM . 0

Vehicle

40 30 TO Change Fold

Figure25(cont.) U . S . Patent Aug . 29, 2017 Sheet 29 of 36 US 9 ,744 , 149 B2

Figure 26A Figure 26B

BR - 0001 TNBC BR -0001 TNBC

Figure 26C

AR negative TNBC U . S . Patent Aug . 29, 2017 Sheet 30 of 36 US 9 ,744 , 149 B2

Figure 27A Experiment 1

inny

is *** . * ** * * * ••• Veh *** * * Formula IX *** formed %changeintumorvolume - « « Enza **** *

og ** * * L the for sine ...... O N 4 Days 6 8

Figure 27B Experiment 2

2000 1800

. . . . Vehicle * Formula IX %changeintumorvolume ...... unefois steogi tocome an sous .. i me O .. . . . wemo. . m h 0 2 4 7Days 9 11 14 U . S . Patent Aug . 29 , 2017 Sheet 31 of 36 US 9 ,744 , 149 B2

Figure 270 Experiment 2 Tumor Weight (gms ) Vehicle

inhouseisvi

. Formula IX

. . . : : : ...... :

: : : : . . : . : . : : : : : : : : : :: : : : : : 1: prende : 1:. 1: 1: 17MAR:

: : 1:3533 . : 0 .5 - : : .: : : : : : : : : : : 33 : 11 U . S . Patent Aug . 29, 2017 Sheet 32 of 36 US 9 ,744 , 149 B2

Figure 28A

Vehicle

Formula IX U . S . Patent Aug . 29, 2017 Sheet 33 of 36 US 9 ,744 , 149 B2

Figure 28B

8 Ki- 67 Staining * *

: :: : : : : :: : : : : : : : : : :: : : : : : KI67 ve : : : :: : : : : : : : : :: * * : : : : : e : : :

: 25 : : : : : : :: : : : : : : 9 20 : : : : : : : : : : :

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9. :: : : : : : : : : : : : : :: . : . : . : . : . : . : . : . : : 2 o Vehicle Formula IX

* * P < 0 . 001 U . S . Patent Aug . 29, 2017 Sheet 34 of 36 US 9 ,744 , 149 B2

Figure 29

MYBL2...... 10 .786 FOXC1 8 . 200 Z - Score FOXAT 6 .225 MMP11 6 .886 UBERT 8 . 864 BCL2 6 . 359 MELK 8 . 990 UBE2C 9 .551 NUF2 8 . 425 EXO1 8 . 743 CCNBI 8 . 232 MLPH 6 .786 CDCO 7 .750 SFRP1 6 .524 TYMS 10 .085 BLVRA 7. 044 MDM2 7 .874 EGFR 7 . 281 CEP55 9 . 049 7 . 210 PTTG1 7 . 217 FGFR4 7 .513 NDC80 9 .503 ???? 7 . 305 CENPF 9 .237 CDH3 7 .010 SLC39A6 9 . 076 KRT14 6 . 149 MK167 10 . 185 KRT5 5 .658 CCNEI 9 . 170 CXXC5 8 . 983 10 .919 5 . 765 ANLN 10 . 149 TMEM4B 6 ,581 RRM2 8 . 969 GPR160 5 ,583 ACTR3B 7099 GRB7 5 . 739 KIF2C 8 .531 ORC6 7 . 284 PHGDH 9 . 006 SLC35A5 8 .264 6 .174 VPS29 7 . 608 MYC 9 . 153 SNX16 8 . 043 KRT17 6 . 872 TMLHE 9 . 121 U . S . Patent Aug . 29, 2017 Sheet 35 of 36 US 9 ,744 , 149 B2

Figure 30A LUI

anes ......

him 1 h

Figure 30B Significant Bonferroni' s Multiple Mean Comparison Test ?i??. * P < 0 .05 95 % CI of difr BLI VS LAR - 0 . 2479 3 . 532 Yes - 0 . 4539 to - 0 . 04183 BL2 vs LAR - 0 .524 5 .999 Yes - 0 . 7804 to - 0 . 2675 IM vs LAR -0 .6731 11. 27 Yes - 0. 8484 to - 0. 4977 LAR vs M 0 . 5733 8 . 817 Yes 0 . 3823 to 0 .7642 LAR vs MSL 1- 0 .01136 0 .2499 No 0 . 1449 to 0 . 1222 U . S . Patent Aug . 29, 2017 Sheet 36 of 36 US 9 ,744 , 149 B2

Figure 31

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METHOD OF TREATING ANDROGEN kinase . Currently , a woman diagnosed with breast cancer RECEPTOR (AR ) - POSITIVE BREAST may be treated preliminarily with surgery , chemotherapy CANCERS WITH SELECTIVE ANDROGEN ( optional in some cases ) , and radiation before targeted RECEPTOR MODULATOR (SARMS ) therapy is initiated . Hormone receptor positive breast can cers are susceptible to hormone therapies with selective CROSS REFERENCE TO RELATED estrogen receptor modulators or SERMs ( e . g ., tamoxifen , APPLICATIONS toremifene ) , aromatase inhibitors ( e . g . , anastrozole ) , or selective estrogen receptor degraders or SERDs ( e . g . , ful This application is a Continuation - In - Part of U . S . patent vestrant ) . Hormone therapies such as aromatase inhibitors application Ser. No . 14 / 293 ,632 , filed Jun . 2 , 2014 , which is 10 (AI ) block production of estrogens in the body (typically a Continuation - In - Part of U . S . patent application Ser. No . used in postmenopausal women ) , whereas SERMs and 13 / 953 . 492 , filed Jul. 29 , 2013 which is a Continuation - In - SERDs block the proliferative action of estrogens on the Part of U . S . patent application Ser. No. 13 /789 , 005 , filed breast cancer cells . HER2 positive breast cancers are sus Mar. 7 , 2013 , which claims the benefit of U .S . Provisional ceptible to HER2 kinase inhibitors ( e . g ., trastuzumab and Ser. No . 61/ 671 , 366 , filed Jul. 13 , 2012 and the benefit of 15 lapatinib ) and are generally used in metastatic disease . U . S . Provisional Ser . No. 61/ 726 , 274 , filed Nov. 14 , 2012 , Anti -angiogenic therapy (bevacizumab ) is also approved in which are incorporated in their entirety herein by reference . metastatic disease . Despite these multiple tiers of targeted treatments , patients often have or develop refractory forms FIELD OF INVENTION of breast cancer. Examples of refractory breast cancer 20 include primary tumors which are triple -negative ( lacking This invention relates to the treatment of androgen recep - ER , PR , HER2) , hormone resistant ( SERM - , SERD -, or tor- positive breast cancer in a subject , for example a female AI- resistant ) , or kinase inhibitor resistant, or metastatic subject. Accordingly , this invention provides methods of: a ) breast cancer tumors. Once the targeted therapies fail or treating a subject suffering from breast cancer ; b ) treating a tumors metastasize , radiation and high dose chemotherapy subject suffering from metastatic breast cancer; c ) treating a 25 are required to ablate the refractory breast cancer tumors . subject suffering from refractory breast cancer ; d ) treating a Current chemotherapies available for the treatment of refrac subject suffering from AR -positive breast cancer; e ) treating tory breast cancer include anthracyclines, taxanes, and a subject suffering from AR - positive refractory breast can - epothilones , which are toxic , dangerous, costly , and often cer ; f ) treating a subject suffering from AR - positive meta - are ineffective , especially in the treatment of metastatic static breast cancer; g ) treating a subject suffering from 30 disease . AR - positive and ER -positive breast cancer; h ) treating a Abundant clinical evidence suggests that androgens nor subject suffering from AR -positive breast cancer with or mally inhibit breast growth . For instance , women with without expression of estrogen receptor ( ER ) , progesterone androgen deficits have an increased risk for developing receptor (PR ) , and / or human epidermal growth factor recep breast cancer. Androgen signaling plays a crucial role in tor 2 (HER2 ) ; i ) treating a subject suffering from triple 35 breast homeostasis , negating the proliferative effects of negative breast cancer ( TNBC ); j ) treating a subject suffer estrogen signaling in the breast . However, when androgens ing from advanced breast cancer ; k ) treating a subject transform into estrogens (aromatase pathway ), they increase suffering from breast cancer that has failed selective estro cell proliferation and mammary carcinogenesis risk . Histori gen receptor modulator (SERM ) ( tamoxifen , toremifene ) , cally , the steroidal androgen receptor agonists testosterone, aromatase inhibitor (AI ) , trastuzumab (Herceptin , ado - tras - 40 fluoxymesterone, and calusterone were used in advanced tuzumab emtansine ), pertuzumab (Perjeta ), lapatinib , breast cancer. These agents suffered from side effects such as exemestane (Aromasin ), bevacizumab (Avastin ), and / or ful- excessive virilization , cross -reactivity with the estrogen vestrant treatments ; 1) treating a subject suffering from ER receptor , and aromatization to estrogens . The use of steroidal positive breast cancer ; m ) treating , preventing , suppressing androgens in advanced breast cancer pre -dates the screening or inhibiting metastasis in a subject suffering from breast 45 of breast cancers for hormone and kinase receptors . cancer ; n ) prolonging survival of a subject with breast Recently , it was found that the AR is expressed in 50 - 90 % cancer ; o ) slowing the progression of breast cancer in a of breast tumors , providing a mechanism to use androgens subject; and /or p ) prolonging progression - free survival of a as targeted therapy for AR - positive breast cancers . subject with breast cancer ; comprising administering to the Although the majority of breast cancers are considered subject a therapeutically effective amount of a selective 50 hormone receptor positive (ER , PR , or HER2) , 15 - 20 % of androgen receptor modulator ( SARM ) compound. women diagnosed with breast cancer will have Triple Nega tive Breast Cancer ( TNBC ) which is characterized by a lack BACKGROUND OF THE INVENTION of expression of ER , PR , or HER2 . TNBC occurs more frequently in younger patients (< 50 years of age ) and Breast cancer is a disease that kills over 45 ,000 women 55 generally shows a more aggressive behavior . For those each year in the United States alone . Over 180 , 000 new patients with advanced TNBC , standard palliative treatment cases of breast cancer are diagnosed annually , and it is options are limited to cytotoxic chemotherapy. However , estimated that one in eight women will develop breast even after initial response to chemotherapy , the duration of cancer. These numbers indicate that breast cancer is one of the response may be short and there is a higher likelihood of the most dangerous diseases facing women today . Cancer 60 visceralmetastases , rapidly progressive disease , and inferior research has been unable to determine the cause of breast survival compared to hormone positive breast cancer . There cancer , and has not found a suitable method of therapy or fore , research is focused on identifying therapeutic targets in prevention . TNBC . One such target is the androgen receptor ( AR ). The The standard of care currently includes screening the AR is the most highly expressed steroid receptor in breast tumor for the expression levels of the hormone receptors , 65 cancer with up to 95 % of ER -positive breast cancers estrogen receptor (ER ) and progesterone receptor (PR ) , and expressing AR (see Example 9 infra ). In TNBC , up to 30 % the human epidermal growth factor receptor 2 (HER2 ) of cancers may express AR . Historically , AR has been US 9 ,744 , 149 B2 considered anti- proliferative and beneficial in hormone posi tive breast cancers. In TNBC , data demonstrates that the presence of AR and androgen synthesizing enzymes is associated with lower proliferation , lower tumor grade , better overall survival, and more favorable clinical outcomes 5 as compared to those patients with TNBC not expressing or AR . Evidence also suggests that the AR target gene prostate specific antigen ( PSA ) is a favorable prognostic marker in breast cancer . Based on these findings , research is focused on AR as a potential therapeutic target. 10 Selective androgen receptor modulators (SARMs ) are Z is NO2, CN , COR , COOH , or CONHR ; compounds which demonstrate AR -mediated tissue selec tive activity . Unlike their steroidal precursors , SARMs are Y is CF3, F , Br, C1, I, CN , or Sn ( R )3 ; non - aromatizable , generally demonstrate no activity at other Q is CN , alkyl, halogen , N ( R ) 2, NHCOCH3, NHCOCF3, steroidal receptors including ER and PR , and are non - 15 NHCOR , NHCONHR , NHCOOR , OCONHR , virilizing . Further, SARMsmay be beneficial in refractory CONHR , NHCSCHz, NHCSCF3, NHCSR , breast cancer patients due to their hypermyoanabolic effects NHSO , CH3, NHSO R , OR , COR , OCOR , OSO , R , that should improve their tolerance of high -dose chemo SO _ R or SR ; therapy . or together with the benzene ring to which it is attached New innovative approaches are urgently needed at both 20 is a fused ring system represented by structure A , B or the basic science and clinical levels to develop compounds C : which are useful for: a ) treating a subject suffering from breast cancer; b ) treating a subject suffering from metastatic breast cancer; c ) treating a subject suffering from refractory breast cancer; d ) treating a subject suffering from AR - 23 NH positive breast cancer; e ) treating a subject suffering from AR - positive refractory breast cancer ; f ) treating a subject suffering from AR - positive metastatic breast cancer ; g ) treating a subject suffering from AR - positive and ER - posi tive breast cancer ; and /or h ) treating, preventing , suppress - 30 ing or inhibiting metastasis in a subject suffering from breast cancer .

NH SUMMARY OF THE INVENTION 35 In one embodiment, this invention is directed to a method of treating a subject suffering from triple - negative breast cancer , comprising the step of administering to said subject a selective androgen receptor modulator (SARM ) compound 40 n is an integer of 1 - 4 ; and represented by a structure of Formula I: m is an integer of 1 -3 . In another embodiment, the SARM compound is repre I sented by a structure of Formula XIII : (R3 ) m 45

9G z = - (R2 ) n XIIHII - CN N 011111 RT 50 F C NH X is a bond , O , CH2, NH , S , Se, PR , NO or NR ; H? ?? G is O or S ; T is OH , OR , NHCOCHz, or NHCOR ; 55 or Formula XIV : R is alkyl , haloalkyl, dihaloalkyl, trihaloalkyl, CH F , CHF2, CF3, CF CF3, aryl, phenyl, halogen , alkenyl or OH ; XIV R , is CH3, CH F , CHF2 , CF3, CH2CH3, or CF CF3; R2 is H , F , C1, Br, I, CH3, CF3 , OH , CN , NO2, NHCOCHZ, NHCOCF3, NHCOR , alkyl, arylalkyl, OR , NH , NHR , Fzc ?? N ( R ) 2, or SR ; H3COH Rz is H , F , CI, Br, I, CN , NO2, COR , COOH , CONHR , CF3, Sn (R ) 3, or Rz together with the benzene ring to 65 which it is attached forms a fused ring system repre In another embodiment, the SARM compound is repre sented by the structure: sented by a structure of Formula II : US 9 , 744 , 149 B2

- continued XI INCNC a

NH CYNHF H3C ?H Or hittRI amo XII wherein 10 021 NHCOCH3 X is a bond , O , CH , NH , Se, PR , or NR ; G is O or S ; T is OH , OR , - NHCOCH3, or NHCOR ; F3CFac NH Z is NO2, CN , COR , COOH or CONHR ; HCH Y is I, CF3 , Br, Cl, or Sn ( R )3 ; 15 Q is CN , alkyl , halogen , N ( R ) 2 , NHCOCH3, NHCOCF3, NHCOR . NHCONHR . NHCOOR , OCONHR , In another embodiment, the method of this invention CONHR , NHCSCHZ, NHCSCF3, NHCSR , comprises administering an isomer, a racemic mixture con NHSO ,CH3 , NHSO , R , OR , COR , OCOR , OSO , R , taining a SARM compound of this invention , a metabolite , SO , R or SR ; 20 pharmaceutically acceptable salt , pharmaceutical product , or Q together with the benzene ring to which it is attached hydrate , N - oxide , or crystal of said selective androgen is a fused ring system represented by structure A , B or receptor modulator , or any combination thereof. C : In another embodiment, said administering comprises intravenously , intraarterially, or intramuscularly injecting to 25 said subject said pharmaceutical product in liquid form ; A subcutaneously implanting in said subject a pellet containing NH 20 said pharmaceutical product; orally administering to said subject said pharmaceutical product in a liquid or solid form ; or topically applying to the skin surface of said subject said 30 pharmaceutical product . B NH LO In another embodiment, said pharmaceutical product is a pellet, a tablet , a capsule , a solution , a suspension , an emulsion , an elixir, a gel, a cream , a suppository or a parenteral formulation . C 35 In another embodiment, the pharmaceutical composition / NH product comprises 18 mg of the compound of this invention . In another embodiment, the TNBC is an AR positive TNBC . 40 BRIEF DESCRIPTION OF THE DRAWINGS R is a C1 -C4 alkyl, aryl, phenyl, alkenyl, hydroxyl, a CZ - C4 haloalkyl, halogen , or haloalkenyl ; and The subject matter regarded as the invention is particu R? is CH3, CF3, CH2CH3, or CF2CF3. larly pointed out and distinctly claimed in the concluding In another embodiment, said SARM compound is repre portion of the specification . The invention , however, both as sented by a structure of Formula : 45 to organization and method of operation , together with objects , features , and advantages thereof , may best be under stood by reference to the following detailed description IX when read with the accompanying drawings in which : NC FIG . 1A - 1J illustrates that DHT and a compound of 50 Formula IX inhibit MDA -MB - 231 triple negative breast cancer cell growth . FIG . 1A shows MDA -MB - 231 cell F3C NH expression of AR following transfection . FIG . 1B shows the ? , ? ?? IC50 in AR positive MDA -MB -231 cells . FIGS. 1C , 1D , 1E , VIII 1F, 1G , 1H , 11 and 14 show the effects of DHT, Formula IX , NC 55 bicalutamide and the ( R ) enantiomer of Formula IX on percent ( % ) cell survival. (FIGS . 1C , 1E , 16 and 11 cells were treated in charcoal stripped FBS . FIGS. 1D , 1F , 1H and NH 13 cells were treated in full serum ) . • MDA -MB - 231 with lacZ ; o MDA -MB -231 with AR 200 uL ; A MDA -MB - 231 H3C ?? X 60 withwith 'AR 500 uL . NCDuo . I FIG . 2A - 2H illustrates that DHT and Formula IX inhibit HCC - 38 triple negative breast cancer cell growth . FIG . 2A shows HCC - 38 cell expression of AR following transfec tion . FIG . 2B shows the ICs in AR positive HCC - 38 cells . F3C NH 65 FIGS . 2C , 2D , 2E , 2F , 2G and 2H show the effects of DHT, H3COH Formula IX and Bicalutamide on percent ( % ) cell survival. ????? (FIGS . 2C , 2E and 2G cells were treated in charcoal stripped US 9 ,744 , 149 B2 FBS. FIGS. 2D , 2F and 2H cells were treated in full serum ). FIG . 13A -13C demonstrates binding and transactivation • HCC - 38 with lacZ ; O HCC - 38 with AR 200 uL ; A . of the indicated ligands to HEK - 293 ( A ) or MDA -MB -231 HCC -38 with AR 500 uL . ( B & C ) cells . DHT, Formula IX and Formula VIII are FIG . 3A - 3E illustrates that the effect of DHT and Formula agonists of AR in breast cancer cells . (Example 16 ) IX on MDA -MB - 231 cells was reversed by bicalutamide . 5 FIG . 14 demonstrates anti - proliferative activity of DHT FIGS . 3A , 3B , 3C and 3D show the effects of DHT or and SARMs in MDA -MB - 231 breast cancer cells stably Formula IX in the presence or absence of bicalutamide , on transfected with AR . MDA -MB - 231 cells stably transfected percent ( % ) cell survival. (FIGS . 3A and 3C cells were with AR using lentivirus were treated with the indicated treated in charcoal stripped FBS . FIGS . 3B and 3D cells were treated in full serum ). • lacZ and with 10 UM 10 ligands for 6 days and the number of cells counted using bicalutamide ; o lacZ ; A AR with 10 um bicalutamide ; A coulter counter. DHT and SARMs, but not the AR antago AR . FIG . 3E shows IC50 values in AR positive cells in the nist, bicalutamide , inhibited the proliferation of MDA -MB presence or absence of pretreatment with bicalutamide. 231 triple negative breast cancer cells stably transfected with FIG . 4A - 4Q illustrates that AR agonists inhibit triple AR . negative breast cancer cell growth . FIGS. 4A , 4B , 4E , 4F , 155 FIG . 15 presents micro -array results showing that acti 4G , 4H , 4K , 4L , 4M , 4N , 40 and 4P show effect of AR vated AR ( AR activated by compound of Formula VIII ) agonists on percent ( % ) cell survival . FIGS. 4C and 4D show suppressed the expression ofmore genes than it induced in the effect of AR antagonist on percent ( % ) cell survival. MDA -MB -231 - AR xenograft breast cancer cells . FIGS. 41 and 4J show the effect of AR non -binder on percent FIG . 16 depicts validation of micro -array results . ( % ) cell survival. FIGS . 4A , 4C , 4E , 4G , 41, 4M and 40 cells 20 FIG . 17 illustrates that Formula VIII inhibited the growth were treated in charcoal stripped FBS . FIGS. 4B , 4D , 4F , of MCF -7 - AR triple positive xenograft . 4H , 4J, 4L , 4N and 4P cells were treated in full serum . FIG . FIG . 18 presents inhibition of uterus weight gain in 4Q shows EC50 and IC50 values in AR positive cells . estrogen supplemented animals treated with Formula VIII, FIG . 5 illustrates that growth inhibitory ligands are AR demonstrating the ability of a SARM to counteract estro agonists in MDA -MB - 231 cells . 25 genic stimuli in vivo . FIG . 6A -6E illustrates that growth inhibitory effects in FIG . 19 shows that the AR expression pattern in response MDA -MB - 231 cells are selective to AR . FIGS . 6A and 6B to an AR - agonist ( Formula VIII ) is similar to that observed show the expression of ERa or ERB in MDA -MB - 231 cells in prostate cancer cells . following transfection , respectively . FIGS . 6C , 6D and 6E FIG . 20 depicts validation of micro - array results . show the effects of estradiol (E2 ) or ICI 182, 780 ( ICI) on 30 FIG . 21 demonstrates up - regulation of JNK phosphory percent ( % ) cell survival. (FIG . 6C cells were treated in lation in MCF7- AR tumors using Formula VIII . charcoal stripped serum . FIGS. 6D and 6E cells were treated FIG . 22 shows inhibition of triple negative breast cancer in full serum ) . ( TNBC ) growth using Formulae VIII and IX . Formula VIII FIG . 7 shows DHT alters the morphology of MDA -MB and Formula IX demonstrated - 85 % TGI at all doses tried 231 cells . 35 (5 , 10 mg per kg for Formula VIII, 5 , 10 , 30 mg per kg for FIG . 8 illustrates the effect of Formula VIII on steroid Formula IX ) in the TNBC model using MDA -MB - 231- AR receptor transactivation (agonist mode ) . cells in nude mice . FIG . 9 depicts a dose response curve of PR activity FIG . 23 demonstrates inhibition of triple negative breast ( antagonist mode ) for compound of Formula VIII , Formula cancer using Formulae VIII and IX . The tumor weights were IX , R -enantiomer of Formula IX and RU486 . The closed 40 likewise reduced for all doses of Formula VIII and Formula circles O ( correspond to Formula VIII data points IX . Spleen enlargement (680 mg vs . 200 - 300 mg for normal (IC50 = 17 .05 nM ) ; open circles ( o ) correspond to Formula IX mice ) was seen only in vehicle treated mice , possibly (IC50 = 162. 9 nM ) ; closed triangles ( 4 ) correspond to indicative of prevention by the SARMs of tumor metastasis R - enantiomer of Formula IX (IC50 = 1689 nM ) ; and open to the spleen . triangles ( 4 ) correspond to RU486 ( IC50 = 0 . 048 nM ) . 45 FIG . 24 shows increase of body weight by the SARMsat FIG . 10A - 10B demonstrates that SARM (Formula VIII ) all doses of Formula VIII and Formula IX , indicative of inhibits MDA -MB - 231 - AR tumor growth . Body weight ( A ) healthy growth and a lack of toxicity . By comparison , the and tumor size ( B ) were measured for 35 days in intact vehicle treated animal did not grow as robustly . female nude mice having 150 - 200 mm tumors from MDA - FIGS . 25 A to 25E depict antagonism by SARM regarding MB - 231 - AR triple negative breast cancer cells and then 50 the ability of estradiol to activate ER target genes in MCF orally administered vehicle ( * ) or 30 mg/ kg of Formula 7 - AR cells . FIGS. 25B and 25D show that adding AR ( as VIII ( O ) . opposed to Green Fluorescent Protein (GFP ) as seen in FIG . 11A - 11C demonstrates that SARM ( Formula VIII) FIGS. 25A and 25C ) to MCF - 7 - AR cells increases the inhibits MDA -MB - 231 - AR tumor growth . Tumor size in effects of estradiol (when unopposed ) on the ER target genes mm (A ) and % change in tumor size (B ), as well as tumor 55 PR and PS2 , respectively . Adding AR to MCF - 7 -AR cells weight ( C ) were measured after 35 days in intact female suppressed the activation of these ER targets in the presence nude mice having 150 - 200 mm tumors from MDA -MB of SARM alone or SARM + estradiol (E2 ) as compared to 231 - AR triple negative breast cancer cells and then receiv - GFP transfected cells ( i. e . no AR ; FIGS . 25A and 25C ). FIG . ing oral administration of vehicle or 30 mg /kg of Formula 25E shows that AR target genes are enhanced by SARM VIII. 60 even in the presence of estradiol . FIG . 12 demonstrates the morphology of MDA -MB - 231 FIGS. 26A and 26B depict immunohistochemistry of two breast cancer cells stably transfected with AR (MDA -MB - regions of the same BR -0001 tumor, a triple negative breast 231- AR cells ). The results indicate that AR agonists , DHT, cancer ( TNBC ). They show that AR expression is consistent Formula IX , and Formula VIII altered the morphology into throughout this formalin - fixed , paraffin - embedded (FFPE ) a more anchored phenotype compared to vehicle , bicaluta - 65 tissue stained with AR antibody ( AR N20 from SCBT) . FIG . mide or an inactive isomer of Formula IX . This may be 26C depicts immunohistochemistry staining of an AR nega indicative of a less metastatic breast cancer phenotype. tive TNBC FFPE tumor as a negative control . US 9 ,744 , 149 B2 10 FIGS . 27A - 27C depict BR - 0001 tumor xenograft data (Herceptin , ado -trastuzumab emtansine ), pertuzumab ( Per comparing the effect of Formula IX or enzalutamide ( Enza ) jeta ), lapatinib , exemestane ( Aromasin ) , bevacizumab on breast cancer tumor volume ( FIGS . 27A and 27B ) and (Avastin ) , and / or fulvestrant treatment; 1 ) treating a subject weight (FIG . 27C ) with time. Experiments 1 and 2 were suffering from ER positive breast cancer; m ) treating , pre duplicate experiments run at different times with n = 5 and 5 venting , suppressing or inhibiting metastasis in a subject n = 10 animals , respectively . FIG . 27A provides results for suffering from breast cancer ; n ) prolonging survival of a Experiment 1 , FIG . 27B provides results for Experiment 2 subject with breast cancer ; o ) slowing the progression of and FIG . 27C provides results for Experiment 2 . BR -0001 breast cancer in a subject; and/ or p ) prolonging progression TNBC fragments of 1 mm (approximately ) were implanted free survival of a subject with breast cancer ; q ) treating , subcutaneously in NOD scid gamma (NSG ) mice . Once the 10 preventing , suppressing or inhibiting AR positive triple tumors reach 100 - 200 mm " , the animals were randomized negative breast cancer; by administering to the subject a and treated with vehicle , 10 mg/ kg / day Formula IX or therapeutically effective amount of a compound of Formulae enzalutamide orally . Tumor volume was measured thrice I -XIV of this invention and / or its analog , derivative , isomer, weekly . Animals were sacrificed and tumors were weighed . metabolite , pharmaceutically acceptable salt , pharmaceuti FIGS . 28A - 28B depict immunohistochemistry of 15 cal product, hydrate , N -oxide , crystal, polymorph , prodrug BR -0001 tumors from animals treated with vehicle or For - or any combination thereof, as described herein . In one mula IX and stained for Ki- 67 . Ki- 67 was reduced in tumors embodiment, the subject is a male . In one embodiment, the of animals treated with Formula IX . Quantification of Ki- 67 subject is a female . indicated an approximately 50 % reduction in Ki- 67 staining In one embodiment of the present invention , a method is in 2 weeks of treatment. Tumors from experiment 2 were 20 provided for treating a subject suffering from breast cancer, fixed in formalin and paraffin embedded . Slides were cut and comprising the step of administering to the subject a com stained with Ki- 67 antibody ( FIG . 28A ) , Ki- 67 staining was pound of Formulae I -XIV of this invention and / or its analog , reduced in tumors of animals treated with Formula IX . Ki- 67 derivative , isomer, metabolite , pharmaceutically acceptable positive cells in each slide ( total of 200 cells per view ) were salt , pharmaceutical product, hydrate , N -oxide , crystal , counted and represented as % stained cells (FIG . 28B ) . As 25 polymorph , prodrug or any combination thereof, in an a reference , inset into the graphics are bars which are 200 amount effective to treat breast cancer in the subject . In one microns ( um ) in length . embodiment, the subject is a female subject. In another FIG . 29 depicts Z - scores of 50 genes (PAM50 ) used to embodiment, the subject is a male subject. identify BR - 0001 . PAM50 is a set of 50 genes used to in another embodiment of the present invention , a method classify breast cancers . PAM50 gene expression data indi- 30 is provided for treating a subject suffering from metastatic cated that the BR - 0001 tumor belonged to basal- like breast breast cancer , comprising the step of administering to the cancer (BLBC ) subtype of TNBC . The expression ( Z -score ) subject a compound of Formulae I - XIV of this invention of 50 genes required to classify the breast cancer is given and /or its analog , derivative , isomer, metabolite , pharma here . ceutically acceptable salt, pharmaceutical product, hydrate , FIGS . 30A and 30B depict gene expression data which is 35 N -oxide , crystal, polymorph , prodrug or any combination compared to the genes published ( Pietenpol group ) as useful thereof, in an amount effective to treat metastatic breast to classify the Basal- Like Breast Cancer (BLBC ) into sub cancer in the subject . In one embodiment, the subject is a classification . Sub -classification indicated that BR -0001 female subject. In another embodiment, the subject is a male belonged to luminal androgen receptor (LAR ) and mesen - subject. chymal stem - like (MSL ) subtypes . The six TNBC subtypes 40 In another embodiment of the present invention , a method according to the Pietenpol group include two basal - like is provided for treating a subject suffering from refractory (BL1 and BL2 ), an immunomodulatory (IM ) , a mesenchy - breast cancer, comprising the step of administering to the mal ( M ) , a mesenchymal stem - like (MSL ) , and a luminal subject a compound of Formulae I - XIV of this invention androgen receptor (LAR ) subtype . GE - gene expression . and / or its analog , derivative , isomer , metabolite , pharma FIG . 31 depicts gene expression changes in BR - 0001 45 ceutically acceptable salt , pharmaceutical product, hydrate , tumors treated with Formula IX . N - oxide , crystal , polymorph , prodrug or any combination thereof, in an amount effective to treat refractory breast DETAILED DESCRIPTION OF THE cancer in the subject. In one embodiment, the subject is a INVENTION female subject. In another embodiment, the subject is a male 50 subject. In one embodiment, this invention relates to the treatment In another embodiment of the present invention , a method of androgen receptor- positive breast cancer in a subject. is provided for treating a subject suffering from AR - positive Accordingly , this invention provides methods of: a ) treating breast cancer , comprising the step of administering to the a subject suffering from breast cancer ; b ) treating a subject subject a compound of Formulae I - XIV of this invention suffering from metastatic breast cancer; c ) treating a subject 55 and / or its analog , derivative, isomer , metabolite , pharma suffering from refractory breast cancer ; d ) treating a subject ceutically acceptable salt , pharmaceutical product, hydrate , suffering from AR - positive breast cancer ; e ) treating a N - oxide, crystal, polymorph , prodrug or any combination subject suffering from AR -positive refractory breast cancer ; thereof , in an amount effective to treat AR - positive breast f ) treating a subject suffering from AR - positive metastatic cancer in the subject . In one embodiment, the subject is a breast cancer ; g ) treating a subject suffering from AR - 60 female subject . In another embodiment, the subject is a male positive and ER - positive breast cancer ; h ) treating a subject subject. suffering from AR -positive breast cancer with or without In one embodiment, the AR - positive breast cancer is ER , expression of ER , PR , and /or HER2; i) treating a subject PR and HER2 positive. In another embodiment, the AR suffering from triple negative breast cancer ; j ) treating a positive breast cancer is ER , PR and HER2 negative. In one subject suffering from advanced breast cancer; k ) treating a 65 embodiment, the AR - positive breast cancer is ER positive , subject suffering from breast cancer that has failed SERM and PR and HER2 negative . In another embodiment, the ( tamoxifen , toremifene ) , aromatase inhibitor, trastuzumab AR -positive breast cancer is ER and PR positive , and HER2 US 9 ,744 , 149 B2 12 negative . In yet another embodiment, the AR - positive breast bination thereof, in an amount effective to treat triple nega cancer is ER and HER2 positive , and PR negative . In still tive breast cancer in the subject. In one embodiment, the another embodiment, the AR - positive breast cancer is ER subject is a female subject. In another embodiment , the negative , and PR and HER2 positive . In a further embodi- subject is a male subject. ment, the AR - positive breast cancer is ER and PR negative , 5 In another embodiment of the present invention , a method and HER2 positive . In still a further embodiment, the is provided for treating a subject suffering from AR positive AR - positive breast cancer is ER and HER2 negative , and PR triple negative breast cancer , comprising the step of admin positive . In one embodiment, the AR - positive breast cancer istering to the subject a compound of Formulae I - XIV of this is ER - negative . In another embodiment, the AR -positive invention and /or its analog , derivative , isomer, metabolite , breast cancer is ER -positive . 10 pharmaceutically acceptable salt , pharmaceutical product , In another embodiment of the present invention , a method hydrate , N -oxide , crystal, polymorph , prodrug or any com is provided for treating a subject suffering from AR - positive bination thereof, in an amount effective to AR positive treat refractory breast cancer, comprising the step of administer - triple negative breast cancer in the subject. In one embodi ing to the subject a compound of Formulae I -XIV of this ment, the subject is a female subject. In another embodi invention and / or its analog , derivative , isomer, metabolite , 15 ment , the subject is a male subject. pharmaceutically acceptable salt , pharmaceutical product, In another embodiment of the present invention , a method hydrate, N - oxide, crystal , polymorph , prodrug or any com - is provided for treating a subject suffering from advanced bination thereof, in an amount effective to treat AR - positive breast cancer, comprising the step of administering to the refractory breast cancer in the subject. In one embodiment, subject a compound of Formulae I - XIV of this invention the subject is a female subject. In another embodiment, the 20 and / or its analog , derivative , isomer , metabolite , pharma subject is a male subject . ceutically acceptable salt , pharmaceutical product, hydrate , In another embodiment of the present invention , a method N -oxide , crystal, polymorph , prodrug or any combination is provided for treating a subject suffering from AR -positive thereof, in an amount effective to treat advanced breast metastatic breast cancer, comprising the step of administer cancer in the subject. In one embodiment, the subject is a ing to the subject a compound of Formulae I -XIV of this 25 female subject. In another embodiment, the subject is a male invention and / or its analog , derivative , isomer, metabolite , subject. pharmaceutically acceptable salt, pharmaceutical product, In another embodiment of the present invention , a method hydrate, N - oxide , crystal , polymorph , prodrug or any com - is provided for treating a subject suffering from breast cancer bination thereof , in an amount effective to treat AR - positive that has failed ( SERM ) (tamoxifen , toremifene ) , aromatase metastatic breast cancer in the subject. In one embodiment, 30 inhibitor , trastuzumab (Herceptin , ado -trastuzumab the subject is a female subject. In another embodiment, the emtansine ) , pertuzumab (Perjeta ), lapatinib , exemestane subject is a male subject. ( Aromasin ) , bevacizumab (Avastin ) , and / or fulvestrant In another embodiment of the present invention , a method treatments , comprising the step of administering to the is provided for treating a subject suffering from AR -positive subject a compound of Formulae I -XIV of this invention and ER - positive breast cancer , comprising the step of 35 and / or its analog , derivative, isomer , metabolite , pharma administering to the subject a compound of Formulae I - XIV ceutically acceptable salt, pharmaceutical product, hydrate , of this invention and / or its analog, derivative , isomer, N - oxide , crystal, polymorph , prodrug or any combination metabolite , pharmaceutically acceptable salt, pharmaceuti- thereof , in an amount effective to treat breast cancer that has cal product , hydrate , N -oxide , crystal, polymorph , prodrug failed SERM ( tamoxifen , toremifene ), aromatase inhibitor, or any combination thereof, in an amount effective to treat 40 trastuzumab (Herceptin , ado - trastuzumab emtansine ) , per AR -positive metastatic breast cancer in the subject. In one tuzumab (Perjeta ), lapatinib , exemestane (Aromasin ), beva embodiment, the subject is a female subject. In another cizumab (Avastin ) , and / or fulvestrant treatments in the sub embodiment, the subject is a male subject. ject. In one embodiment, the subject is a female subject. In In another embodiment of the present invention , a method another embodiment, the subject is a male subject . is provided for treating a subject suffering from ER - positive 45 As used herein , in one embodiment the term " treating " breast cancer, comprising the step of administering to the may refer to treating , preventing, delaying the progression , subject a compound of Formulae I- XIV of this invention preventing the recurrence or treating the recurrence . In one and / or its analog , derivative , isomer, metabolite , pharma- embodiment , the term “ treating” refers to a reduction in ceutically acceptable salt , pharmaceutical product, hydrate , morbidity , mortality, or a combination thereof, in association N -oxide , crystal, polymorph , prodrug or any combination 50 with breast cancer. thereof, in an amount effective to treat ER - positive breast As used herein , the term “ breast cancer ” may refer to cancer in the subject. In one embodiment, the subject is a breast cancer ; advanced breast cancer; metastatic breast female subject. In another embodiment, the subject is a male cancer ; AR - positive breast cancer; ER -positive breast can subject . cer ; AR - positive breast cancer with or without expression of In one embodiment, the ER -positive breast cancer is 55 ER , PR and /or HER2; triple- positive breast cancer ( ER , PR AR -positive . In another embodiment, the ER - positive breast and HER2 positive ), AR -positive breast cancer with or cancer is AR - negative . In one embodiment, ER -positive without expression of ER ; ER -positive breast cancer with or breast cancer is triple positive (ER , PR , HER2 ) breast without expression of AR ; AR -positive and ER -positive cancer . In another embodiment, ER -positive breast cancer is breast cancer ; refractory breast cancer ; AR - positive refrac not triple positive breast cancer. 60 tory breast cancer ; ER -positive refractory breast cancer ; In another embodiment of the present invention , a method AR - positive metastatic breast cancer ; ER - positive meta is provided for treating a subject suffering from triple static breast cancer ; breast cancer that has failed SERM negative breast cancer, comprising the step of administering ( tamoxifen , toremifene ), aromatase inhibitor, trastuzumab to the subject a compound of Formulae I - XIV of this (Herceptin , ado - trastuzumab emtansine ) , pertuzumab (Per invention and / or its analog , derivative , isomer, metabolite , 65 jeta ) , lapatinib , exemestane Aromasin ), bevacizumab pharmaceutically acceptable salt , pharmaceutical product, (Avastin ) , and / or fulvestrant treatments; or triple negative hydrate , N - oxide, crystal , polymorph , prodrug or any com breast cancer ; or any combination thereof. US 9 , 744 , 149 B2 13 14 In one embodiment, the term “ breast cancer ” refers to a tasis in the subject . In one embodiment, the subject is a condition characterized by anomalous rapid proliferation of female subject. In another embodiment, the subject is a male abnormal cells in one or both breasts of a subject. The subject. abnormal cells often are referred to as “ neoplastic cells , ” In another embodiment of the present invention , a method which refers to , in some embodiments , transformed cells 5 is provided for prolonging the survival of a subject with that can form a solid tumor. The term “ tumor” , in some breast cancer , comprising the step of administering to the embodiments , refers to an abnormal mass or population of subject a compound of Formulae I - XIV of this invention cells ( i . e . two or more cells ) that result from excessive or and / or its analog , derivative , isomer , metabolite , pharma abnormal cell division , whether malignant or benign , and ceutically acceptable salt , pharmaceutical product, hydrate , pre - cancerous and cancerous cells . Malignant tumors are 10 N - oxide , crystal, polymorph , prodrug or any combination distinguished from benign growths or tumors in that , in thereof, in an amount effective to prolong the survival of a addition to uncontrolled cellular proliferation , they can subject with breast cancer. In one embodiment, the subject invade surrounding tissues and can metastasize . is a female subject. In another embodiment, the subject is a In breast cancer , neoplastic cells may be identified in onee male subject. or both breasts only and not in another tissue or organ , in one 15 In another embodiment of the present invention , a method or both breasts and one or more adjacent tissues or organs is provided for slowing the progression of breast cancer in ( e . g . lymph node ) , or in a breast and one or more non - a subject, comprising the step of administering to the subject adjacent tissues or organs to which the breast cancer cells a compound of Formulae I -XIV of this invention and / or its have metastasized . analog , derivative , isomer, metabolite , pharmaceutically The term " metastasis ” , in some embodiments , refers to a 20 acceptable salt, pharmaceutical product , hydrate , N - oxide , process in which cancer cells travel from one organ or tissue crystal, polymorph , prodrug or any combination thereof, in to another non -adjacent organ or tissue . Cancer cells in the an amount effective to slow the progression of breast cancer breast ( s ) can spread to tissues and organs of a subject , and in the subject . In one embodiment, the subject is a female conversely , cancer cells from other organs or tissue can subject. In another embodiment, the subject is a male invade or metastasize to a breast . Cancerous cells from the 25 subject . breast ( s ) may invade or metastasize to any other organ or I n another embodiment of the present invention , a method tissue of the body . Breast cancer cells often invade lymph is provided for prolonging progression - free survival of a node cells and /or metastasize to the liver , brain and / or bone subject with breast cancer , comprising the step of adminis and spread cancer in these tissues and organs . The term tering to the subject a compound of Formulae 1 -XIV of this “ invasion " , in some embodiments, refers to the spread of 30 invention and/ or its analog, derivative, isomer , metabolite , cancerous cells to adjacent surrounding tissues. pharmaceutically acceptable salt , pharmaceutical product , As used herein , the term “ advanced breast cancer ” refers hydrate , N - oxide, crystal, polymorph , prodrug or any com to cancer that has spread to other places in the body and bination thereof, in an amount effective to prolong progres usually cannot be cured or controlled with current treatment . sion - free survival of a subject with breast cancer. In one As used herein , the term “ AR -positive breast cancer ” may 35 embodiment , the subject is a female subject. In another refer to breast cancer wherein at least a portion of the cancer embodiment, the subject is a male subject . cells express at least the androgen receptor ( AR ) . In one embodiment, breast cancer of this invention refers As used herein , the term “ ER - positive breast cancer ” may to in one embodiment to ER - positive metastatic breast refer to breast cancer wherein at least a portion of the cancer cancer; In another embodiment to ER -positive refractory cells express at least the estrogen receptor (ER ) . 40 breast cancer; In another embodiment to ER positive PR As used herein , the term “ triple negative breast cancer ” positive HER2 negative breast cancer ; In another embodi may refer to breast cancer cells that do not have estrogen ment to AR -positive ER -positive breast cancer ; In another receptors ( ER ) , progesterone receptors ( PR ) , or large embodiment to AR -positive ER - positive refractory breast amounts of HER2/ neu protein . “ Triple negative breast can cancer ; In another embodiment to AR -positive ER -positive cer ” may also be referred to herein as " ER -negative PR - 45 metastatic breast cancer ; In another embodiment to triple negative HER2/ neu -negative breast cancer ” . positive breast cancer ; In another embodiment to advanced As used herein , the term “ triple positive breast cancer " ER - positive breast cancer ; In another embodiment to AR may refer to breast cancer cells that express estrogen recep - positive ; In another embodiment to ER - positive breast can tors ( ER ), progesterone receptors (PR ) , and large amounts of cer ; and in another embodiment to breast cancer that has HER2 /neu (HER2 ) protein . “ Triple positive breast cancer” 50 failed selective estrogen receptor modulator ( tamoxifen , may also be referred to herein as “ ER -positive PR - positive toremifene ), aromatase inhibitor, trastuzumab (Herceptin , HER2/ neu - positive breast cancer ” or “ ER , PR , and HER2 ado - trastuzumab emtansine ), pertuzumab (Perjeta ), lapa breast cancer ” . tinib , exemestane (Aromasin ) , bevacizumab (Avastin ) , and / As used herein , the term “ refractory ” may refer to breast or fulvestrant treatments . cancer that does not respond to treatment. The breast cancer 55 In another embodiment of the present invention , a method may be resistant at the beginning of treatment or it may is provided for lowering biomarker levels in a subject with become resistant during treatment. “ Refractory breast can breast cancer comprising the step of administering to the cer ” may also be referred to herein as “ resistant cancer ” . subject a compound of Formulae I - XIV of this invention In another embodiment of the present invention , a method and /or its analog , derivative , isomer, metabolite , pharma is provided for treating , preventing, suppressing or inhibit - 60 ceutically acceptable salt , pharmaceutical product, hydrate , ing metastasis in a subject suffering from breast cancer, N -oxide , crystal, polymorph , prodrug or any combination comprising the step of administering to the subject a com - thereof, in an amount effective to lower the biomarker level pound of Formulae I- XIV of this invention and /or its analog , in said subject . In another embodiment, the method com derivative , isomer , metabolite , pharmaceutically acceptable prises administering a compound of Formulae I - XIV of this salt, pharmaceutical product , hydrate , N -oxide , crystal, 65 invention . polymorph , prodrug or any combination thereof, in an As used herein , the term “ biomarker” may refer to a amount effective to treat, prevent, suppress or inhibit metas - substance used as an indicator of a process, event, or US 9 ,744 , 149 B2 15 16 condition . A biomarker can be a biomolecule such as a subject, for example for increasing libido ; and / or for c ) nucleic acid molecule ( e . g . microRNA , genomic DNA , etc . ), improving quality of life in a subject. a protein , a polysaccharide , and the like . Biomarkers include Osteoporosis is a systemic skeletal disease , characterized tumor antigens and tumor markers . In one embodiment, a by low bone mass and deterioration of bone tissue , with a biomarker indicates the presence of cancer, e . g . , breast 5 consequent increase in bone fragility and susceptibility to cancer. In one embodiment, a biomarker may be used to fracture . In the U . S ., the condition affects more than 25 determine the efficacy of treatment. In one embodiment, a million people and causes more than 1 . 3 million fractures biomarker may be used to determine the progression of a each year , including 500 , 000 spine , 250 , 000 hip and 240 , 000 condition , e . g . , breast cancer. wrist fractures annually . Hip fractures are the most serious The MUC - 1 associated antigen , or CA 27 . 29 , is a cancer 10 consequence of osteoporosis , with 5 - 20 % of patients dying antigen highly associated with breast cancer . As used herein , the term “ CA27 . 29 biomarker ” refers to a biomarker for within one year , and over 50 % of survivors being incapaci breast cancer. In one embodiment, CA27 . 29 is a biomarker tated . The elderly are at greatest risk of osteoporosis , and the for advanced breast cancer. problem is therefore predicted to increase significantly with “ PSA (prostate - specific antigen ) biomarker " is used as a 15 the aging of the population . Worldwide fracture incidence is biomarker for prostate cancer, however PSA was also found forecasted to increase three - fold over the next 60 years , and in the blood of women with breast cancer at higher levels one study estimated that there will be 4 . 5 million hip compared to women without breast cancer . PSA is useful fractures worldwide in 2050 . also as a biomarker for breast cancer. Women are at greater risk of osteoporosis than men . " CTX biomarker ” and “NTX biomarker ” are the C - telo - 20 Women experience a sharp acceleration of bone loss during peptide and N - telopeptide of collagen type I, respectively , the five years following menopause . Other factors that which are used as biomarkers of bone turnover. NTX and increase the risk include smoking, alcohol abuse , a sedentary CTX biomarkers may be sensitive indicators of the presence lifestyle and low calcium intake . However, osteoporosis also of bone metastases in breast cancer patients. occurs frequently in males. It is well established that the In one embodiment, a method of this invention lowers 25 bone mineral density of males decreases with age . CA27 . 29 biomarker in a subject. In one embodiment , a Decreased amounts of bone mineral content and density method of this invention lowers PSA in a subject. In one correlates with decreased bone strength , and predisposes to embodiment, a method of this invention lowers CTX bio - fracture . The molecular mechanisms underlying the pleio marker in a subject. In one embodiment of this invention , a tropic effects of sex -hormones in non -reproductive tissues method of this invention lowers NTX biomarker in a subject . 30 are only beginning to be understood , but it is clear that In another embodiment, a method of this invention main - physiologic concentrations of androgens and estrogens play tains the level of CA27 . 29 in a subject. In another embodi - an important role in maintaining bone homeostasis through ment, a method of this invention maintains the level of PSA out the life - cycle . Consequently , when androgen or estrogen in a subject . In another embodiment, a method of this deprivation occurs there is a resultant increase in the rate of invention maintains the level of CTX biomarker in a subject. 35 bone remodeling that tilts the balance of resorption and In another embodiment, a method of this invention main formation to the favor of resorption that contributes to the tains the level of NTX biomarker. In one embodiment, the overall loss of bone mass. In males, the natural decline in subject has breast cancer. In one embodiment , the subject sex - hormones at maturity ( direct decline in androgens as has advanced breast cancer. In another embodiment, the well as lower levels of estrogens derived from peripheral subject has refractory breast cancer . In yet another embodi- 40 aromatization of androgens ) is associated with the frailty of ment, the subject has AR - positive breast cancer. In still bones. This effect is also observed in males who have been another embodiment, the subject has ER - positive breast castrated . cancer . In one embodiment , this invention provides for the use of In one embodiment, the compound of this invention is an a compound as herein described , or its prodrug, analog, antagonist . In another embodiment, the compound of this 45 isomer , metabolite , derivative , pharmaceutically acceptable invention is an agonist. In yet another embodiment, the salt , pharmaceutical product, polymorph , crystal, impurity , compound of this invention is a partial agonist/ partial N -oxide , hydrate or any combination thereof, for: a ) treating antagonist . In one embodiment, a compound of this inven - a bone related disorder ; b ) preventing a bone related disor tion is an AR agonist. In another embodiment, a compound der ; c ) suppressing a bone related disorder; d ) inhibiting a is an AR antagonist . In yet another embodiment, a com - 50 bone related disorder ; e ) increasing a strength of a bone of pound is a partial AR agonist and AR antagonist . In one a subject ; increasing a bone mass in a subject; g ) use for embodiment, a compound of this invention is a PR agonist . osteoclastogenesis inhibition . In another embodiment, a compound is a PR antagonist. In In one embodiment, this invention provides for the use of yet another embodiment, a compound is a partial PR agonista compound as herein described , or its prodrug , analog , and PR antagonist . 55 isomer , metabolite , derivative , pharmaceutically acceptable In one embodiment, a compound of this invention is an salt, pharmaceutical product , polymorph , crystal, impurity , AR agonist and a PR antagonist . N -oxide , hydrate or any combination thereof, for : a ) accel The SARM compounds of this invention may be useful, erating bone repair ; b ) treating bone disorders ; c ) treating in some embodiments , for : a ) treatment, prevention , delay - bone density loss; d ) treating low bone mineral density ing onset of, increasing time to first skeletal related event 60 (BMD ) ; e ) treating reduced bone mass ; f ) treating metabolic (SRE ) , suppression or inhibition of, or the reduction of the bone disease ; g ) promoting bone growth or regrowth ; h ) risk of developing a skeletal- related event (SRE ) , such as promoting bone restoration ; i) promoting bone fracture pathologicalbone fractures, surgery of the bone, radiation of repair ; j ) promoting bone remodeling ; k ) treating bone the bone , spinal cord compression , new bone metastasis , damage following reconstructive surgery including of the and / or bone loss in a subject; b ) treatment, prevention , 65 face , hip , or joints ; 1 ) enhancing of bone strength and suppression or inhibition of, or the reduction of the risk of function ; m ) increasing cortical bone mass ; and / or n ) developing a variety of hormone - related conditions in a increasing trabecular connectivity . US 9 ,744 , 149 B2 17 18 In one embodiment, the bone related disorder is a genetic osteoporosis is type II primary osteoporosis . Each type of disorder, or in another embodiment, is induced as a result of osteoporosis represents a separate embodiment of the pres a treatment regimen for a given disease . For example , and in ent invention . one embodiment , the compounds as herein described are According to this aspect of the invention and in one useful in treating a bone - related disorder that arises as a 5 embodiment , the bone - related disorder is treated with a result of cancer metastasis to bone , or in another embodi- compound as herein described , or a combination thereof. In ment, as a result of androgen - deprivation therapy, for another embodiment, other bone -stimulating compounds example , given in response to prostate carcinogenesis in the can be provided to the subject, prior to , concurrent with or subject. following administration of a compound or compounds as As used herein , “ Estrogen - deprivation therapy ” may refer 10 herein described . In one embodiment, such a bone stimu to therapy which is given in response to breast cancer in a lating compound may comprise natural or synthetic mate subject. Known treatments include treatment with SERMs, rials . SERDs, or aromatase inhibitors (AI ) . For example , and in In one embodiment, the bone stimulating compound may one embodiment, the compounds as herein described are comprise a bone morphogenetic protein (BMP ) , a growth useful in treating a bone - related disorder that arises as a 15 factor, such as epidermal growth factor (EGF ) , a fibroblast result of cancer metastasis to bone , or in another embodi- growth factor (FGF ), a transforming growth factor ( TGF , an ment, as a result of estrogen - deprivation therapy, for insulin growth factor ( IGF) , a platelet -derived growth factor example , given in response to breast cancer in the subject. (PDGF ) hedgehog proteins such as sonic , indian and desert In one embodiment, the bone -related disorder is a loss of hedgehog, a hormone such as follicle stimulating hormone , bone mineral density (BMD ) . In another embodiment, the 20 parathyroid hormone, parathyroid hormone related peptide , bone -related disorder is osteoporosis . In another embodi - activins , inhibins , follistatin , frizzled , frzb or frazzled pro ment, the bone - related disorder is osteopenia . In another teins , BMP binding proteins such as chordin and fetuin , a embodiment, the bone - related disorder is increased bone cytokine such as IL - 3 , IL - 7 , GM - CSF , a chemokine , such as resorption . In another embodiment, the bone- related disor - eotaxin , a collagen , osteocalcin , osteonectin and others, as der is bone fracture . In another embodiment, the bone - 25 will be appreciated by one skilled in the art. related disorder is bone frailty . In another embodiment , the In another embodiment, the compositions for use in bone -related disorder is any combination of osteoporosis , treating a bone disorder of this invention may comprise a osteopenia , increased bone resorption , bone fracture , bone compound or compounds as herein described , an additional frailty and loss of BMD . Each disorder represents a separate bone stimulating compound , or compounds , and osteogenic embodiment of the present invention . 30 cells . In one embodiment, an osteogenic cell may be a stem " Osteoporosis ” refers , in one embodiment, to a thinning cell or progenitor cell , which may be induced to differentiate of the bones with reduction in bonemass due to depletion of into an osteoblast . In another embodiment, the cell may be calcium and bone protein . In another embodiment, osteo - an osteoblast. In another embodiment, nucleic acids which porosis is a systemic skeletal disease, characterized by low encode bone- stimulating compounds may be administered bone mass and deterioration of bone tissue , with a conse - 35 to the subject , which is to be considered as part of this quent increase in bone fragility and susceptibility to fracture . invention . In osteoporotic patients , bone strength is abnormal, in one I n one embodiment, this invention provides for the treat embodiment, with a resulting increase in the risk of fracture . ment , prevention , suppression or inhibition of, or the reduc In another embodiment, osteoporosis depletes both the cal- tion of the risk of developing a skeletal- related event (SRE ) , cium and the protein collagen normally found in the bone , 40 such as bone fractures , surgery of the bone , radiation of the in one embodiment , resulting in either abnormal bone qual- bone , spinal cord compression , new bone metastasis , bone ity or decreased bone density . In another embodiment, bones loss , or a combination thereof in a subject with cancer, that are affected by osteoporosis can fracture with only a comprising administering a compound as herein described minor fall or injury that normally would not cause a bone and / or its analog , derivative , isomer , metabolite, pharma fracture . The fracture can be , in one embodiment, either in 45 ceutically acceptable salt , pharmaceutical product, hydrate , the form of cracking (as in a hip fracture ) or collapsing ( as N -oxide , or any combination thereof. The invention relates , in a compression fracture of the spine ). The spine , hips , and inter alia , to treatment of an SRE with the compound of wrists are common areas of osteoporosis - induced bone Formulae I - XIV of this invention : ( a ) in a subject with fractures , although fractures can also occur in other skeletal prostate cancer undergoing or having undergone androgen areas . Unchecked osteoporosis can lead , in another embodi - 50 deprivation therapy (ADT ) ; or ( b ) in a subject with breast ment, to changes in posture , physical abnormality , and cancer undergoing or having undergone estrogen - depriva decreased mobility . tion therapy . In one embodiment, the osteoporosis results from andro - In one embodiment, the skeletal -related events treated gen deprivation . In another embodiment, the osteoporosis using the methods provided herein and / or utilizing the follows androgen deprivation . In another embodiment, the 55 compositions provided herein , are fractures, which in one osteoporosis results from estrogen -deprivation therapy . In embodiment, are pathological fractures, non - traumatic frac another embodiment, the osteoporosis follows estrogen - tures , vertebral fracture , non - vertebral fractures, morpho deprivation therapy . In another embodiment, the osteoporo - metric fractures, or a combination thereof. In some embodi sis is primary osteoporosis . In another embodiment, the ments , fractures may be simple , compound , transverse , osteoporosis is secondary osteoporosis . In another embodi- 60 greenstick , or comminuted fractures . In one embodiment, ment, the osteoporosis is postmenopausal osteoporosis . In fractures may be to any bone in the body , which in one another embodiment , the osteoporosis is juvenile osteopo - embodiment , is a fracture in any one or more bones of the rosis . In another embodiment, the osteoporosis is idiopathic arm , wrist , hand , finger, leg, ankle , foot, toe , hip , collar osteoporosis . In another embodiment, the osteoporosis is bone , or a combination thereof. senile osteoporosis . 65 In another embodiment , the methods and / or compositions In another embodiment, the primary osteoporosis is type provided herein , are effective in treatment, prevention , sup I primary osteoporosis . In another embodiment, the primary pression , inhibition or reduction of the risk of skeletal US 9 ,744 , 149 B2 19 20 related events such as pathologic fractures , spinal cord breast cancer ; b ) treating a subject suffering from metastatic compression , hypercalcemia , bone -related pain , or their breast cancer ; c ) treating a subject suffering from refractory combination . breast cancer ; d ) treating a subject suffering from AR In another embodiment, the skeletal- related events sought positive breast cancer; e ) treating a subject suffering from to be treated using the methods provided herein and / or 5 AR -positive refractory breast cancer ; f ) treating a subject utilizing the compositions provided herein , comprise the suffering from AR -positive metastatic breast cancer; g ) necessity for bone surgery and / or bone radiation , which in treating a subject suffering from AR -positive and ER - posi some embodiments , is for the treatment of pain resulting in tive breast cancer ; h ) treating a subject suffering from one embodiment from bone damage, or nerve compression . AR -positive breast cancer with or without expression of ER , In another embodiment, the skeletal- related events sought to PR , and /or HER2; i ) treating a subject suffering from triple be treated using the methods provided herein and / or utilizing 10 negative breast cancer ; j ) treating a subject suffering from the compositions provided herein , comprise spinal cord advanced breast cancer; k ) treating a subject suffering from compression , or the necessity for changes in antineoplastic breast cancer that has failed SERM ( tamoxifen , toremifene ), therapy, including changes in hormonal therapy, in a subject. aromatase inhibitor, trastuzumab (Herceptin , ado - trastu In some embodiments , skeletal- related events sought to be zumab emtansine ), pertuzumab (Perjeta ) , lapatinib , exemes treated using the methods provided herein and / or utilizing 15 tane ( Aromasin ) , bevacizumab ( Avastin ) , and /or fulvestrant the compositions provided herein , comprise treating , sup pressing , preventing , reducing the incidence of, or delaying treatment; 1 ) treating a subject suffering from ER positive progression or severity of bone metastases , or bone loss . In breast cancer ; m ) treating , preventing , suppressing or inhib one embodiment , bone loss may comprise osteoporosis , iting metastasis in a subject suffering from breast cancer ; n ) osteopenia , or a combination thereof. In one embodiment, prolonging survival of a subject with breast cancer ; o ) skeletal- related events may comprise any combination of the 20o Sslowing the progression of breast cancer in a subject ; and / or embodiments listed herein . p ) prolonging progression - free survival of a subject with In one embodiment, the methods provided herein and / or breast cancer; is a compound represented by a structure of utilizing the compositions provided herein , are effective in Formula I , and / or its analog , derivative , isomer, metabolite , reducing metastases to the bone, such as in terms of number pharmaceutically acceptable salt , pharmaceutical product , of foci, the size of foci, or a combination thereof. According whydrate , N -oxide , crystal, polymorph , prodrug or any com to this aspect of the invention and in one embodiment, 25 bination thereof: provided herein is a method of preventing or inhibiting cancer metastasis to bone in a subject , comprising the step of administering to the subject a composition comprising toremifene , raloxifene , tamoxifen or an analogue , functional (R3 ) m derivative , metabolite or a combination thereof, or a phar - 30 maceutically acceptable salt thereof. In one embodiment, 1 (R2 ) n such metabolites may comprise ospemifene, fispemifene or their combination . In one embodiment, the cancer is prostate IZ cancer . In one embodiment, the cancer is breast cancer. In one embodiment, the skeletal- related events are a result RiT of cancer therapy . In one embodiment , the skeletal- related 55 events are a result of hormone deprivation therapy , while in another embodiment, they are a product of androgen depri X is a bond , O , CH?, NH , S , Se, PR , NO or NR ; vation therapy (ADT ) , and in another embodiment they are G is O or S ; a product of estrogen - deprivation therapy T is OH , OR , — NHCOCHz, or NHCOR ; As used herein , the term " libido ” , may refer to sexual 40 R is alkyl, haloalkyl, dihaloalkyl , trihaloalkyl, CH , F , desire , or as defined in Example 9 . CHF2, CF3, CF2CF3, aryl, phenyl , halogen , alkenyl or As used herein , the term “ quality of life " may refer to the OH ; focuses on the health and life of a subject suffering from a R? is CH3, CH , F , CHF2 , CF3 , CH2CH3, or CF2CFz; condition or disease , for example suffering from breast R , is H , F , C1, Br, I , CH3, CF3 , OH , CN , NO2, NHCOCH3, cancer , post treatment until the end of life. It covers the NHCOCF3, NHCOR , alkyl, arylalkyl, OR , NH , NHR , physical, psychosocial, and economic issues faced by the 45 subject, beyond the diagnosis and treatment phases . The N ( R ) 2, or SR ; term " quality of life” may also be referred to herein as Rz is H , F , CI, Br, I , CN , NO2, COR , COOH , CONHR , " survivorship " . In one embodiment, survivorship includes CF3, Sn (R ) 3, or Rz together with the benzene ring to issues related to the ability to get health care and follow - up which it is attached forms a fused ring system repre treatment, late effects of treatment, second cancers , and sented by the structure : quality of life Family members , friends, and caregivers are also considered part of the survivorship experience . In one embodiment, the methods of this invention are useful to a subject, which is a human . In one embodiment, the subject is male . In another embodiment, the subject is female . In some embodiments , while the methods as 55 described herein may be useful for treating either males or females , females may respond more advantageously to administration of certain compounds, for certain methods. In other embodiments , while the methods as described herein may be useful for treating either males or females , males o may respond more advantageously to administration of Z is NO ,, CN , COR , COOH , or CONHR ; certain compounds , for certain methods . Y is CF3, F , Br, C1, I, CN , or Sn (R ) 3; Selective Androgen Receptor Modulator (SARM ) Q is CN , alkyl, halogen , N ( R ) 2, NHCOCH3, NHCOCF3, Compounds NHCOR , NHCONHR , NHCOOR , OCONHR , 65 CONHR, NHCSCH , NHCSCF , NHCSR , In one embodiment, the compound of this invention NHSO ,CH3 , NHSO , R , OR , COR , OCOR , OSO , R , which is effective at: a ) treating a subject suffering from SOR or SR ; US 9 ,744 , 149 B2 21 22 or Q together with the benzene ring to which it is attached R is alkyl, haloalkyl, dihaloalkyl , trihaloalkyl, CH , F , is a fused ring system represented by structure A , B or CHF2, CF3, CF CF3, aryl, phenyl, halogen , alkenyl or C : OH ; R is CH3, CH _ F , CHF2, CF3, CH2CH3, or CF2CF3; NH 0 5 R , is H , F , C1, Br, I, CH2, CF2 , OH , CN , NO , NHCOCHZ, NHCOCF3, NHCOR , alkyl, arylalkyl, OR , NH , NHR , N ( R ) , or SR ; Rz is H , F, C1, Br, I, CN , NO ,, COR , COOH , CONHR , B CF3, Sn ( R )z , or Rz together with the benzene ring to NH 10 which it is attached forms a fused ring system repre sented by the structure :

Z L n is an integer of 1 - 4 ; and 20 OB m is an integer of 1 - 3 . In one embodiment, this invention relates to the treatment of androgen receptor- positive breast cancer in a subject, for example a female subject. Accordingly , this invention pro Z is NO ,, CN , COR , COOH , or CONHR ; vides methods for : a ) treating AR -positive breast cancer in Y is CF3, F , Br, C1, I , CN , or Sn ( R ) 3 ; a subject; b ) treating metastatic AR -positive breast cancer , or 25 Q is CN , alkyl, halogen , N ( R ) 2, NHCOCH3, NHCOCF3, advanced AR -positive breast cancer ; c ) treating refractory NHCOR , NHCONHR , NHCOOR , OCONHR , AR - positive breast cancer; d ) treating , preventing , suppress CONHR, NHCSCH , NHCSCF , NHCSR , ing or inhibiting metastasis in a subject suffering from breast NHSO ,CH3 , NHSO R , OR , COR , OCOR , OSO , R , cancer ; e ) prolonging progression - free survival of a subject SO , R or SR ; suffering from breast cancer; f ) treating a subject suffering 30 or Q together with the benzene ring to which it is attached from ER - positive breast cancer ; g ) treating a subject suffer is a fused ring system represented by structure A , B or ing from metastatic ER - positive breast cancer ; h ) treating a C : subject suffering from refractory ER -positive breast cancer ; i) treating a subject suffering from AR -positive ER -positive breast cancer ; j) treating a subject suffering from AR - 35 < positive ER -positive refractory breast cancer ; k ) treating a NH 20 subject suffering from AR -positive ER -positive metastatic breast cancer ; 1 ) treating a subject suffering from AR positive and ER - positive breast cancer ; m ) treating a subject suffering from AR -positive ER - positive breast cancer with 40 or without expression of PR , and / or HER2 ; n ) treating a LNH 20 subject suffering from advanced ER - positive breast cancer; o ) treating a subject suffering from ER - positive breast cancer that has failed SERM (tamoxifen , toremifene ), aro matase inhibitor, trastuzumab (Herceptin , ado -trastuzumab 0 emtansine ), pertuzumab (Perjeta ) , lapatinib , exemestane 45 NH (Aromasin ) , bevacizumab (Avastin ) , and /or fulvestrant treatments ; p ) treating , preventing , suppressing or inhibiting metastasis in a subject suffering from ER -positive breast cancer; q ) prolonging survival of a subject with ER - positive breast cancer ; r ) slowing the progression of ER - positive 50 n is an integer of 1 - 4 ; and breast cancer in a subject ; and / or s ) prolonging progression m is an integer of 1 - 3 ; free survival of a subject with ER -positive breast cancer ; and /or its analog , derivative , isomer, metabolite , pharma comprising administering to the subject a therapeutically c eutically acceptable salt , pharmaceutical product, hydrate , effective amount of a selective androgen receptormodulator N -oxide , crystal, polymorph , prodrug or any combination ( SARM ) compound represented by a compound of Formula 55 thereof, as described herein . In one embodiment, the subject is a female subject. In one embodiment, the subject is a male subject. I (R3 ) In one embodiment, G in Formula I is 0 . In another (R3 ) m embodiment, X in Formula I is O . In another embodiment, G (R2 ) n 60 T in Formula I is OH . In another embodiment, R , in Formula Z I is CHz. In another embodiment, Z in Formula I is NO2. In another embodiment, Z in Formula I is CN . In another N embodiment, Y in Formula I is CF3. In another embodiment, Y in Formula I is C1. In another embodiment, Q in Formula X is a bond , O , CH , NH , S , Se, PR , NO or NR ; 65 I is CN . In another embodiment , Q in Formula I is halogen . G is O or S ; In another embodiment, Q in Formula I is F . In another T is OH , OR , - NHCOCH3, or NHCOR ; embodiment, Q in Formula I is C1. In another embodiment, US 9 ,744 , 149 B2 23 24 Q in Formula I is NHCOCHz. In another embodiment, Q in Z is NO , , CN , COR , COOH or CONHR ; Formula I is CN and R , is F . In another embodiment, Q in Y is I , CF3 , Br, Cl, or Sn ( R ) ; Formula 1 is Cl and R , is F . In another embodiment, Q in Q is CN , alkyl, halogen , N ( R ) 2 , NHCOCHZ, NHCOCF3, Formula I is in the para position . In another embodiment, Z NHCOR , NHCONHR , NHCOOR , OCONHR , in Formula I is in the para position . In another embodiment, 5 CONHR , NHCSCHz, NHCSCF3, NHCSR , Y in Formula I is in the meta position . NHSO , CH3, NHSO R , OR , COR , OCOR , OSO , R , The substituents Z , Y and Rz can be in any position of the SO , R or SR ; ring carrying these substituents (hereinafter “ A ring ” ) . In one or Q together with the benzene ring to which it is attached embodiment, the substituent Z is in the para position of the is a fused ring system represented by structure A , B or A ring . In another embodiment, the substituent Y is in the 10 C : meta position of the A ring . In another embodiment, the substituent Z is in the para position of the A ring and substituent Y is in the meta position of the A ring . ANH 0 < The substituents Q and R , can be in any position of the 15 ring carrying these substituents (hereinafter “ B ring ” ) . In one embodiment, the substituent Q is in the para position of the Bring . In another embodiment, the substituent R , is in the meta position of the B ring . In another embodiment, the NH substituent Q is CN and is in the para position of the B ring . 20 As contemplated herein , when the integers m and n are greater than one , the substituents R2 and Rz are not limited 0 to one particular substituent , and can be any combination of NH the substituents listed above . In another embodiment, the compound of this invention 25 which is effective at: a ) treating a subject suffering from breast cancer; b ) treating a subject suffering from metastatic breast cancer; c ) treating a subject suffering from refractory R is a C . - C . alkyl, aryl, phenyl, alkenyl , hydroxyl, a breast cancer ; d ) treating a subject suffering from AR C -C4 haloalkyl, halogen , or haloalkenyl; and positive breast cancer; e ) treating a subject suffering from 30 R , is CH , CF , CH , CH , , or CFCF . AR -positive refractory breast cancer ; f) treating a subject In one embodiment , this invention relates to the treatment suffering from AR - positive metastatic breast cancer ; g ) of androgen receptor -positive breast cancer in a subject , for treating a subject suffering from AR -positive and ER -posi example a female subject . Accordingly , this invention pro tive breast cancer; h ) treating a subject suffering from vides methods for: a ) treating AR -positive breast cancer in AR -positive breast cancer with or without expression of ER , 35 a subject; b ) treating metastatic AR -positive breast cancer, or PR , and / or HER2; i ) treating a subject suffering from triple advanced AR -positive breast cancer ; c ) treating refractory negative breast cancer ; j) treating a subject suffering from AR - positive breast cancer; d ) treating , preventing , suppress advanced breast cancer ; k ) treating a subject suffering from ing or inhibiting metastasis in a subject suffering from breast breast cancer that has failed SERM (tamoxifen , toremifene ), cancer : e ) prolonging progression - free survival of a subject aromatase inhibitor, trastuzumab (Herceptin , ado - trastu - 40 suffering from breast cancer ; f ) treating a subject suffering zumab emtansine ), pertuzumab (Perjeta ) , lapatinib , exemes from ER - positive breast cancer; g ) treating a subject suffer tane (Aromasin ), bevacizumab ( Avastin ), and /or fulvestrant ing from metastatic ER -positive breast cancer; h ) treating a treatment; 1 ) treating a subject suffering from ER positive subject suffering from refractory ER -positive breast cancer ; breast cancer ; m ) treating , preventing , suppressing or inhib - i ) treating a subject suffering from AR -positive ER - positive iting metastasis in a subject suffering from breast cancer ; n ) 45 breast cancer ; j) treating a subject suffering from AR prolonging survival of a subject with breast cancer ; 0 ) positive ER -positive refractory breast cancer ; k ) treating a slowing the progression of breast cancer in a subject ; and / or subject suffering from AR - positive ER -positive metastatic p ) prolonging progression - free survival of a subject with breast cancer ; 1 ) treating a subject suffering from AR breast cancer ; is a compound represented by a compound of positive and ER -positive breast cancer ; m ) treating a subject Formula II , and /or its analog , derivative, isomer, metabolite , 50 suffering from AR -positive ER -positive breast cancer with pharmaceutically acceptable salt, pharmaceutical product , or without expression of PR , and/ or HER2; n ) treating a hydrate , N - oxide , crystal , polymorph , prodrug or any com subject suffering from advanced ER - positive breast cancer ; bination thereof: o ) treating a subject suffering from ER - positive breast cancer that has failed SERM ( tamoxifen , toremifene ) , aro 55 matase inhibitor , trastuzumab (Herceptin , ado - trastuzumab II emtansine ) , pertuzumab (Perjeta ), lapatinib , exemestane ( Aromasin ) , bevacizumab (Avastin ), and/ or fulvestrant treatments ; p ) treating , preventing , suppressing or inhibiting metastasis in a subject suffering from ER -positive breast ?? 60 cancer ; q ) prolonging survival of a subject with ER -positive til breast cancer ; r ) slowing the progression of ER - positive breast cancer in a subject; and /or s ) prolonging progression free survival of a subject with ER - positive breast cancer ; wherein comprising administering to the subject a therapeutically X is a bond , O , CH2, NH , Se, PR , or NR ; 65 effective amount of a selective androgen receptor modulator G is O or S ; (SARM ) compound represented by a compound of Formula T is OH , OR , - NHCOCHz, or NHCOR ; II: US 9 , 744 , 149 B2 25 26 is CN or F . In another embodiment, G in Formula II is 0 , T II is OH , R is CH3, X is O , Z is NO2, Y is CF , and Q is NHCOCH3, F or Cl. The substituents Z and Y can be in any position of the ring cQ 5 carrying these substituents (hereinafter “ A ring ” ) . In one NH embodiment, the substituent Z is in the para position of the A ring . In another embodiment, the substituent Y is in the mew position of the A ring . In another embodiment , the substituent Z is in the para position of the A ring and wherein substituent Y is in the meta position of the A ring . X is a bond , O , CH ,, NH , Se, PR , or NR ; The substituent Q can be in any position of the ring G is O or S ; carrying this substituent (hereinafter “ B ring ” ) . In one T is OH , OR , - NHCOCHz, or NHCOR ; embodiment, the substituent Q is in the para position of the Z is NO2, CN , COR , COOH or CONHR ; Bring . In another embodiment, the substituent Q is CN and Y is I, CF3, Br, Cl, or Sn ( R ) 3 ; is in the para position of the B ring . O is CN , alkyl, halogen , N ( R ) , NHCOCHZ, NHCOCFz, In another embodiment, the compound of this invention NHCOR , NHCONHR , NHCOOR , OCONHR , which is effective at: a ) treating a subject suffering from CONHR , NHCSCHZ, NHCSCF3, NHCSR , breast cancer; b ) treating a subject suffering from metastatic NHSO ,CH3 , NHSO , R , OR , COR , OCOR , OSO R , 20 breast cancer; c ) treating a subject suffering from refractory SO , R or SR ; breast cancer; d ) treating a subject suffering from AR or Q together with the benzene ring to which it is attached positive breast cancer ; e ) treating a subject suffering from is a fused ring system AR - positive refractory breast cancer ; f) treating a subject represented by structure A , B or C : suffering from AR -positive metastatic breast cancer; g ) 25 treating a subject suffering from AR -positive and ER -posi tive breast cancer; h ) treating a subject suffering from AR -positive breast cancer with or without expression of ER , PR , and / or HER2 ; i ) treating a subject suffering from triple negative breast cancer; j ) treating a subject suffering from U advanced breast cancer; k ) treating a subject suffering from ? breast cancer that has failed SERM ( tamoxifen , toremifene ), NH 0 aromatase inhibitor, trastuzumab (Herceptin , ado -trastu zumab emtansine ) , pertuzumab (Perjeta ), lapatinib , exemes 35 tane ( Aromasin ), bevacizumab (Avastin ), and /or fulvestrant treatment; 1 ) treating a subject suffering from ER positive NH breast cancer; m ) treating , preventing , suppressing or inhib iting metastasis in a subject suffering from breast cancer; n ) prolonging survival of a subject with breast cancer ; 0 ) 40 slowing the progression of breast cancer in a subject ; and / or p ) prolonging progression - free survival of a subject with R is a C . - C4 alkyl, aryl, phenyl, alkenyl, hydroxyl, a breast cancer ; is a compound represented by a structure of CZ- C4 haloalkyl, halogen , or haloalkenyl; and Formula III, and / or its analog , derivative , isomer, metabo R , is CH3, CF3, CH2CH3, or CF2CF3 ; lite , pharmaceutically acceptable salt, pharmaceutical prod and / or its analog, derivative, isomer , metabolite , pharma- 45 uct , hydrate , N -oxide , crystal, polymorph , prodrug or any ceutically acceptable salt , pharmaceutical product, hydrate , combination thereof: N - oxide , crystal, polymorph , prodrug or any combination thereof, as described herein . In one embodiment, the subject is a female subject. In one embodiment, the subject is a male o III subject. 50 In one embodiment, G in Formula II is O . In another embodiment, X in Formula II is O . In another embodiment, T in Formula II is OH . In another embodiment, R , in NH Formula II is CHz. In another embodiment, Z in Formula II H3COH is NO , . In another embodiment, Z in Formula II is CN . In 55 another embodiment, Y in Formula II is CF3 . In another embodiment, Y in Formula II is halogen . In another embodi wherein ment, Y in Formula II is Cl. In another embodiment, Q in Z is NO , , CN , COOH , COR , NHCOR or CONHR ; Formula II is CN . In another embodiment, Q in Formula II Y is CF2 , F , I , Br, C1, CN , C ( R ) , or Sn ( R ) z ; is halogen . In another embodiment, Q in Formula II is C1. In 60 Ois CN , alkyl, halogen , N ( R ) , , NHCOCH , NHCOCF2 , another embodiment, Q in Formula II is F. In another NHCOR , NHCONHR , NHCOOR , OCONHR , embodiment, Q in Formula II is NHCOCHz. In another CONHR , NHCSCH , NHCSCF , NHCSR , embodiment, Q in Formula II is in the para position . In NHSO ,CH3 , NHSO , R , OR , COR , OCOR , OSO , R , another embodiment, Z in Formula II is in the para position . SO , R or SR ; In another embodiment, Y in Formula II is in the meta 65 or Q together with the benzene ring to which it is attached position . In another embodiment, G in Formula II is O , T is is a fused ring system represented by structure A , B or OH , R , is CH?, X is 0 , Z is CN , Y is CF , or halogen and Q C : US 9 , 744 , 149 B2 27 28 Q is CN , alkyl, halogen , N ( R ) 2, NHCOCH3, NHCOCF3, A NHCOR , NHCONHR , NHCOOR , OCONHR , NHO CONHR, NHCSCH , NHCSCF , NHCSR , NHSO ,CH , NHSO , R , OR , COR , OCOR , OSO , R , 55 SO , R or SR ; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A , B or NHO C :

< NH NH 0 andR is alkyl , haloalkyl, dihaloalkyl, trihaloalkyl, CH , F , CHF2, CF3, CF CF3, aryl, phenyl, halogen , alkenyl or OH . In one embodiment, this invention relates to the treatment 20 0 of androgen receptor -positive breast cancer in a subject, for example a female subject . Accordingly , this invention pro vides methods for : a ) treating AR -positive breast cancer in a subject; b ) treating metastatic AR -positive breast cancer , or advanced AR -positive breast cancer; c ) treating refractory 25 AR - positive breast cancer; d ) treating , preventing , suppress - and ing or inhibiting metastasis in a subject suffering from breast R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH F , cancer ; e ) prolonging progression - free survival of a subject suffering from breast cancer; f ) treating a subject suffering CHF2, CF3, CF CF3, aryl, phenyl, halogen , alkenyl or from ER - positive breast cancer; g ) treating a subject suffer - 20 OH ; ing from metastatic ER - positive breast cancer; h ) treating a 30 and /or its analog , derivative , isomer, metabolite , pharma subject suffering from refractory ER - positive breast cancer; ceutically acceptable salt, pharmaceutical product , i ) treating a subject suffering from AR - positive ER - positive hydrate , N - oxide, crystal , polymorph , prodrug or any breast cancer ; j ) treating a subject suffering from AR combination thereof, as described herein . In one positive ER -positive refractory breast cancer; k ) treating a embodiment, the subject is a female subject . In one subject suffering from AR -positive ER -positive metastatic 35 embodiment, the subject is a male subject. breast cancer; 1 ) treating a subject suffering from AR In one embodiment, Z in Formula III is NO2. In another positive and ER - positive breast cancer ; m ) treating a subject embodiment , Z in Formula III is CN . In another embodi suffering from AR -positive ER - positive breast cancer with ment, Y in Formula III is CF3 . In another embodiment, Y in or without expression of PR , and / or HER2 ; n ) treating a Formula III is Cl. In another embodiment, Y in Formula III subject suffering from advanced ER -positive breast cancer; 40 is halogen . In another embodiment, Q in Formula III is CN . o ) treating a subject suffering from ER -positive breast In another embodiment , Q in Formula III is halogen . In cancer that has failed SERM (tamoxifen , toremifene ) , aro - another embodiment, Q in Formula III is F . In another matase inhibitor, trastuzumab (Herceptin , ado - trastuzumab embodiment, Q in Formula III is Cl. In another embodiment, emtansine ), pertuzumab (Perjeta ) , lapatinib , exemestane in Formula III is NHCOCHz. In another embodiment, Z ( Aromasin ) , bevacizumab ( Avastin ) , and/ or fulvestrant 45 is CN , Y is CF , or halogen , and Q is CN or F . In another treatments ; p ) treating , preventing, suppressing or inhibiting embodiment , Z is NO2, Y is CF3 , and Q is NHCOCH3, F or metastasis in a subject suffering from ER -positive breast Cl. cancer ; q ) prolonging survival of a subject with ER -positive In another embodiment, the compound of this invention breast cancer ; r ) slowing the progression of ER - positive which is effective at: a ) treating a subject suffering from breast cancer in a subject ; and / or s ) prolonging12g progression progression .- 50sobre breast cancer ; b ) treating a subject suffering from metastatic free survival of a subject with ER -positive breast cancer; breast cancer; c ) treating a subject suffering from refractory comprising administering to the subject a therapeutically breast cancer ; d ) treating a subject suffering from AR effective amount of a selective androgen receptor modulator positive breast cancer ; e ) treating a subject suffering from (SARM ) compound represented by a compound of Formula AR -positive refractory breast cancer ; f) treating a subject III: 55 suffering from AR - positive metastatic breast cancer ; g ) treating a subject suffering from AR - positive and ER -posi III tive breast cancer; h ) treating a subject suffering from AR - positive breast cancer with or without expression of ER , PR , and / or HER2; i ) treating a subject suffering from triple 60 negative breast cancer ; j ) treating a subject suffering from advanced breast cancer; k ) treating a subject suffering from breast cancer that has failed SERM ( tamoxifen , toremifene ) , ????H3COH aromatase inhibitor, trastuzumab (Herceptin , ado - trastu zumab emtansine ) , pertuzumab ( Perjeta ), lapatinib , exemes wherein 65 tane (Aromasin ), bevacizumab ( Avastin ) , and /or fulvestrant Z is NO2, CN , COOH , COR , NHCOR or CONHR ; treatment; 1) treating a subject suffering from ER positive Y is CF3, F , I , Br, C1, CN , C (R ); or Sn ( R )3 ; breast cancer ; m ) treating , preventing , suppressing or inhib US 9 ,744 , 149 B2 30 iting metastasis in a subject suffering from breast cancer ; n ) NHCOCF , NHCOR, NHCONHR , NHCOOR , prolonging survival of a subject with breast cancer; 0 ) OCONHR , CONHR , NHCSCHZ , NHCSCF3, NHCSR , slowing the progression of breast cancer in a subject ; and / or NHSO ,CH3 , NHSO , R , OR , COR , OCOR , OSO , R , p ) prolonging progression - free survival of a subject with SO _ R , SR , breast cancer ; is a compound represented by a structure of 5 Formula IV , and/ or its analog, derivative , isomer, metabo lite , pharmaceutically acceptable salt, pharmaceutical prod HNW , uct, hydrate , N -oxide , crystal , polymorph , prodrug or any Ox combination thereof: P4 10 2

IV Q3 and Q4 are independently of each other a hydrogen , B alkyl , halogen , CF3 , CN , C ( R ) 3 , Sn ( R ) 3 , N ( R ) 2 , ?? NHCOCHE, NHCOCF4, NHCOR , NHCONHR , RT NHCOOR , OCONHR , CONHR , NHSCH , NHC RPB SCF3 , NHCSR , NHSO , CH3, NHSO , R , OR , COR , OCOR , OSO , R , SO2R or SR ; wherein W is O , NH , NR , NO or S ; and X is a bond, O , CH?, NH , S , Se , PR , NO or NR ; 20 W , is N or NO . G is O or S ; In one embodiment, this invention relates to the treatment Ri is CH3, CH F , CHF2 , CF3 , CH2CH3, or CF2CF3 ; of androgen receptor -positive breast cancer in a subject , for T is OH , OR , — NHCOCHz, or NHCOR ; example a female subject. Accordingly, this invention pro R is alkyl , haloalkyl, dihaloalkyl , trihaloalkyl, CH F , vides methods for : a ) treating AR -positive breast cancer in CHF2, CF3, CF , CFz, aryl, phenyl, halogen , alkenyl or 25 a subject ; b ) treating metastatic AR -positive breast cancer, or advanced AR -positive breast cancer ; c ) treating refractory OH ; AR -positive breast cancer ; d ) treating , preventing, suppress A is a ring selected from : ing or inhibiting metastasis in a subject suffering from breast cancer ; e ) prolonging progression - free survival of a subject suffering from breast cancer; f ) treating a subject suffering from ER - positive breast cancer ; g ) treating a subject suffer ing from metastatic ER - positive breast cancer ; h ) treating a Z subject suffering from refractory ER -positive breast cancer ; i ) treating a subject suffering from AR -positive ER - positive W breast cancer; j) treating a subject suffering from AR positive ER -positive refractory breast cancer; k ) treating a II and subject suffering from AR -positive ER - positive metastatic breast cancer ; 1) treating a subject suffering from AR 2. positive and ER -positive breast cancer ; m ) treating a subject W suffering from AR - positive ER - positive breast cancer with NIN 40 or without expression of PR , and /or HER2; n ) treating a subject suffering from advanced ER - positive breast cancer ; o ) treating a subject suffering from ER - positive breast cancer that has failed SERM ( tamoxifen , toremifene ) , aro matase inhibitor, trastuzumab (Herceptin , ado -trastuzumab B is a ring selected from : 45 emtansine ), pertuzumab (Perjeta ) , lapatinib , exemestane ( Aromasin ) , bevacizumab (Avastin ) , and /or fulvestrant treatments ; p ) treating , preventing , suppressing or inhibiting metastasis in a subject suffering from ER -positive breast cancer ; q ) prolonging survival of a subject with ER - positive breast cancer; r ) slowing the progression of ER - positive 50 breast cancer in a subject ; and/ or s ) prolonging progression free survival of a subject with ER - positive breast cancer ; comprising administering to the subject a therapeutically effective amount of a selective androgen receptor modulator Foy (SARM ) compound represented by a compound of Formula ? 55 IV :

and IV W2 60 NH wherein A and B cannot simultaneously be a benzene ring; Z is NO ,, CN , COOH , COR , NHCOR or CONHR ; RPB Y is CF3, F , I , Br, C1, CN , C ( R ) ; or Sn ( R ) 3 ; 65 wherein Qi and Q2 are independently hydrogen , alkyl , halogen , X is a bond , O , CH2, NH , S , Se , PR , NO or NR ; CF3 , CN , C ( R )3 , Sn ( R )3 , N ( R ) 2, NHCOCH3, G is O or S ; US 9 ,744 , 149 B2 31 32 R , is CH3, CH F , CHF2, CF3, CH2CH3, or CF2CF3; and / or its analog , derivative , isomer , metabolite , pharma T is OH , OR , — NHCOCHz, or NHCOR ; ceutically acceptable salt , pharmaceutical product, hydrate , R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH F , N -oxide , crystal, polymorph , prodrug or any combination CHF2, CF3, CF2CF3, aryl, phenyl, halogen , alkenyl or thereof, as described herein . In one embodiment, the subject OH ; 5 is a female subject . In one embodiment, the subject is a male A is a ring selected from : subject. In one embodiment, G in Formula IV is O . In another embodiment, X in Formula IV is O . In another embodiment, T in Formula IV is OH . In another embodiment, R , in 10 Formula IV is CH2. In another embodiment , Z in Formula IV is NO , . In another embodiment, Z in Formula IV is CN . ? In another embodiment, Y in Formula IV is CF2 . In another embodiment, Y in Formula IV is halogen . In another and embodiment, Y in Formula IV is C1. In another embodiment , Qi in Formula II is CN . In another embodiment, Q . in Formula IV is F . In another embodiment, Q , in Formula IV is Cl. In another embodiment, Q in Formula II is NHCOCHZ. In another embodiment, Q , in Formula IV is in Y 20 the para position . In another embodiment , Z in Formula IV is in the para position . In another embodiment, Y in Formula IV is in the mew position . In another embodiment, G in Formula IV is O , T is OH , R , is CH3 , X is O , Z is NO , or B is a ring selected from : CN , Y is CF , or halogen and Q , is CN , F , C1, or NHCOCHZ. 25 The substituents Z and Y can be in any position of the ring carrying these substituents (hereinafter “ A ring ” ) . In one embodiment, the substituent Z is in the para position of the e A ring . In another embodiment, the substituent Y is in the mew position of the A ring . In another embodiment, the 30 substituent Z is in the para position of the A ring and substituent Y is in the mew position of the A ring . The substituents Q , and Q2 can be in any position of the za ring carrying these substituents ( hereinafter “ Bring ” ) . In one embodiment, the substituent Q1 is in the para position of the 02 Bring. In another embodiment, the substituent is Q is H . In another embodiment, the substituent Qi is in the para posi and tion of the B ring and the substituent is , is H . In another embodiment, the substituent Qi is CN and is in the para -W2 position of the B ring , and the substituent is Q2 is H . 40 As contemplated herein , other specific embodiments of compounds included within the scope of the present inven wherein A and B cannot simultaneously be a benzene tion , and which are useful in : a ) treating a subject suffering ring ; from breast cancer ; b ) treating a subject suffering from Z is NO2, CN , COOH , COR , NHCOR or CONHR ; metastatic breast cancer; c ) treating a subject suffering from Y is CF3, F , I , Br, C1, CN , C ( R ) 3 or Sn (R ) 3 ; 45 refractory breast cancer; d ) treating a subject suffering from Qi and Q2 are independently hydrogen , alkyl, halogen , AR -positive breast cancer ; e ) treating a subject suffering CF3, CN , C ( R ) 3 , Sn ( R ) 3 , N ( R ) 2 , NHCOCHZ, from AR - positive refractory breast cancer ; f ) treating a NHCOCF4, NHCOR , NHCONHR, NHCOOR , subject suffering from AR - positive metastatic breast cancer ; OCONHR , CONHR , NHCSCH3, NHCSCF3 , NHCSR , g ) treating a subject suffering from AR -positive and ER NHSO ,CH3 , NHSO2R , OR , COR , OCOR , OSOR, 50 positive breast cancer ; h ) treating a subject suffering from SO R , SR , AR - positive breast cancer with or without expression of ER , PR , and / or HER2; i ) treating a subject suffering from triple negative breast cancer ; j ) treating a subject suffering from LHNN W1 . HNW advanced breast cancer ; k ) treating a subject suffering from Or 55 breast cancer that has failed SERM ( tamoxifen , toremifene ) , . aromatase inhibitor, trastuzumab (Herceptin , ado - trastu W2 O zumab emtansine ), pertuzumab (Perjeta ) , lapatinib , exemes tane (Aromasin ), bevacizumab ( Avastin ), and /or fulvestrant treatment; 1 ) treating a subject suffering from ER positive Q3 and Q4 are independently of each other a hydrogen , 60 breast cancer ; m ) treating , preventing , suppressing or inhib alkyl, halogen , CF3, CN , C ( R ) 3 , Sn ( R ) 3 , N ( R ) 2 , iting metastasis in a subject suffering from breast cancer ; n ) NHCOCHZ, NHCOCF3 , NHCOR , NHCONHR , prolonging survival of a subject with breast cancer ; o ) NHCOOR , OCONHR, CONHR , NHCSCH , NHC slowing the progression of breast cancer in a subject ; and /or SCF3, NHCSR , NHSO , CH3, NHSO , R , OR , COR p ) prolonging progression - free survival of a subject with OCOR , OSOR , SO , R or SR ; 65 breast cancer ; are Formula V or VI. It is understood that W , is O , NH , NR , NO or S ; and included within the scope of the present invention are W , is N or NO ; analogs , derivatives, metabolites , isomers , pharmaceutically US 9 ,744 , 149 B2 33 34 acceptable salts , pharmaceutical products , hydrates , N -ox suffering from AR -positive ER - positive breast cancer with ides , polymorphs, crystals , prodrugs or combinations thereof or without expression of PR , and / or HER2 ; n ) treating a of these compounds: subject suffering from advanced ER - positive breast cancer ; o ) treating a subject suffering from ER - positive breast 5 cancer that has failed SERM ( tamoxifen , toremifene ) , aro matase inhibitor, trastuzumab (Herceptin , ado - trastuzumab ON emtansine) , pertuzumab (Perjeta ) , lapatinib , exemestane ( Aromasin ), bevacizumab (Avastin ) , and /or fulvestrant treatments ; p ) treating, preventing , suppressing or inhibiting HzC NH 10 metastasis in a subject suffering from ER -positive breast .H3COH cancer; q ) prolonging survival of a subject with ER - positive breast cancer; r) slowing the progression of ER - positive CN breast cancer in a subject; and /or s ) prolonging progression o= free survival of a subject with ER - positive breast cancer ; 15 comprising administering to the subject a therapeutically HC NH Y effective amount of a selective androgen receptor modulator H3COH (SARM ) compound represented by the following structures of Formula V or VI: wherein Q is CN , alkyl , halogen , N (R )2 , NHCOCH3, 20 NHCOCF , NHCOR , NHCONHR, NHCOOR , OCONHR , CONHR , NHCSCH3, NHCSCF3, NHCSR , NHSO , CH3, NHSO , R , OR , COR , OCOR , OSO , R , 02N ó SO R or SR ; or Q together with the benzene ring to which it is attached 25 is a fused ring system represented by structure A , B or H3C NH C : ?? ?? s CN. A 30 ?? HzCH2C VNNH Y * Ano?; ? ?? w B 35 wherein Q is CN , alkyl, halogen , N ( R ) 2, NHCOCH3, NHCOCF3, NHCOR , NHCONHR , NHCOOR , OCONHR , ? CONHR, NHCSCH , NHCSCF , NHCSR , NHSO , CH3, NHSO , R , OR , COR , OCOR , OSO , R , SO R or SR ; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A , B or C : and 45 R is alkyl, haloalkyl, dihaloalkyl , trihaloalkyl, CH , F, CHF2, CF3 , CF CF3, aryl, phenyl , halogen , alkenyl or OH . NH 0 In one embodiment, this invention relates to the treatment of androgen receptor- positive breast cancer in a subject, for 50 example a female subject . Accordingly , this invention pro vides methods for: a ) treating AR -positive breast cancer in ?? a subject ; b ) treating metastatic AR - positive breast cancer , or advanced AR -positive breast cancer; c ) treating refractory AR - positive breast cancer; d ) treating, preventing , suppress - 55 ing or inhibiting metastasis in a subject suffering from breast cancer; e ) prolonging progression - free survival of a subject suffering from breast cancer; f ) treating a subject suffering from ER - positive breast cancer; g ) treating a subject suffer ing from metastatic ER - positive breast cancer ; h ) treating a 60 subject suffering from refractory ER - positive breast cancer; i) treating a subject suffering from AR -positive ER -positive and breast cancer ; j) treating a subject suffering from AR - Ris alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH F , CHF2, positive ER - positive refractory breast cancer ; k ) treating a CF3, CF2CF3, aryl , phenyl, halogen , alkenyl or OH ; subject suffering from AR - positive ER - positive metastatic 65 and / or its analog , derivative, isomer , metabolite , pharma breast cancer ; 1 ) treating a subject suffering from AR - ceutically acceptable salt , pharmaceutical product, hydrate , positive and ER - positive breast cancer ; m ) treating a subject N - oxide , crystal , polymorph , prodrug or any combination US 9 ,744 , 149 B2 35 36 thereof, as described herein . In one embodiment, the subject positive and ER - positive breast cancer; m ) treating a subject is a female subject. In one embodiment, the subject is a male suffering from AR - positive ER -positive breast cancer with subject. or without expression of PR , and / or HER2 ; n ) treating a In one embodiment, Q in Formula V or VI is CN . In one subject suffering from advanced ER -positive breast cancer; embodiment, Q in Formula V or VI is halogen . In one 5 o ) treating a subject suffering from ER -positive breast embodiment, Q in Formula V or VI is F . In one embodiment, cancer that has failed SERM ( tamoxifen , toremifene ) , aro 0 in Formula V or VI is Cl. In one embodiment, Q in matase inhibitor, trastuzumab (Herceptin , ado - trastuzumab Formula V or VI is NHCOCHZ. emtansine ), pertuzumab (Perjeta ), lapatinib , exemestane In another embodiment, the compound of this invention ( Aromasin ), bevacizumab ( Avastin ) , and /or fulvestrant which is effective at: a ) treating a subject suffering from treatments ; p ) treating , preventing, suppressing or inhibiting breast cancer; b ) treating a subject suffering from metastatic metastasis in a subject suffering from ER -positive breast breast cancer; c ) treating a subject suffering from refractory cancer ; q ) prolonging survival of a subject with ER -positive breast cancer ; d ) treating a subject suffering from AR breast cancer; r ) slowing the progression of ER -positive positive breast cancer ; e ) treating a subject suffering from breast cancer in a subject ; and / or s ) prolonging progression AR -positive refractory breast cancer; f ) treating a subject free survival of a subject with ER -positive breast cancer ; suffering from AR -positive metastatic breast cancer ; g ) comprising administering to the subject a therapeutically treating a subject suffering from AR - positive and ER - posi effective amount of a selective androgen receptor modulator tive breast cancer; h ) treating a subject suffering from (SARM ) compound represented by the following structures AR -positive breast cancer with or without expression of ER , PR , and / or HER2; i) treating a subject suffering from triple 20 of Formula VII: negative breast cancer ; 1 ) treating a subject suffering from advanced breast cancer ; k ) treating a subject suffering from VII breast cancer that has failed SERM ( tamoxifen , toremifene ) , NC . -CN aromatase inhibitor , trastuzumab (Herceptin , ado - trastu zumab emtansine ) , pertuzumab (Perjeta ) , lapatinib , exemes 25 tane ( Aromasin ) , bevacizumab ( Avastin ) , and / or fulvestrant V NH X treatment; 1 ) treating a subject suffering from ER positive breast cancer ; m ) treating , preventing , suppressing or inhib H3COH iting metastasis in a subject suffering from breast cancer; n ) prolonging survival of a subject with breast cancer ; 0 ) " wherein Z is Cl or CFz; slowing the progression of breast cancer in a subject; and /or and /or its analog , derivative, isomer, metabolite , pharma p ) prolonging progression - free survival of a subject with ceutically acceptable salt, pharmaceutical product , hydrate , breast cancer ; is a compound represented by a structure of N -oxide , crystal , polymorph , prodrug or any combination Formula VII, and / or its analog, derivative , isomer , metabo- 35 thereof, as described herein . In one embodiment, the subject lite , pharmaceutically acceptable salt , pharmaceutical prod is a female subject. In one embodiment, the subject is a male uct , hydrate , N -oxide , crystal, polymorph , prodrug or any subject. combination thereof : In another embodiment, the compound which is effective at: a ) treating a subject suffering from breast cancer; b ) VI 40 treating a subject suffering from metastatic breast cancer; c ) treating a subject suffering from refractory breast cancer ; d ) NC - CN treating a subject suffering from AR -positive breast cancer ; e ) treating a subject suffering from AR -positive refractory breast cancer; f ) treating a subject suffering from AR ainoNHNH 45 positive metastatic breast cancer ; g ) treating a subject suf H3COH fering from AR -positive and ER -positive breast cancer; h ) treating a subject suffering from AR - positive breast cancer wherein Z is Cl or CF3. with or without expression of ER , PR , and /or HER2 ; i ) In one embodiment, this invention relates to the treatment 50 treating a subject suffering from triple negative breast can of androgen receptor- positive breast cancer in a subject, for cer ; j) treating a subject suffering from advanced breast example a female subject. Accordingly , this invention pro cancer ; k ) treating a subject suffering from breast cancer that vides methods for: a ) treating AR -positive breast cancer in has failed SERM ( tamoxifen , toremifene ), aromatase inhibi a subject; b ) treating metastatic AR - positive breast cancer , or tor, trastuzumab (Herceptin , ado -trastuzumab emtansine ) , advanced AR -positive breast cancer ; c ) treating refractory 55 pertuzumab ( Perjeta ), lapatinib , exemestane ( Aromasin ) , AR -positive breast cancer; d ) treating , preventing, suppress bevacizumab ( Avastin ) , and / or fulvestrant treatment; 1 ) ing or inhibiting metastasis in a subject suffering from breast treating a subject suffering from ER positive breast cancer; cancer ; e ) prolonging progression - free survival of a subject m ) treating , preventing, suppressing or inhibiting metastasis suffering from breast cancer; f ) treating a subject suffering in a subject suffering from breast cancer; n ) prolonging from ER - positive breast cancer ; g ) treating a subject suffer - 60 survival of a subject with breast cancer; o ) slowing the ing from metastatic ER -positive breast cancer; h ) treating a progression of breast cancer in a subject ; and /or p ) prolong subject suffering from refractory ER -positive breast cancer; ing progression - free survival of a subject with breast cancer ; i ) treating a subject suffering from AR - positive ER -positive is a compound represented by a structure of Formula VIII , breast cancer ; j ) treating a subject suffering from AR - and /or its analog , derivative , isomer, metabolite , pharma positive ER - positive refractory breast cancer ; k ) treating a 65 ceutically acceptable salt , pharmaceutical product, hydrate , subject suffering from AR - positive ER - positive metastatic N - oxide, crystal, polymorph , prodrug or any combination breast cancer ; 1) treating a subject suffering from AR - thereof : US 9 ,744 , 149 B2 37 38 in a subject suffering from breast cancer ; n ) prolonging VIII survival of a subject with breast cancer; o ) slowing the progression of breast cancer in a subject; and / or p ) prolong NC CN . ing progression - free survival of a subject with breast cancer ; 5 is a compound represented by a structure of Formula X , and / or its analog , derivative, isomer , metabolite , pharma NHY ceutically acceptable salt, pharmaceutical product, hydrate , N -oxide , crystal , polymorph , prodrug or any combination H3COOH thereof: In another embodiment, the compound which is effective 10 at: a ) treating a subject suffering from breast cancer ; b ) treating a subject suffering from metastatic breast cancer ; c ) NC . FX treating a subject suffering from refractory breast cancer ; d ) treating a subject suffering from AR - positive breast cancer ; e ) treating a subject suffering from AR -positive refractory 15 F3C NHNH breast cancer ; f ) treating a subject suffering from AR H3CH positive metastatic breast cancer ; g ) treating a subject suf fering from AR - positive and ER - positive breast cancer ; h ) treating a subject suffering from AR - positive breast cancer In another embodiment, the compound which is effective with or without expression of ER , PR , and / or HER2; i ) 20 at : a ) treating a subject suffering from breast cancer; b ) treating a subject suffering from triple negative breast can treating a subject suffering from metastatic breast cancer; c ) cer ; j ) treating a subject suffering from advanced breast treating a subject suffering from refractory breast cancer ; d ) cancer ; k ) treating a subject suffering from breast cancer that treating a subject suffering from AR -positive breast cancer ; has failed SERM ( tamoxifen , toremifene ) , aromatase inhibi- e ) treating a subject suffering from AR -positive refractory tor, trastuzumab (Herceptin , ado - trastuzumab emtansine ) , 25 breast cancer; f ) treating a subject suffering from AR pertuzumab (Perjeta ), lapatinib , exemestane ( Aromasin ) , positive metastatic breast cancer; g ) treating a subject suf bevacizumab ( Avastin ) , and / or fulvestrant treatment; 1 ) fering from AR -positive and ER -positive breast cancer; h ) treating a subject suffering from ER positive breast cancer; treating a subject suffering from AR - positive breast cancer m ) treating , preventing , suppressing or inhibiting metastasis with or without expression of ER , PR , and / or HER2 ; i ) in a subject suffering from breast cancer ; n ) prolonging 30 treating a subject suffering from triple negative breast can survivalsu of a subject with breast cancer ; o ) slowing the cer ; j ) treating a subject suffering from advanced breast progression of breast cancer in a subject ; and / or p ) prolong cancer ; k ) treating a subject suffering from breast cancer that ing progression - free survival of a subject with breast cancer; has failed SERM ( tamoxifen , toremifene ), aromatase inhibi is a compound represented by a structure of Formula IX , tor , trastuzumab (Herceptin , ado - trastuzumab emtansine ) , and /or its analog , derivative , isomer, metabolite , pharma - ne pertuzumab (Perjeta ) , lapatinib , exemestane ( Aromasin ) , ceutically acceptable salt , pharmaceutical product, hydrate , bevacizumab ( Avastin ) , and /or fulvestrant treatment; 1) N - oxide , crystal, polymorph , prodrug or any combination treating a subject suffering from ER positive breast cancer ; thereof: m ) treating , preventing, suppressing or inhibiting metastasis in a subject suffering from breast cancer; n ) prolonging survival of a subject with breast cancer ; o ) slowing the IX 40 progression of breast cancer in a subject ; and /or p ) prolong ing progression - free survival of a subject with breast cancer ; NCNCA . CN. is a compound represented by a structure of Formula XI, and / or its analog , derivative, isomer, metabolite , pharma ceutically acceptable salt , pharmaceutical product, hydrate , Fain C 45 N -oxide , crystal, polymorph , prodrug or any combination H3COH thereof: In another embodiment, the compound which is effective at : a ) treating a subject suffering from breast cancer; b ) 50 NC treating a subject suffering from metastatic breast cancer; c ) treating a subject suffering from refractory breast cancer ; d ) treating a subject suffering from AR -positive breast cancer; F3CF3C ?? e ) treating a subject suffering from AR -positive refractory breast cancer ; f ) treating a subject suffering from AR H? ?? positive metastatic breast cancer ; g ) treating a subject suf fering from AR - positive and ER - positive breast cancer ; h ) In another embodiment, the compound which is effective treating a subject suffering from AR - positive breast cancer a t : a ) treating a subject suffering from breast cancer ; b ) with or without expression of ER , PR , and / or HER2 ; 1 ) treating a subject suffering from metastatic breast cancer ; c ) treating a subject suffering from triple negative breast can - treating a subject suffering from refractory breast cancer ; d ) cer ; j ) treating a subject suffering from advanced breast 60 treating a subject suffering from AR -positive breast cancer ; cancer ; k ) treating a subject suffering from breast cancer that e ) treating a subject suffering from AR - positive refractory has failed SERM ( tamoxifen , toremifene ) , aromatase inhibi - breast cancer ; f ) treating a subject suffering from AR tor, trastuzumab (Herceptin , ado - trastuzumab emtansine ), positive metastatic breast cancer; g ) treating a subject suf pertuzumab ( Perjeta ) , lapatinib , exemestane ( Aromasin ) , fering from AR -positive and ER -positive breast cancer ; h ) bevacizumab ( Avastin ) , and / or fulvestrant treatment; 1 ) 65 treating a subject suffering from AR -positive breast cancer treating a subject suffering from ER positive breast cancer ; with or without expression of ER , PR , and / or HER2; i ) m ) treating, preventing, suppressing or inhibiting metastasis treating a subject suffering from triple negative breast can US 9 ,744 , 149 B2 39 40 cer; j) treating a subject suffering from advanced breast treating a subject suffering from refractory breast cancer ; d ) cancer ; k ) treating a subject suffering from breast cancer that treating a subject suffering from AR -positive breast cancer ; has failed SERM ( tamoxifen , toremifene ) , aromatase inhibi- e ) treating a subject suffering from AR -positive refractory tor, trastuzumab (Herceptin , ado - trastuzumab emtansine ), breast cancer; f ) treating a subject suffering from AR pertuzumab ( Perjeta ), lapatinib , exemestane (Aromasin ), 5 positive metastatic breast cancer ; g ) treating a subject suf bevacizumab (Avastin ), and / or fulvestrant treatment ; 1) fering from AR - positive and ER -positive breast cancer; h ) treating a subject suffering from ER positive breast cancer ; treating a subject suffering from AR -positive breast cancer m ) treating, preventing , suppressing or inhibiting metastasis with or without expression of ER , PR , and /or HER2; i) in a subject suffering from breast cancer; n ) prolonging treating a subiect suffering from triple negative breast can survival of a subject with breast cancer ; o ) slowing the 10 cer : j ) treating a subject suffering from advanced breast progression of breast cancer in a subject ; and /or p ) prolong cancer; k ) treating a subject suffering from breast cancer that ing progression - free survival of a subject with breast cancer ; has failed SERM ( tamoxifen , toremifene ) , aromatase inhibi is a compound represented by a structure of Formula XII, tor, trastuzumab (Herceptin , ado - trastuzumab emtansine ), and / or its analog , derivative , isomer, metabolite , pharma pertuzumab ( Perjeta ) , lapatinib , exemestane ( Aromasin ) , ceutically acceptable salt , pharmaceutical product , hydrate , 15 bevacizumab (Avastin ) , and / or fulvestrant treatment: 1) N - oxide , crystal, polymorph , prodrug or any combination treating a subject suffering from ER positive breast cancer ; thereof: m ) treating , preventing , suppressing or inhibiting metastasis XII in a subject suffering from breast cancer ; n ) prolonging survival of a subject with breast cancer; o ) slowing the O2N NHCOCH3 20 progression of breast cancer in a subject ; and /or p ) prolong ing progression - free survival of a subject with breast cancer; is a compound represented by a structure of Formula XIV , FgC NHA and / or its analog , derivative, isomer , metabolite , pharma ceutically acceptable salt, pharmaceutical product, hydrate , H3COH 25 N -oxide , crystal, polymorph , prodrug or any combination In another embodiment, the compound which is effective thereof: at: a ) treating a subject suffering from breast cancer ; b ) treating a subject suffering from metastatic breast cancer; c ) treating a subject suffering from refractory breast cancer ; d ) XIV treating a subject suffering from AR -positive breast cancer; 30 NC e ) treating a subject suffering from AR -positive refractory breast cancer ; f ) treating a subject suffering from AR positive metastatic breast cancer ; g ) treating a subject suf F3CDina NH fering from AR - positive and ER - positive breast cancer; h ) ?? ?? treating a subject suffering from AR - positive breast cancer 35 with or without expression of ER , PR , and / or HER2 ; i ) treating a subject suffering from triple negative breast can In one embodiment, this invention relates to the treatment cer ; j ) treating a subject suffering from advanced breast of androgen receptor -positive breast cancer in a subject, for cancer ; k ) treating a subject suffering from breast cancer that example a female subject . Accordingly , this invention pro has failed SERM ( tamoxifen , toremifene ) , aromatase inhibi- 40 vides methods for: a ) treating AR - positive breast cancer in tor. trastuzumab (Herceptin . ado - trastuzumab emtansine ), a subject; b ) treating metastatic AR - positive breast cancer , or pertuzumab (Perjeta ), lapatinib , exemestane (Aromasin ), advanced AR -positive breast cancer; c) treating refractory bevacizumab ( Avastin ) , and / or fulvestrant treatment; 1) AR - positive breast cancer ; d ) treating , preventing, suppress treating a subject suffering from ER positive breast cancer ; ing or inhibiting metastasis in a subject suffering from breast m ) treating , preventing , suppressing or inhibiting metastasis 45 cancer; e ) prolonging progression - free survival of a subject in a subject suffering from breast cancer; n ) prolonging suffering from breast cancer ; f ) treating a subject suffering survival of a subject with breast cancer ; o ) slowing the from ER - positive breast cancer ; g ) treating a subject suffer progression of breast cancer in a subject; and / or p ) prolong ing from metastatic ER - positive breast cancer ; h ) treating a ing progression - free survival of a subject with breast cancer ; subject suffering from refractory ER - positive breast cancer; is a compound represented by a compound of Formula XIII . 50 1 ) treating a subject suffering from AR -positive ER - positive and / or its analog, derivative, isomer , metabolite , pharma breast cancer; j) treating a subject suffering from AR ceutically acceptable salt, pharmaceutical product, hydrate , positive ER -positive refractory breast cancer ; k ) treating a N -oxide , crystal, polymorph , prodrug or any combination subject suffering from AR -positive ER - positive metastatic thereof: breast cancer ; 1 ) treating a subject suffering from AR 55 positive and ER - positive breast cancer ; m ) treating a subject suffering from AR -positive ER -positive breast cancer with XIII or without expression of PR , and /or HER2; n ) treating a subject suffering from advanced ER -positive breast cancer ; NC a L CNCN . o ) treating a subject suffering from ER -positive breast 60 cancer that has failed SERM ( tamoxifen , toremifene ) , aro matase inhibitor, trastuzumab (Herceptin , ado - trastuzumab F 30 NHNH Y emtansine ) , pertuzumab (Perjeta ) , lapatinib , exemestane Der?? ?? (Aromasin ) , bevacizumab (Avastin ), and / or fulvestrant treatments ; p ) treating, preventing , suppressing or inhibiting In another embodiment, the compound which is effective 65 metastasis in a subject suffering from ER -positive breast at : a ) treating a subject suffering from breast cancer ; b ) cancer; q ) prolonging survival of a subject with ER - positive treating a subject suffering from metastatic breast cancer; c ) breast cancer; r ) slowing the progression of ER -positive US 9 , 744 ,149 B2 41 breast cancer in a subject; and / or s ) prolonging progression embodiment, the methods of this invention make use of a free survival of a subject with ER -positive breast cancer; compound of Formula XI. In one embodiment, the methods comprising administering to the subject a therapeutically of this invention make use of a compound of Formula XII . effective amount of a selective androgen receptormodulator In one embodiment, the methods of this invention make use ( SARM ) compound represented by the following structures 5 of a compound of Formula XIII . In one embodiment, the of Formulae VIII, IX , X , XI, XII , XIII or XIV : methods of this invention make use of a compound of Formula XIV . In one embodiment, the methods of the present invention VI comprise administering an analog of the compound of NO 10 Formulae I -XIV . In another embodiment, the methods of the present invention comprise administering a derivative of the compound of Formulae I - XIV . In another embodiment, the methods of the present invention comprise administering an isomer of the compound of Formulae I -XIV . In another Dard?? ?? 15 embodiment, the methods of the present invention comprise administering a metabolite of the compound of Formulae I - XIV . In another embodiment, the methods of the present invention comprise administering a pharmaceutically acceptable salt of the compound of Formulae I- XIV . In NHNH Y 20 another embodiment , the methods of the present invention ???? , comprise administering a pharmaceutical product of the compound of Formulae I - XIV . In another embodiment, the methods of the present invention comprise administering a hydrate of the compound of Formulae I - XIV . In another 25 embodiment, the methods of the present invention comprise NH administering an N -oxide of the compound of Formulae HzC OH I - XIV . In another embodiment, the methods of the present ???? invention comprise administering a polymorph of the com pound of Formulae I - XIV . In another embodiment, the 30 methods of the present invention comprise administering a crystal of the compound of Formulae I - XIV . In another Fac NH embodiment, the methods of the present invention comprise administering a prodrug of the compound of Formulae H3C ' ?? I - XIV . In another embodiment, the methods of the present ??? XIIA 35 invention comprise administering a combination of any of NHCOCH3 an analog , derivative , metabolite , isomer , pharmaceutically acceptable salt, pharmaceutical product, hydrate , N -oxide , polymorph , crystal or prodrug of the compound of Formulae NH I - XIV . 40 In one embodiment, the methods of this invention com ?? ; ?? prise administering a compound of Formulae I - XIV . In ??? XIII another embodiment, the methods of this invention comprise CN administering a compound of Formula I . In another embodi ment, the methods of this invention comprise administering 45 a compound of Formula II . In another embodiment , the NH methods of this invention comprise administering a com pound of Formula III . In another embodiment, the methods H?C OH ; or of this invention comprise administering a compound of ?? XIV Formula IV . In another embodiment, the methods of this a 50 invention comprise administering a compound of Formula V . In another embodiment, the methods of this invention comprise administering a compound of Formula VI. In NH X another embodiment, the methods of this invention comprise H3COH administering a compound of Formula VII . In another embodiment, themethods of this invention comprise admin istering a compound of Formula VIII . In another embodi and / or its analog, derivative , isomer, metabolite , pharma ment , the methods of this invention comprise administering ceutically acceptable salt, pharmaceutical product, hydrate , a compound of Formula IX . In another embodiment , the N -oxide , crystal, polymorph , prodrug or any combination methods of this invention comprise administering a com thereof, as described herein . In one embodiment, the subject 60 pound of Formula X . In another embodiment, the methods is a female subject. In one embodiment, the subject is a male of this invention comprise administering a compound of subject. Formula XI. In another embodiment, the methods of this In one embodiment, the methods of this invention make invention comprise administering a compound of Formula use of a compound of Formula VIII . In one embodiment , the XII. In another embodiment, the methods of this invention methods of this invention make use of a compound of 65 comprise administering a compound of Formula XIII . In Formula IX . In one embodiment, the methods of this inven - another embodiment, the methods of this invention comprise tion make use of a compound of Formula X . In one administering a compound of Formula XIV . US 9 ,744 , 149 B2 43 44 The compounds of the present invention , either alone or like . As used herein , the term “ isomer " may also be referred as a pharmaceutical composition , are useful for: a ) treating to herein as an “ enantiomer " having all of the qualities and a subject suffering from breast cancer ; b ) treating a subject properties of an “ isomer” . suffering from metastatic breast cancer ; c ) treating a subject In one embodiment, this invention encompasses the use of suffering from refractory breast cancer ; d ) treating a subject 5 various optical isomers of the selective androgen receptor suffering from AR -positive breast cancer ; e ) treating a modulator . It will be appreciated by those skilled in the art subject suffering from AR -positive refractory breast cancer; that the selective androgen receptor modulators of the pres f ) treating a subject suffering from AR - positive metastatic ent invention contain at least one chiral center. Accordingly, breast cancer; g ) treating a subject suffering from AR - the selective androgen receptor modulators used in the positive and ER - positive breast cancer ; h ) treating a subject 10 methods of the present invention may exist in , and be suffering from AR -positive breast cancer with or without isolated in , optically -active or racemic forms. Some com expression of ER , PR , and / or HER2; i) treating a subject pounds may also exhibit polymorphism . It is to be under suffering from triple negative breast cancer; j ) treating a stood that the present invention encompasses any racemic , subject suffering from advanced breast cancer; k ) treating a optically -active , polymorphic , or stereoisomeric form , or subject suffering from breast cancer that has failed SERM 15 any combination thereof, which form possesses properties (tamoxifen , toremifene ) , aromatase inhibitor, trastuzumab useful in the treatment of androgen -related conditions (Herceptin , ado - trastuzumab emtansine) , pertuzumab ( Per - described herein . In one embodiment, the selective androgen jeta ) , lapatinib , exemestane ( Aromasin ) , bevacizumab receptor modulators are the pure ( R ) - isomers . In another ( Avastin ) , and / or fulvestrant treatment; 1) treating a subject embodiment, the selective androgen receptor modulators are suffering from ER positive breast cancer ; m ) treating , pre - 20 the pure ( S ) - isomers . In another embodiment , the selective venting, suppressing or inhibiting metastasis in a subject androgen receptor modulators are a mixture of the ( R ) and suffering from breast cancer; n ) prolonging survival of a the ( S ) isomers . In another embodiment, the selective andro subject with breast cancer ; o ) slowing the progression of gen receptor modulators are a racemic mixture comprising breast cancer in a subject; and /or p ) prolonging progression an equal amount of the ( R ) and the ( S ) isomers . It is well free survival of a subject with breast cancer. 25 known in the art how to prepare optically -active forms ( for The compounds of the present invention offer a significant example , by resolution of the racemic form by recrystalli advance over steroidal androgen treatment since treatment zation techniques , by synthesis from optically -active starting of breast cancer with these compounds will not be accom materials , by chiral synthesis , or by chromatographic sepa panied by serious side effects , inconvenientmodes of admin - ration using a chiral stationary phase ). istration , or high costs and still have the advantages of oral 30 The invention includes " pharmaceutically acceptable bioavailability , lack of cross - reactivity with other steroid salts ” of the compounds of this invention , which may be receptors, and long biological half -lives . produced , by reaction of a compound of this invention with In one embodiment, this invention relates to the treatment an acid or base . of androgen receptor- positive breast cancer in a subject. The invention includes pharmaceutically acceptable salts Accordingly , this invention provides methods of: a ) treating 35 of amino -substituted compounds with organic and inorganic a subject suffering from breast cancer ; b ) treating a subject acids , for example , citric acid and hydrochloric acid . The suffering from metastatic breast cancer; c ) treating a subject invention also includes N -oxides of the amino substituents suffering from refractory breast cancer; d ) treating a subject of the compounds described herein . Pharmaceutically suffering from AR -positive breast cancer; e ) treating a acceptable salts can also be prepared from the phenolic subject suffering from AR -positive refractory breast cancer; 40 compounds by treatment with inorganic bases, for example , f ) treating a subject suffering from AR -positive metastatic sodium hydroxide . Also , esters of the phenolic compounds breast cancer ; g ) treating a subject suffering from AR can be made with aliphatic and aromatic carboxylic acids , positive and ER -positive breast cancer; h ) treating a subject for example , acetic acid and benzoic acid esters . suffering from AR -positive breast cancer with or without Suitable pharmaceutically - acceptable salts of the com expression of ER , PR , and / or HER2; i ) treating a subject 45 pounds of Formulae I - XIV may be prepared from an inor suffering from triple negative breast cancer; j ) treating a ganic acid or from an organic acid . In one embodiment, subject suffering from advanced breast cancer ; k ) treating a examples of inorganic salts of the compounds of this inven subject suffering from breast cancer that has failed SERM tion are bisulfates, borates , bromides, chlorides , hemisul ( tamoxifen , toremifene) , aromatase inhibitor, trastuzumab fates , hydrobromates , hydrochlorates , 2 - hydroxyethylsul (Herceptin , ado - trastuzumab emtansine ) , pertuzumab (Per - 50 fonates ( hydroxyethanesulfonates ) , iodates , iodides , jeta ), lapatinib , exemestane (Aromasin ), bevacizumab isothionates , nitrates, persulfates , phosphate , sulfates , sulfa ( Avastin ), and / or fulvestrant treatment; 1) treating a subject mates, sulfanilates, sulfonic acids ( alkylsulfonates, arylsul suffering from ER positive breast cancer ; m ) treating , pre - fonates , halogen substituted alkylsulfonates , halogen substi venting , suppressing or inhibiting metastasis in a subject tuted arylsulfonates ), sulfonates and thiocyanates . suffering from breast cancer; n ) prolonging survival of a 55 In one embodiment, examples of organic salts of the subject with breast cancer ; o ) slowing the progression of compounds of this invention may be selected from aliphatic , breast cancer in a subject; and /or p ) prolonging progression cycloaliphatic , aromatic , araliphatic , heterocyclic , carbox free survival of a subject with breast cancer ; by administer - ylic and sulfonic classes of organic acids , examples of which ing to the subject a therapeutically effective amount of a are acetates, arginines , aspartates, ascorbates , adipates , selective androgen receptormodulator of Formulae I - XIV of 60 anthranilates , algenates, alkane carboxylates, substituted this invention , and /or its analog , derivative , isomer , metabo - alkane carboxylates, alginates, benzenesulfonates, benzo lite , pharmaceutically acceptable salt , pharmaceutical prod - ates, bisulfates , butyrates, bicarbonates , bitartrates, citrates , uct , hydrate , N - oxide, crystal, polymorph , prodrug or any camphorates , camphorsulfonates, cyclohexylsulfamates, combination thereof, as described herein . cyclopentanepropionates, calcium edetates , camsylates , car As defined herein , the term “ isomer " includes , but is not 65 bonates, clavulanates, cinnamates , dicarboxylates, diglucon limited to , optical isomers and analogs , structural isomers ates, dodecylsulfonates, dihydrochlorides, decanoates , and analogs, conformational isomers and analogs, and the enanthuates, ethanesulfonates , edetates , edisylates, esto US 9 ,744 , 149 B2 45 46 lates , esylates, fumarates, formates, fluorides, galacturonates in the subject. In one embodiment, the subject is a female gluconates, glutamates , glycolates , glucorate , glucoheptano subject. In another embodiment, the subject is a male ates, glycerophosphates , gluceptates , glycollylarsanilates, subject . glutarates , glutamate , heptanoates, hexanoates, hydroxy In another embodiment of the present invention , a method maleates , hydroxycarboxlic acids, hexylresorcinates, 5 is provided for treating a subject suffering from metastatic hydroxybenzoates, hydroxynaphthoate , hydrofluorate , lac - breast cancer, comprising the step of administering to the tates , lactobionates , laurates, malates , maleates, methylen subject a selective androgen receptor modulator of Formulae ebis ( beta - oxynaphthoate ) , malonates, mandelates , mesy - I -XIV of this invention and/ or its analog , derivative , isomer , lates , methane sulfonates , methylbromides, methylnitrates, metabolite , pharmaceutically acceptable salt , pharmaceuti methylsulfonates, monopotassium maleates , mucates , 10 cal product, hydrate , N - oxide , crystal, polymorph , prodrug monocarboxylates, nitrates, naphthalenesulfonates , 2 - naph - or any combination thereof, in an amount effective to treat thalenesulfonates , nicotinates , napsylates , N -methylglu - metastatic breast cancer in the subject. In one embodiment, camines , oxalates , octanoates, oleates , pamoates , phenylac - the subject is a female subject. In another embodiment, the etates, picrates, phenylbenzoates, pivalates, propionates, subject is a male subject. phthalates , phenylacetate , pectinates , phenylpropionates , 15 In another embodiment of the present invention , a method palmitates , pantothenates, polygalacturates , pyruvates, qui- is provided for treating a subject suffering from refractory nates, salicylates , succinates, stearates, sulfanilate , subac - breast cancer, comprising the step of administering to the etates, tartrates , theophyllineacetates , p - toluenesulfonates subject a selective androgen receptor modulator of Formulae ( tosylates ), trifluoroacetates, terephthalates, tannates , teo - I -XIV of this invention and/ or its analog , derivative , isomer , clates , trihaloacetates , triethiodide , tricarboxylates, unde - 20 metabolite , pharmaceutically acceptable salt , pharmaceuti canoates and valerates. cal product, hydrate , N -oxide , crystal , polymorph , prodrug In one embodiment, the salts may be formed by conven or any combination thereof , in an amount effective to treat tional means , such as by reacting the free base or free acid refractory breast cancer in the subject. In one embodiment, form of the product with one or more equivalents of the the subject is a female subject. In another embodiment, the appropriate acid or base in a solvent or medium in which the 25 subject is a male subject. salt is insoluble or in a solvent such as water , which is In another embodiment of the present invention , a method removed in vacuo or by freeze drying or by exchanging the is provided for treating a subject suffering from AR - positive ions of a existing salt for another ion or suitable ion - breast cancer , comprising the step of administering to the exchange resin . subject a selective androgen receptor modulator of Formulae This invention further includes derivatives of the selective 30 I- XIV of this invention and /or its analog , derivative , isomer, androgen receptor modulators . The term " derivatives ” metabolite , pharmaceutically acceptable salt , pharmaceuti includes but is not limited to ether derivatives, acid deriva cal product, hydrate , N -oxide , crystal, polymorph , prodrug tives , amide derivatives , ester derivatives and the like . In or any combination thereof , in an amount effective to treat addition , this invention further includes hydrates of the AR -positive breast cancer in the subject . In one embodi selective androgen receptor modulators . The term “ hydrate ” 35 ment, the subject is a female subject. In another embodi includes but is not limited to hemihydrate , monohydrate , ment, the subject is a male subject . dihydrate, trihydrate and the like. In one embodiment, the AR -positive breast cancer is ER , This invention further includes metabolites of the selec - PR and HER2 positive . In another embodiment, the AR tive androgen receptor modulators. The term “ metabolite " positive breast cancer is ER , PR and HER2 negative . In one means any substance produced from another substance by 40 embodiment , the AR - positive breast cancer is ER positive , metabolism or a metabolic process . and PR and HER2 negative . In another embodiment, the This invention further includes pharmaceutical products AR - positive breast cancer is ER and PR positive, and HER2 of the selective androgen receptor modulators. The term negative . In yet another embodiment, the AR - positive breast " pharmaceutical product” means a composition suitable for cancer is ER and HER2 positive, and PR negative . In still pharmaceutical use (pharmaceutical composition ) , as 45 another embodiment, the AR - positive breast cancer is ER defined herein . negative, and PR and HER2 positive. In a further embodi This invention further includes prodrugs of the selective ment, the AR -positive breast cancer is ER and PR negative , androgen receptor modulators . The term " prodrug ” means a and HER2 positive . In still a further embodiment, the substance which can be converted in vivo into a biologically AR -positive breast cancer is ER and HER2 negative , and PR active agent by such reactions as hydrolysis , esterification , 50 positive . In one embodiment, the AR - positive breast cancer de -esterification , activation , salt formation and the like . is ER -negative . In another embodiment, the AR - positive This invention further includes crystals of the selective breast cancer is ER -positive . androgen receptor modulators . Furthermore, this invention in another embodiment of the present invention , a method provides polymorphs of the selective androgen receptor is provided for treating a subject suffering from AR - positive modulators . The term " crystal " means a substance in a 55 refractory breast cancer, comprising the step of administer crystalline state . The term “ polymorph ” refers to a particular ing to the subject a selective androgen receptor modulator of crystalline state of a substance , having particular physical Formulae I- XIV of this invention and /or its analog, deriva properties such as X - ray diffraction , IR spectra , melting tive, isomer , metabolite , pharmaceutically acceptable salt , point, and the like . pharmaceutical product , hydrate , N -oxide , crystal, poly In one embodiment of the present invention , a method is 60 morph , prodrug or any combination thereof, in an amount provided for treating a subject suffering from breast cancer, effective to treat AR - positive refractory breast cancer in the comprising the step of administering to the subject a selec - subject. In one embodiment, the subject is a female subject. tive androgen receptor modulator of Formulae I - XIV of this In another embodiment, the subject is a male subject. invention and / or its analog , derivative , isomer , metabolite , In another embodiment of the present invention , a method pharmaceutically acceptable salt , pharmaceutical product, 65 is provided for treating a subject suffering from AR -positive hydrate , N -oxide , crystal, polymorph , prodrug or any com - metastatic breast cancer, comprising the step of administer bination thereof, in an amount effective to treat breast cancer ing to the subject a selective androgen receptormodulator of US 9 ,744 , 149 B2 47 48 Formulae I -XIV of this invention and / or its analog , deriva In another embodiment of the present invention , a method tive , isomer, metabolite , pharmaceutically acceptable salt , is provided for treating a subject suffering from AR -positive pharmaceutical product, hydrate , N -oxide , crystal, poly and ER -positive breast cancer , comprising the step of morph , prodrug or any combination thereof, in an amount administering to the subject a selective androgen receptor effective to treat AR - positive metastatic breast cancer in the 5 modulator of Formulae I -XIV of this invention and / or its subject . In one embodiment , the subject is a female subjectject. analog , derivative , isomer , metabolite , pharmaceutically In another embodiment, the subject is a male subject . acceptable salt, pharmaceutical product, hydrate , N -oxide , In another embodiment of the present invention , a method crystal, polymorph , prodrug or any combination thereof, in is provided for treating a subject suffering from ER -positive an amount effective to treat AR -positive and ER - positive breast cancer , comprising the step of administering to the refractory breast cancer in the subject . In one embodiment, subject a selective androgen receptor modulator ofFormulae the subject is a female subject. In another embodiment, the I -XIV of this invention and /or its analog , derivative , isomer, subject is a male subject . metabolite , pharmaceutically acceptable salt , pharmaceuti - In another embodiment of the present invention , a method cal product , hydrate , N - oxide , crystal, polymorph , prodrug 15 is provided for treating a subject suffering from AR - positive or any combination thereof, in an amount effective to treat and ER -negative breast cancer, comprising the step of ER -positive breast cancer in the subject. In one embodiment, administering to the subject a selective androgen receptor the subject is a female subject. In another embodiment, the modulator of Formulae I - XIV of this invention and / or its subject is a male subject. analog , derivative , isomer, metabolite , pharmaceutically In another embodiment of the present invention , a method 20 acceptable salt, pharmaceutical product, hydrate , N -oxide , is provided for treating a subject suffering from AR -positive crystal, polymorph , prodrug or any combination thereof, in and ER -positive breast cancer , comprising the step of an amount effective to treat AR - positive and ER - negative administering to the subject a selective androgen receptor metastatic breast cancer in the subject. In one embodiment, modulator of Formulae I - XIV of this invention and / or its the subject is a female subject . In another embodiment, the analog , derivative , isomer, metabolite , pharmaceutically 25 subject is a male subject. acceptable salt, pharmaceutical product, hydrate , N -oxide , In another embodiment of the present invention , a method crystal , polymorph , prodrug or any combination thereof, in is provided for treating a subject suffering from triple an amount effective to treat AR - positive metastatic breast negative breast cancer , comprising the step of administering cancer in the subject. In one embodiment, the subject is a to the subject a selective androgen receptor modulator of female subject. In another embodiment, the subject is a male 30 Formulae I -XIV of this invention and /or its analog , deriva subject . tive , isomer, metabolite , pharmaceutically acceptable salt , In another embodiment of the present invention , a method pharmaceutical product , hydrate , N - oxide , crystal, poly is provided for treating a subject suffering from ER - positive morph , prodrug or any combination thereof, in an amount refractory breast cancer, comprising the step of administer- effective to treat triple negative breast cancer in the subject . ing to the subject a selective androgen receptor modulator of 35 In one embodiment , the subject is a female subject. In Formulae I - XIV of this invention and / or its analog , deriva - another embodiment, the subject is a male subject . tive , isomer , metabolite , pharmaceutically acceptable salt, In another embodiment of the present invention , a method pharmaceutical product, hydrate , N -oxide , crystal, poly - is provided for treating a subject suffering from breast cancer morph , prodrug or any combination thereof, in an amount that has failed SERM ( tamoxifen , toremifene) , aromatase effective to treat ER - positive refractory breast cancer in the 40 inhibitor, trastuzumab (Herceptin , ado -trastuzumab subject . In one embodiment, the subject is a female subject. emtansine ) , pertuzumab ( Perjeta ) , lapatinib , exemestane In another embodiment, the subject is a male subject . ( Aromasin ) , bevacizumab ( Avastin ) , and/ or fulvestrant In another embodiment of the present invention , a method treatments , comprising the step of administering to the is provided for treating a subject suffering from ER - positive subject a selective androgen receptormodulator of Formulae metastatic breast cancer , comprising the step of administer - 45 1 -XIV of this invention and/ or its analog , derivative , isomer , ing to the subject a selective androgen receptor modulator of metabolite , pharmaceutically acceptable salt, pharmaceuti Formulae I -XIV of this invention and / or its analog , deriva cal product , hydrate , N - oxide , crystal, polymorph , prodrug tive , isomer , metabolite , pharmaceutically acceptable salt , or any combination thereof, in an amount effective to treat pharmaceutical product , hydrate , N -oxide , crystal, poly - breast cancer that has failed SERM ( tamoxifen , toremifene ) , morph , prodrug or any combination thereof , in an amount 50 aromatase inhibitor , trastuzumab (Herceptin , ado - trastu effective to treat ER -positive metastatic breast cancer in the zumab emtansine ), pertuzumab (Perjeta ) , lapatinib , exemes subject. In one embodiment, the subject is a female subject . tane (Aromasin ) , bevacizumab (Avastin ) , and / or fulvestrant In another embodiment, the subject is a male subject. treatments in the subject. In one embodiment , the subject is In one embodiment, an ER -positive breast cancer is a female subject . In another embodiment, the subject is a AR - positive . In another embodiment, an ER - positive breast 55 male subject. cancer is AR -negative . In another embodiment of the present invention , a method In another embodiment of the present invention , a method is provided for treating , preventing , suppressing or inhibit is provided for treating a subject suffering from advanced ing metastasis in a subject suffering from breast cancer , breast cancer, comprising the step of administering to the comprising the step of administering to the subject a selec subject a selective androgen receptor modulator of Formulae 60 tive androgen receptor modulator of Formulae I - XIV of this I - XIV of this invention and / or its analog , derivative , isomer , invention and / or its analog , derivative , isomer , metabolite , metabolite , pharmaceutically acceptable salt , pharmaceuti- pharmaceutically acceptable salt , pharmaceutical product , cal product , hydrate , N -oxide , crystal, polymorph , prodrug hydrate , N - oxide , crystal, polymorph , prodrug or any com or any combination thereof, in an amount effective to treat bination thereof, in an amount effective to treat, prevent, advanced breast cancer in the subject. In one embodiment , 65 suppress or inhibit metastasis in the subject. In one embodi the subject is a female subject. In another embodiment, the ment, the subject is a female subject. In another embodi subject is a male subject . ment, the subject is a male subject. US 9 ,744 , 149 B2 49 50 In another embodiment of the present invention , a method lamido , nitro , amino , alkylamino , dialkylamino , carboxy or is provided for treating and /or preventing skeletal related thio or thioalkyl. Nonlimiting examples of aryl rings are events in a subject suffering , comprising the step of admin - phenyl , naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl , istering to the subject a selective androgen receptor modu - pyrazolyl, pyridinyl, furanyl, thiophenyl , thiazolyl, imida lator of Formulae I -XIV of this invention and / or its analog , 5 zolyl , isoxazolyl, and the like . derivative , isomer, metabolite , pharmaceutically acceptable A “ hydroxyl ” group refers to an OH group . An “ alkenyl” salt, pharmaceutical product, hydrate , N - oxide , crystal , group refers to a group having at least one carbon to carbon polymorph , prodrug or any combination thereof, in an double bond . A halo group refers to F , C1, Br or 1 . amount effective to treat and / or prevent skeletal related events in the subject . In one embodiment, the subject is a 10 An “ arylalkyl” group refers to an alkyl bound to an aryl, female subject . In another embodiment , the subject is a male wherein alkyl and aryl are as defined above. An example of subject. an aralkyl group is a benzyl group . In another embodiment of the present invention , a method Biological Activity of Selective Androgen Receptor Modu is provided for improving libido in a subject , comprising the lators step of administering to the subject a selective androgen 15 The selective androgen receptor modulators provided receptor modulator of Formulae 1- XIV of this invention herein are a new class of compounds, which suppress growth and / or its analog , derivative , isomer , metabolite , pharma - ofAR - positive breast cancers . The compounds of this inven ceutically acceptable salt , pharmaceutical product, hydrate , tion have a tissue -selective myoanabolic activity profile of a N -oxide , crystal, polymorph , prodrug or any combination nonsteroidal ligand for the androgen receptor. Furthermore thereof, in an amount effective to improve libido in the 20 compounds of the present invention are non -aromatizable , subject . In one embodiment, the subject is a female subject. non - virilizing, and are not commonly cross -reactive with ER In another embodiment, the subject is a male subject . and PR . In addition , in one embodiment, the selective In another embodiment of the present invention , a method androgen receptor modulators (SARMs ) of the present is provided for improving quality of life in a subject, invention are beneficial to refractory breast cancer patients comprising the step of administering to the subject a selec - 25 undergoing chemotherapy due to anabolism . tive androgen receptor modulator of Formulae I -XIV of this As contemplated herein , the appropriately substituted invention and/ or its analog , derivative , isomer, metabolite , selective androgen receptor modulators of the present inven pharmaceutically acceptable salt, pharmaceutical product t ion are useful for : a ) treating a subject suffering from breast hydrate , N - oxide , crystal , polymorph , prodrug or any com - cancer; b ) treating a subject suffering from metastatic breast bination thereof, in an amount effective to quality of life in 30 cancer; c ) treating a subject suffering from refractory breast the subject . In one embodiment , the subject is a female cancer ; d ) treating a subject suffering from AR -positive subject . In another embodiment, the subject is a male breast cancer ; e ) treating a subject suffering from AR subject. positive refractory breast cancer; f ) treating a subject suf In another embodiment of the present invention , a method fering from AR -positive metastatic breast cancer ; g ) treating is provided for treating , preventing , suppressing or inhibit - 35 a subject suffering from AR - positive and ER - positive breast ing metastasis in a subject suffering from breast cancer, cancer; h ) treating a subject suffering from AR -positive comprising the step of administering to the subject a selec - breast cancer with or without expression of ER , PR , and /or tive androgen receptor modulator of Formulae I - XIV of this HER2 ; i ) treating a subject suffering from triple negative invention and / or its analog , derivative , isomer, metabolite , breast cancer ; j ) treating a subject suffering from advanced pharmaceutically acceptable salt, pharmaceutical product , 40 breast cancer ; k ) treating a subject suffering from breast hydrate , N -oxide , crystal , polymorph , prodrug or any com cancer that has failed SERM ( tamoxifen , toremifene ), aro bination thereof, in an amount effective to treat, prevent, matase inhibitor , trastuzumab (Herceptin , ado - trastuzumab suppress or inhibit metastasis in the subject. In one embodi - emtansine ) , pertuzumab (Perjeta ), lapatinib , exemestane ment, the subject is a female subject . In another embodi- ( Aromasin ), bevacizumab ( Avastin ) , and / or fulvestrant ment, the subject is a male subject. 45 treatments ; 1) treating a subject suffering from ER positive The substituent R is defined herein as an alkyl, haloalkyl , breast cancer; m ) treating , preventing , suppressing or inhib dihaloalkyl, trihaloalkyl , CH F , CHF2 , CF3, CF2CFz; aryl, iting metastasis in a subject suffering from breast cancer; n ) phenyl, halogen , alkenyl, or hydroxyl (OH ) . prolonging survival of a subject with breast cancer ; o ) An “ alkyl” group refers to a saturated aliphatic hydrocar - slowing the progression of breast cancer in a subject; and /or bon , including straight - chain , branched - chain and cyclic 50 p ) prolonging progression - free survival of a subject with alkyl groups. In one embodiment, the alkyl group has 1 - 12 breast cancer. carbons . In another embodiment, the alkyl group has 1 - 7 In one embodiment, a " refractory breast cancer " is a carbons . In another embodiment, the alkyl group has 1 - 6 breast cancer that has not responded to treatment. In another carbons . In another embodiment, the alkyl group has 1 - 4 embodiment, a " refractory breast cancer” is a breast cancer carbons . The alkyl group may be unsubstituted or substituted 55 resistant to treatment. In one embodiment , refractory breast by one or more groups selected from halogen , hydroxy , cancer is refractory metastatic breast cancer . In one embodi alkoxy carbonyl, amido , alkylamido , dialkylamido , nitro , ment, refractory breast cancer has not responded to treat amino , alkylamino , dialkylamino , carboxyl, thio and thio - ment with anthracyclines , taxanes , capecitabine , ixabepi alkyl. lone , SERM ( tamoxifen , toremifene ), aromatase inhibitor, A “ haloalkyl" group refers to an alkyl group as defined 60 trastuzumab (Herceptin , ado - trastuzumab emtansine ), per above , which is substituted by one or more halogen atoms, tuzumab (Perjeta ), lapatinib , exemestane ( Aromasin ) , beva e . g . by F , C1, Br or I . cizumab ( Avastin ) , fulvestrant or any combination thereof. An “ aryl" group refers to an aromatic group having at In one embodiment, a “ triple negative breast cancer " is least one carbocyclic aromatic group or heterocyclic aro - defined by lack of expression of estrogen , progesterone , and matic group , which may be unsubstituted or substituted by 65 ErbB2 (also known as human epidermal growth factor one or more groups selected from halogen , haloalkyl, receptor 2 (HER2 ) ) receptors . This subgroup accounts for hydroxy, alkoxycarbonyl, amido, alkylamido, dialky - 15 % of all types of breast cancer. This subtype of breast US 9 ,744 , 149 B2 51 52 cancer is clinically characterized as more aggressive and less the binding site more frequently . Once bound , signals may responsive to standard treatment and associated with poorer be sent through the receptor into the cells , causing the cell overall patient prognosis . to respond in some fashion . This is called activation . On In one embodiment, the methods of this invention are activation , the activated receptor then directly regulates the directed to treating a subject suffering from AR - positive 5 transcription of specific genes . But the substance and the breast cancer , regardless of grade , stage or prior treatments . receptor may have certain attributes , other than affinity , in In one embodiment, the methods of this invention are order to activate the cell . Chemical bonds between atoms of first, second , third , or fourth line therapies for breast cancer . the substance and the atoms of the receptors may form . In A first line therapy refers to a medical therapy recommended some cases , this leads to a change in the configuration of the for the initial treatment of a disease , sign or symptom . A 10 receptor, which is enough to begin the activation process second line therapy is given when initial treatment ( first -line (called signal transduction ) . therapy ) does not work , or stops working . Third line therapy In one embodiment, the compounds of this invention is given when both initial treatment ( first- line therapy ) and inhibit the intratumoral expression of genes and pathways subsequent treatment ( second - line therapy ) does not work , that promote breast cancer development through their or stop working , etc . 15 actions on the AR . In one embodiment, a compound of this As used herein , “ kinases ” are a group of enzymes that invention inhibits intratumoral expression of Muc1 , SLUG , catalyze the transfer of a phosphate group from a donor, such VCAMI, SPARC or MMP2 , or any combination thereof. In as ADP or ATP, to an acceptor. In one embodiment, phos - another embodiment, Formula VIII inhibits gene expression phorylation results in a functional change of the target that promotes breast cancer. protein ( substrate ) by changing enzyme activity , cellular 20 In one embodiment, a receptor antagonist is a substance location , or association with other protein kinases . Kinases which binds receptors and inactivates them . In one embodi regulate the majority of cellular pathways , especially those ment, a selective androgen receptor modulator is a molecule involved in signal transduction . In one embodiment, deregu - that exhibits in vivo tissue selectivity , activating signaling lated kinase activity is a frequent cause of disease , in activity of the androgen receptor (AR ) in anabolic (muscle , particular cancer , wherein kinases regulate many aspects 25 bone, etc . ) tissues to a greater extent than in the androgenic that control cell growth , movement and death . In one tissues . Thus, in one embodiment, the selective androgen embodiment , drugs that inhibit specific kinases are used to receptor modulators of the present invention are useful in treat kinase -related diseases , including cancer. In one binding to and activating steroidal hormone receptors . In embodiment, HER2 positive breast cancers are susceptible one embodiment , the SARM compound of the present to HER2 kinase inhibitors ( e . g ., trastuzumab and lapatinib ) 30 invention is an agonist which binds the androgen receptor. In and are generally used in metastatic disease . However , some another embodiment, the compound has high affinity for the breast cancers are refractory to HER2 kinase inhibitor androgen receptor. treatment. Assays to determine whether the compounds of the pres As used herein , receptors for extracellular signaling mol- ent invention are AR agonists or antagonists are well known ecules are collectively referred to as " cell signaling recep - 35 to a person skilled in the art. For example , AR agonistic tors ” . Many cell signaling receptors are transmembrane activity can be determined by monitoring the ability of the proteins on a cell surface ; when they bind an extracellular selective androgen receptor modulators to maintain and / or signaling molecule ( i . e . , a ligand ) , they become activated so stimulate the growth of AR containing androgenic tissue as to generate a cascade of intracellular signals that alter the such as prostate and seminal vesicles, as measured by behavior of the cell . In contrast , in some cases , the receptors 40 weight, in castrated animals . AR antagonistic activity can be are inside the cell and the signaling ligand has to enter the determined by monitoring the ability of the selective andro cell to activate them ; these signaling molecules therefore gen receptor modulators to inhibit the growth of AR con must be sufficiently small and hydrophobic to diffuse across taining tissue in intact animals or counter the effects of the plasma membrane of the cell. testosterone in castrated animals . Steroid hormones are one example of small hydrophobic 45 An androgen receptor (AR ) is an androgen receptor of any molecules that diffuse directly across the plasma membrane species , for example a mammal . In one embodiment, the of target cells and bind to intracellular cell signaling recep - androgen receptor is an androgen receptor of a human . Thus, tors . These receptors are structurally related and constitute in another embodiment, the selective androgen receptor the intracellular receptor superfamily ( or steroid -hormone modulators bind reversibly to an androgen receptor of a receptor superfamily ) Steroid hormone receptors include but 50 human . In another embodiment , the selective androgen are not limited to progesterone receptors, estrogen receptors, receptormodulators bind reversibly to an androgen receptor androgen receptors , glucocorticoid receptors , and mineralo - of a mammal. corticoid receptors . In one embodiment, the present inven - As contemplated herein , the term “ selective androgen tion is directed to androgen receptors . In one embodiment , receptor modulator” (SARM ) refers to , in one embodiment, the present invention is directed to androgen receptor ago - 55 a molecule that exhibits in vivo tissue selectivity , activating nists . In one embodiment, the present invention is directed signaling activity of the Androgen Receptor in anabolic to progesterone receptors. In one embodiment, the present (muscle , bone , etc .) tissues to a greater extent than in the invention is directed to progesterone receptor antagonists . androgenic tissues . In another embodiment , a selective In addition to ligand binding to the receptors , the recep - androgen receptor modulator selectively binds the androgen tors can be blocked to prevent ligand binding . When a 60 receptor. In another embodiment, a selective androgen substance binds to a receptor, the three - dimensional struc - receptor modulator selectively affects signaling through the ture of the substance fits into a space created by the androgen receptor. In one embodiment, the SARM is a three -dimensional structure of the receptor in a ball and partial agonist . In one embodiment, the SARM is a tissue socket configuration . The better the ball fits into the socket, selective agonist, or in some embodiments , a tissue- selective the more tightly it is held . This phenomenon is called 65 antagonist. affinity . If the affinity of a substance is greater than the In one embodiment, a SARM of this invention exerts its original hormone , it will compete with the hormone and bind effects on the androgen receptor in a tissue- dependent man US 9 ,744 , 149 B2 53 54 ner . In one embodiment, a SARM of this invention will have As used herein , the term “ administering ” refers to bring an IC50 or EC50 with respect to AR , as determined using AR ing a subject in contact with a compound of the present transactivation assays , as known in the art , or , in other invention . As used herein , administration can be accom embodiments , as described herein . plished in vitro , i . e . in a test tube, or in vivo , i . e . in cells or The term “ IC ” refers , in some embodiments , to a 5 tissues of living organisms, for example humans . In one concentration of the SARM which reduces the activity of a embodiment, the present invention encompasses adminis tering the compounds of the present invention to a subject. target (e . g ., AR ) to half -maximal level . In one embodiment, a compound of the present invention The term “ EC50 ” refers , in some embodiments , to a is administered to a subject once a week . In another embodi concentration of the SARM that produces a half -maximal 10 ment, a compound of the present invention is administered effect. to a subject twice a week . In another embodiment, a com For example , utilizing transactivation assays , FIG . 5 pound of the present invention is administered to a subject shows that compounds of this invention exhibit AR agonist three times a week . In another embodiment, a compound of activity in MDA -MB - 231 cells transfected with AR . the present invention is administered to a subject four times As defined herein , " contacting " means that the selective 15 a week . In another embodiment, a compound of the present androgen receptor modulators of the present invention are invention is administered to a subject five times a week . In introduced into a sample containing the receptor in a test another embodiment , a compound of the present invention is tube , flask , tissue culture , chip , array, plate , microplate , administered to a subject daily . In another embodiment, a capillary , or the like, and incubated at a temperature and time compound of the present invention is administered to a sufficient to permit binding of the selective androgen recep - 20 subject weekly . In another embodiment, a compound of the tor modulators to the receptor. Methods for contacting the present invention is administered to a subject bi -weekly . In samples with the selective androgen receptor modulators or another embodiment, a compound of the present invention is other specific binding components are known to those administered to a subject monthly . skilled in the art and may be selected depending on the type In one embodiment, the methods of the present invention of assay protocol to be run . Incubation methods are also 25 comprise administering a selective androgen receptor modu standard and are known to those skilled in the art . lator as the sole active ingredient. However , also encom In another embodiment, the term " contacting ” means that passed within the scope of the present invention are methods the selective androgen receptor modulators of the present for hormone therapy , for treating breast cancer, for delaying invention are introduced into a subject receiving treatment, the progression of breast cancer , and for preventing and and the selective androgen receptor modulator is allowed to 30 treating the recurrence of breast cancer and / or breast cancer come in contact with the androgen receptor in vivo . metastasis , which comprise administering the selective As used herein , the term “ treating ” includes preventative androgen receptor modulators in combination with one or as well as disorder remitative treatment. As used herein , the more therapeutic agents. These agents include , but are not terms “ reducing ” , “ suppressing ” and “ inhibiting” have their limited to : selective estrogen receptor modulators (SERM ) , commonly understood meaning of lessening or decreasing . 35 selective estrogen receptor degraders ( fulvestrant) , HER2 As used herein , the term “ progression ” means increasing in inhibitors ( lapatinib , trastuzumab ) , bevacizumab , chemo scope or severity , advancing, growing or becoming worse . therapeutic agents , taxanes, anthracyclines , epothilones , As used herein , the term “ recurrence ” means the return of a LHRH analogs , reversible antiandrogens , antiestrogens, disease after a remission . As used herein , the term " delay - anticancer drugs , 5 -alpha reductase inhibitors, aromatase ing ” means stopping , hindering , slowing down , postponing , 40 inhibitors ( exemestane , anastrozole , letrozole , vorozole , holding up or setting back . As used herein , the term “metas formestane, fadrozole ) , progestins, agents acting through tasis ” refers to the transfer of a disease from one organ or other nuclear hormone receptors such as progesterone and part thereof to another not directly connected with it . Metas - estrogen receptors , estrogens , progestins , PDE5 inhibitors , tasis can occur for example as a result of transfer of apomorphine , bisphosphonate , growth factor inhibitors malignant cells from one organ ( for example breast ) to other 45 ( such as those that inhibit VEGF , IGF and the like ) , or one organs. or more additional selective androgen receptor modulators In one embodiment, “ treating” refers to reducing tumor (SARMs ) . growth by 75 % , as demonstrated in Example 8 . In another Additional therapeutic agents thatmay be administered in embodiment, treating refers to reducing tumor growth by at combination with a selective androgen receptor modulator least 75 % . In another embodiment , treating refers to reduc - 50 compound of this invention include , but are not limited to : ing tumor growth by at least 50 % . In another embodiment, Abitrexate ( R ) (methotrexate ) , Abraxane (paclitaxel albu treating refers to reducing tumor growth by at least 25 % . In min -stabilized nanoparticle formulation ), ado - trastuzumab another embodiment, treating refers to reducing tumor emtansine , adriamycin PFS (doxorubicin hydrochloride ), growth by 50 - 100 % . In another embodiment, treating refers adriamycin RDF (doxorubicin hydrochloride ), Adrucil to reducing tumor growth by 70 - 80 % . In another embodi - 55 ( fluorouracil) , Afinitor ( everolimus) , anastrozole , Arimidex ment, treating refers to reducing tumor growth by 25 - 125 % . ( anastrozole ) , Aromasin (exemestane ) , capecitabine , Clafen In another embodiment , " treating ” refers to reducing (cyclophosphamide ) , cyclophosphamide , Cytoxan (cyclo tumor weight by 50 % , as demonstrated in Example 8 . In phosphamide ) , docetaxel, doxorubicin hydrochloride , Efu another embodiment, treating refers to reducing tumor dex ( fluorouracil ) , Ellence ( epirubicin hydrochloride ) , epi weight by at least 50 % . In another embodiment, treating 60 rubicin hydrochloride , everolimus, exemestane , Fareston refers to reducing tumor weight by at least 40 % . In another ( toremifene ) , Faslodex ( fulvestrant) , Femara ( letrozole ) , embodiment, treating refers to reducing tumor weight by at Fluoroplex ( fluorouracil) , fluorouracil, Folex (methotrex least 30 % . In another embodiment, treating refers to reduc ate ), Folex PFS (methotrexate ), fulvestrant, gemcitabine ing tumor weight by at least 20 % . In another embodiment , hydrochloride , Gemzar ( gemcitabine hydrochloride ) , Her treating refers to reducing tumor growth by 25 - 75 % . In 65 ceptin ( trastuzumab ), ixabepilone, Ixempra (ixabepilone ), another embodiment, treating refers to reducing tumor lapatinib ditosylate , letrozole , methotrexate , methotrexate growth by 25 - 100 % . LPF (methotrexate ), Mexate (methotrexate ), Mexate -AQ US 9 ,744 , 149 B2 55 56 (methotrexate ) , Neosar ( cyclophosphamide ), Nolvadex ( ta - methods of the present invention comprise administering a moxifen citrate ) , paclitaxel, paclitaxel albumin - stabilized selective androgen receptor modulator of this invention , in nanoparticle formulation , Perjeta ( pertuzumab ) , pertu - combination with a bisphosphonate . In another embodiment, zumab , tamoxifen citrate , Taxol ( paclitaxel) , Taxotere (doc - the methods of the present invention comprise administering etaxel) , trastuzumab , toremifene , Tykerb ( lapatinib ditosy - 5 a selective androgen receptor modulator of this invention , in late ), Xeloda ( capecitabine) . combination with a growth factor inhibitor. In another Thus, in one embodiment , the methods of the present embodiment, the methods of the present invention comprise invention comprise administering the selective androgen administering a selective androgen receptor modulator of receptor modulator, in combination with a selective estrogen this invention , in combination with one or more additional receptor modulator. Thus, in one embodiment, the methods 10 selective androgen receptor modulators (SARMs ) . of the present invention comprise administering the selective In another embodiment , the methods of the present inven androgen receptor modulator, in combination with a selec t ion comprise administering a selective androgen receptor tive estrogen receptor degrader ( fulvestrant) . Thus , in one modulator of this invention , in combination with Abitrexate embodiment , the methods of the present invention comprise (methotrexate ) . In another embodiment, the methods of the administering the selective androgen receptor modulator, in 15 present invention comprise administering a selective andro combination with a HER2 inhibitor ( lapatinib , trastuzumab ) . gen receptor modulator of this invention , in combination Thus, in one embodiment , the methods of the present with Abraxane (paclitaxel albumin -stabilized nanoparticle invention comprise administering the selective androgen formulation ) . In another embodiment, the methods of the receptor modulator, in combination with a VEGF - A inhibi present invention comprise administering a selective andro tor (bevacizumab ) . Thus , in one embodiment , the methods 20 gen receptor modulator of this invention , in combination of the present invention comprise administering the selective with ado - trastuzumab emtansine . In another embodiment, androgen receptor modulator, in combination with a che the methods of the present invention comprise administering motherapeutic agent. In one embodiment , the chemothera - a selective androgen receptor modulator of this invention , in peutic agent is a taxane . In another embodiment, the che combination with Adriamycin PFS ( doxorubicin hydrochlo motherapeutic agent is an anthracycline . In one 25 ride ) . In another embodiment , the methods of the present embodiment, the chemotherapeutic agent is an epothilone invention comprise administering a selective androgen ( ixabepilone ) . Thus , in one embodiment, the methods of the receptor modulator of this invention , in combination with present invention comprise administering the selective Adriamycin RDF ( doxorubicin hydrochloride ) . In another androgen receptor modulator, in combination with an LHRH embodiment, the methods of the present invention comprise analog . In another embodiment, the methods of the present 30 administering a selective androgen receptor modulator of invention comprise administering a selective androgen this invention , in combination with Adrucil ( fluorouracil ) . In receptor modulator, in combination with a reversible anti - another embodiment, the methods of the present invention androgen . In another embodiment, the methods of the pres - comprise administering a selective androgen receptor modu ent invention comprise administering a selective androgen lator of this invention , in combination with Afinitor (everoli receptor modulator, in combination with an antiestrogen . In 35 mus ) . In another embodiment, the methods of the present another embodiment , the methods of the present invention invention comprise administering a selective androgen comprise administering a selective androgen receptor modu - receptor modulator of this invention , in combination with lator, in combination with an anticancer drug . In another anastrozole . In another embodiment, the methods of the embodiment, the methods of the present invention comprise present invention comprise administering a selective andro administering a selective androgen receptor modulator , in 40 gen receptor modulator of this invention , in combination combination with a 5 -alpha reductase inhibitor. In another with Arimidex (anastrozole ) . In another embodiment, the embodiment, the methods of the present invention comprise methods of the present invention comprise administering a administering a selective androgen receptor modulator of selective androgen receptor modulator of this invention , in this invention , in combination with an aromatase inhibitor. combination with Aromasin ( exemestane ) . In another In another embodiment, the methods of the present inven - 45 embodiment, the methods of the present invention comprise tion comprise administering a selective androgen receptor administering a selective androgen receptor modulator of modulator of this invention , in combination with a progestin . this invention , in combination with capecitabine. In another In another embodiment, the methods of the present inven - embodiment, the methods of the present invention comprise tion comprise administering a selective androgen receptor administering a selective androgen receptor modulator of modulator of this invention , in combination with an agent 50 this invention , in combination with Clafen ( cyclophosph acting through other nuclear hormone receptors . In another amide) . In another embodiment , the methods of the present embodiment, the methods of the present invention comprise invention comprise administering a selective androgen administering a selective androgen receptor modulator of receptor modulator of this invention , in combination with this invention , in combination with a selective estrogen cyclophosphamide . In another embodiment, the methods of receptor modulators (SERM ) . In another embodiment, the 55 the present invention comprise administering a selective methods of the present invention comprise administering a androgen receptor modulator of this invention , in combina selective androgen receptor modulator of this invention , in tion with Cytoxan ( cyclophosphamide ) . In another embodi combination with a progestin or anti- progestin . In another ment , the methods of the present invention comprise admin embodiment, the methods of the present invention comprise istering a selective androgen receptor modulator of this administering a selective androgen receptor modulator, in 60 invention , in combination with docetaxel. In another combination with an estrogen . In another embodiment, the embodiment, the methods of the present invention comprise methods of the present invention comprise administering a administering a selective androgen receptor modulator of selective androgen receptor modulator of this invention , in this invention , in combination with doxorubicin hydrochlo combination with a PDE5 inhibitor. In another embodiment, ride . In another embodiment, the methods of the present the methods of the present invention comprise administering 65 invention comprise administering a selective androgen a selective androgen receptor modulator of this invention , in receptor modulator of this invention , in combination with combination with apomorphine . In another embodiment, the Efudex ( fluorouracil ) . In another embodiment, the methods US 9 ,744 , 149 B2 57 58 of the present invention comprise administering a selective embodiment, the methods of the present invention comprise androgen receptor modulator of this invention , in combina - administering a selective androgen receptor modulator of tion with Ellence ( epirubicin hydrochloride ). In another this invention , in combination with Mexate (methotrexate ) . embodiment, the methods of the present invention comprise In another embodiment, the methods of the present inven administering a selective androgen receptor modulator of 5 tion comprise administering a selective androgen receptor this invention , in combination with epirubicin hydrochlo - modulator of this invention , in combination with Mexate ride . In another embodiment, the methods of the present AQ (methotrexate ). In another embodiment, the methods of invention comprise administering a selective androgen the present invention comprise administering a selective receptor modulator of this invention , in combination with androgen receptor modulator of this invention , in combina everolimus . In another embodiment, the methods of the 10 tion with Neosar ( cyclophosphamide ) . In another embodi present invention comprise administering a selective andro - ment, the methods of the present invention comprise admin gen receptor modulator of this invention , in combination istering a selective androgen receptor modulator of this with exemestane . In another embodiment, the methods of invention , in combination with Nolvadex tamoxifen cit the present invention comprise administering a selective rate ) . In another embodiment, the methods of the present androgen receptor modulator of this invention , in combina - 15 invention comprise administering a selective androgen tion with Fareston ( toremifene ). In another embodiment, the receptor modulator of this invention , in combination with methods of the present invention comprise administering a paclitaxel . In another embodiment, the methods of the selective androgen receptor modulator of this invention , in present invention comprise administering a selective andro combination with Faslodex ( fulvestrant ). In another embodi gen receptor modulator of this invention , in combination ment, the methods of the present invention comprise admin - 20 with paclitaxel albumin - stabilized nanoparticle formulation . istering a selective androgen receptor modulator of this In another embodiment, the methods of the present inven invention , in combination with Femara ( letrozole ) . In tion comprise administering a selective androgen receptor another embodiment, the methods of the present invention modulator of this invention , in combination with Perjeta comprise administering a selective androgen receptor modu (pertuzumab ) . In another embodiment, the methods of the lator of this invention , in combination with Fluoroplex 25 present invention comprise administering a selective andro ( fluorouracil) . In another embodiment , the methods of the gen receptor modulator of this invention , in combination present invention comprise administering a selective andro - with pertuzumab . In another embodiment, the methods of gen receptor modulator of this invention , in combination the present invention comprise administering a selective with fluorouracil . In another embodiment, the methods of androgen receptor modulator of this invention , in combina the present invention comprise administering a selective 30 tion with tamoxifen citrate . In another embodiment, the androgen receptor modulator of this invention , in combina methods of the present invention comprise administering a tion with Folex (methotrexate ) . In another embodiment, the selective androgen receptor modulator of this invention , in methods of the present invention comprise administering a combination with Taxol (paclitaxel ) . In another embodi selective androgen receptor modulator of this invention , in ment, the methods of the present invention comprise admin combination with Folex PFS (methotrexate ) . In another 35 istering a selective androgen receptor modulator of this embodiment , the methods of the present invention comprise invention , in combination with Taxotere ( docetaxel) . In administering a selective androgen receptor modulator of another embodiment , the methods of the present invention this invention , in combination with fulvestrant . In another comprise administering a selective androgen receptor modu embodiment, the methods of the present invention comprise lator of this invention , in combination with trastuzumab . In administering a selective androgen receptor modulator of 40 another embodiment , the methods of the present invention this invention , in combination with gemcitabine hydrochlo - comprise administering a selective androgen receptor modu ride. In another embodiment, the methods of the present lator of this invention , in combination with toremifene. In invention comprise administering a selective androgen another embodiment , the methods of the present invention receptor modulator of this invention , in combination with comprise administering a selective androgen receptor modu Gemzar ( gemcitabine hydrochloride ). In another embodi- 45 lator of this invention , in combination with Tykerb (lapatinib ment, the methods of the present invention comprise admin - ditosylate ) . In another embodiment, the methods of the istering a selective androgen receptor modulator of this present invention comprise administering a selective andro invention , in combination with Herceptin (trastuzumab ) . In gen receptor modulator of this invention , in combination another embodiment, the methods of the present invention with Xeloda ( capecitabine ). comprise administering a selective androgen receptor modu - 50 In one embodiment , the methods of the present invention lator of this invention , in combination with ixabepilone . In comprise administering a pharmaceutical composition ( or another embodiment, the methods of the present invention pharmaceutical preparation , used herein interchangeably ) comprise administering a selective androgen receptor modu - comprising the selective androgen receptor modulator of the lator of this invention , in combination with Ixempra (ix present invention and /or its analog , derivative, isomer , abepilone ) . In another embodiment , the methods of the 55 metabolite , pharmaceutical product, hydrate, N - oxide , poly present invention comprise administering a selective andro - morph , crystal, prodrug or any combination thereof, and a gen receptor modulator of this invention , in combination suitable carrier or diluent. with lapatinib ditosylate . In another embodiment, the meth - Pharmaceutical Compositions : ods of the present invention comprise administering a selec - As used herein , " pharmaceutical composition " means tive androgen receptor modulator of this invention , in com - 60 therapeutically effective amounts of the selective androgen bination with letrozole . In another embodiment, the methods receptor modulator together with suitable diluents , preser of the present invention comprise administering a selective vatives , solubilizers , emulsifiers , adjuvant and / or carriers . A androgen receptor modulator of this invention , in combina - " therapeutically effective amount” as used herein refers to tion with methotrexate . In another embodiment, themethods that amount which provides a therapeutic effect for a given of the present invention comprise administering a selective 65 condition and administration regimen . Such compositions androgen receptor modulator of this invention , in combina are liquids or lyophilized or otherwise dried formulations tion with methotrexate LPF (methotrexate ). In another and include diluents of various buffer content (e .g ., Tris US 9 ,744 , 149 B2 59 60 HCI. , acetate , phosphate ) , pH and ionic strength , additives Parenteral vehicles include sodium chloride solution , such as albumin or gelatin to prevent absorption to surfaces , Ringer ' s dextrose , dextrose and sodium chloride , lactated detergents ( e . g . , Tween 20 , Tween 80 , Pluronic F68 , bile Ringer ' s and fixed oils . Intravenous vehicles include fluid acid salts ), solubilizing agents ( e . g . , glycerol, polyethylene and nutrient replenishers, electrolyte replenishers such as glycerol ) , anti -oxidants ( e . g . , ascorbic acid , sodium meta - 5 those based on Ringer ' s dextrose , and the like. Preservatives bisulfite ) , preservatives ( e . g . , Thimerosal, benzyl alcohol, and other additives may also be present, such as , for parabens) , bulking substances or tonicity modifiers ( e . g ., example , antimicrobials , antioxidants , collating agents, inert lactose , mannitol ) , covalent attachment of polymers such as gases and the like . polyethylene glycol to the protein , complexation with metal Controlled or sustained release compositions include for ions, or incorporation of the material into or onto particulate 10 mulation in lipophilic depots ( e. g . fatty acids, waxes, oils ). preparations of polymeric compounds such as polylactic Also comprehended by the invention are particulate com acid , polyglycolic acid , hydrogels , etc , or onto liposomes, positions coated with polymers ( e . g . poloxamers or polox microemulsions , micelles, unilamellar or multilamellar amines ) and the compound coupled to antibodies directed vesicles , erythrocyte ghosts , or spheroplasts ) . Such compo against tissue - specific receptors , ligands or antigens or sitions will influence the physical state , solubility, stability , 15 coupled to ligands of tissue -specific receptors. rate of in vivo release , and rate of in vivo clearance . Other embodiments of the compositions of the invention Controlled or sustained release compositions include for- incorporate particulate forms, protective coatings, protease mulation in lipophilic depots ( e. g ., fatty acids , waxes , oils ). inhibitors or permeation enhancers for various routes of In one embodiment, the pharmaceutical compositions administration , including parenteral, pulmonary , nasal and comprising the compounds of this invention make use in the 20 oral . methods of this invention of a dosage of between 1 and 50 Compounds modified by the covalent attachment of mg of a compound of this invention . In another embodiment , water -soluble polymers such as polyethylene glycol, copo the dosage is 1 mg, 3 mg, 9 mg, 10 mg, 18 mg or 30 mg of lymers of polyethylene glycol and polypropylene glycol, the compound of this invention . In another embodiment, the carboxymethyl cellulose , dextran , polyvinyl alcohol, poly pharmaceutical compositions comprising the compounds of 25 vinylpyrrolidone or polyproline are known to exhibit sub this invention make use in the methods of this invention of stantially longer half- lives in blood following intravenous a dosage of 1 mg of a compound of this invention . In another injection than do the corresponding unmodified compounds embodiment, the pharmaceutical compositions comprising ( Abuchowski et al. , 1981; Newmark et al. , 1982; and Katre the compounds of this invention make use in the methods of et al. , 1987 ) . Such modifications may also increase the this invention of a dosage of 3 mg of a compound of this 30 compound ' s solubility in aqueous solution , eliminate aggre invention . In another embodiment, the pharmaceutical com - gation , enhance the physical and chemical stability of the positions comprising the compounds of this invention make compound , and greatly reduce the immunogenicity and use in the methods of this invention of a dosage of 9 mg of reactivity of the compound . As a result , the desired in vivo a compound of this invention . In another embodiment, the biological activity may be achieved by the administration of pharmaceutical compositions comprising the compounds of 35 such polymer - compound abducts less frequently or in lower this invention make use in the methods of this invention of doses than with the unmodified compound . a dosage of 10 mg of a compound of this invention . In In yet another embodiment , the pharmaceutical compo another embodiment, the pharmaceutical compositions com - sition can be delivered in a controlled release system . For prising the compounds of this invention make use in the example , the agent may be administered using intravenous methods of this invention of a dosage of 18 mg of a 40 infusion , an implantable osmotic pump , a transdermal patch , compound of this invention . In another embodiment, the liposomes , or other modes of administration . In one embodi pharmaceutical compositions comprising the compounds of ment , a pump may be used ( see Langer , supra ; Sefton , CRC this invention make use in the methods of this invention of Crit. Ref . Biomed . Eng . 14 : 201 ( 1987 ); Buchwald et al ., a dosage of 30 mg of a compound of this invention . Surgery 88 : 507 ( 1980 ) ; Saudek et al. , N . Engl. J . Med . Also comprehended by the invention are particulate com - 45 321 : 574 ( 1989 ) . In another embodiment , polymeric materi positions coated with polymers ( e . g . , poloxamers or polox - als can be used . In yet another embodiment, a controlled amines ) . Other embodiments of the compositions of the release system can be placed in proximity to the therapeutic invention incorporate particulate forms protective coatings , target , i . e . , the brain , thus requiring only a fraction of the protease inhibitors or permeation enhancers for various systemic dose ( see, e . g ., Goodson , in Medical Applications routes of administration , including parenteral , pulmonary , 50 of Controlled Release , supra , vol. 2 , pp . 115 - 138 ( 1984 ) . nasal and oral. In one embodiment the pharmaceutical Other controlled release systems are discussed in the review composition is administered parenterally , paracancerally , by Langer (Science 249 : 1527 - 1533 ( 1990 ) . transmucosally , transdermally, intramuscularly , intrave The pharmaceutical preparation can comprise the selec nously , intradermally , subcutaneously , intraperitoneally , tive androgen receptor modulator alone , or can further intraventricularly , intravaginally , intracranially and intratu - 55 include a pharmaceutically acceptable carrier , and can be in morallym . solid or liquid form such as tablets , powders, capsules , Further, as used herein " pharmaceutically acceptable car - pellets , solutions, suspensions, elixirs , emulsions, gels , riers” are well known to those skilled in the art and include , creams, or suppositories , including rectal and urethral sup but are not limited to , 0 .01 - 0 . 1 M and preferably 0 . 05 M positories. Pharmaceutically acceptable carriers include phosphate buffer or about 0 . 8 % saline . Additionally , such 60 gums, starches, sugars , cellulosic materials , and mixtures pharmaceutically acceptable carriers may be aqueous or thereof . The pharmaceutical preparation containing the non - aqueous solutions , suspensions , and emulsions . selective androgen receptor modulator can be administered Examples of non -aqueous solvents are propylene glycol, to a subject by , for example , subcutaneous implantation of a polyethylene glycol, vegetable oils such as olive oil , and pellet; in a further embodiment, the pellet provides for injectable organic esters such as ethyl oleate . Aqueous 65 controlled release of selective androgen receptor modulator carriers include water, alcoholic/ aqueous solutions, emul- over a period of time . The preparation can also be admin sions or suspensions, including saline and buffered media . istered by intravenous, intraarterial, or intramuscular injec US 9 ,744 , 149 B2 62 tion of a liquid preparation , oral administration of a liquid or For topical administration to body surfaces using , for solid preparation , or by topical application . Administration example , creams , gels , drops, and the like, the selective can also be accomplished by use of a rectal suppository or androgen receptor modulators or their physiologically tol a urethral suppository . erated derivatives such as salts , esters , N -oxides , and the like The pharmaceutical preparations of the invention can be 5 are prepared and applied as solutions , suspensions , or emul prepared by known dissolving , mixing , granulating , or tab - sions in a physiologically acceptable diluent with or without a pharmaceutical carrier. let - forming processes . For oral administration , the selective In another embodiment, the active compound can be androgen receptor modulators or their physiologically tol delivered in a vesicle , in particular a liposome (see Langer , erated derivatives such as salts , esters, N -oxides , and the like 10 Science 249 : 1527 - 1533 (1990 ); Treat et al. , in Liposomes in are mixed with additives customary for this purpose , such as the Therapy of Infectious Disease and Cancer, Lopez - Ber vehicles, stabilizers , or inert diluents , and converted by estein and Fidler ( eds . ) , Liss , New York , pp . 353 - 365 ( 1989 ) ; customary methods into suitable forms for administration , Lopez - Berestein , ibid . , pp . 317 - 327 ; see generally ibid ) . such as tablets , coated tablets , hard or soft gelatin capsules, For use in medicine, the salts of the selective androgen aqueous, alcoholic or oily solutions. Examples of suitable 15 receptor modulator will be pharmaceutically acceptable inert vehicles are conventional tablet bases such as lactose , salts . Other salts may, however, be useful in the preparation sucrose , or cornstarch in combination with binders such as of the compounds of the invention or of their pharmaceuti acacia , cornstarch , gelatin , with disintegrating agents such cally acceptable salts . Suitable pharmaceutically acceptable as cornstarch , potato starch , alginic acid , or with a lubricant salts of the compounds of this invention include acid addi such as stearic acid or magnesium stearate . 20 tion salts which may, for example , be formed by mixing a Examples of suitable oily vehicles or solvents are veg - solution of the compound of the invention with a solution of etable or animal oils such as sunflower oil or fish - liver oil. a pharmaceutically acceptable acid such as hydrochloric Preparations can be effected both as dry and as wet granules . acid , sulphuric acid , methanesulphonic acid , fumaric acid , For parenteral administration ( subcutaneous, intravenous, maleic acid , succinic acid , acetic acid , benzoic acid , oxalic intraarterial, or intramuscular injection ) , the selective andro - 25 acid , citric acid , tartaric acid , carbonic acid or phosphoric gen receptor modulators or their physiologically tolerated acid . derivatives such as salts , esters , N -oxides , and the like are In one embodiment, the term “ about” , refers to a deviance converted into a solution , suspension , or emulsion , if desired of between 0 .0001 - 5 % from the indicated number or range with the substances customary and suitable for this purpose , of numbers . In one embodiment, the term “ about” , refers to for example , solubilizers or other auxiliaries . Examples are 30 a deviance of between 1 - 10 % from the indicated number or sterile liquids such as water and oils, with or without the range of numbers . In one embodiment, the term “ about " , addition of a surfactant and other pharmaceutically accept refers to a deviance of up to 25 % from the indicated number able adjuvants . Illustrative oils are those of petroleum , or range of numbers . animal, vegetable , or synthetic origin , for example, peanut In some embodiments , the term " comprise ” or grammati oil, soybean oil , or mineral oil. In general , water , saline , 35 cal forms thereof, refers to the inclusion of the indicated aqueous dextrose and related sugar solutions , and glycols active agent, such as the compound of this invention , as well such as propylene glycols or polyethylene glycol are pre as inclusion of other active agents , and pharmaceutically ferred liquid carriers , particularly for injectable solutions . acceptable carriers , excipients , emollients , stabilizers , etc . , The preparation of pharmaceutical compositions which as are known in the pharmaceutical industry . In some contain an active component is well understood in the art . 40 embodiments , the term " consisting essentially of” refers to Such compositions can be prepared as aerosols of the active a composition , whose only active ingredient is the indicated component delivered to the nasopharynx or as injectables, active ingredient, however, other compounds may be either as liquid solutions or suspensions ; however, solid included which are for stabilizing , preserving , etc . the for forms suitable for solution in , or suspension in , liquid prior m ulation , but are not involved directly in the therapeutic to injection can also be prepared . The preparation can also 45 effect of the indicated active ingredient. In some embodi be emulsified . The active therapeutic ingredient is often ments , the term " consisting essentially of" may refer to mixed with excipients which are pharmaceutically accept - components , which exert a therapeutic effect via a mecha able and compatible with the active ingredient. Suitable nism distinct from that of the indicated active ingredient. In excipients are , for example , water , saline , dextrose , glycerol, some embodiments , the term “ consisting essentially of may ethanol, or the like or any combination thereof. 50 refer to components , which exert a therapeutic effect and In addition , the composition can contain minor amounts belong to a class of compounds distinct from that of the of auxiliary substances such as wetting or emulsifying indicated active ingredient. In some embodiments , the term agents , pH buffering agents which enhance the effectiveness " consisting essentially of" may refer to components , which of the active ingredient. exert a therapeutic effect and belong to a class of compounds An active component can be formulated into the compo - 55 distinct from that of the indicated active ingredient, by sition as neutralized pharmaceutically acceptable salt forms. acting via a different mechanism of action , for example , and Pharmaceutically acceptable salts include the acid addition representing an embodiment of this invention , polypeptides salts ( formed with the free amino groups of the polypeptide comprising T cell epitopes present in a composition may be or antibody molecule ) , which are formed with inorganic specifically combined with polypeptides comprising B cell acids such as , for example , hydrochloric or phosphoric 60 epitopes . In some embodiments , the term " consisting essen acids , or such organic acids as acetic , oxalic , tartaric , man - tially of ” may refer to components which facilitate the delic , and the like. Salts formed from the free carboxyl release of the active ingredient. In some embodiments , the groups can also be derived from inorganic bases such as , for term “ consisting” refers to a composition , which contains example , sodium , potassium , ammonium , calcium , or ferric the active ingredient and a pharmaceutically acceptable hydroxides , and such organic bases as isopropylamine , 65 carrier or excipient. trimethylamine , 2 - ethylamino ethanol, histidine , procaine , Further, as used herein , the term “ comprising ” is intended and the like . to mean that the system includes the recited elements , but US 9 ,744 , 149 B2 63 64 not excluding others which may be optional. By the phrase 3 . Cultures were fixed with 50 UL 50 % TCA (4° C . ) . (see " consisting essentially of” it is meant a method that includes cell fixation protocol for details ) . the recited elements but exclude other elements that may 4 . Fixed cells were stained with 50 uL 0 .4 % ( wt/vol ) SRB have an essential significant effect on the performance of the in 1 % acetic acid for 10 minutes . method . “ Consisting of” shall thus mean excluding more 5 ausW5 . SRB was removed and the cultures were quickly * rinsed 5 times with 1 % acetic acid to remove unbound than traces of other elements . Embodiments defined by each dye. * * of these transition terms are within the scope of this inven 6 . Cultures were air - dried overnight until there was no tion . visible moisture . In one embodiment, the present invention provides com 7 . The cellular protein -bound SRB was dissolved with bined preparations. In one embodiment, the term “ a com - 10 200 uL unbuffered Tris base ( 10 mM , PH 10 . 5 ) for 30 bined preparation " defines especially a " kit of parts ” in the minutes on a rocking platform shaker. sense that the combination partners as defined above can be 8 . Absorbance was read at 540 nm . dosed independently or by use of different fixed combina - * quickly performing rinsing process was to prevent des tions with distinguished amounts of the combination part- orption of protein - bound SRB ners i . e . , simultaneously , concurrently , separately or sequen - 15 * * completely removed residual wash solution by sharply tially . In some embodiments , the parts of the kit of parts can flicking plates over sink . then , e . g . , be administered simultaneously or chronologi- Fixation of Cells Attached to the Plastic Substratum cally staggered , that is at different time points and with equal The following protocol was used for fixing cells : or different time intervals for any part of the kit of parts . The a . 50 uL of 50 % TCA (4° C . ) was gently layered on the top ratio of the total amounts of the combination partners , in 20 of growth medium in each well to make a final TCA some embodiments , can be administered in the combined concentration of 10 % . preparation . In one embodiment, the combined preparation b . Cultures were incubated at 4° C . for 1 hour. can be varied , e . g . , in order to cope with the needs of a c . Cultures were washed 5 times with tap water to remove patient subpopulation to be treated or the needs of the single TCA , growth medium , low -molecular -weight metabo patient which different needs can be due to a particular 25 lites , and serum protein . disease , severity of a disease , age , sex , or body weight asscan can d . Plates were air -dried until there was no visible moisture . be readily made by a person skilled in the art . Example 1 In one embodiment, the term " a " or " one " or " an ” refers to at least one . In one embodiment the phrase " two or more " may be of any denomination , which will suit a particular 30 Effect of Formula IX on Growth in Different Breast purpose . In one embodiment , " about " may comprise a Cancers Cell Lines Expressing Androgen Receptor deviance from the indicated term of + 1 % , or in some Materials and Methods embodiments, - 1 % , or in some embodiments , + 2 . 5 % , or in some embodiments , + 5 % , or in some embodiments , + 7 . 5 % , MDA -MB - 231 and HCC - 38 triple negative breast cancer or in some embodiments , + 10 % , or in some embodiments , 35 cells were used to analyze growth effects of various com - 15 % , or in some embodiments, 120 % , or in some embodi pounds . ments , + 25 % . MDA -MB - 231 and HCC - 38 triple negative breast cancer The following examples are presented in order to more cells were infected with 200 uL or 500 ul adenovirus fully illustrate the preferred embodiments of the invention containing LacZ (negative control) or AR , and were treated They should in no way be construed , however, as limiting 40 with various AR ligands (agonists : DHT and Formula IX , and antagonist : bicalutamide ) or a non - AR binder that is the broad scope of the invention . structurally similar to Formula IX , R -enantiomer of Formula EXPERIMENTAL DETAILS SECTION IX . Cells were treated in charcoal stripped FBS ( FIGS . 1C , 1E , 1G and 11 ; 2C , 2E and 2G ) or full serum ( FIGS . 1D , 1F , General Experimental Methods 45 1H and 1J; 2D , 27 and 2H ) for 3 days , fixed and stained with Cell Growth Conditions sulforhodamine blue ( SRB ) to measure cell viability . IC50 HCC 1937 , HCC 1954, HCC 38 , T47D -Kbluc , MDA values were calculated MB -453 , and MDA -MB - 231 cells were grown in RPMI 1640 medium containing 2 mM L - glutamine supplemented Results with 10 % fetal bovine serum ( FBS ) . Cells were maintained 50 Expression of AR in cells infected with AR or LacZ was in a 5 % CO , / 95 % air humidified atmosphere at 37° C . evaluated using Western blotting (FIG . 1A and FIG . 2A ). MCF - 7 cells were grown in Minimum Essential Medium Only the AR agonists , DHT and Formula IX , inhibited supplemented with 10 % FBS . MDA -MB -231 and HCC - 38 triple negative breast cancer Breast cancer tumors typically express AR 70 - 90 % of the cell growth (FIGS . 1C , 10 , 1E , 1F and FIGS . 2C , 2D , 2E time, however breast cancer cell lines typically do not 55 and 2F ). This inhibition was observed only in the presence express AR . This makes development of a preclinicalmodel of AR ( compare w / lacZ and w / AR ) . IC50 values in AR for the study of androgen effects on breast cancer very positive cells for DHT and Formula IX are presented in FIG . difficult . Consequently , the AR has been introduced by 1B and FIG . 2B . adenoviral infection ( stably incorporated into the genome) into some breast cancer cell lines used in the studies below . 60 Example 2 Sulforhodamine B (SRB ) Assay The SRB Assay was used to determine cell number during Reversal of Effect of Formula IX on Growth cytotoxocity experiments . The following protocol was used : 1 . Cells were detached with 0 .25 % trypsin . Materials and Methods 2 . Experimental cultures were cultured in 96 - well micro - 65 titer plates ( 200 uL growth medium per well ; 1 , 000 To determine if the growth inhibition observed with DHT 200 , 000 cells per well ). and Formula IX in AR positive cells is AR dependent , US 9 ,744 , 149 B2 65 66 MDA -MB - 231 cells were infected with adenovirus contain - trol. The cells were treated 24 h after transfection and ing LacZ (negative control) or AR and were treated with AR luciferase assay performed 48 h after transfection . agonists , DHT or Formula IX , in the presence or absence of the AR antagonist , bicalutamide. Cells were treated in Results charcoal stripped FBS (FIGS . 3A and 3C ) or full serum 5 FIG . 5 shows that all AR ligands that elicited anti ( FIGS. 3B and 3D ) for 3 days , fixed and stained with proliferative activity are agonists in MDA -MB -231 cells sulforhodamine blue ( SRB ) to measure cell viability . IC50 transfected with AR and their agonist and growth inhibitory values were calculated . properties compare well . In other words , growth inhibitory Results 10 ligands are AR agonists in MDA -MB - 231 cells transfected with AR Both DHT and Formula IX required AR to inhibit MDA MB - 231 cell growth , as demonstrated by the weakened Example 5 growth inhibitory effects in the presence of bicalutamide ( FIG . 3A , 3B , 3C , 3D ) . ICs, values for DHT and Formula IX 15 Analysis of Growth Inhibitory Effects in Breast in AR positive cells pretreated with or without bicalutamide Cancer Cells Expressing Estrogen Receptor are presented in FIG . 3E . Materials and Methods Example 3 To ensure that growth inhibitory effects in MDA -MB - 231 20 cells are selective to AR , and to determine if the ligand Effect of AR Ligands on Breast Cancer Cell dependent - growth - inhibitory effects are exclusive to AR and Growth also to ensure that the effects are not artifacts of adenoviral infection , MDA -MB - 231 triple negative breast cancer cells Materials and Methods were infected with ER - a or ER - ß adenovirus constructs and 25 werewere treated withwith ERE agonist : estradiol ( E2 ) or ER antago To determine if all AR ligands inhibit the growth of triple nist : ICI 182 ,780 (ICI ) in charcoal stripped serum (FIG . 6C ) negative breast cancer cells , MDA -MB - 231 cells were or full serum (FIGS . 6D and 6E ) for 3 days . Cells were fixed infected with adenovirus containing LacZ or AR and were and stained with sulforhodamine blue ( SRB ) to measure cell treated with various AR ligands ( agonists : DHT, Formula viability . Expression of ER in infected cells was evaluated VIII , Formula IX , Formula X , Formula XIII , Formula XIV ; 30 using Western blotting. antagonist: bicalutamide ) and a non - AR - binder : R - enantiomer of Formula IX . Cells were treated in charcoal Results stripped FBS ( FIGS. 4A , 4C , 4E , 46 , 41, 4K , 4M and 40 ) or full serum (4B , 4D , 4F , 4H , 41, 4L , 4N and 4P ) for 3 days, FIGS. 6A -6B show the presence or absence of ERa or fixed and stained with sulforhodamine blue ( SRB ) to mea : 35 ERß in MDA -MB -231 cells following transfection . These results show that the anti - proliferative effects observed with sure cell viability . Anti - proliferative IC50 values were cal androgens is unique to ligand activated AR and not an culated in breast cancer cells and compared to transactiva artifact of adenovirus . FIGS . 6C -6E show that over- expres tion values , i . e ., EC50 ( agonists ) and IC50 (antagonists ) sion of ER - a or ER - B in MDA -MB - 231 cells failed to values, generated in HEK - 293 cells . The growth regulatory i promote growth inhibition either in the presence of ER properties in breast cancer cells of these molecules in breast 40 agonists or antagonists. Thus, the observed growth inhibi cancer cells are comparable to the transactivation values tory effects in MDA -MB - 231 cells are selective to the obtained in HEK -293 cells . presence of the AR and AR agonists. Results Example 6 45 Only AR agonists inhibited the growth ofMDA -MB -231 Effect of AR Agonist on Morphology of Breast cells (FIGS . 4A -4B , 4E -4H , and 4K -4P ) and the growth Cancer Cells inhibitory potential of these ligands rank order with their agonistic activity observed in HEK - 293 cells ( FIG . 4Q ) . Materials and Methods Example 14 demonstrates as well that AR agonists inhib - 50 ited the proliferation of MDA -MB - 231 cells stably trans MDA -MB - 231 cells were stably transfected with AR fected with AR . using lentivirus. Following transfection , cells were treated for 3 days with the indicated concentrations of DHT or Example 4 bicalutamide. Live cells were visualized using a light 55 microscope and photographed . The cells were imaged at the same magnification and under the samemicroscopic condi AR Transactivation Assays in Breast Cancer Cells tions . Materials and Methods Results To ensure that the ligands that elicited growth inhibitory 60 FIG . 7 shows that DHT altered the morphology of MDA properties are agonists in MDA -MB - 231 cells , AR transac - MB - 231 cells into more anchorage dependent and differen tivation assays were performed in MDA -MB - 231 cells . tiated cells , indicating that AR agonist -bound AR expressing Though AR transactivation assay was performed in HEK breast cancer cells will have less invasive and migratory 293 cells , the ability of ligands to function as agonists or properties ( e. g ., less likely to metastasize ). antagonists depends on cellular microenvironment. Hence , 65 DHT and SARMs alter the morphology of AR -positive MDA -MB - 231 cells were transfected using lipofectamine MDA -MB -231 cells .MDA -MB - 231 cells were stably trans with AR , GRE - LUC and CMV - LUC as normalization con - fected with AR using lentivirus and were treated with US 9 ,744 , 149 B2 67 68 vehicle or AR agonists at the indicated concentrations . At the A dose response curve for a compound of Formula VIII in end of 3 days of incubation , the cells were imaged under a antagonist mode demonstrated potent partial inhibition of microscope ( 40x ) . PR activity (FIG . 9 ) . In comparison to Formula IX , Formula DHT and SARMs, but not the AR antagonist, bicaluta - VIII is was 10 - times more potent, and 100 - times more mide (data not shown ) , or the inactive isomer of Formula IX , 5 potent than R - enantiomer of Formula IX . In comparison to altered the morphology of the cells into a more anchorage RU486 , Formula VIII was about 1 , 000 fold weaker as a PR dependent phenotype. (FIG . 12 ). antagonist , than RU486 . Compounds of Formulae VIII and IX are specific for the Example 7 AR and do not stimulate or inhibit receptor -mediated trans 10 activation of ERA , ERB , GR , or MR . Unexpectedly , For Cross -Reactivity of Formula VIII with Other mula VIII exhibited moderate potency partial agonist activ Nuclear Hormone Receptors ity for PR , and potent PR partial antagonism ( see FIG . 9 ) . Combined AR -agonism and PR - antagonism will be benefi In order to determine whether compounds of this inven - cial in certain breast cancers ( e . g ., PR - positive breast can tion affected other nuclear hormone receptor signaling , the 15 cers ) . ability of a compound represented by Formula VIII to stimulate (agonist ) or inhibit ( antagonist ) ERa - , ERB -, GR - , Example 8 PR - , or MR -mediated transcriptional activation , was ana lyzed . Formula VIII and Formula IX Inhibit Triple 20 Negative Breast Cancer Cell Tumor Growth in Materials and Methods Mice Transient Transfection Materials and Methods Rat GR , MR , PR , ER - a and ER - B were individually MDA -MB - 231 - AR triple negative breast cancer cells (2 cloned into a PCR3. 1 vector backbone. Sequencing was 25 million cells /mouse ; MDA -MB - 231 cells stably transfected performed to verify the absence of any mutations. HEK - 293 with AR using lentivirus ) were mixed with matrigel ( 1 : 1 ) cells were plated at 90 , 000 cells per well of a 24 well plate and injected subcutaneously into the flanks of intact female in Dulbecco ' s Minimal Essential Media supplemented with nude mice ( n = 5 /group ) . When the tumors reached 150 - 200 5 % charcoal - stripped FBS . The cells were transfected using mm3. the animals were separated into two groups , one Lipofectamine ( Invitrogen , Carlsbad , Calif. ) with 0 . 25 ug 30 receiving vehicle and the other receiving 30 mg/ kg Formula GRE -LUC for GR , MR and PR and ERE -LUC for ER - a and VIII orally . Tumor volumewas measured thrice weekly and ER - B , 0 . 5 ng CMV- LUC (renilla luciferase ) and 12 . 5 -25 ng % tumor growth inhibition ( TGI) was calculated . At the end of the respective expression vector for each receptor. The of 35 days of treatment, the animals were sacrificed , tumors cells were treated 24 h after transfection with Formula VIII excised , weighed , and collected for various analyses . Blood in the absence (agonist mode ) and presence ( antagonist 35 was collected and serum separated for drug concentration mode ) of known agonists ( estradiol for ER ; dexamethasone measurement. for GR ; aldosterone for MR ; progesterone for PR ) as con trols . Luciferase assays were performed 48 h after transfec Results tion . Transcriptional activation values are represented as firefly luciferase normalized to renilla luciferase . Formula VIII significantly reduced the tumor growth with 40 TGI of ~ 75 % ( FIG . 10B ) . Tumor weights were also reduced Results by more than 50 % by Formula VIII treatment ( FIG . 11C ) as were tumor size (FIGS . 11A - 11B ) . Formula VIII elicited The agonist effects of Formula VIII on ER - B , ER - a , GR , these results without any associated toxicity or changes in PR and MR were tested and compared to the activities of the body weight ( FIG . 10A ) . Uterus weight also increased in known ligands, as well ( FIG . 8 ) . A compound of Formula 45 response to Formula VIII treatment ( not shown ), indicative VIII failed to activate ER - B or ER - a even at the highest of in vivo androgenic response . tested concentration ( 1 uM ) whereas 1 nM estradiol induced The results presented in FIG . 24 shows the increase of ERa - and ERB -mediated transactivation by 3 - and 5 - fold , body weight by the SARMs at all doses of Formula VIII and respectively . A compound of Formula VIII failed to activate Formula IX , indicative of healthy growth and a lack of GR - or MR -mediated transactivation . A compound of For - 50 toxicity . By comparison , the vehicle treated animal did not mula VIII at all the tested concentrations did not induce GR grow as robustly . or MR -mediated transactivation , whereas the known ligands In summary, the Formula VIII SARM is extremely effec ( dexamethasone and aldosterone ) induced the activities of tive in regressing the growth of AR expressing triple nega GR or MR by 70 - and 60 - fold , respectively, at a concentra - tive breast cancer xenografts in mice, and is likely to be tion of 1 nM . However , a compound of Formula VIII ss effective in a wide variety of AR -positive breast cancers in increased the transactivation of PR at 1 uM and 10 UM by humans, as described supra and infra . 3 and 8 fold , respectively . Progesterone activated PR by 23 fold at a 1 nM concentration , indicating that a compound of Example 9 Formula VIII is greater than 10 , 000 - fold weaker than the endogenous agonist for PR . Effect of Formula IX in Women with Metastatic or The ability of a compound of Formula VIII to inhibit the 60 Er and / or AR Positive Refractory Breast Cancer effects of a known agonist for each of the above mentioned receptors was tested as well . This clinical trial assessed the safety and efficacy of 9 mg Co - incubation of HEK 293 cells with the indicated con - of the compound represented by the structure of Formula IX centrations of Formula VIII failed to alter the estradiol (Formula IX ) , in 22 postmenopausal women who have induced ER - B or ER - a activity , dexamethasone - induced 65 estrogen receptor (ER ) positive metastatic breast cancer , and GR -mediated transactivation or aldosterone - induced MR who have responded previously to adjuvant and / or salvage mediated transactivation . endocrine therapy . The goal of this study was to determine US 9 ,744 , 149 B2 69 70 the importance of the AR status as a therapeutic target in tigator, a clinically significant concurrent illness or psycho women with ER positive metastatic breast cancer (MBC ) logical, familial, sociological, geographical or other con that had previously responded to hormone therapy . The comitant condition that would not permit adequate follow treatment was continued until disease progression (PD ) . up and compliance with the study protocol; have Primary endpoint was clinical benefit response (CBR ) by 5 uncontrolled hypertension , congestive heart failure or 6 months (m ) defined as patients having a complete response angina ; have Stage 4 chronic obstructive pulmonary disease (CR ) , partial response (PR ), or stable disease (SD ) . CBR (COPD ) ; have positive screen for Hepatitis B consisting of will be correlated with AR status ofmetastatic tumor biopsy. HBsAg (Hepatitis B Surface Antigen ), unless subject was Serum prostate specific antigen (PSA ) was evaluated as a diagnosed > 10 years prior to enrollment and no evidence of biomarker of AR activity . active liver disease ; have ALT /SGOT or AST / SGPT above Results : Formula IX was well -tolerated , with no drug 1 .5 times the upper limit of normal (ULN ) ; have positive related serious adverse events and none exceeding Grade 3 . screen for hepatitis A antibody IgM or HIV ; have received Conclusions : Formula IX demonstrated promise as a novel chemotherapy for metastatic breast cancer within the 3 targeted therapy for AR positive MBC . The primary end - months prior to enrollment in the study or be expected to point has been achieved , with 6 / 17 AR + patients meeting receive chemotherapy for metastatic breast cancer during the statistical threshold for success , as outline in the Table 15 study ; be currently taking testosterone , methyltestosterone , herein below . Serum PSA appeared to be a surrogate marker oxandrolone (Oxandrin® ), oxymetholone , danazol, flu for AR activity and disease response. oxymesterone (Halotestin® ), testosterone - like agents ( such as dehydroepiandrosterone (DHEA ) , androstenedione , and Materials and Methods other androgenic compounds , including herbals ) , or antian 20 drogens ; previous therapy with testosterone and testoster Subject Population one - like agents is acceptable with a 30 - day washout ( if Female subjects with ER positive metastatic breast cancer previous testosterone therapy was long term depot within the who have previously been treated with up to 3 prior hor - past 6 months, the site should contact the medical monitor monal therapies for the treatment of breast cancer. Subjects for this study to determine appropriate washout period ) ; must have been treated with and responded to previous 75 have untreated or uncontrolled brain metastasis ; have been adjuvant therapy for 3 years or hormonal therapy for diagnosed with or treated for cancer within the previous two metastatic disease for X6 months prior to progression . years , other than breast cancer or non -melanoma carcinoma Details of subject selection criteria are presented below : of the skin To be eligible for participation in this study , subjects must Androgen receptor (AR ) status was assessed in all sub meet all of the following criteria , including give voluntary , jects from primary and /or metastatic lesions after enroll signed informed consent in accordance with institutional > ment. It was observed that the majority ( 17 / 19 ) of subjects policies ; be a woman that has been diagnosed with ER with ER positive breast cancer also expressed AR ) in their positive metastatic breast cancer ; and be clinically con primary tumor samples , which correlated well with previous firmed as postmenopausal. Subjects must have undergone literature which predicted 70 - 95 % would be AR -positive the onset of spontaneous , medical or surgical menopause (Niemeier L A , et. al. Androgen receptor in breast cancer : prior to the start of this study . (Spontaneous menopause is 35 expression in estrogen receptor- positive tumors and in estro defined as the natural cessation of ovarian function as gen -negative tumors with apocrine differentiation . Modern indicated by being amenorrheic for at least 12 months . If the Pathology 23 : 205 - 212 , 2010 ; Narita D , et al . Immunohis subject has been amenorrheic for 6 months but < 12 months tochemical expression of androgen receptor and prostate they must have a serum FSH concentration of 250 mIU /mL specific antigen in breast cancer . Folia Histochemica Et and an estradiol concentration of 25 pg /mL ; medical meno - 40 Cytobiologica 44 : 165 - 172 , 2006 ) . High percentages (72 pause is defined as treatment with a luteinizing hormone 84 % ) of metastatic lesions obtained from women with receptor hormone agonist ; and surgical menopause is advanced breast cancer have also been found to be AR defined as bilateral oophorectomy ) . positive ( Lea O A . et al . Improved measurement of androgen Additional requirement that subjects must meet include receptors in human breast cancer. Cancer Research 49 :7162 that they have been treated and responded to previous 15 7167 , 1989 ) . adjuvant hormonal therapy for 3 years or previous hor - As 70 % or greater of the women with ER positive breast monal therapy for metastatic disease for z6 months prior to cancer were expected to have tumors that are AR positive , disease progression ; that they have not had radiation therapy the study was designed to enroll approximately 27 subjects for breast cancer within 2 weeks of randomization in this ( of 40 originally intended to be enrolled ) with AR positive study and are not planned to have radiation therapy during breast cancer in each dose arm , enabling assessment of the participation in this study . Subjects must be willing to 30 primary endpoint in AR positive subjects , as well as the provide tissue sample from a biopsy of a metastatic tumor secondary and tertiary endpoints in subsets based on AR lesion (s ) for determination of AR and ER status. Tissue status (i . e ., all subjects , AR positive subjects , and AR samples from a biopsy of a primary tumor lesion will also be negative subjects ) . provided if available . Further subjects must have ECOG At the time of this writing, patient demographics were : score s2 and be age 18 years. 55 mean age 63 . 7 years , mean time from diagnosis 11 . 0 years, Subjects with any of the following exclusion criteria will 72 . 7 % prior chemotherapy , 89 % ( 17 / 19 ) AR + , 41 % detect NOT be eligible for enrollment in this study : have triple able baseline PSA and 86 . 4 % previous radiation . negative breast cancer ; have , in the judgment of the Inves The baseline characteristic by response was as follows :

Clinical Benefit at Best Clinical Benefit at 6 Progressive Disease at 6 Response Months Months or Prior N = 9 N = 7 N = 12 Mean age 65. 5 Mean age 64 . 6 Mean age 60 . 5 AR status 7 / 7 AR + AR status 6 / 6 AR + AR status 8 / 10 AR + Years from Diagnosis (Dx ) Years from Diagnosis ( Dx ) Years from Diagnosis (Dx ) Mean 13 . 7 Mean 15 . 7 Mean 8 . 6 US 9 , 744 , 149 B2 71 - continued Clinical Benefit at Best Clinical Benefit at 6 Progressive Disease at 6 Response Months Months or Prior Median 11 . 4 (5 . 1 - 27 . 2 ) Median 15 .0 ( 8 .5 - 27 . 2 ) Median 7 . 8 ( 1 . 9 - 22 . 8 ) Years from Dx to Years from Dx to Years from Dx to Metastasis (Mets ) Metastasis (Mets ) Metastasis (Mets ) Mean 8 . 6 Mean 9 . 8 Mean 4 . 4 Median 9 . 3 ( 0 - 15 . 8 ) Median 9 . 8 ( 0 - 15 . 8 ) Median 4 .1 ( 0 - 17. 2 ) Chemotherapy (NA + A ) : 6 / 9 Chemotherapy (NA + A ) : 5 / 7 Chemotherapy (NA + A ) : 9 /12 Everolimus : 0 / 9 Everolimus : 0 / 7 Everolimus: 4 /12 Bone only disease : 4 / 9 Bone only disease : 4 /7 Bone only disease: 1 / 12 Visceral only disease : 2/ 9 Visceral only disease : 2/ 7 Visceral only disease: 2 / 12

Table of Subjects Assessed as Having Clinical Benefit as Best Response Time (y ) Number of Time ( y ) Time ( y ) From From Lines of From Dx Metastatic Previous Initial to Metastatic Dx to Hormonal Subject Age AR BC Dx Disease Enrollment Therapy Metastases 73. 9 + 8 . 7 8 . 5 0 . 2 Lymph Nodes , Bone 64 . 1 5 . 1 0 5 . 1 Peritoneum , Bone 08 52 . 5 + 11 . 4 9 . 8 1 . 6 Bone 14 65 . 6 + 27 . 2 13 . 5 13 . 7 Liver, Bone 16 80 . 1 + 21. 6 12 .5 9 . 1 Lung, Chest Wall, Skin 67 . 6 + 9 . 5 Bone 54 . 4 + 15 9 . 3 Bone 62 . 8 + 16 . 6 15 . 8 0 . 8 Bone 11 69 8 . 5 8. 5 NAAAWUNNN Liver

Table of Subjects Assessed as Having Clinical Benefit at 6 Months Time ( y ) Number of Time ( y ) Time ( y ) From Lines of From From Dx to Metastatic Previous Initial Metastatic Dx to Hormonal Subject Age AR BC Dx Disease Enrollment Therapy Metastases

08 52 . 5 + 11 . 4 9 . 8 1 . 6 Bone 14 65 . 6 + 27 . 2 13 . 5 13 . 7 Liver, Bone 80 . 1 + 21. 6 12 . 5 9 . 1 Lung , Chest Wall, Skin 67 . 6 + 9 . 5 Bone 9- 8 54 . 4 + 15 9 . 3 NAAAWIN Bone 03 62 . 8 + 16 . 6 15 . 8 oour Bone 11 69 8 .5 avü Liver

Table of Subjects Assessed as Having Progressive Disease at 6 Months or Prior Time ( y ) Number of Time ( y ) Time ( y ) From From Lines of From Dx Metastatic Previous Initial to Metastatic Dx to Hormonal Subject Age AR BC Dx Disease Enrollment Therapy Metastases 20 66 .9 + 1. 9 1 . 8 Lymph Nodes , Bone 64 . 1 5 . 1 5 . 1 Peritoneum , Bone 49 . 1 + 7 . 6 2 . 5 Pleura , Liver, Lymph Nodes 9 67 . 3 3 + 7 . 9 9 3 . 9 Lymph Nodes, Liver, Bone 48 . 5 14 . 4 zoa+Fooi 10 . 3 ANNwawWNU Lung , Liver , Bone 63. 5 + 5. 8 5. 8 Abd Wall , Lung , Bone , Skin 56 . 3 + ??? 7 Liver, Bone 67 . 3 + ww Lung , Liver , Bone g 62 . 1 wN ?? Bone , Adrenal Nodule US 9 ,744 , 149 B2 73 74 - continued Table of Subjects Assessed as Having Progressive Disease at 6 Months or Prior Time ( y ) Number of Time ( y ) Time ( y ) From From Lines of From Dx Metastatic Previous Initial to Metastatic Dx to Hormonal Subject Age AR BC Dx Disease Enrollment Therapy Metastases

04 45 . 7 T 5 . 3 O 5 . 3 Bone 17 84 . 7 + 22 . 8 17 . 2 5 .6 ??? Bone , Pleura 10 50 . 8 + 16 12 . 7 3 . 3 Lymph Nodes , Neck

Treatment To assess objective response rate (ORR ) in subjects with Subjects received 9 mg daily dose of Formula IX , with 15 breast cancer treated with Formula IX . Objective baseline and regular on study assessments of safety and response rate is defined as the proportion of subjects efficacy . with a CR or PR at 6 months as measured by modified Measurable and non -measurable lesions ( primary and/ or metastatic ) will be identified and assessed by a modified RECIST 1 . 1 . For subjects with non -measurable ( non Response Evaluation Criteria In Solid Tumors (RECIST 1 . 1 ) 20 target ) disease only at baseline, ORR is defined as the classification over the course of this study (described in proportion of subjects with a CR at 6 months as detail below ) . measured by modified RECIST 1 . 1 . Study Duration To assess progression free survival (PFS ) in subjects with Each subject enrolled into this study received intervention breast cancer treated with Formula IX . PFS is defined until a progression free survival (PFS ) endpoint has been 25 as the time elapsed between treatment initiation and reached (tumor progression or death ) . Subjects will be tumor progression as measured by modified RECIST followed after treatment has been discontinued for vital 1 . 1 OR death . status only . To assess time to progression ( TTP ) in subjects with Efficacy Endpoints breast cancer treated with Formula IX . Time to tumor The primary efficacy analysis was the clinical benefit in 30 progression is defined as the time elapsed between subjects with AR positive breast cancer at 6 months as treatment initiation and tumor progression as measured measured by a modified Response Evaluation Criteria In by modified RECIST 1 . 1 . Solid Tumors (RECIST 1 . 1 ) classification . Key secondary To assess duration of response in subjects with breast endpoints of clinical benefit in all subjects and AR negative cancer treated with Formula IX . subjects , as well as objective response rate , progression free 35 To assess incidence of skeletal related events (SREs ) in survival , time to progression , duration of response , inci subjects treated with Formula IX . dence of SREs, and time to first SRE in subsets based on AR To assess time to first skeletal related event ( SRE ) in status (i . e ., all subjects , AR positive subjects , and AR subjects treated with Formula IX . negative subjects ) was also assessed . Effects on CA 27 - 29 , Tertiary Endpoints PSA , bone turnover markers , QOL , and libido were assessed 40 To assess serum CA 27 -29 changes in subjects with breast as tertiary endpoints . cancer treated with Formula IX . Primary Endpoint To assess serum PSA changes in subjects with breast Clinical benefit in a subject is defined as a complete cancer treated with Formula IX response (CR ) , a partial response ( PR ) or stable disease ( SD ) To assess changes in bone turnover markers ( serum as measured by modified RECIST 1. 1, which is described in 45 osteocalcin , serum collagen type I cross linked C - telo detailbelow . ( Eisenhauer E A et al. New response evaluation peptide [CTX ), serum collagen type I cross linked criteria in solid tumors: revised RECIST guideline ( version N - telopeptide [NTX ], serum bone specific alkaline 1 . 1 ) . European Journal of Cancer 45 : 228 - 247 , 2009 ) . phosphatase , and urinary NTX in subjects treated with For subjects with non -measurable ( non - target ) disease Formula IX . only at baseline, SD was defined as those with non - CR /non - 50 To assess the effect of Formula IX on quality of life PD combined response . The primary endpoint of the study (POL ) asmeasured by FACIT - F questionnaire in sub was to assess the proportion of subjects with clinical benefit jects treated with Formula IX . ( PCB ) at 6 months (CR + PR + SD ) in subjects with AR To assess the effect of Formula IX on libido as measured positive breast cancer. by female sexual function index ( FSFI) questionnaire Secondary Endpoints 55 in subjects treated with Formula IX . The secondary efficacy endpoints include : To explore the relationship of various levels of AR To assess the clinical benefit in all subjects with breast expression as determined by immunohistochemistry cancer treated with Formula IX . The clinical benefit is with primary, secondary and tertiary objectives . defined as the proportion of subjects with complete response [CR ] + partial response [PR ] + stable disease 60 Results [SD ] as measured by modified RECIST 1 .1 (Eisen hauer E A et al. New response evaluation criteria in After a median follow -up of 81 days ( d ) (range 7 -304 d ) , solid tumors : revised RECIST guideline ( Version 1. 1) . preliminary results of the 22 patients were as follows : 9 SD European Journal of Cancer 45 : 228 - 247 , 2009 ) . was observed as best response , median duration 212 d . For subjects with non -measurable (non - target ) disease 65 Current disposition of all patients : 15 PD after a median 80 only at baseline , SD was defined as those with non - d ( range 15 - 304 d ) , 4 SD , and 3 early discontinuations ( d 7 , CR /non - PD combined response . 28 , 255 ) . Among patients who reached 6 in , six are AR US 9 , 744 ,149 B2 75 76 positive with SD and increased PSA . 1 has yet to reach 6 m Modified RECIST 1 . 1 and no CR or PR has been observed . Formula IX was The modified RECIST 1 . 1 definitions described below well - tolerated , with no drug related serious adverse events was applied : and none exceeding Grade 3 . Measurable Lesions No useful trends were seen with the biomarkers of bone 5 A measurable lesion is defined as one lesion whose turnover hone specific alkaline phosphatase C - telonen longest diameter (LD ) can be accurately measured as 210 tides , N - telopeptides , and osteocalcin . Likewise breast can mm CT or MRI technique by using a 5 mm contiguous reconstruction algorithm . cer biomarker CA 27 - 29 did not demonstrate any useful Measurable lesions must be at least 2 times the slice trends. thickness or at least two times the size of the CT scan PSA levels appeared to increase in response to Formula 10 interval cut. IX treatment as was observed in 20 of the 22 patients Lesions seen on chest x - ray but not confirmed by CT or measured , but correlation with clinical benefit or disease MRI scan are not acceptable as measurable lesions for this progression is not yet evident. study . The following non serous adverse events were observed : To be considered pathologically enlarged and measurable , A - fib ( 1 ); anxiety / emotional changes ( 5 ), arthralgia (6 ) , 15 a lymph node must be > 15 mm in short axis when assessed bloating ( 2 ) , bruising ( 1 ) , cellulitis ( 1 ) , chills ( 1 ) , constipa by CT scan (CT scan slice thickness recommended to be no tion ( 2 ) , cough ( 1 ) , dehydration ( 1 ) , diarrhea ( 3 ) , dizziness greater than 5 mm ) At baseline and in follow - up , only the ( 2 ) , dysgeusia ( 1 ) , dyspepsia ( 1 ) , dyspnea ( 3 ), edema ( 2 ) , short axis will be measured and followed . fatigue (14 ) , fever ( 1 ), flatulence ( 1 ) , glaucoma ( 1 ) , head - Measurable disease is defined as the presence of at least ache ( 4 ) , hot flash night sweats ( 7 ) , hypertension ( 2 ) , infec - 20 one measurable lesion . tion ( 1 ) , insomnia ( 2 ) , myalgia ( 5 ) , nail discoloration ( 1 ) , All measurements will be taken and recorded in millime nausea ( 11 ) , pain (22 ) , paresthesia ( 1 ), pleural effusion ( 1 ) , ters using an electronic measurement method . polyuria ( 1 ) , post menopausal bleeding ( 3 ), rash / acne ( 3 ) , Non -Measurable Lesions stiffness ( 1 ) , tendonitis ( 1 ) , vision changes ( 3 ) , vomiting ( 2 ) , Non -measurable lesions are defined as any lesion ( s ) that weight gain ( 2 ) , and weight loss ( 2 ) . 25 are smaller than the criteria for measurable lesions stated The liver enzymes (ALT , AST and bilirubin ) returned to above (non -nodal lesions with longest diameter < 10 mm or baseline with no interruption of therapy and no increase in pathological lymph nodes with 210 mm to < 15 mm in short total bilirubin . axis ) or truly non measurable lesions ( or sites of disease ) . Conclusions : Formula IX demonstrated promise as a Lesions considered to be truly non -measurable are bone novel targeted therapy for AR -positive MBC . The primary 30 lesions (lytic lesions or mixed lytic - blastic lesions without endpoint was achieved , with 6 / 17 AR - positive patients identifiable soft tissue components , and blastic lesions ) , meeting statistical threshold for success . Serum PSA leptomeningeal disease , ascites, pleural/ pericardial effu appeared to be a surrogate marker for AR activity and sions , lymphangitis cutis /pulmonis , inflammatory breast dis disease response . ease , abdominal masses not confirmed by imaging tech AR Status and Patient Disposition niques, and cystic lesions .

Days Primary Metastatic MAX Day 84 Day 168 Current on Lesion Lesion PSA PSA Patient # RECIST RECIST Disposition Study H Score ER % H Score ER % Day 0 F / U 01 PD N / A Deceased 100 245 40 270 90 0 .220 0 .046 02 PD ?? PD 91 200 50 0 0 < 0 .007 0 .092 03 SD SD D / C 260 80 265 90 0 . 010 2 . 430 04 PD N / A PD 105 0 20 0 60 < 0 . 007 0 .058 05 D / C SAE N / A D / C 300 100 100 < 0 . 007 0 . 008 (D2 ) 06 PD N / A Deceased ü 70 < 0 .007 < 0 . 007 (D15 ) O SD PD PD 158 < 0 .007 0 .078 O SD SD PD 308 120 95 0 . 104 0 .217 OO PD SAE N / A Deceased 52 150 70 0 .009 9 .610 (D52 ) PD N / A PD 63 195 40 < 0 .007 0 .450 SD SD PD 230 300 100 0 . 104 3 .540 PD N / A PD 84 < 0 .007 0 .238 SNS? PD N / A PD 84 210 100 0 .023 8 . 180 14 SD SD PD 252 95 1 < 0 .007 0 . 548 (D56 ) (D140 ) D / C N / A Deceased 28 160 95 < 0 .007 0 .062 16 SDSD SD SD 239 240 95 < 0 .007 0 .024 17 PD N / A PD 86 70 30 2 .850 13 . 160 SD SD SD 202 285 90 < 0 .007 0 .069 19 SD SD SD 190 110 < 0 .007 0 . 031 202 PDPD N / A PD 99 300 100 0 . 080 0 . 795 PD N / A PD 84 160 100 0 . 298 0 . 301 22 SD 137 285 90 < 0 .007 0 .028 Subject 02 and 04 were the only two AR - negative subjects on trial. Subjects 03 , 07 , 08 , 11, 14 , 16 , 18 , 19 and 22 were assessed as having clinical benefit as their best response ( 9 of 22 total subjects ) . Subjects with clinical benefit at Day 168 ( 6 months which was the clinical endpoint) were 03 , 08 , 14 , 16 , 18 , and 19 ( 6 of 19 AR positive subjects ). Subject 11 was missing a metastasis biopsy and hence could not be counted toward the primary endpoint. Subject 22 has not yet reached the 6 month ( day 168 ) on study date such that she could be counted toward the primary endpoint. US 9 ,744 , 149 B2 77 78 Target Lesions size (< 10 mm short axis ) . Disappearance of bone lesions Target lesions must be measurable lesions. identified on bone scintigraphy. All target lesions up to a maximum of two lesions per Non - CR /Non - PD : Persistence of one or more non - target organ and five lesions in total , representative of all involved lesions . Stability , decrease , or mild increase in uptake of organs , will be selected / confirmed as target lesions , recorded 5 bone lesions on bone scintigraphy. and measured at baseline . Progressive Disease ( PD ): Unequivocal progression of Target lesions should be selected on the basis of their size existing non - target lesions. A perceived increase in bone ( lesions with the longest diameter ) and their suitability for disease in a preexisting area will not be considered progres accurate repetitive measurements by CT /MRI imaging tech sion . For bone scintigraphy, at least two new lesions are niques and be most representative of the subject ' s tumor 10 required to conclude to a definite presence of new lesions burden . unless one or more of these lesions are confirmed by Target lesions will be measured in one dimensionnsion by the radiography, CT or MRI. size estimation of their diameter . A sum of the diameters ( longest for non -nodal lesions and shortest for nodal lesions ) Not Evaluable (NE ): NE can be applied if repeated for all target lesions will be calculated and reported for each 15 evaluations cannot be assessed for reasons such as inad time point. The baseline sum of diameters will be used as equate or missing imaging . reference to further characterize the objective tumor Definitions of Combined Response at Each Time Point response of the measurable dimension of the disease . Determination of an overall response for each time point Non - Target Lesions is based on the combination of responses for target, non All other lesions ( or sites of disease ) and any measurable 20 target, and the presence or absence of new lesions using the lesions that were not selected as target lesions ) should be algorithm outlined on tables C1 and C2 below . identified as non - target lesions and indicated as present at baseline . TABLE C1 Measurements of the non - target lesions may be per Summary of Definitions of Response for Patients formed , however the continued presence or absence as well 25 with Measurable ( Target ) Disease at Baseline as the disappearance or progression status of these lesions Response of Combined Lesion Types will be noted throughout follow - up assessments . New Lesions Target Non - Target New Combined New lesions will be called at follow -up visits regardless Lesions Lesions Lesions Response of whether they occur in anatomic regions that were rou - 30 CR CR No CR tinely subjected to follow -up , or in regions without disease Š Non - CR / No PR non -PD or NE at baseline and for which a follow - up scan is performed for Ž CR , non - CR No PR clinical suspicion of new disease . New lymph nodes need to non - PD , orNE have a minimum size of 10 mm in their shortest axis . New CR , non - CR No SD non -nodal lesions need not to be measurable or to have a 35 non - PD , orNE PD Any Yes or No PD minimum size . Measurements of new lesions may be per Any PD Yes or No PD formed . Any Any Yes PD Response Criteria Definitions NE Non - PD No NE The following response criteria will be applied for target Non - PD Non - PD NE NE and non - target lesions : 40 Target Lesion Response Criteria Complete Response (CR ) : Disappearance of all target TABLE C2 lesions. Target lymph node lesions that become < 10 mm in their shortest diameter will be considered to be normal Summary of Definitions of Response for Patients with ( non - pathologic ) and their actual measurement will be 45 Non -Measurable (Non - Target) Disease only at Baseline recorded . Thus , it follows that if all target node lesions have Response of Combined Lesion Types become < 10 mm , and all other non - nodal lesions have Non - Target New Combined disappeared ( whether target or non - target type ) , the overall Lesions Lesions Response response will be considered to be a CR . CR No CR Partial Response (PR ): Atleast a 30 % decrease in the sum 50 Non - CR / non -PD No Non - CR / non - PD of diameters of target lesions, taking as reference the base NE No NE line sum of the diameters. PD Yes or No PD Stable Disease (SD ): Neither sufficient shrinkage to Any Yes PD qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters (nadir ) . 55 Progressive Disease (PD ) : At least a 20 % increase in the Example 10 susum of the diameters of target lesions taking as reference the smallest sum of diameters (nadir ) recorded since the treat ment started . In addition to the relative increase of 20 % , the Synthesis of ( S ) Enantiomer of Formula VIII sum of diameters must also demonstrate an absolute increase 60 of at least 5 mm . Not evaluable (NE ): NE can be applied if repeated measurements cannot be assessed for reasons such as inad „ COH 2N NaOH /acetone equate or missing imaging . st mm Non - Target Lesion Response Criteria 05 03 0 -5° C ./ RT / 3 hrs Complete Response (CR ): Disappearance of all non IZ 1 target lesions. All lymph nodesmust be non -pathological in US 9 ,744 , 149 B2 79 80 -continued dried to give 18 .6 g (81 % ) ( smaller weight when dried ~ 34 % ) of the titled compound as a yellow solid : mp 152 111111CO CO2H 154° C .; ' H NMR ( 300 MHz, DMSO -do ) d 4 .69 (dd , J = 9. 6 Hz, J = 6 . 7 Hz , 1H , CH at the chiral center) , 4 . 02 (d , J = 11 .4 5 Hz, 1H , CHH ,) , 3 . 86 ( d , J = 11. 4 Hz, 1H , CHH , ) , 3 . 53 - 3 . 24 ( m , 4H , CH , ) , 2 . 30 - 2 . 20 ( m , 1H , CH ), 2 .04 - 1 . 72 ( m , 3H , CH , and CH ), 1. 56 (s , 2H , Me) ; 13C NMR (75 MHz, DMSO - D ) & 167. 3 , 163 . 1 , 83. 9 , 57 . 2 , 45. 4 , 37 . 8 , 29. 0 , 22 . 9 , 21 . 6 ; IR (KBr ) 3474 , 1745 ( C = O ) , 1687 ( C = O ) , 1448 , 10 1377 , 1360 , 1308, 1227 , 1159 , 1062 cm - ? ; [ a ] , 26 + 124 .5° ( 2R ) - 1 -Methacryloylpyrrolidin - 2 -carboxylic Acid ( c = 1 . 3 , chloroform ) ; Anal . Calcd . for C H , „ BrNOZ: C , 41. 24 ; H , 4 .61 ; N , 5 . 34 . Found : C , 41 . 46 ; H , 4 .64 ; N , 5 .32 . D - Proline , 14 . 93 g , 0 . 13 mol) was dissolved in 71 mL of 2 N NaOH and cooled in an ice bath ; the resulting alkaline solution was diluted with acetone (71 mL ) . An acetone solution ( 71 mL ) of methacryloyl chloride ( 13. 56 g , 0 . 13 mol) and 2 N NaOH solution (71 mL ) were simultaneously 24 % HBr added over 40 min to the aqueous solution of D - proline in HO Y Br an ice bath . The pH of the mixture was kept at 10 - 11° C . Reflux during the addition of the methacryloyl chloride . After 20 H3COH stirring ( 3 h , room temperature ), the mixture was evaporated Br ( R ) - 3 -bromo - 2 - hydroxy - 2 in vacuo at a temperature at 35 -45° C . to remove acetone . HzC methylpropanoic acid The resulting solution was washed with ethyl ether and was acidified to pH 2 with concentrated HCl. The acidic mixture was saturated with NaCl and was extracted with EtoAc ( 100 mLx3 ) . The combined extracts were dried over Na2SO4, ( 2R ) - 3 -Bromo - 2 -hydroxy - 2 -methylpropanoic Acid filtered through Celite , and evaporated in vacuo to give the crude product as a colorless oil . Recrystallization of the oil A mixture of bromolactone ( 18 . 5 g , 71 mmol) in 300 mL from ethyl ether and hexanes afforded 16 . 2 g (68 % ) of the 20 of 24 % HBr was heated at reflux for 1 h . The resulting desired compound as colorless crystals : mp 102 - 103° C . ; the NMR spectrum of this compound demonstrated the exis solution was diluted with brine (200 mL ), and was extracted tence of two rotamers of the title compound . ' H NMR (300 with ethyl acetate ( 100 mLx4 ) . The combined extracts were MHz, DMSO - do ) 8 5 . 28 ( s ) and 5 . 15 ( s ) for the first rotamer, washed with saturated NaHCO3 ( 100 mLx4 ) . The aqueous 5 . 15 ( s ) and 5 . 03 ( s ) for the second rotamer ( totally 2H for solution was acidified with concentrated HCl to pH = 1 , both rotamers , vinyl CH , ) , 4 . 48 - 4 . 44 for the first rotamer , 35 which , in turn , was extracted with ethyl acetate ( 100 mLx4) . 4 . 24 - 4 . 20 ( m ) for the second rotamer ( totally 1H for both The combined organic solution was dried over Na2SO4 , rotamers , CH at the chiral canter ), 3 .57 -3 .38 (m , 2H , CH ), filtered through Celite , and evaporated in vacuo to dryness . 2 .27 -2 .12 (1H , CH ) , 1. 97 - 1. 72 (m , 6H , CH , CH ,Me ) ; 13C Recrystallization from toluene afforded 10 .2 g ( 86 % ) of the NMR (75 MHz, DMSO - d ) 8 for major rotamer 173 . 3, desired compound as colorless crystals :mp 107 - 109° C . ; 1H 169 . 1 , 140 . 9 , 116 . 4 , 58 . 3 , 48 . 7 . 28 . 9 . 24 . 7 . 19 . 5 : for minor 40 NMR ( 300 MHz, DMSO -do ) o 3 . 63 (d , J = 10 . 1 Hz, 1H , rotamer 174 . 0 , 170 . 0 , 141. 6 , 115 . 2 , 60 . 3 , 45 . 9 , 31. 0 , 22 . 3 , CHH2) , 3 . 52 ( d , J = 10 . 1 Hz, 1H , CHH ) , 1 . 35 ( s , 3H , Me) ; 19 . 7 ; IR (KBr ) 3437 (OH ), 1737 ( C = 0 ) , 1647 (CO , IR (KBr ) 3434 (OH ) , 3300 - 2500 (COOH ) , 1730 ( C = O ) , COOH ) , 1584 , 1508, 1459, 1369 , 1348, 1178 cm - ?; [ a ] , 26 + 1449 , 1421, 1380 , 1292, 1193, 1085 cm ; [a ] 20 + 10 .5° 80 . 8° (c = 1 , MeOH ) ; Anal. Calcd . for C , H , 3NOZ: C , 59. 00 ; ( c = 2 .6 , MeOH ) ; Anal. Calcd . for C _ H _ BrOz : C , 26 . 25 ; H , H , 7. 15 ; N , 7 .65 . Found : C , 59 .13 ; H , 7 . 19 ; N , 7 .61 . 3 . 86 . Found : C , 26 .28 ; H , 3 .75 .

unCO2H 50 NBS / DMF N 50 I RT HO y Br SOCI / THF / 0 -5° C . H3COH Br (R )- 3 -bromo -2 - hydroxy -2 H3C 55 methylpropanoic acid R - 18 ( 3R ,8aR ) - 3 - Bromomethyl- 3 -methyl - tetrahydro -pyr rolo [ 2 , 1 - c ] [ 1 , 4 ]oxazine - 1 , 4 -dione y Br 60 A solution of NBS ( 23 .5 g , 0 .132 mol) in 100 mL of DMF H3COH was added dropwise to a stirred solution of the (methyl NC acryloyl) -pyrrolidine ( 16 .1 g, 88 mmol) in 70 mL of DMF EtzN /RT under argon at room temperature , and the resulting mixture 01 y Br + was stirred 3 days . The solvent was removed in vacuo , and 65 a yellow solid was precipitated . The solid was suspended in CH ; OH NH2 water, stirred overnight at room temperature , filtered , and US 9 , 744 , 149 B2 81 82 and brine, successively . The organic layer was dried over NCcontinued . MgSO , and then concentrated under reduced pressure to give an oil which was purified by column chromatography using EtOAc /hexane (50 :50 ) to give a solid . The solid was NH X Br 5 recrystallized from CH , C1, / hexane to give 1 .4 g (61 .6 % ) of HC OH (S ) - N -( 3 - chloro - 4 -cyanophenyl ) - 3 - ( 4 -cyanophenoxy )- 2 hydroxy - 2 -methylpropanamide as a colorless solid . ' H NMR (CDC12 / TMS) 8 1 .61 (s , 3H , CH3) , 3 . 25 (s , 1H ,OH ), 4 . 06 (d , J= 9 . 15 Hz , 1H , CH ), 4 .50 (d , J = 9 . 15 Hz, Synthesis of ( 2R ) - 3 - bromo - N - ( 3 - chloro - 4 -cyano 101H , CH ), 6 . 97 -6 . 99 ( m , 2H , ArH ), 7 .53 - 7 . 59 ( m , 4H , ArH ) , phenyl) - 2 -hydroxy - 2 -methylpropanamide 7 . 97 ( d , J= 2 .01 Hz , 1H , ArH ), 8. 96 (s , 1H , NH ). Calculated Thionyl chloride (7 . 8 g , 65 . 5 mmol) was added dropwise Mass : 355. 1 , [ M + Na ] * 378 . 0 . Mp: 103 - 105° C . to a cooled solution ( less than 4° C . ) of (R )- 3 -bromo - 2 Example 11 hydroxy - 2 -methylpropanoic acid ( 9 . 0 g , 49. 2 mol) in 50 mL 15 of THF under an argon atmosphere . The resulting mixture Synthesis of ( S ) Enantiomer of Formula IX was stirred for 3 h under the same condition . To this was added Et3N (6 .6 g , 65 . 5 mol) and stirred for 20 min under the same condition . After 20 min , 4 -amino - 2 - chlorobenzo nitrile ( 5 . 0 g , 32 . 8 mmol) and 100 mL of THF were added 20 and then the mixture was allowed to stir overnight at room temperature . The solvent was removed under reduced pres sure to give a solid which was treated with 100 mL of H20 , HO Y Br SOCI / THF/ 0 .5° C . extracted with EtOAC (2x150 mL ). The combined organic 75 HzC OH extracts were washed with saturated NaHCO3 solution ( R )- 3 - bromo- 2 -hydroxy - 2 ( 2x100 mL ) and brine (300 mL ) , successively . The organic methylpropanoic acid layer was dried over MgSO4 and concentrated under reduced pressure to give a solid which was purified from column chromatography using EtoAc/ hexane (50 : 50 ) to give 7 . 7 g 30 C1 y Br (49 . 4 % of target compound as a brown solid . ' H NMR (CDC12 / TMS) d 1 . 7 ( s , 3H , CH3) , 3 . 0 ( s , 1H , H3COH OH ), 3 . 7 ( d , 1H , CH ) , 4 . 0 (d , 1H , CH ), 7 . 5 ( d , 1H , ArH ), 7 . 7 F3C NH2 ( d , 1H , ArH ) , 8 .0 ( s , 1H , ArH ) , 8 . 8 ( s , 1H , NH ) . MS : 342 . 1 Et3N /RT ( M + 23 ) . Mp 129° C . 35 014 Br + CH ; OH NC NC NC

40 F NH y Br + ???? , ?? ?? CN K2CO3 2- propanol 45 Synthesis of ( 2R ) - 3 -Bromo - N - [ 4 -cyano - 3 - ( trifluo romethyl ) phenyl] - 2 - hydroxy - 2 -methylpropanamide NC HO Thionyl chloride ( 46 .02 g , 0 .39 mol) was added dropwise to a cooled solution ( less than 4° C . ) of ( R ) - 3 - bromo- 2 C ANH* NH 50 hydroxy - 2 -methylpropanoic acid (51 . 13 g , 0 . 28 mol) in 300 mL of THF under an argon atmosphere . (R ) - 3 - bromo - 2 H3COH hydroxy - 2 -methylpropanoic acid was prepared as described in Example 10 . The resulting mixture was stirred for 3 h under the same condition . To this was added EtZN ( 39 . 14 g , Synthesis of ( S ) - N -( 3 -chloro -4 -cyanophenyl ) - 3 - (4 - 55 0 .39 mol) and stirred for 20 min under the same condition . cyanophenoxy ) -2 -hydroxy - 2 -methylpropanamide After 20 min , 5 -amino - 2 -cyanobenzotrifluoride ( 40 . 0 g , 0 .21 mol ), 400 mL of THF were added and then the mixture was A mixture of bromoamide ( 2 . 0 g , 6 . 3 mmol) , anhydrous allowed to stir overnight at room temperature . The solvent K2CO3 ( 2 . 6 g , 18 . 9 mmol) in 50 mL of acetone was heated was removed under reduced pressure to give a solid which to reflux for 2 h and then concentrated under reduced 60 was treated with 300 mL of H , O , extracted with EtOAC pressure to give a solid . The resulting solid was treated with (2x400 mL ) . The combined organic extracts were washed 4 -cyanophenol (1 . 1 g , 9 .5 mmol) and anhydrous K2CO3 ( 1 .7 with saturated NaHCO3 solution (2x300 mL ) and brine ( 300 g , 12. 6 mmol) in 50 mL of 2 -propanol was heated to reflux mL ) . The organic layer was dried over MgSO4 and concen for 3 h and then concentrated under reduced pressure to give trated under reduced pressure to give a solid which was a solid . The residue was treated with 100 mL of H , O and 65 purified from column chromatography using CH , C1 , /EtOAC then extracted with EtoAc (2x100 mL ) . The combined (80 : 20 ) to give a solid . This solid was recrystallized from EtoAc extracts were washed with 10 % NaOH (4x100 mL ) CH C12/ hexane to give 55. 8 g (73 . 9 % ) of (2R ) - 3 -bromo - N US 9 ,744 , 149 B2 83 84 [ 4 - cyano - 3 - ( trifluoromethyl )phenyl ] - 2 -hydroxy - 2 -methyl Example 12 propanamide as a light- yellow solid . 'H NMR (CDC1z / TMS) 8 1. 66 (s , 3H , CH3 ), 3. 11 (s , 1H , Synthesis of (R ) Enantiomer of Formula IX OH ) , 3 .63 ( d , J = 10 . 8 Hz, 1H , CH2) , 4 .05 ( d , J = 10 . 8 Hz, 1H , CH , ), 7 .85 ( d , J = 8 . 4 Hz , 1H , ArH ) , 7 . 99 (dd , J = 2 . 1 , 8 . 4 Hz , 1H , ArH ), 8 .12 ( d, J= 2 .1 Hz, 1H , ArH ) , 9 .04 (bs , 1H , NH ). Calculated Mass : 349. 99, [ M - H ] - 349 .0 . M . p . : 124 - 126° C . 1. SOCI2 , 0° C . to 4° C ./ 3 hrs NC 10 HOX Br – HO CH3 2. Et3N ,NC NH2 - Br + F3C SZ ?? ?? 15 NC FC (2R ) - 3 -bromo - N - [ 4 - cyano - 3 (trifluoromethyl ) phenyl ] - 2 -hydroxy - 2 methylpropanamide F C Br CN K2CO3 20 HOCHZ 2 -propanol NC Synthesis of (2S ) - 3 - bromo- N - [ 4 - cyano - 3 - ( trifluo - CN 25 romethyl) phenyl] - 2 -hydroxy - 2 -methylpropanamide ILITY (precursor to R - enantiomer of Formula IX ) ?? ?? Thionyl chloride (46 .02 g , 0 .39 mol) was added dropwise ( S ) - N -( 4 -cyano - 3 - (trifluoromethyl )phenyl ) - 3 - ( 4 30 to a cooled solution ( less than 4° C . ) of ( S ) - 3 - bromo- 2 cyanophenoxy ) - 2- hydroxy - 2 -methylpropanamide hydroxy - 2 -methylpropanoic acid (51 . 13 g , 0 .28 mol) in 300 mL of THF under an argon atmosphere . The resulting mixture was stirred for 3 h under the same condition . To this Synthesis of ( S ) - N - ( 4 - Cyano - 3 - ( trifluoromethyl) was added Et3N (39 . 14 g , 0 .39 mol ) and stirred for 20 min phenyl) - 3 -( 4 -cyanophenoxy )- 2 -hydroxy -2 -methyl 35 under the same condition . After 20 min , 5 - amino - 2 -cya nobenzotrifluoride ( 40 . 0 g , 0 .21 mol) , 400 mL of THF were propanamide added and then the mixture was allowed to stir overnight at room temperature . The solvent was removed under reduced A mixture of bromoamide ( 2R ) - 3 -bromo - N - [ 4 - cyano - 3 pressure to give a solid which was treated with 300 mL of ( trifluoromethyl) phenyl) - 2 -hydroxy - 2 -methylpropanamide , 40 H2O , extracted with EtoAc (2x400 mL ) . The combined 50 g . 0 . 14 mol) , anhydrous K . CO . (59 .04 g . 0 .43 mol) . organic extracts were washed with saturated NaHCO3 solu tion ( 2x300 mL ) and brine ( 300 mL ) . The organic layer was 4 -cyanophenol ( 25 .44 g, 0 .21 mol) in 500 mL of 2 -propanol dried over MgSO4 and concentrated under reduced pressure was heated to reflux for 3 h and then concentrated under to give a solid which was purified from column chromatog reduced pressure to give a solid . The resulting residue was 45 raphy using CH , C1, /EtOAC (80 : 20 ) to give a solid . This treated with 500 mL of H , O and then extracted with EtoAc solid was recrystallized from Eto Ac/ hexane to give 55 . 8 g (2x300 mL ) . The combined EtoAc extracts were washed (73 . 9 % ) of target compound as a light- yellow solid . with 10 % NaOH (4x200 mL ) and brine . The organic layer lH NMR (CDC1 . / TMS) 8 1 .66 ( s . 3H . CH . ). 3 . 11 ( s , 1H . was dried over MgSO , and then concentrated under reduced OH ) , 3 .63 ( d . J = 10 . 8 Hz, 1H , CH ) , 4 .05 ( d , J = 10 . 8 Hz, 1H , pressure to give an oil which was treated with 300 mL of 50 CH ) , 7 .85 ( d , J = 8 .4 Hz, 1H , ArH ), 7 . 99 (dd , J= 2 . 1, 8. 4 Hz, ethanol and an activated carbon . The reaction mixture was 1H , ArH ) , 8 . 12 ( d , J = 2 . 1 Hz, 1H , ArH ) , 9 . 04 (bs , 1H , NH ) . heated to reflux for 1 h and then the hot mixture was filtered Calculated Mass : 349. 99, [ M - H ] – 349 .0 . Mp: 124 - 126° C . through Celite . The filtrate was concentrated under reduced pressure to give an oil . This oil was purified by column chromatography using CH2Cl2/ EtOAC ( 80 : 20 ) to give an oil N which was crystallized from CH2Cl2 /hexane to give 33 .2 g HO (59 . 9 % ) of ( S ) N - ( 4 - cyano - 3 - (trifluoromethyl ) phenyl ) - 3 K2CO3/ 2 -propanol ( 4 - cyanophenoxy )- 2 -hydroxy - 2 -methylpropanamide as a F3C IZ y Br colorless solid ( a cotton type ). HOCHZ ' H NMR (CDC1z / TMS) 8 1. 63 (s , 3H , CH3) , 3 .35 (s , 1H , OH ) , 4 .07 ( d , J = 9 .04 Hz , 1H , CH ) , 4 .51 ( d , J = 9 .04 Hz , 1H , CH ) , 6 . 97 - 6 . 99 ( m , 2H , ArH ) , 7 .57 - 7 .60 ( m , 2H , ArH ) , CN 7 .81 ( d , J = 8 . 55 Hz , 1H , ArH ), 7 .97 (dd , J = 1 .95 , 8 .55 Hz , 1H , 65 F3C ArH ) , 8 .12 ( d , J = 1 .95 Hz, 1H , ArH ) , 9 . 13 ( bs, 1H , NH ) . HOCHZ Calculated Mass : 389 .10 , [M -H ]- 388 . 1 . Mp: 92 -94° C . Duka US 9 ,744 , 149 B2 85 86 Synthesis of ( R ) - N - ( 4 -cyano - 3 - ( trifluoromethyl) dried over MgSO4 and concentrated under reduced pressure phenyl) - 3 -( 4 -cyanophenoxy )- 2 - hydroxy - 2 -methyl to give a solid which was purified by column chromatog raphy using CH , C1, / EtOAC (80 : 20 ) to give a solid . This propanamide ( R - enantiomer of Formula IX ) solid was recrystallized from CH2Cl2 /hexane to give a target compound ( 55 . 8 g , 73. 9 % ) as a light- yellow solid . A mixture of bromoamide (50 .0 g, 0 .14 mol) , anhydrous 5 C H NMR (CDC12 / TMS ) 8 1 .66 ( s , 3H , CH ) , 3 . 11 (s , 1H , K2CO3 (59 . 04 g , 0 .43 mol) , 4 - cyanophenol (25 .44 g, 0. 21 OH ) , 3 .63 ( d , J = 10 . 8 Hz, 1H , CH ) , 4 . 05 ( d , J = 10 . 8 Hz, 1H , mol) in 500 mL of 2 -propanol was heated to reflux for 3 h CH ) , 7 .85 (d , J = 8 . 4 Hz , 1H , ArH ), 7. 99 (dd , J = 2 .1 , 8. 4 Hz , and then concentrated under reduced pressure to give a solid . 1H , ArH ), 8. 12 (d , J= 2 . 1 Hz , 1H , ArH ), 9 .04 (bs , 1H , NH ). The resulting residue was treated with 500 mL of H2O and Calculated Mass : 349 . 99 , M - H ] - 349 . 0 . Mp: 124 - 126° C . then extracted with EtOAC (2x300 mL ). The combined 10 EtOAc extracts were washed with 10 % NaOH (4x200 mL ) and brine . The organic layer was dried over MgSO4 and then concentrated under reduced pressure to give an oil which NO ?? was treated with 300 mL of ethanol and an activated carbon . The reaction mixture was heated to reflux for 1 h and then 15 Br K2CO3/ 2 - propanol the hot mixture was filtered through Celite . The filtrate was # X concentrated under reduced pressure to give an oil. This oil H3COH was purified by column chromatography using hexane / NC EtoAc (20 : 80 ) to give an oil which was crystallized from EtOAc / hexane to give 33 . 2 g (59 . 9 % ) of ( R ) - N - ( 4 -cyano - 20 F 3 - ( trifluoromethyl) phenyl ) - 3 - ( 4 -cyanophenoxy ) - 2 -hydroxy F C 2 -methylpropanamide ( R - isomer of Formula IX ) as a col NH orless solid . ?3??? ' H NMR (CDC12 / TMS) 8 1 .63 (s , 3H , CH3) , 3 .44 (s , 1H , OH ) . 4 . 07 ( d . J = 9 . 16 Hz , 1H , CH ) , 4 .51 ( d , J = 9 . 16 Hz, 1H , CH ) , 6 .97 -6 . 99 ( m , 2H , ArH ) , 7 .57 - 7 .59 ( m , 2H , ArH ) , Synthesis of ( S ) N - ( 4 - cyano - 3 - ( trifluoromethyl) 7 .81 ( d , J = 8 . 54 Hz, 1H , ArH ), 7 . 97 ( dd , J = 2 .07 , 8 . 54 Hz, 1H , phenyl) - 3 - ( 4 -fluorophenoxy )- 2 -hydroxy - 2 -methyl ArH ) , 8 . 12 ( d , J = 2 .07 Hz, 1H , ArH ) , 9 . 15 (bs , 1H , NH ) . propanamide (Formula X ) Calculated Mass : 389 . 10 , [ M - H ] - 388 . 1 . Mp : 92 - 94° C . A mixture of bromoamide ( 10 . 0 g , 28 . 5 mmol ), anhydrous Example 13 K , CO , ( 11 . 8 g , 85 . 4 mmol ) in 150 mL of acetone was heated to reflux for 1 h and then concentrated under reduced Synthesis of (S ) Enantiomer of Formula X pressure to give a solid . The resulting residue was treated with 4 - fluorophenol ( 4 . 8 g , 42 . 7 mmol) , anhydrous K , CO , ( 7 . 9 g , 57 . 0 mmol) , 150 mL of 2 - propanol and then heated 35 to reflux for 2 h . The resulting mixture was concentrated under reduced pressure to give a solid . This solid was treated 1 . SOC12, 0° C . to 4° C . / 3 hrs with 300 mL of H , O and extracted with EtoAc ( 2x250 mL ) . HO Y . Br The combined EtoAc extracts were washed with a saturated NaHCO3 solution (2x250 mL ) and brine. The organic layer HO 111110CH3 2 . Et3N , NC NH 40 was dried over MgSO4 and then concentrated under reduced pressure to give an oil which was purified by column chromatography using CH , C1, / EtOAC ( 80 : 20 ) to give a F3C solid . This solid was recrystallized from CH2C1y /hexane to NC . give ( S ) - N - ( 4 - cyano - 3 - ( trifluoromethyl ) phenyl) - 3 - ( 4 45 fluorophenoxy )- 2 -hydroxy - 2 -methylpropanamide (Formula X , 10 .04 g . 92 . 2 % ) as a colorless solid . F C X BpBr H NMR (CDC1z / TMS ) / 1 . 59 ( s , 3H , CH3) , 3 .36 ( s , 1H , OH ) , 3 .95 ( d , J = 9 .00 Hz , 1H , CH ) , 4 .43 ( d , J = 9 .00 Hz , ?? ?? 1H , CH ) , 6 .87 - 6 . 88 ( m , 2H , ArH ) , 6 . 96 - 7 .02 ( m , 2H , ArH ) , 7 .81 ( d , J = 8 .45 Hz, 1H , ArH ), 7 . 94 -7 . 98 ( m , 1H , ArH ), 8 . 10 50 ( d , J = 1. 79 Hz, 1H , ArH ), 9. 11 ( s, 1H , NH ). Calculated Mass : Synthesis of (2R ) - 3 - bromo- N - [ 4 - cyano - 3 - ( trifluo 382 .31 , [ M - H ] - 380 . 9 . Mp : 139 - 141° C . romethyl) phenyl ] - 2 - hydroxy - 2 -methylpropanamide Example 14 Thionyl chloride ( 46 .02 g , 0 .39 mol) was added dropwise 55 to a cooled solution ( less than 4° C .) of (R ) - 3 -bromo - 2 Synthesis of ( S ) Enantiomer of Formula XIII hydroxy - 2 -methylpropanoic acid (51 . 13 g , 0 .28 mol) in 300 mL of THF under an argon atmosphere . The resulting mixture was stirred for 3 h under the same condition . To this was added Et N ( 39 . 14 g , 0 . 39 mol ) and stirred for 20 min under the same condition . After 20 min , 5 - amino - 2 -cya - 60 nobenzotrifluoride (40 . 0 g , 0 . 21 mol) , 400 mL of THF were HO y Br SOCI / THF/ 0 .5° C . added and then the mixture was allowed to stir overnight at room temperature . The solvent was removed under reduced HzCOH pressure to give a solid which was treated with 300 mL of (R ) -3 -bromo -2 - hydroxy -2 H2O , extracted with EtoAc (2x400 mL ). The combined 65 methylpropanoic acid organic extracts were washed with saturated NaHCO , solu R - 18 tion ( 2x300 mL ) and brine (300 mL ) . The organic layer was US 9 , 744 , 149 B2 87 88 - continued -continued NC - CN

01 Br 5 Fac NH X H3COOH H3COH FjCF3C . NH2 N Et3N ho/RT aina H2 Et3N /RT CI X Br + 10 Synthesis of ( S ) - N - ( 4 - cyano - 3 - ( trifluoromethyl) phenyl) - 3 - ( 4 -cyano - 3 - fluorophenoxy ) - 2 - hydroxy - 2 H3COH NC methylpropanamide (Formula XIII ) NC . A mixture of bromoamide ( 2R ) - 3 -bromo -N -[ 4 -cyano -3 Br 15 ( trifluoromethyl) phenyl ] - 2 -hydroxy - 2 -methylpropanamide Fzc R - 19 ( 2 . 0 g , 5 .70 mmol ) ) , anhydrous K2CO3 ( 2 . 4 g , 17 . 1 mmol) in 50 mL of acetone was heated to reflux for 2 h and H3C H then concentrated under reduced pressure to give a solid . R - 19 The resulting solid was treated with 2 - fluoro - 4 -hydroxyben zonitrile ( 1 . 2 g , 8 . 5 mmol) and anhydrous K COZ ( 1 . 6 g , 20 11 . 4 mmol ) in 50 mL of 2 -propanol was heated to reflux for 3 h and then concentrated under reduced pressure to give a Synthesis of (2R )- 3 -Bromo - N -[ 4 -cyano - 3 -( trifluo solid . The residue was treated with 100 mL of H20 and then romethyl )phenyl ]- 2 -hydroxy -2 -methylpropanamide extracted with EtoAc (2x100 mL ) . The combined EtOAC extracts were washed with 10 % NaOH (4x100 mL ) and 25 brine , successively . The organic layer was dried over Thionyl chloride ( 46 .02 g , 0 .39 mol) was added dropwise MgSO , and then concentrated under reduced pressure to to a cooled solution ( less than 4° C . ) of R - 18 (51 .13 g, 0 .28 give an oil which was crystallized from CH2Cly/ hexane to mol) in 300 mL of THF under an argon atmosphere. R - 18 is give 0 .5 g ( 23 % ) of (S ) - N -( 4 -cyano -3 - (trifluoromethyl ) (R )- 3 -bromo - 2- hydroxy -2 -methylpropanoic acid was pre 5phenyl ) - 3 - ( 4 - cyano - 3 - fluorophenoxy ) - 2- hydroxy - 2 -methyl pared as described in Example 10 . The resulting mixture was 30 propanamide as a colorless solid . stirred for 3 h under the same condition . To this was added ' H NMR (CDC12 / TMS ) 8 1 .63 ( s , 3H , CH2 ), 3 .34 ( bs , Et- N (39 . 14 g . 0 . 39 mol) and stirred for 20 min under the H2OH ) , 4 .08 ( d , J = 9 . 17 Hz, 1H , CH ) , 4 . 50 ( d , J = 9 .17 Hz, same condition . After 20 min , 5 - amino - 2 -cyanobenzotrif zotrif - 1H , CH ) , 6 . 74 - 6 .82 ( m , 2H , ArH ) , 7 .50 - 7 .55 ( m , 1H , ArH ) , luoride (40 . 0 g , 0 .21 mol) , 400 mL of THF were added and 7 .81 ( d , J = 8 . 50 Hz, 1H , ArH ) , 7 . 97 ( q , J = 2 . 03 , 8 .50 Hz, 1H , then the mixture was allowed to stir overnight at room 355 ArH ) , 8 .11 ( d , J = 2 . 03 Hz, 1H , ArH ) , 9 . 12 ( s , 1H , NH ) . temperature . The solvent was removed under reduced pres Calculated Mass : 407. 1, [M +Na ] * 430 .0 . Mp : 124 - 125° C . sure to give a solid which was treated with 300 mL of H , O , Example 15 extracted with EtoAc (2x400 mL ) . The combined organic extracts were washed with saturated NaHCO , solution Synthesis of (S ) Enantiomer of Formula XIV ( 2x300 mL ) and brine ( 300 mL ). The organic layer was 40 dried over MgSO4 and concentrated under reduced pressure to give a solid which was purified from column chromatog raphy using CH2Cl2 / EtOAC (80 :20 ) to give a solid . This solid was recrystallized from CH C1, /hexane to give 55. 8 g 45 ( 73 . 9 % ) of ( 2R )- 3 - bromo - N -[ 4 - cyano - 3 - (trifluoromethyl ) HO Br SOCI /THF /0 .5° C . phenyl] - 2 -hydroxy - 2 -methylpropanamide ( R - 19 ) as a light H COH yellow solid . ( R )- 3 -bromo - 2 -hydroxy - 2 ' H NMR (CDC1z / TMS) 8 1 .66 ( s , 3H , CH3) , 3 . 11 ( s , 1H , methylpropanoic acid OH ), 3 .63 ( d , J = 10 .8 Hz, 1H , CH2) , 4 .05 ( d , J = 10 . 8 Hz, 1H , 50 R - 18 CH2) , 7 .85 ( d , J = 8 . 4 Hz, 1H , ArH ) , 7 . 99 (dd , J = 2 . 1 , 8 . 4 Hz, 1H , ArH ), 8. 12 ( d , J = 2 . 1 Hz, 1H , ArH ), 9 .04 (bs , 1H , NH ). Calculated Mass: 349 .99 , [M - H ] - 349 . 0 . M . p. : 124 - 126° C . C1 x Br 55 ?; ? ?? NC FC ANH Et3N /RT ci Y . BrBr +

NH Br + H?c OH NC H3COH NC R - 19 CN Br K2CO3 Fzc 2- propanol H3COH HO VF R - 19 US 9 ,744 , 149 B2 89 90 Synthesis of ( 2R ) - 3 - Bromo - N - [ 4 -cyano - 3 - ( trifluo sively . The organic layer was dried over MgSO4 and then romethyl) phenyl ] - 2 -hydroxy - 2 -methylpropanamide concentrated under reduced pressure to give an oil which was purified by column chromatography using EtOAc / Thionyl chloride (46 .02 g , 0 .39 mol) was added dropwise hexane (50 :50 ) to give a solid which was recrystallized from to a cooled solution ( less than 4° C . ) of R - 18 (51 . 13 g , 0 . 28 5 CH C12 / hexane to give 1 . 7 g (70 . 5 % ) of ( S ) - 3 - ( 4 - chloro - 3 mol) in 300 mL of THF under an argon atmosphere . R - 18 is fluorophenoxy ) - N - ( 4 - cyano - 3 - ( trifluoromethyl ) phenyl) - 2 ( R ) - 3 -bromo -2 -hydroxy -2 -methylpropanoic acid was pre - hydroxy - 2 -methylpropanamide as a colorless solid . pared as described in Example 10 . The resulting mixture was ' H NMR (CDC12 / TMS) 1 .60 (s , 3H , CH3) , 3 .28 (s , 1H , stirred for 3 h under the same condition . To this was added OH ), 3 .98 (d , J= 9 .05 Hz , 1H , CH ), 6 .64 -6 .76 ( m , 2H , ArH ), Et2N (39 . 14 g , 0 . 39 mol) and stirred for 20 min under the 10 7 . 30 ( d , J = 8 .67 Hz, 1H , ArH ) , 7 . 81 ( d , J = 8 .52 Hz, 1H , ArH ) , same condition . After 20 min . 5 -amino - 2 - cyanobenzotrif- 7 . 96 ( q , J = 2 .07 , 8 . 52 Hz, 1H , ArH ) , 8 . 10 ( d , J = 2 .07 Hz, 1H , luoride (40 .0 g , 0 .21 mol) , 400 mL of THF were added and ArH ), 9. 10 (s , 1H , NH ). Calculated Mass: [M -H ]- 414 . 9 . then the mixture was allowed to stir overnight at room Mp: 132 - 134° C . temperature . The solvent was removed under reduced pres - 1 sure to give a solid which was treated with 300 mL ofH20 , Example 16 extracted with EtoAc (2x400 mL ) . The combined organic extracts were washed with saturated NaHCO3 solution Binding and Transactivation of SARMs in Breast ( 2x300 mL ) and brine ( 300 mL ) . The organic layer was Cancer Cells driedto give over a solidMQDUn , which and concentratedwas purified underfrom reducedcolumn pressurechroma 20 In order to determine whether compounds of this inven . tography using CH . C1 .JETOAc ( 80 :20 ) to give a solid . This tion are agonists in breast cancer cells , HEK - 293 or MDA solid was recrystallized from CH C12/ hexane to give 55. 8 g MB - 231 cells were transfected with 0 . 25 ug GRE - LUC , 10 ( 73. 9 % ) of ( 2R ) - 3 - bromo- N - [ 4 - cyano - 3 - (trifluoromethyl ) ng CMV - renilla LUC , and 25 ng CMV -HAR using lipo phenyl) - 2 -hydroxy - 2 -methylpropanamide ( R - 19 ) as a light- , fectamine . Twenty four hours after transfection , the cells yellow solid . 25 were treated with DHT, compound of Formula VIII or TH NMR (CDC1 . / TMS ) 8 1 .66 ( s . 3H . CH . ). 3 . 11 ( s . 14 . compound of Formula IX and luciferase assay was performed 48 hrs after transfection . Competitive OH ), 3 .63 ( d, J= 10 . 8 Hz , 1H , CH2) , 4 .05 (d , J = 10 .8 Hz , 1H , binding of DHT, compound of Formula VIII and compound CH2) , 7 .85 ( d , J = 8 . 4 Hz, 1H , ArH ) , 7 .99 (dd , J = 2 . 1 , 8 . 4 Hz , of Formula IX were measured using an in vitro competitive 1H , ArH ) , 8 . 12 ( d , J = 2 . 1 Hz, 1H , ArH ) , 9 . 04 ( bs, 1H , NH ) . 30 radioligand binding assay with [17a -methyl - 3H ] -mibole Calculated Mass : 349 . 99 , [ M - H ] - 349. 0 . M . p .: 124 - 126° C . rone ([ H ]MIB ) , a known steroidal and high affinity AR ligand , and purified AR - LBD protein . NC Results 35 DHT, compound of Formula VIII and Formula IX are FC NH Br + agonists of AR in breast cancer cells as presented in FIG . 13A - 13C (HEK - 293 cells in FIG . 13A and MDA -MB - 231 H3COH cells in FIGS. 13B - 13C ) . The relative binding affinities R - 19 (RBAS ) for AR of DHT, Formula IX , Formula VIII , and K2CO3 bicalutamide were 1 . 0 , 0 .330 , 0 .314 , and 0 .016 , respectively , 2 - propanol demonstrating high affinity AR binding for the SARM HOW compounds of this invention ( data not shown ) . NC HO OT) 2 Example 17 45 Inhibition of Intratumoral Gene Expression Fac NH T AR agonists differentially regulate genes in AR -positive H3COOH and AR - negative breast cancer cells . MDA -MB - 231 and 50 MCF - 7 cells infected with AR or GFP containing adenovirus were maintained in charcoal stripped serum containing Synthesis of ( S ) - 3 - ( 4 - chloro - 3 - fluorophenoxy ) - N medium for 3 days and were treated with DHT or Formula ( 4 -cyano -3 -( trifluoromethyl) phenyl ) - 2 -hydroxy -2 VIII . After overnight treatment, the cells were harvested , methylpropanamide (Formula XIV ) RNA isolated and realtime PCR for the indicated genes 55 were performed . The expression of various genes in A mixture of bromoamide ( ( 2R ) - 3 -bromo - N - 14 - cyano - 3 - response to either DHT or Formula VIII were measured and ( trifluoromethyl) phenyl ] - 2 - hydroxy - 2- methylpropanamide normalizednor to GAPDH , and are presented as composite data ( R - 19) 2 . 0 g , 5 . 70 mmol )) , anhydrous K2CO3 ( 2 . 4 g , 17 . 1 (same effects for DHT and Formula VIII ) in Table 2 . mmol) was heated to reflux for 2 h and then concentrated under reduced pressure to give a solid . The resulting solid 60 TABLE 2 was treated with 4 - chloro - 3 - fluorophenol ( 1 . 3 g , 8 . 5 mmol) Differential Regulation of Gene Expression by AR Ligands in ER and anhydrous K2CO3 ( 1 . 6 g , 11 . 4 mmol) in 50 mL of Positive (MCF7 ) and ER - Negative (MDA -MB - 231) Breast Cancers 2 -propanol was heated to reflux for 3 h and then concen trated under reduced pressure to give a solid . The residue AR PSA Muc1 SLUG VCAM1 SPARC MMP2 was treated with 100 mL of H , O and then extracted with 65 MDA -MB EtOAC ( 2x100 mL ) . The combined EtoAc extracts were 231/ GFP washed with 10 % NaOH (4x100 mL ) and brine , succes US 9 , 744 , 149 B2 91 92 TABLE 2 -continued Results Differential Regulation of Gene Expression by AR Ligands in ER Positive (MCF7 ) and ER - Negative MDA( -MB - 231 ) Breast Cancers The graph presented in FIG . 17 demonstrates inhibition of Triple -Positive Breast Cancer (ER , PR , and HER2 ) using AR PSA Mucl SLUG VCAM1 SPARC MMP2 5 Formula VIII. The results show that Formula VIII inhibited MDA -MB - III the growth of MCF - 7 breast cancer cell xenografts by 231 / AR greater than 50 % . MDA -MB - 231 / AR The results presented in FIG . 18 show Formula VIII cs FBS 10 inhibited uterus weight in these estrogen supplemented MCF7 /GFP no no MCF7 / AR |1 no no animals . MCFT / AR no 11 no The results presented in FIG . 19 demonstrate that the AR cs FBS expression pattern in response to agonist (Formula VIII) is ofVCAMI cells and — Vascularalso is a cellchemoattractant adhesion protein. - 1 - Important for anchorage - dependent growth 15 similar to that observed in prostate cancer cells (data not SPARC — Secreted protein acidic and rich in cysteine (aka Osteonectin ) - extracellular shown ). glycoprotein important for angiogenesis . MUC1 - Mucinl - Extracellular glycoprotein associated with cancers - Its promoter has a strong ARE . SLUG - Zinc finger transcription factor - Its promoter has a strong ARE . Example 20 MMP2 - matrix metalloproteinase - 2 - gene that is activated by cell - cell clustering . 20 Formula VIII Up- Regulates JNK Phosphorylation Example 18 in MCF7 - AR Tumors Protein from MCF - 7 - AR tumors that were treated with Gene Expression Array of MDA -MB -231 -AR vehicle or compound of Formula VIII were extracted and Xenograft incubated with phospho MAPK array to determine the effect of compound of Formula VIII on phosphorylation of various RNA was extracted from MDA -MB - 231 - AR tumors ( n = 5 / group ) treated with vehicle or compound of Formula kinases. VIII. RNA was pooled and Affymetrix microarray was 30 Results performed to determine the change in expression of gene signature . The results presented in FIG . 21 show that JNK phos phorylation is upregulated in MCF - 7 - AR tumors by treat Results ment with compound of Formula VIII. JNK plays a critical 35 role in death receptor -mediated intrinsic and extrinsic apop The results presented in FIG . 15 show that activation of totic pathways. JNK activates apoptotic signaling by up AR in MDA - MB - 231- AR xenografts suppressed the expres - regulating pro - apoptotic genes . The observed phosphory sion of more genes than it induced in these tumors . This lation of the pro - apoptotic kinase , JNK , may be suggestive pattern is unique in breast cancer cells and is different from 40 of a possible mechanistic explanation of the anti -prolifera gene expression results observed in prostate cancer cells , tion . where more genes are induced than repressed (data not shown ). Example 21 The results presented in FIG . 16 validate the micro -array results presented in FIG . 15 by analyzing selected genes 45 Gene Expression Analysis ofMDA -MB - 231- AR using realtime PCR TaqMan primers and probe in ABI 7900 . and MCF - 7 - AR Xenografts Following Treatment with Formula VIII and Formula IX Example 19 Microarray Analysis was performed on RNA from MDA Formula VIII Inhibits the Growth of MCF - 7 -AR 50M MPB _- 921 231. - AR .and MCF - 7 - AR tumors in order to identify and Xenograft compare changes in gene expression in ER - negative (MDA MB -231 -AR ; triple negative ) an ER -positive (MCF -7 - AR ; MCF- 7 cells stably transfected with AR using lentivirus triple positive ) breast cancer tumors treated with a com were implanted ( 2 million cells /mouse ; n = 5 ) in nude mice 55 pound of Formula VIII (30 mg/ kg /day p .o . for 4 weeks) . that were ovariectomized and supplemented with estradiol Affymetrix analysis of the xenografts was done on pooled (50 ug /day ) . Once tumors reached 100 - 200 mm " , the ani - samples of the xenografts . The analysis included ~ 70 , 000 mals were randomized and treated with vehicle or 30 mg/ kg sequences with ~ 30 ,000 genes and variations thereof repre per day of Formula VIII . Tumor volumes and body weights sented , as well as microRNA ' s . RNA was isolated and were measured thrice weekly . At the end of 5 weeks of 60 expression of genes was evaluated using microarray (Af treatment, the animals were sacrificed , tumors weighed and fymetrix Human Gene ST 2 .0 array ) . Expression of genes in stored for RNA and protein isolation and histology. * compound of Formula VIII - treated samples was compared significance at P < 0 . 05 . with the expression in vehicle - treated samples . Genes that In addition , uterus weights were measured in these xeno - 65 were up - or down - regulated by more than 2 fold were graft studies, and Western blot from MCF -7 tumor xeno considered differentially regulated by compound of Formula grafts were probed for AR . VIII. US 9 ,744 ,149 B2 93 94 Results TABLE 4 Breast cancer relevant genes modulated Table 3 below presents the sum totals of up - regulated and in MDA -MB -231 - AR tumors down - regulated genes in MDA -MB - 231 - AR and MCF - 7 - 5 Formula AR tumors . Gene Function VIII NQO1 Anti- proliferative , reduces oxidative stress Increased TABLE 3 of cells , regulates p53 - dependent apoptosis Increases proliferation and metastasis of Decreased 10 Adrenoceptor2 breast cancer, increases inflammation Type Up DownDown TotalTotal Aurora Increase proliferation of breast cancer and Decreased kinase aurora kinase inhibitors are effective MCF - 7 - AR 566566 981 1547 preclinically BUB1 expression correlates with tumor status , Decreased MDA -MB - 231 - AR 720720 816 15361536 S / T kinase node - and distant- metastasis , and 15 histological grade in BC ENPE Promotes breast cancer growth , small Decreased molecule inhibitors of CENPE inhibit Of particular interest was that of the 1547 regulated genes BC cell growth EHMT2 Up - regulated in variety of cancers, Decreased identified in MCF- 7 - AR tumors and the 1536 regulated including breast genes identified in MDA -MB - 231- AR tumors , the subset of ERCCI Expressed in 70 % TNBCs and its expression Decreased overlapping genes was only 245 genes. This result indicated 20 leads to resistance to chemotherapy IGFBP3 Increases proliferative disease , higher Decreased that Formula VIII regulated distinct sets of genes in MCF IGFBP3 in serum correlates with higher 7 - AR (ER - positive; triple positive ) and MDA -MB - 231 -AR grade disease ITGA2 Cancer development and metastasis Decreased (ER -negative ; triple negative ) breast cancer cells . PARP1 PARP inhibitors are currently under Decreased Tables 4 and 5 below presents genes involved in mam - 25 development for breast cancer POLD1 Associated with multiple cancers , Decreased mary tumorigenesis that were differentially regulated (by at including breast cancer least 2 fold ) by Formula VIII in MDA -MB - 231 - AR tumors PTPRJ Tumor suppressor Increased ( Table 4 ) and MCF - 7 - AR tumors ( Table 5 ) . Indications of SERPINE1 Tumor suppressor and inhibitor of Increased up - regulation or down - regulation are presented in the right angiogenesis , invasion and metastasis most column . TABLE 5

Breast cancer relevant genes modulated in MCF - 7 -AR tumors

Formula Gene Function VIII

MTR Increases breast cancer risk Decreased FACGD2 Inhibition increases the sensitivity to cancer therapeutics Decreased TIMP3 Silenced in several aggressive cancers due to promoter Increased methylation XRCC1 High XRCC1 leads to poor survival of cancer patients Decreased AHR Increases sensitivity to anti - cancer agents , good prognostic Increased marker, agonists are used for cancers Catalase Inversely correlates with breast cancer risk , good marker, Increased prevents DNA damage CDT1 Promotes replication , increases cancer incidence Decreased ER - a Promotes breast cancer proliferation Decreased EHMT1 Tumor suppressor complex protein Increased ERCC2 Promotes breast cancer and other cancers through DNA Decreased damage IRS1 Highly expressed in breast cancer, over -expression in mice Decreased increases breast cancer incidence KLK3 KLK3 ( PSA ) increase is highly correlative of positive Increased breast cancer outcome; good prognostic marker PR Increases proliferation of breast cancer Decreased PON2 Anti -oxidative properties ; cells over - expressing PON2 Increased have reduced oxidative stress ; anti -cancer NPAS2 Tumor suppressor gene Increased US 9 ,744 , 149 B2 95 96 The results presented in Tables 3 and 4 show that SARM Formula VIII and Formula IX demonstrated ~ 85 % TGI at all treatment (Formula VIII ) caused net down - regulation of doses tried ( 5 , 10 mg per kg for Formula VIII; 5 , 10 , 30 mg genes in MDA -MB -231 - AR tumors ( N = 1042 suppressed ; per kg for Formula IX ) in the triple negative breast cancer N = 640 induced ; threshold of 2 - 2 . 5 - fold increase or decrease ( note : plot is log of fold change ; follow - up RT -PCR dem - 5 model using MDA -MB - 231 - AR cells in nude mice. onstrated 10 - 20 - fold changes ). Well known androgen - de The results presented in FIG . 23 demonstrate inhibition of pendent genes ( e . g . FKP5 and MUC1; See Table 6 below ) triple negative breast cancer using Formulae VIII and IX . were elevated , showing SARM penetration into the tumor. Tumor weights were likewise reduced for all doses of Also 29/ 36 known breast cancer - related genes were shown Formula VIII and Formula IX . Spleen enlargement (680 mg to be decreased , supporting a rational basis for the anti vs. 200 - 300 mg for normal mice) was seen only in vehicle proliferation activity of Formula VIII in ER -negative breast treated mice, possibly indicative of prevention by the cancer . SARMs of tumor metastasis to the spleen . Further analysis of the results in MDA -MB - 231 - AR The in vitro data shown in MCF - 7 cells with and without tumors showed that Formula VIII induced known androgen AR (FIGS . 25A -25E ) support that SARM -activated AR may responsive genes ( Table 6 below ) . Thus , breast cancer 16 sequester the co - factors that are used by ER . Adding AR to relevant genes such as beta2 - adrenergic receptor and PARPI the MCF - 7 cells increased the effect of estradiol (when were suppressed by Formula VIII ; whereas ARE - dependent unopposed ) on the ER target genes PR and PS2, but the genes were induced by treatment of Formula VIII . antagonism caused by SARM alone or SARM + estradiol (E2 ) was enhanced in this setting ( FIGS. 25B and 25D ) as TABLE 6 20 compared to GFP ( i. e . no AR ; FIGS. 25A and 25C ). FIG . Gene Fold Function 25E shows that AR target genes are enhanced by SARM even in the presence of estradiol. TFPi2 4 .76 Tumor suppressor, protease inhibitor family F3 6 . 94 Coagulation factor Example 22 Carboxipeptidase 3 .25 Androgen responsive gene 25 SNAI2 / SLUG 2 . 10 Androgen responsive gene Xenograft Experiment with Formula IX ASAM 3 .27 DUSP1 4 .14 Inactivates MAPK , androgen responsive gene Xenograft Experiment. Col12al 5 .93 Amphiregulin 4 .47 Regulated by androgens and estrogens NSG mice obtained from JAX labs were housed with five Protein S 3 .69 Regulated by estrogen ( down ) and 30 animals per cage and were allowed free access to tap water progestin (up ) and commercial rat chow (Harlan Teklad 22 /5 rodent diet PDLIM1 2 .06 PR regulated gene 8640 ) . During the course of the study, the animals were FBX032 6 .62 Very interesting gene. Androgens inhibit maintained on a 12 hr light: dark cycle . Animals were in muscle , Promotes muscle atrophy , ubiquitin , Mixed functions in cancer anesthetized and BR -0001 TNBC fragments of 1 mm3 RASD1 18 .62 GC -stimulated gene , Down- regulated in ( approximately ) were implanted subcutaneously in NSG GC - resistant melanoma mice . Once the tumor size reached 100 - 200 mm ” , the IRS2 4 . 40 FKBP51 0 Androgen and GC stimulated gene animals were randomized and treated with vehicle control MUC1 9 Androgen and estrogen stimulated gene ( polyethylene glycol: DMSO 9 : 1 ratio ) or 10 mg/ kg /day DUSP23 7 .35 Androgen stimulated an Formula IX ( n = 12 ) or enzalutamide orally . Tumor volume PTGS2 14 Androgen stimulated was measured thrice weekly . Tumor volume was calculated RHOB 7 .92 Androgen regulated using the formula lengthxwidthxwidthx0 .5236 . Once tumors reached greater than 1500 - 2000 mm , animals were The results presented in Tables 3 and 5 show that Formula sacrificed and tumors weighted and stored for various analy VIII did not have as strong of a gene suppressive tone in 45 sis. Two regions of the same BR - 0001 tumor, an AR - positive MCF - 7 -AR triple positive (ER - positive ) tumors as in triple TNBC xenograft , were immunohistochemically stained with negative ( ER -negative ) tumors . Interestingly though , the AR antibody ( AR N20 from SCBT) ( FIGS . 26A and 26B ) MCF -7 - AR analysis showed that androgen -dependent genes and compared to an AR - negative (FIG . 26C ) TNBC as a were up regulated and estrogen -dependent genes were sup negative control. FIGS . 26A and 26B show that AR expres pressed ( Table 7 below ), as validated by RT- PCR . 50 sion is consistent throughout this formalin - fixed , paraffin embedded ( FFPE ) tissue , whereas similar FFPE in AR TABLE 7 negative TNBC demonstrated no staining (no AR Androgen Target Estrogen Target expression ) . The tumor xenograft efficacy experimental results are provided in 27A - 27C , with FIGS. 27A and 27B KLK3 (PSA ) PR SNAI2 ER 55 being replicate experiments . MUC1 IGFBP4 IRS2 PS2 Example 23 FKBP5 DUSP23 Ki -67 Staining was Reduced in Tumors of Animals miR21 60 Treated with Formula IX The results presented in FIG . 20 validate the micro -array FIG . 28 demonstrated an approximately 50 % reduction in results presented in the above analyses, by analyzing Ki-67 staining in 2 weeks of treatment. Tumors from rep selected genes using realtime PCR TaqMan primers and licate experiment 2 (FIG . 27B ) were fixed in formalin and probe in ABI 7900 . 65 paraffin embedded . Slides were cut and stained with Ki-67 The results presented in FIG . 22 shows inhibition of triple antibody. Ki- 67 positive cells ( total 200 cells were counted negative breast cancer growth using Formulae VIII and IX . in each slide ) in each slide were counted and represented as US 9 ,744 , 149 B2 97 98 % stained cells , as shown in FIG . 28B . Ki- 67 staining was the SARM - treated tumors, gene markers for LAR and MSL reduced in tumors of the animals treated with Formula IX . subtypes are highly expressed . Gene expression data was compared to PAM50 to deter Example 24 mine the tumor type that BR - 0001 belonged to . The expres 5 sion ( Z - score ) of 50 genes required to classify the breast Gene Expression Study and ChIP - SEQ Study in cancer is given in FIG . 29 , in which PAM50 indicated that Tumor Xenografts the tumor belonged to basal - like breast cancer (BLBC ) TNBC . Methods Triple - negative breast cancer ( TNBC ) is a heterogeneous Chromatin Immunoprecipitation Assay (CHIP ). 10 breast cancer group , and identification of its subtypes is Proteins were cross - linked by incubation with 1 % form essential for understanding the biological characteristics and aldehyde ( final concentration ) at 37° C . for 10 min . Tumors clinical behaviors of TNBC as well as for developing were homogenized using a probe hand -held homogenizer . personalized treatments . Based on 3 , 247 gene expression The cells were washed with 1xPBS twice , scraped in 1 mL profiles from 21 breast cancer data sets , six TNBC subtypes, of PBS containing protease inhibitors ([ 1 mg each of apro - 15 including 2 basal- like (BL1 and BL2 ) , an immunomodula tinin , leupeptin , antipain , benzamidine HCl, and pepstatin tory ( IM ), a mesenchymal ( M ) , a mesenchymal stem - like ml] , 0 . 2 mM phenylmethylsulfonyl fluoride, and 1 mM (MSL ) , and a luminal androgen receptor (LAR ) subtype sodium vanadate ), pelleted , and resuspended in SDS lysis from 587 TNBC samples with unique gene expression buffer ( 1 % SDS, 10 mM EDTA , 50 mM Tris -HC1 [pH 8 . 1 ]) . patterns and ontologies , were discovered ( J Clin Invest After lysis on ice for 10 min , the cell extract was sonicated 20 Brian D . Lehman et al. , 2011, 121 ( 7 ) , 2750 - 2767 ) . Cell line ( Branson sonifier 250 ) in a cold room eight times for 10 s models representing each of the TNBC subtypes also dis each at constant duty cycle , with an output of 3 and with plaved different sensitivities to targeted therapeutic agents . incubation on ice after every sonication . The debris was Gene expression data was compared to the genes published pelleted at 13 ,000 rpm for 10 min at 4° C ., and the (Pietenpol group ) to classify the BLBC into sub - classifica supernatant was diluted 10 - fold with ChIP dilution buffer 25 tion . FIG . 30 depicts that Pietenpol classification of TNBC ( 0 .01 % SDS , 1 . 1 % Triton X - 100 , 1 . 2 mM EDTA , 16 . 7 mM suggests that the BR -0001 tumor is LAR and MSL subtypes . Tris HC1 [ pH 8 . 1 ] , 167 mM NaCl) . The proteins were precleared with 50 uL of 1 : 1 protein A - Sepharose beads in Example 25 TE . An aliquot ( 300 UL ) was reserved as input, while the remaining solution was incubated with 5 ug of AR antibody 30 Gene Expression Changes in Xenograft Tumors ( AR N20 SCBT ) and 2 ug of sheared salmon sperm DNA (Stratagene , La Jolla , Calif. ) rotating overnight at 4° C . FIG . 31 demonstrates that in BR -0001 Formula IX up The protein -DNA -antibody complex was precipitated by regulated gene expression . Approximately 4200 genes were incubating with 100 uL of 1 : 1 protein A -Sepharose beads up - regulated by Formula IX compared to vehicle, while and 2 ug of salmon sperm DNA at 4° C . for 2 h . The beads 35 approximately 1170 genes were down - regulated by Formula were pelleted and washed three times with low - salt wash IX compared to vehicle . Formula IX recruited AR to 176 buffer (0 . 1 % sodium dodecyl sulfate (SDS ) , 1 % Triton promoters ( - 5 kb to + 1 kb ) . 20 % of the promoters occupied X - 100 , 2 mM EDTA , 20 mM Tris HC1 (pH 8 . 1 ] , 0 . 15 M by the AR in response to Formula IX also had the gene NaCl) , and twice with 1xTE ( 10 mM Tris HC1, 1 mM up - regulated by Formula IX . This showed that these genes EDTA ; PH 8 . 0 ) . DNA - protein complexes were obtained by 40 were direct targets of the AR rather than an indirect effect . extracting the beads with 50 uL of freshly prepared extrac - The Ingenuity Pathway Analysis ( http : // www . ingenuity tion buffer (1 % SDS, 0 . 1 M NaHCO3 ) three times. Cross .com /; QIAGEN , Redwood City , Calif .) suggests that genes linking of the DNA protein complexes was reversed by involved in cell cycle were altered by Formula IX . incubating at 65° C . for 6 h . The DNA was extracted with a QIAquick PCR purification kit ( QIAGEN , Valencia , Calif . ) 45 Example 26 in 25 uL final volume of TE . The purified DNA was given to University of Tennessee Health Science Center Molecular The Efficacy and Safety of Formula IX on Resource Center (UTHSC MRC ) for next generation Metastatic or Locally Advanced ER + / AR + Breast sequencing using ion proton sequencer. Cancer (BC ) in Postmenopausal Women RNA Analysis and Microarray. 50 Tumors were homogenized , RNA isolated , purified and Study Design : submitted to the UTHSC MRC core facility for microarray This is an open label, multicenter , multinational , random analysis (ST2 . 0 array from Affymetrix ) . ized , parallel design Phase 2 study, and is to assess the Results efficacy and safety of Formula IX in postmenopausal sub In the gene expression study described above , RNA was 55 jects with ER + / AR + BC . Subjects will be randomized to isolated from the TNBC tumors and the expression of genes receive either Formula IX 9 mg or 18 mg given PO daily for in the entire genome was measured by microarray (Affyme - up to 24 months . Each dose arm will be treated indepen trix , ST2 . 0 array ) . In the ChIP - Seq study, chromatin immu- dently and each assessed for efficacy using Simon ' s two noprecipitation was performed in untreated BR - 0001 speci- stage ( optimal ) design (Simon R . Optimal two - stage designs men and the DNA immunoprecipitated with AR antibody 60 for Phase 2 clinical trials . Controlled Clinical Trials 1989 ; was sequenced using ion torrent next- generation sequencer. 10 : 1 - 10 ) . Subjects will be randomized in a 1 : 1 fashion to It was shown that ~ 20 % of AR -occupied promoters ( - 5 kb one of the two dose arms. to + 1 kb ) were activated by androgen (mRNA increased by Randomization will be stratified by subjects presenting > 1 . 5 fold ) ( data not shown ) . Androgen treatment primarily with bone only metastases and all other subjects , and further affected cell cycle and metabolic process according to gene 65 by setting of immediately preceding therapy (adjuvant set set enrichment analysis (GSEA ) (FIG . 31 ) . Expression of ting or metastatic setting ) in order to balance the proportion TNBC subtype markers in FIGS. 30A and 30B show that in of subjects with these presenting features in each dose arm . US 9 ,744 , 149 B2 99 100 There is no intent to statistically compare the two dose arms, 24 months ) . Subjects who continue to demonstrate a CB but to determine whether either or both doses result in an from the study treatment at 24 months will be offered to acceptable clinical benefit response (CBR ) , defined as the continue in a safety extension study under a separate pro proportion of evaluable subjects ( i . e . , subjects with centrally tocol. For safety purposes , all subjects will be followed - up confirmed AR + and who receive at least one dose of study 5 for one month after the last dose of Formula IX is received . drug ) with either CR , PR , or SD by RECIST 1 . 1 at week 24 , For safety purposes , all subjects will be followed -up for consistent with 30 % while maintaining an acceptable safety one month after the last dose of Formula IX is received . profile . Given such a result, future exploration of Formula Target Population : IX in ER + AR + BC would be warranted at that dose level . Thirty - six to eighty - eight ( 36 - 88 ) subjects with centrally 10 Adult postmenopausal women with metastatic or recur confirmed AR + who receive at least one dose of study drug rent locally advanced ER + /AR + BC . ( evaluable subjects ) will be needed for primary efficacy Study Duration : analysis purposes and will be a subset of the full analysis set The study duration is estimated at 3 years . ( FAS) . Thirty - six to one hundred and eighteen ( 36 - 118 ) Description of Agent or Intervention : subjects , including replacement subjects , will be random - 15 Three ( 3 ) Formula IX 3 . 0 mg softgels for a 9 mg daily ized in a 1 : 1 fashion to receive a daily PO dose of either dose or six (6 ) Formula IX 3 . 0 mg softgels for an 18 mg Formula IX 9 mg or 18 mg. Thirty of the aforementioned daily dose will be taken PO with water at approximately the subjects may be considered replacement subjects to account same time each day, with or without food . for lack of centrally confirmed AR + status or for the rare Potential Benefits : subject who is randomized but does not receive study drug 20 Formula IX 9 mg once daily has been studied in 22 (assumes 25 % of enrolled subjects are not evaluable for the postmenopausal women with metastatic ER + BC who have primary efficacy analysis ) . Other statistical parameters that previously responded to hormonal therapy . The primary are part of the sample size calculation are a = 0 .025 (one endpoint was assessed in 17 AR positive subjects . Six of sided ) and power = 90 % . The first stage in each study arm these 17 subjects demonstrated CB (SD ) at six months . In will be assessed among the first 18 evaluable subjects . If at 25 one subject with SD (RECIST 1 . 1 ), tumor regression of 27 % least 3 / 18 subjects achieve CB (defined as CR , PR , or SD ) in a single target lesion was demonstrated . Seven subjects in at week 24 , the arm will proceed to the second stage of total ( one subject with indeterminate AR status ) achieved recruitment up to a total of 44 evaluable subjects per arm . CB at six months. Among the seven subjects who achieved Otherwise , the arm will be discontinued for lack of efficacy. CB at six months , time to progression ( TTP ) was estimated Statistical significance , i. e . , rejection of the null hypothesis 30 as 10 . 2 months . The results also demonstrated that , after a of an unacceptably low CBR of s10 % in favor of the median duration on study of 81 days , 41 percent of all alternative hypothesis that indicates the higher rate , 30 % , subjects ( 9 / 22 ) achieved CB as best response and also had is more likely, will be declared if at least 9 /44 subjects increased PSA , which appears to be an indicator of AR achieve CB at week 24 in that arm . activity . As of the finalization of this protocol, the study is Subjects who are not centrally confirmed AR + may 35 still ongoing with one subject whose disease remains stable remain on the trial, but will not be part of the primary beyond 336 days . efficacy analysis — these subjects will contribute to second Preclinical data with Formula IX suggests that it is also ary and tertiary analyses. anaanabolic in bone and decreases bone turn over markers . Subjects on the 18 mg treatment arm who experience an Treatmentwith Formula IX may decrease bone turn over as adverse event (AE ) with Grade 23 intensity (National Can - 40 compared with other hormonal therapies for the treatment of cer Institute - Common Terminology Criteria for Adverse hormone receptor positive BC . Stronger bone microenvi Events [NCI - CTCAE ) , Version 4 . 0 ) and / or intolerance may ronment may decrease metastases to bone or delay time to have a dose reduction from 18 mg to 9 mg per day or a drug skeletal related events. interruption based on the medical judgment of the Investi Efficacy Objectives gator and after confirmation by the study Medical Monitor. 45 The primary efficacy objective of this trial is to estimate The drug interruption may last for a period of up to 5 days the CBR at 24 weeks (defined as complete response (CR ) , after which the subject must be rechallenged with study drug partial response [ PR ] , or SD ) (by RECIST 1 . 1 ) of Formula ( 18 mg or 9 mg) or discontinued from the study . In the case IX 9 mg and of Formula IX 18 mg given PO daily in subjects of a dose reduction , once the AE has resolved or reduced in with estrogen receptor positive and androgen receptor posi intensity to Grade 1 , the subject may be rechallenged with 50 tive (ER + /AR + ) BC who have centrally confirmed AR + 18 mg or maintained at 9 mg at the discretion of the status. Investigator. The Secondary efficacy objectives are to estimate the Subjects on the 9 mg treatment arm who experience an AE CBR at 24 weeks (by RECIST 1 . 1 ) of Formula IX 9 mg and with Grade 23 intensity (NCI - CTCAE 4 . 0 ) and /or intoler- 18 mg in all subjects randomized who receive at least one ance may have a drug interruption based on the medical 55 dose of study medication ( the full analysis set [ FAS ]) judgment of the Investigator and after confirmation by the regardless of AR status as determined by the central labo study Medical Monitor. The drug interruption may last for a ratory . period of up to 5 days after which the subject must be The additional secondary efficacy objectives apply to both rechallenged with study drug ( 9 mg ) or discontinued from centrally confirmed AR + subjects ( the evaluable subset of the study. 60 the FAS ) as well as to all subjects in the FAS : ( a ) Estimate For safety analysis, subjects will be analyzed in the the objective response rate (ORR ; defined as CR or PR ) (by treatment arm in which they are initially dosed . For efficacy RECIST 1 . 1 ) of Formula IX 9 mg and 18 mg at 24 weeks ; analysis , subjects will be analyzed according to the treat - ( b ) Estimate the best overall response rate (BOR ) of For ment arm to which they were randomized . mula IX 9 mg and 18 mg; ( c ) Estimate the progression free The subjects who demonstrate CB will be treated for up 65 survival ( PFS ) of subjects receiving Formula IX 9 mg and 18 to 24 months from the date of randomization (as long as they mg ; ( d ) Estimate the TTP of subjects receiving Formula IX continue to demonstrate CB from the treatment during these 9 mg and 18 mg; and (e ) Estimate duration of response ( time US 9 ,744 , 149 B2 101 102 from documentation of tumor response to disease progres ately after collection , the tubes will be gently inverted sion or death ) of subjects receiving Formula IX 9 mg and 18 several times to mix the anticoagulant with the blood mg. sample . The tertiary objectives apply to both centrally confirmed Blood samples will be kept on wet ice ice packs in a AR + subjects ( the evaluable subset of the FAS ) as well as to 5 water bath is also acceptable ) for up to 20 minutes until all subjects in the FAS ( a ) Assess the effect of Formula IX processed . The plasma fraction will be separated by placing 9 mg and 18 mg on serum PSA ; (b ) Assess the effect of the collection tube into a centrifuge for 10 minutes at Formula IX 9 mg and 18 mg on Quality of Life (QOL ) as 1 ,500xg . The plasma fraction will be withdrawn by pipette measured by EO -5D - 5L : ( c ) Assess the effect of Formula IX and divided into two 2 mL polypropylene transfer vials (with TCs ) ( d ) 10 each tube receiving approximately equal aliquots ). 9 mg and 18 mg on circulating tumor cells (CTCs ) ; ( d ) All sample collection and freezing tubes will be clearly Assess the impact of duration of prior CB on outcome ; ( e ) labeled in a fashion which identifies the subject , the study Assess the impact of time from diagnosis of metastases to number , the visit number, and freezing tube aliquot letter. randomization on outcome; ( f ) Describe the effect of For Labels will be fixed to freezing tubes in a manner that will mula IX 9 mg and 18 mg on tumor volumetrics; ( g ) Assess 15 prevent the label from becoming detached after freezing . the effect of plasma concentrations of Formula IX and Samples will be stored in a freezer at - 20° C . or lower . Formula IX glucuronide on CBR at 24 weeks. Samples will be shipped in a thermal insulated container The safety objective is to describe the safety profile of with sufficient dry ice to assure they remain frozen . Formula IX 9 mg and 18 mg PO daily in subjects with Any remaining plasma samples after completion of the ER + AR + BC with centrally confirmed AR + as well as in all 20 protocol outlined pharmacokinetic analysis may be used to subjects randomized and treated . identify and quantify the metabolites of Formula IX . The pharmacokinetic objective : To describe the plasma concentrations of Formula IX and Formula IX glucuronide Example 27 at each of the assessed time points . Formulation , Packaging, and Labelling : 25 The Efficacy and Safety of Formula IX on Formula IX 3 . 0 mg Softgels will be supplied as opaque , Advanced , Androgen Receptor -Positive Triple white to off -white , size 5 , oval Softgel capsules containing Negative Breast Cancer ( AR + TNBC ) 3 . 0 mg of Formula IX . The liquid Softgel fill is composed of Formula IX dissolved in polyethylene glycol 400 . Formula Ongoing and Completed Clinical Trials with Formula IX : IX 3 . 0 mg Softgels will be packaged in blister packs . Each 30 Twenty - one Phase 1 , 2 , and 3 clinical trials have been blister pack will contain sufficient study drug for one ( 1 ) completed or are ongoing with Formula IX . These include : week of dosing . At randomization ( Visit 2 ) and at Visits 3 , 1 . ProtocolG100401 , a Phase 1 single ascending dose study 4 , and 5 ) , subjects will be provided with a carton of study in 96 healthy, young , male volunteers; 2 . ProtocolG100402 , drug containing 7 blister packs, equivalent to 7 weeks of a Phase 1 multiple ascending dose study in 50 healthy , dosing . At Visits 6 , 8 , 9 , 10 , 11, 12 , and 13 , in order to 35 young , male volunteers , and 23 elderly male volunteers with accommodate the visit schedule of every 12 weeks ( + 7 truncal obesity ; 3 . Protocol G100503 , a Phase 1 single dose days ), the subjects will receive two carton boxes of study pharmacokinetic study to assess the effect of a dosage drug ( each containing 7 blisters ) to cover study treatment for regimen that simulates a sustained release formulation to an 14 weeks . Subjects will be requested to bring with them the immediate release formulation in 18 healthy, young male carton box with all blister packs at every visit. 40 volunteers and 18 postmenopausal women ; 4 . Protocol Each blister pack will be comprised of an appropriate G100506 , a Phase 1 single dose pharmacokinetic study to number of blister strips ( 1 blister for the 9 mg treatment arm assess the relative bioavailability of a 3 mg hard shell and 2 blisters for the 18 mg treatment arm ) encased in a capsule formulation to be used during continued clinical child -resistant heat -sealed card . The blister strips are com - development and to assess the effect of food on the phar posed of a PVC /ACLAR base and an aluminum foil/ PVC ) 45 macokinetics of the 3 mg softgel formulation in 27 healthy , PVAC copolymer and polymethacrylate ( product contact ) young , male volunteers ; 5 . Protocol 006 , a Phase 1 single lidding . Perforations on the back of the heat -seal card dose and multiple dose pharmacokinetic study in 24 post overlay the foil lidding . To remove the study drug , subjects menopausal , Japanese women ; 6 . Protocol G200501, a will release the appropriate perforation by depressing a Phase 2 study in 60 postmenopausal women and 60 elderly release button on the inside of the card . Once released , the 50 men to assess lean body mass and physical function ; 7 . perforation can be removed and the study drug pushed Protocol 003 , a Phase 1b study in 44 postmenopausal through the foil . women ; 8 . Protocol G200502 , a Phase 2b study in 159 men Pharmacokinetic Assessment: and postmenopausal women with cancer to assess lean body Blood samples for pharmacokinetic assessment will be mass and physical function ; 9 . Protocol G100511 , a Phase 1 collected at baseline (pre - dose ), Visit 3 (week 6 ), Visit 5 55 study to assess the effect of severe renal impairment on the (week 18 ) , and Visit 6 (week 24 ). One blood sample will be pharmacokinetics of Formula IX ; 10 . Protocol G100508 , a collected in a 6 mL KZ- ethylenediaminetetraacetic acid Phase 1 study to assess the effect of mild and moderate (EDTA ) blood collection tube on each of these days. The hepatic impairment on the pharmacokinetics of Formula IX ; exact time (hh :mm ) and date that each blood sample is 11 . Protocol G100509 , a Phase 1 mass balance study of collected will be recorded on the electronic Case Repot 60 Formula IX in healthy volunteers ; 12 . Protocol G100507 , a Form . At the baseline visit , the blood sample should be Phase 1 study to assess the pharmacokinetics and absolute collected before the subject is given their first dose of oral bioavailability of Formula IX in Caucasian and African Formula IX . At Visits 3 ( week 6 ) , 5 (week 18 ) , and 6 (week American men and women ; 13 . ProtocolG100510 , a single 24 ) , the date and approximate time of the last dose of dose , randomized , double - blind , comparative , positive and Formula IX prior to the blood sample should be recorded ; 65 placebo -controlled , four -period crossover Phase 1 study to i . e . , it should be documented whether the subject took the define the electrocardiogram (ECG ) effects of Formula IX , previous dose that morning or the evening before Immedi- at therapeutic and supratherapeutic doses , in healthy male US 9 ,744 , 149 B2 103 104 and female subjects : a thorough ECG trial; 14 . Protocol demonstrated . Consistent with the previous studies, Formula G100512 , a Phase 1 study to assess the effect of ketocon - IX remained safe and well tolerated (see Example 9 ). azole ( Cytochrome P450 , Family 3 , Subfamily A [CYP3A4 ] Reductions in sex hormone binding globulin (SHBG ) inhibitor ) on the pharmacokinetics of Formula IX ; 15 . have been identified as one of the most sensitive serum Protocol G100513 , a Phase 1 study to assess the effect of 5 biomarkers for AR signaling in healthy volunteers and rifampin (CYP3A4 inducer ) on the pharmacokinetics of patients. SHBG was reduced by 15 . 1 % , 15 .6 % , 18 . 2 % , and Formula IX ; 16 . ProtocolG100514 , a Phase 1 study to assess 18 . 4 % in young , healthy volunteers who received PO For mula IX 1 mg, 3 mg, 10 mg, and 30 mg daily for 14 days , the pharmacokinetic drug : drug interaction of Formula IX respectively, in ProtocolG100402 ( listed as trial # 2 above ) , and celecoxib (CYP2C9 ) ; 17 . ProtocolG100515 , a Phase 1f 10 suggesting that doses of 10 mg and above maximally study to assess the pharmacokinetic drug drug interaction of stimulate AR activity . Formula IX and probenecid (UGT2B7 ) ; 18 . Protocol Dosing Formula IX at 15 - 20 mg per day may provide G100516 , a Phase 1 study to assess the pharmacokinetic therapeutic benefit in hormone receptor positive breast can drug :drug interaction of Formula IX and rosuvastatin (breast cer by two separate mechanisms: activating AR and inhib cancer resistance protein [ BCRP ]) ; 19 . Protocol G300504 , a 1515 iting progesterone receptor, thereby increasing potential Phase 3 randomized , double -blind , placebo - controlled study efficacy . Progesterone receptor expression in cancer stem of the effect of Formula IX on muscle wasting in 321 cells has been shown to be involved in proliferation of subjects with non -small cell lung cancer receiving first line cancer epithelial cells , and inhibiting progesterone recep platinum plus a taxane chemotherapy ; 20 . Protocol tor ' s activity is now considered a novel approach to treating G300505, a Phase 3 randomized , double - blind , placebo - 20 breast cancer. Hence , Formula IX at higher doses might controlled study of the effect of Formula IX on muscle provide dual anti -proliferative effects in breast cancer. In wasting in 320 subjects with non - small cell lung cancer TNBC , doses of 15 - 20 mg per day should provide saturation receiving first line platinum plus a non - taxane chemo- of the AR potentially providing better efficacy as opposed to therapy ; 21 . Protocol G200801 , an ongoing , Phase 2 , open a lower dose with partial occupancy of the AR and absence label study to examine AR status and the activity of Formula 25 of any progesterone receptor inhibitory effect. IX hormonal therapy in 22 women with ER positive meta - Based on the safety data collected to date in both pre static breast cancer who have previously responded to clinical and clinical settings, the 18 mg dose is expected to hormone therapy . be safe and generally well tolerated . However , in the event The 18 mg Dose : that a subject has a Grade 3 or greater toxicity , the 18 mg Formula IX has been evaluated in 21 completed and 30 dose may be reduced to 9 mg until the AE resolves or for the ongoing clinical studies enrolling over 1 ,500 total subjects . remainder of treatment based on the Investigator' s discre Formula IX has been generally well - tolerated , including tion . The 9 mg dose has been previously studied in post single doses up to 100 mg and multiple doses up to 30 mg menopausal women with metastatic breast cancer and was once daily for up to 14 days . In longer studies, Formula IX safe and well tolerated . has also been generally well tolerated , including 1 , 3 , and 9 35 In TNBC patients , the 18 mg dose is preferred over a mg daily doses for up to 184 days . lower dose due to the aggressive phenotype of the disease Previous clinical studies demonstrated that daily doses up and poor prognosis . Based on preclinical data , the 18 mg to 30 mg of Formula IX were well tolerated in healthy male dose is more likely to saturate the AR and may lead to better volunteers . Both 10 mg and 30 mg daily doses were evalu - clinical outcomes than a lower dose without receptor satu ated in ProtocolG100402 for up to 14 days . Elevated alanine 40 ration or progesterone receptor inhibition . transaminase (ALT ) ( any elevation outside upper limit of The 18 mg dose may provide greater efficacy in TNBC normal [ULN ]) was the most common adverse event (AE ) without compromising subject safety . However , in the event experienced . None of the subjects in the 10 mg dose group that a subject has a Grade 3 or greater toxicity , the 18 mg were discontinued from the study due to ALT elevations . In dose may be reduced to 9 mg until the AE resolves or for the the 30 mg dose group , six subjects experienced ALT 45 remainder of treatment based on the Investigator ' s discre increases above two times the ULN . tion . The 9 mg dose has been previously studied in post Formula IX 3 mg given daily was evaluated in two menopausal women with metastatic breast cancer and was completed Phase 3 trials , in over 600 subjects, for the safe and well tolerated . prevention and treatment of muscle wasting ( cachexia ) in In TNBC patients , the 18 mg dose is preferred over a subjects with advanced non - small cell lung cancer receiving 50 lower dose due to the aggressive phenotype of the disease chemotherapy . Formula IX 3 mg increased lean body mass and poor prognosis . Based on preclinical data , the 18 mg in both studies and was safe and well tolerated when dosed dose is more likely to saturate the AR and may lead to better for up to 168 days . Subjects in the Formula IX and placebo clinical outcomes than a lower dose without receptor satu groups experienced similar AEs and these AEs were con ration or progesterone receptor inhibition . 18 mg dose may sistent with the background chemotherapy regimen . 55 provide greater efficacy in TNBC without compromising Although Formula IX 3 mg was chosen for its anabolic subject safety . activity in muscle for the completed Phase 3 program , a dose Study Design : of 9 mg once daily was selected for hormonal therapy in the This is an open label, multicenter, multinational, Phase 2 ongoing Phase 2 trial in ER + and AR + metastatic breast study to assess the efficacy and safety of Formula IX in cancer in order to achieve a higher exposure that is both safe 60 female subjects with androgen receptor -positive , triple nega and more likely to be efficacious in women with advanced tive breast cancer ( AR + TNBC ) . Subjects will be adminis breast cancer. Seven out of twenty - two subjects with tered Formula IX , 18 mg orally (PO ) daily for up to 12 advanced , heavily pretreated (hormonal therapy , radiation , months. Simon ' s two- stage (optimal ) design will be used to and chemotherapy ) breast cancer demonstrated clinical ben - assess primary efficacy and will require up to 41 evaluable efit (CB ) (stable disease [SD ]) at 6 months. In one subject 65 subjects ; i. e ., subjects with centrally confirmed AR + who with SD (by Response Evaluation Criteria in Solid Tumors receive at least one dose of study drug . In order to obtain [ RECIST] , Version 1. 12 ), tumor regression of 27 % was these numbers of evaluable subjects , 21 to 55 subjects , US 9 ,744 , 149 B2 105 106 including over -enrollees ( see below ), will be enrolled to Tertiary Objectives : receive a daily PO dose of GTx - 024 18 mg. Fourteen of the The following tertiary efficacy objectives apply to both aforementioned subjects may be over- enrollees to allow for centrally confirmed AR + subjects (the evaluable subset of replacement of subjects to account for lack of centrally the FAS ) as well as to all subjects in the FAS : confirmed AR + status, or for the rare subject who is enrolled 5 Assess the effect of Formula IX 18 mg on serum prostate but does not receive study drug . The trial will test for an specific antigen (PSA ) . Assess the effect of Formula IX 18 mg on Quality of Life unacceptably low clinical benefit rate ( CBR ) of s5 % versus (QOL ) as measured by EQ -5D -5L . a CBR more consistent with 20 % . The first stage will be Assess the effect of Formula IX 18 mg on circulating assessed among the first 21 evaluable subjects . If at least tumor cells (CTCs ). 2 /21 subjects achieve clinical benefit (CB ) (defined as Assess the impact of duration of prior CB on outcome. complete response [ CR ] , partial response [PR ], or stable Assess the impact of time from diagnosis ofmetastases to disease [SD ], per Response Evaluation Criteria in Solid study enrollment on outcome. Tumors [RECIST ] , Version 1 . 12 ) at week 16 , then the trial Describe the effect of Formula IX 18 mg on tumor will proceed to the second stage of recruitment of up to a 15 volumetrics . total of 41 subjects in the evaluable subset of the Full Assess the effect of plasma concentrations of Formula IX Analysis Set (FAS ). Otherwise, the trial will be discontinued and Formula IX glucuronide on CBR at 16 and 24 for lack of efficacy . weeks. Subjects who are not confirmed AR + may remain on the Safety Objective : trial , but will not be part of the primary efficacy analysis — 20 To describe the safety profile of Formula IX 18 mg PO these subjects will contribute to secondary and tertiary daily in subjects with TNBC and centrally confirmed AR + as analyses . Subjects who experience an adverse event ( AE ) well as in all subjects enrolled and treated . with Grade 3 intensity (National Cancer Institute Common Pharmacokinetic Objective : Terminology Criteria for Adverse Events [NCI -CTCAE ), To describe the plasma concentrations of Formula IX and Version 4 . 0 ) and /or intolerance may have a dose reduction 25 Formula IX glucuronide at each of the assessed time points . from 18 mg to 9 mg per day or a drug interruption based on Target Population : the medical judgment of the Investigator and after confir Adult women with advanced TNBC with centrally con firmed AR + . mation by the study Medical Monitor. The subjects who Subject Inclusion Criteria : demonstrate clinical benefit (CB ) will be treated for up to 12 30 Subjects eligible for inclusion in this study must meet all months from the date of the first dose of study treatment ( as 30 of the following criteria : long as they continue to demonstrate CB from the treatment Able and willing to give voluntary , written and signed , during these 12 months) . Subjects who continue to demon informed consent; strate a beneficial response from the study treatment at 12 Women 18 years of age ; months will be offered to continue in a safety extension of Women with TNBC who have received at least one but no study under a separate protocol . All subjects will be fol more than two prior chemotherapy regimens for the lowed - up for onemonth after the last dose of Formula IX is treatment of advanced or metastatic TNBC ; received , for safety purposes . Confirmation of AR + (defined as > 10 % nuclear AR stain Primary efficacy objective of this trial is to estimate the ing by immunohistochemistry ( IHC ]) TNBC in either clinical beneficial rate (CBR ) at 16 weeks ( defined as 40 the primary or metastatic lesion , assessed during the complete response ( CR ) , partial response (PR ) , or stable screening period by a local laboratory or by medical disease (SD ) ) (by RECIST 1 . 1 ) of Formula IX 18 mg given history ; orally (PO ) daily in subjects with TNBC and centrally TNBC confirmed by medical history as: human epidermal confirmed AR + status . growth factor receptor 2 [HER2 ] - negative ( confirmed Secondary Efficacy Objectives : 45 by IHC 0 , 1 + regardless of fluorescence in situ hybrid Estimate the CBR at 16 weeks of Formula IX 18 mg in all ization [ FISH ] ratio ; IHC 2 + with FISH ratio lower subjects enrolled who receive at least one dose of study than 2 . 0 or HER2 gene copy less than 6 .0 ; FISH ratio medication ( i . e . , the full analysis set ( FAS ) ) regardless of AR of 0 , indicating gene deletion , when positive and nega status as determined by the central laboratory . tive in situ hybridization [ ISH ] controls are present) ; The following secondary efficacy objectives apply to both 50 estrogen receptor (ER ) negative ( confirmed as ER centrally confirmed AR + subjects ( the evaluable subset of expression less than or equal to 1 % positive tumor the FAS) as well as to all subjects in the FAS : nuclei ); progesterone receptor negative ( confirmed as Estimate the objective response rate (ORR ; defined as CR progesterone receptor expression less than or equal to or PR ) (by RECIST 1 . 1 ) of Formula IX 18 mg at 16 1 % positive tumor nuclei) ; weeks . 55 Availability of paraffin embedded or formalin fixed tumor Estimate the CBR of Formula IX 18 mg at 24 weeks . tissue ; OR , a minimum of 10 and up to 20 slides of Estimate the ORR ( defined as CR or PR ) of Formula IX archived tumor tissue for central laboratory confirma 18 mg at 24 weeks . tion of AR status and molecular subtyping . Metastatic Estimate the best overall response rate (BOR ) of Formula tumor tissue is preferred when possible ; IX 18 mg. 60 Subjects must have either measurable disease or bone Estimate the progression free survival (PFS ) of subjects only non -measurable disease , evaluable according to receiving Formula IX 18 mg . RECIST 1 . 1 ; Estimate the time- to -progression ( TTP ) of subjects Eastern Cooperative Oncology Group ( ECOG ) perfor receiving Formula IX 18 mg. mance status of 0 or 1 at the time of screening and Estimate duration of response ( time from documentation 65 enrollment; of tumor response to disease progression or death ) of Negative pregnancy test in women of childbearing poten subjects receiving Formula IX 18 mg. tial (premenopausal or less than 12 months of amen US 9 ,744 , 149 B2 107 108 orrhea post- menopause , and who have not undergone R , is H , F, C1, Br, I, CH3, CF3, OH , CN , NO2, NHCOCHz, surgical sterilization ) , no more than 7 days before the NHCOCF3, NHCOR , alkyl, arylalkyl, OR , NH , NHR , first dose of study treatment; N ( R ) 2 , or SR ; For women of childbearing potential who are sexually active , agreement to use a highly effective , non -hor - 5 Rz is H , F , C1, Br , I, CN , NO2, COR , COOH , CONHR , monal form of contraception during and for at least 6 CF3, or Sn ( R ) 3 ; months after completion of study treatment; OR , a Z is NO2, CN , COR , COOH , or CONHR ; fertile male partner willing and able to use effective Y is CF3 , F , Br, CI, I , CN , or Sn ( R )3 ; non - hormonalmeans of contraception (barrier method of contraception in conjunction with spermicidal jelly , 10 Q is CN , alkyl, halogen , N ( R ) 2, NHCOCHZ, NHCOCF3, or surgical sterilization ) during and for at least 6 NHCOR , NHCONHR , NHCOOR , OCONHR , months after completion of study treatment ; CONHR , NHCSCHZ, NHCSCF3, NHCSR , Adequate organ function as shown by : Absolute neutro NHSO , CH3, NHSO , R , OR , COR , OCOR , OSO , R , phil count > 1 , 500 cells /mmº ; Platelet count 100 ,000 SO R or SR ; cells /mm3 ; Hemoglobin 29 g/ dL ; Serum aspartate ami- 15 n is an integer of 1 -4 ; and notransferase ( AST) and alanine aminotransferase (ALT ) < 2 .5 Upper Limit of the Normal range (ULN ) (or m is an integer of 1 - 3 ; and s5 if hepatic metastases are present ) ; Total serum wherein said treating does not include preventing . bilirubin s2 .OXULN (unless the subject has docu - 2 . The method of claim 1, comprising administering an mented Gilbert Syndrome ) ; Alkaline phosphatase lev - 20 isomer , a racemic mixture containing a SARM compound , a els s2 . 5xULN ( 55XULN in subjects with liver metas - metabolite , pharmaceutically acceptable salt , pharmaceuti tasis ) ; Serum creatinine < 2 . 0 mg / dL or 177 umol/ L ; International normalized ratio ( INR ) or activated1 umol par/ l ; cal product, hydrate , N - oxide , or crystal of said selective tial thromboplastin time (aPTT ) < 1 . 5xULN ( unless on androgen receptor modulator , or any combination thereof. anticoagulant treatment at screening ) ; 3 . The method of claim 2 , wherein said administering Able to swallow capsules ; comprises intravenously , intraarterially , or intramuscularly Any toxicity from prior chemotherapy has resolved or injecting to said subject said pharmaceutical product in Grade 1 (NCI - CTCAE , Version 4 .0 ) . liquid form ; subcutaneously implanting in said subject a Formulation , Packaging , and Labelling pellet containing said pharmaceutical product ; orally admin Formula IX 3 . 0 mg Softgels will be supplied as opaque , 30 istering to said subject said pharmaceutical product in a white to off -white , size 5 , oval Softgels . The liquid Softgel liquid or solid form ; or topically applying to said subject said fill is composed of Formula IX dissolved in polyethylene pharmaceutical product . glycol 400 . Dosing instructions will be provided on the 4 . The method of claim 3 , wherein said pharmaceutical study drug label and in the subject information sheet . product is a pellet, a tablet, a capsule , a solution , a suspen While certain features of the invention have been illus - 35 trated and described herein , many modifications, substitu sion , an emulsion , an elixir , a gel, a cream , a suppository or tions, changes, and equivalents will now occur to those of a parenteral formulation . ordinary skill in the art. It is , therefore , to be understood that 5 . The method of claim 2 , wherein said pharmaceutical the appended claims are intended to cover all such modifi - product comprises a 9 mg or an 18 mg dosage of said SARM cations and changes as fall within the true spirit of the 40 compound . invention . 6 . The method of claim 1 , wherein said SARM compound What is claimed is : is represented by a structure of Formula XIII : 1 . A method of treating, inhibiting , or reducing the sever ity of ER - ( + ) AR - ( + ) metastatic breast cancer in a subject 45 suffering from ER -( + ) AR -( + ) metastatic breast cancer, XIII wherein said breast cancer has been previously treated with at least one prior hormone therapy, the method comprising NCNC . CN administering to said subject a selective androgen receptor modulator (SARM ) compound represented by a structure of 50 Formula I : F3C NH A H3COH (R3 ) 55 or Formula XIV : G (R2 ) n XIVTV NH **1111 NC - C 60 X is O ; Fzc NH 1 G is O ; H3COH T is OH , OR , — NHCOCHz, or NHCOR ; R is alkyl , dihaloalkyl, trihaloalkyl, CH F, CHF2 , CF3, 65 CF CF3, aryl, alkenyl or OH ; 7 . The method of claim 1 , wherein said SARM compound R is CH3, CH F , CHF2, CF3, CH2CH3, or CF CF3; is represented by a structure of Formula II: US 9 , 744 , 149 B2 109109 110 -continued VIII NCNC . CN 5 NH ?? H3COOH o RiT X NC 1 10 wherein X is O ; G is O ; F3CFzcy NHY T is OH , OR , — NHCOCHz, or NHCOR ; H3COH XI Z is NO2, CN , COR , COOH or CONHR ; 15 NC Y is I , CF3, Br, Cl, or Sn ( R ) 3 ; Aho Q is CN , alkyl , halogen , N ( R ) 2 , NHCOCH3, NHCOCF3, NHCOR , NHCONHR , NHCOOR , OCONHR , AyoFaC NH CONHR , NHCSCHZ, NHCSCF3, NHCSR , 220 H3COHH3COOH > Or NHSO , CH3, NHSO , R , OR , COR , OCOR , OSOR , XII SO , R or SR ; R is a CZ -C4 alkyl, aryl, phenyl, alkenyl, or hydroxyl and 02NA NHCOCH3 R , is CH3, CF3, CH2CH3, or CF CF3. 25 8 . The method of claim 7 , comprising administering an F3C NH isomer , a racemic mixture containing a SARM compound , a metabolite , pharmaceutically acceptable salt , pharmaceuti ?? ?? cal product, hydrate , N - oxide, or crystal of said selective 10 . The method of claim 1 , wherein said ER - (+ ) meta androgen receptor modulator , or any combination thereof. 30 static breast cancer is refractory . 9 . The method of claim 7 , wherein said SARM compound 11. The method of claim 1 , wherein said prior hormone is represented by a structure of Formula : therapy is a selective estrogen receptor modulator, aro matase inhibitor , and / or a selective estrogen receptor degrader . IX 35 12 . The methods of claim 11 , wherein said selective NC . estrogen receptor modulator, aromatase inhibitor, and / or selective estrogen receptor degrader is less than or equal to any three of tamoxifen , toremifene , letrozole , vorozole , C F , CNH fadrozole, anastrozole , exemestane , formestane , or fulves H3CH 40 trant . * * * * *