US009622992B2

(12) United States Patent (10) Patent No.: US 9,622,992 B2 Dalton et al. (45) Date of Patent: *Apr. 18, 2017

(54) METHOD OF TREATING 4,670.249 A 6/1987 Ivy et al. 4,753,932 A 6, 1988 Teutsch et al. RECEPTOR (AR)-POSITIVE BREAST 4,837,004 A 6, 1989 Wu et al. CANCERS WITH SELECTIVE ANDROGEN 4,849,447 A 7, 1989 Jacobs et al. RECEPTOR MODULATOR (SARMS) 4,880,839 A 11/1989 Tucker 4,904.473 A 2f1990 Schricker et al. (71) Applicant: GTX, Inc., Memphis, TN (US) 4,977,288 A 12/1990 Kassis et al. 5,030,657 A 7, 1991 Burtle et al. 5,162,504 A 11/1992 Horoszewicz (72) Inventors: James T. Dalton, Lakeland, TN (US); 5,179,080 A 1/1993 Rothkopf et al. Mitchell S. Steiner, Germantown, TN 5,288496 A 2f1994 Lewis et al. (US); Ramesh Narayanan, Cordova, 5,441,868 A 8, 1995 Lin et al. TN (US); Sunjoo Ahn, Daejeon (KR) 5,547.933 A 8, 1996 Lin et al. 5,609,849 A 3/1997 Kung (73) Assignee: GTX, INC., Memphis, TN (US) 5,612,359 A 3/1997 Murugesan et al. 5,618,698 A 4/1997 Lin et al. 5,621,080 A 4/1997 Lin et al. (*) Notice: Subject to any disclaimer, the term of this 5,656,651 A 8, 1997 Sovak et al. patent is extended or adjusted under 35 6,019,957 A 2/2000 Miller et al. U.S.C. 154(b) by 116 days. 6,022,137 A 2/2000 White et al. 6,043,265 A 3/2000 Murugesan et al. This patent is Subject to a terminal dis claimer. (Continued) FOREIGN PATENT DOCUMENTS (21) Appl. No.: 14/293,632 AU 2002364949 6, 2003 (22) Filed: Jun. 2, 2014 AU 2003216,174 9, 2003 CA 1305.665 7, 1992 (65) Prior Publication Data CA 2149240 5, 1994 CA 2247946 10, 1997 US 2014/035.0102 A1 Nov. 27, 2014 CA 2281570 9, 1998 CA 2313O89 6, 1999 CA 234.4316 3, 2000 Related U.S. Application Data CA 242O279 2, 2002 (63) Continuation-in-part of application No. 13/953,492. CA 2458452 A1 2, 2003 filed on Jul. 29, 2013, which is a continuation-in-part (Continued) of application No. 13/789,005, filed on Mar. 7, 2013. OTHER PUBLICATIONS (60) Provisional application No. 61/671.366, filed on Jul. 13, 2012, provisional application No. 61/726.274, De Amicis et al. Breast Cancer Research Treatment, 2010, vol. 121, filed on Nov. 14, 2012. No. 1, pp. 1-11.* Mishra et al. Indian J. Med. Res., Jun. 2012, vol. 135, Iss.6, pp. (51) Int. Cl. 843-852. A6 IK3I/I67 (2006.01) Jones, S.E. Clinical Breast Cancer, 2008, vol. 8, No. 3, pp. 224 (52) U.S. Cl. 233.* CPC ...... A61K 31/167 (2013.01) (Continued) (58) Field of Classification Search CPC ...... A61K 31/167; A61K 233/57 Primary Examiner — Samira Jean-Louis See application file for complete search history. (74) Attorney, Agent, or Firm — Mark S. Cohen: Pearl Cohen Zedek Latzer Baratz LLP (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS This invention relates to the treatment of breast cancer in a 3,239,345 A 3/1966 Hodge et al. Subject, for example a female Subject. Including methods of 3,256,096 A 6, 1966 Tucker et al. 3,865,801 A 2f1975 Chiba et al. treating metastatic breast cancer, refractory breast cancer, 3,875,229 A 4, 1975 Gold AR-positive breast cancer; AR-positive refractory breast 3,946,109 A 3, 1976 Kolb et al. cancer, AR-positive metastatic breast cancer, AR-positive 3,949,085 A 4, 1976 Feuer et al. and ER-positive breast cancer, triple negative breast cancer 3,991,750 A 11/1976 Vickery et al. advanced breast cancer, breast cancer that has failed SERM 4,036.979 A 7, 1977 Asato et al. 4,139,638 A 2f1979 Neri et al. (tamoxifen, toremifene), aromatase inhibitor, trastuzumab 4,191,775 A 3, 1980 Glen (Herceptin, ado-trastuzumab emtansine), pertuzumab (Per 4,211,781 A 7, 1980 Chapman et al. jeta), lapatinib, (Aromasin), bevacizumab 4,239,776 A 12/1980 Glen et al. (Avastin), and/or fulvestrant treatments; metastasis in a 4,282,218 A 8, 1981 Glen et al. Subject suffering from breast cancer, comprising adminis 4,386,080 A 5/1983 Crossley et al. 4411,890 A 10/1983 Momany et al. tering to the Subject a therapeutically effective amount of a 4,447,421 A 5, 1984 Klothen et al. selective modulator (SARM) compound. 4,465,507 A 8, 1984 Konno et al. 4,636,505 A 1, 1987 Tucker 29 Claims, 28 Drawing Sheets US 9,622.992 B2 Page 2

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FG. A FIG. B.

S. S. ICs in AR positive g g Cells

d. ed. Virus Co

d (ii) (nM) OH 2OO O.8 AR 500 0.7 acti?e Forua 2OO 32

5OO 4. FIG. C FIG. D

DHT 120 20. 8 SS Q O o o ss s 70 70 A i

C :

20 : ...... ------, 20 O.O O OOO OOOOO O.O O OOO 10000.0 M M

FIG. E. FIG. F For lax Formula X 120 : 320 8 wg O s s e. O. O. O. O O g A O O & 70.: A O 70 O d A O gf i A a 5 A A O O : 20 ------; 20 i.-- OO 0 1000 10000,C O.O O OO.0 0000.0

FIG. G FIG. H

Bicalutamide Bicalutamide 12: 120 : SS : : O O s a O O e s A. e : e is 70. 70 : s o 3 a 20 jor O i. 0.0 0. 0.0 O OOO OOOOO U.S. Patent Apr. 18, 2017 Sheet 2 of 28 US 9,622,992 B2

FIG. FIG. 1 R. isomer of Formula X R-isomer of Formula X 20 - a A c g e a 0 SS : O O e g > 70 70 : u

O 20 --~~~ 0.0 10 1000 10000.0 air. ------M 0. .0 3 080 88.

FIGURE 2

FIG. 2A FIG. 2B is is ICs in AR positive cells C (a - - i. cd c. co o

AR Formula act - X

FIG. 2C FIG. 2D DH OHT 20 O 120 A : O s O O O. O. e s s A g : A O O 70. A A A A 70 O O. A

2O 20 ico.------0.0 O OOO 100000 OO O 000 OOOOO in? U.S. Patent Apr. 18, 2017 Sheet 3 of 28 US 9,622,992 B2

FIG. 2E FIG. 2F

Formula X Formula X 120 O 20 O & O 8 s° o o 8 o 8 e O

g A A A A. 2 (i. 0. a o as o A A C O

20 ------O O OOC 00000

FIG. 2G FIG. 2H

Bicautamide Bicalutamide 120 O 120 ; O O O i R 8 O O6 e Oo s A s A g : g

s 70 - a 70 O i 5 3

20 --- 20 jor ...... ------0.0 O OOO 100000 0.0 O 100.0 0000.0 r U.S. Patent Apr. 18, 2017 Sheet 4 of 28 US 9,622,992 B2

FIG. 3A FIG. 3B DH DHT 2) 2. i O O SS . . . s 8 g g : A O O A A 70 A 3. A s 3 A. A 3 A is A A 20 2C --- O.O O 0.0 COC. 0.O O OCO 00000 M w

FIG. 3C Formula X

20 a a a co e A A 3 70 A A A

20 ------OO O 00. 0000.0 OO. G.O M

FIG. 3D FIG. 3E

Forla IX 120 IC in AR positive cells

a o 8 Compound Pretreatment s A. 70 A. DHT 10 iM Bical 9 d : A A 2 : Formula IX 10 M Bical 213 20.:------G.O O 0.0 3000.

U.S. Patent Apr. 18, 2017 Sheet S of 28 US 9,622,992 B2

FIG. 4A FIG. 4B

50 - 50 - DHT

t 100 A A A A A A i.s 100 go o o o o 3. A A A i 50 - o O O O 50 A A A A

O 0 or------0.0 O 000 OOOOO 0.0 10 nM. OOO OOOOC M FIG. 4C FIG. 4D 150 150 Bicalutamided Bicalutamide s O O. 100 A A A i i A S 100 O: Q O oO O s A. 3 50 oir 0 O.C. O M 00. 0000 0. O 100.0 0000 M FIG. 4E FIG. 4F 50. Formula X 150 Formula X

O SS s 100 () o O s 100 A A A A A g e O A A i O o A as 50. C. 3 50 A

O ------O : ...... ------0.0 0 000 OOOOO 0.0 O 000 0000. f nv FIG. 4G FIG. 4H 150 150 Formula IX Formula IX g 1006 O g O. O. O. gs° 100 A: A A A A A ww. A A. 3 : O O : 3 50 $ 50 A A

O : ...... ------O :...... ------OO 0 000 OOOO.O OO O 100.0 OOOOO M M U.S. Patent Apr. 18, 2017 Sheet 6 of 28 US 9,622,992 B2

FIG. 4 FIG. 4 150 R-Isomer of Formula IX 15) R-somer of Formula IX

1000 Q o o O s'g 100 A i i A A i 50 3. 50

0 i------Oi------0.0 O 100.0 0000. 0.0 10 O00 00000 M nM. FIG. 4K FIG. 4L 50 50 Formula XV Formula XV 100 O e o a s 100 & .e. a a A , , 3 : A 50 O c s 50 A A

0. 0 O.O. 10 000 0000.0 O.0 1.0 000 10000, n nM. FIG. 4M FIG. 4N 150. Formula XIII " Formula XIII * 1000"? e o O s' 100 A O c O A A A A a , o : 50: O o o 3 50 4 A Oir------OO O OO.O O000.0 O.O O OOO 1000. M M FIG. 4O FIG. 4P 150 Formula VI

as 1000 & 100 Á A g O o O O A AA. A A A O O. O : i O O i : A. 3 50 3 50 A. A

Oir 0 - 00 O 1000 000.0 O.O O 1000 OOOO. w U.S. Patent Apr. 18, 2017 Sheet 7 of 28 US 9,622,992 B2

FIG. 4Q ICs values (nM) Activity Cell growth ECso Cso ria Trial 2 Mean SD DHT 0.2 1.2 O 1 - 0,1 Formula X 9 566 4O7 486 t 13 Formula X 88 65 77 6 Formula XIV Formula XIV 5 184 85 34 it 70 Formula X: 1 61 94 77 + 23 Formula V 2 77 86 8 : 6 Bicautamide 22.4 U.S. Patent Apr. 18, 2017 Sheet 8 of 28 US 9,622,992 B2

FIGURE 5

0.4

O3

D - 2 O For a X D v For a X - A For a XV For a X Orr a W O R - X

0.0

e-4 e-3 e-2 e- e-0 e- e-2 e-3 e-4 e5 M U.S. Patent Apr. 18, 2017 Sheet 9 of 28 US 9,622,992 B2

FIG. 6A FIG. 6B - a 3 S ERa Actin ERb Actin

FIG. 6C E2 in MDA-B-231 C in A-B-231 150 150 100 is O s O O is 1006 g O acz is "" a iss A O Ra-Adw 10 3 : h A Rai-Adw 50 L g so O 50 o O. O 3. OOOOO O ...... ------O.O 10 000 OOOO.O M M

FIG. 6D E2 in NA-WB-23 C in A-B-231 150 150 to o g o O lac2 : R A. A. A 100 a s o O O. O Rai-Adv O LL s is A A i s A Ra-Adv 50 L in : g 50 50 oir O.O O 000 00000 0...... ------OO O OO 100000

FIG. 6E E2 in A-B-23 C in WAB 231 150 150 ; O laCZ O ERb-Adw 50 u & 100 is s 100s a 4 A ERb-Adw 100 u or 50 ; A ERb-Adw 300 u o 0 or------o: 100. OOOO OO 0 000 00000 M U.S. Patent Apr. 18, 2017 Sheet 10 of 28 US 9,622,992 B2

FIGURE 7

Bicalutam de DHT

FIGURE 8

O

)

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------ad c c ad d s c cy - efuel O. po US 9,622,992 B2 1. 2 METHOD OF TREATING ANDROGEN may be treated preliminarily with Surgery, chemotherapy RECEPTOR (AR)-POSITIVE BREAST (optional in Some cases), and radiation before targeted CANCERS WITH SELECTIVE ANDROGEN therapy is initiated. Hormone receptor positive breast can RECEPTOR MODULATOR (SARMS) cers are susceptible to hormone therapies with selective estrogen receptor modulators or SERMs (e.g., tamoxifen, CROSS REFERENCE TO RELATED toremifene), aromatase inhibitors (e.g., anastrozole), or APPLICATIONS selective estrogen receptor degraders or SERDS (e.g., full Vestrant). Hormone therapies such as aromatase inhibitors This application is a Continuation-In-Part of U.S. patent (AI) block production of estrogens in the body (typically application Ser. No. 13/953,492, filed Jul. 29, 2013 which is 10 used in post-menopausal women), whereas SERMs and a Continuation-In-Part of U.S. patent application Ser. No. SERDs block the proliferative action of estrogens on the 13/789,005, filed Mar. 7, 2013, which claims the benefit of breast cancer cells. HER2 positive breast cancers are sus United-States Provisional Ser. No. 61/671,366, filed Jul. 13, ceptible to HER2 kinase inhibitors (e.g., trastuzumab and 2012 and the benefit of U.S. Ser. No. 61/726,274, filed Nov. lapatinib) and are generally used in metastatic disease. 14, 2012, which are incorporated in their entirety herein by 15 Anti-angiogenic therapy (bevacizumab) is also approved in reference. metastatic disease. Despite these multiple tiers of targeted FIELD OF INVENTION treatments, patients often have or develop refractory forms of breast cancer. Examples of refractory breast cancer This invention relates to the treatment of androgen recep include primary tumors which are triple-negative (lacking tor-positive breast cancer in a subject, for example a female ER, PR, HER2), hormone resistant (SERM-, SERD-, or Subject. Accordingly, this invention provides methods of: a) AI-resistant), or kinase inhibitor resistant, or metastatic treating a subject Suffering from breast cancer; b) treating a breast cancer tumors. Once the targeted therapies fail or Subject Suffering from metastatic breast cancer; c) treating a tumors metastasize, radiation and high dose chemotherapy Subject Suffering from refractory breast cancer; d) treating a 25 are required to ablate the refractory breast cancer tumors. Subject Suffering from AR-positive breast cancer; e) treating Current available for the treatment of refrac a subject suffering from AR-positive refractory breast can tory breast cancer include anthracyclines, taxanes, and cer, f) treating a subject Suffering from AR-positive meta epothilones, which are toxic, dangerous, costly, and often static breast cancer, g) treating a Subject Suffering from are ineffective, especially in the treatment of metastatic AR-positive and ER-positive breast cancer, h) treating a 30 disease. subject suffering from AR-positive breast cancer with or Abundant clinical evidence suggests that androgens nor without expression of estrogen receptor (ER), progesterone mally inhibit breast growth. For instance, women with receptor (PR), and/or Human Epidermal Growth Factor androgen deficits have an increased risk for developing Receptor 2 (HER2): i) treating a subject suffering from triple breast cancer. Androgen signaling plays a crucial role in negative breast cancer, j) treating a Subject Suffering from 35 breast homeostasis, negating the proliferative effects of advanced breast cancer, k) treating a subject Suffering from estrogen signaling in the breast. However, when androgens breast cancer that has failed selective estrogen receptor transform into estrogens (aromatase pathway), they increase modulator (SERM) (tamoxifen, toremifene), aromatase cell proliferation and mammary carcinogenesis risk. Histori inhibitor (AI), trastuzumab (Herceptin, ado-trastuzumab cally, the steroidal androgen receptor agonists testosterone, emtansine), pertuzumab (Perjeta), lapatinib, exemestane 40 fluoxymesterone, and were used in advanced (Aromasin), bevacizumab (Avastin), and/or fulvestrant breast cancer. These agents suffered from side effects such as treatments; 1) treating a subject Suffering from ER positive excessive virilization, cross-reactivity with the estrogen breast cancer; m) treating, preventing, Suppressing or inhib receptor, and aromatization to estrogens. The use of steroidal iting metastasis in a subject Suffering from breast cancer, n) androgens in advanced breast cancer pre-dates the screening prolonging Survival of a subject with breast cancer, o) 45 of breast cancers for hormone and kinase receptors. slowing the progression of breast cancer in a subject; and/or Recently, it was found that the AR is expressed in 50-90% p) prolonging progression-free Survival of a subject with of breast tumors, providing a mechanism to use androgens breast cancer, comprising administering to the Subject a as targeted therapy for AR-positive breast cancers. therapeutically effective amount of a selective androgen Selective androgen receptor modulators (SARMs) are receptor modulator (SARM) compound. 50 compounds which demonstrate AR-mediated tissue selec tive activity. Unlike their steroidal precursors, SARMs are BACKGROUND OF THE INVENTION non-aromatizable, generally demonstrate no activity at other steroidal receptors including ER and PR, and are non Breast cancer is a disease that kills over 45,000 women virilizing. Further, SARMs may be beneficial in refractory each year in the United States alone. Over 180,000 new 55 breast cancer patients due to their hypermyoanabolic effects cases of breast cancer are diagnosed annually, and it is that should improve their tolerance of high-dose chemo estimated that one in eight women will develop breast therapy. cancer. These numbers indicate that breast cancer is one of New innovative approaches are urgently needed at both the most dangerous diseases facing women today. Cancer the basic science and clinical levels to develop compounds research has been unable to determine the cause of breast 60 which are useful for: a) treating a Subject Suffering from cancer, and has not found a suitable method of therapy or breast cancer; b) treating a Subject suffering from metastatic prevention. breast cancer; c) treating a Subject Suffering from refractory The standard of care currently includes screening the breast cancer; d) treating a Subject suffering from AR tumor for the expression levels of the hormone receptors, positive breast cancer; e) treating a subject Suffering from estrogen receptor (ER) and progesterone receptor (PR), and 65 AR-positive refractory breast cancer, f) treating a subject the human epidermal growth factor receptor 2 (HER2) Suffering from AR-positive metastatic breast cancer, g) kinase. Currently, a woman diagnosed with breast cancer treating a subject Suffering from AR-positive and ER-posi US 9,622,992 B2 3 4 tive breast cancer, and/or h) treating, preventing, Suppress -continued ing or inhibiting metastasis in a subject Suffering from breast B NH O CaCC.

SUMMARY OF THE INVENTION 21 In one embodiment, this invention is directed to a method C of treating a subject Suffering from a) AR-positive breast cancer in a subject; b) metastatic AR-positive breast cancer, or advanced AR-positive breast cancer; c) refractory AR 10 positive breast cancer; and this invention is further directed to d) treating, preventing, Suppressing or inhibiting metas n is an integer of 1-4; and tasis in a Subject Suffering from breast cancer; and e) m is an integer of 1-3: prolonging progression-free Survival of a subject Suffering and/or its analog, derivative, isomer, metabolite, pharma from breast cancer; comprising the step of administering to 15 ceutically acceptable salt, pharmaceutical product, hydrate, said Subject a selective androgen receptor modulator N-oxide, crystal, polymorph, prodrug or any combination (SARM) compound represented by a structure of formula I: thereof, as described herein. In one embodiment, the subject is a female Subject. In one embodiment, the Subject is a male Subject. In another embodiment, the breast cancer is a breast (R3) Q I cancer that has failed selective estrogen receptor modulator SERM (tamoxifen, toremifene), aromatase inhibitor, trastu Zumab (Herceptin, ado-trastuzumab emtansine), pertu 1-Cl G 21 (R2), Zumab (Perjeta), lapatinib, exemestane (Aromasin), bevaci A4 N 25 Zumab (Avastin), and/or fulvestrant treatments. In another embodiment, the metastatic or advanced breast cancer is AR-positive ER-positive metastatic or advanced breast cancer. In another embodiment, the refractory AR X is a bond, O, CH, NH, S, Se, PR, NO or NR; positive breast cancer is AR-positive ER-positive refractory G is O or S; 30 breast cancer. In another embodiment, the AR-positive breast cancer is AR-positive ER-positive breast cancer. In T is OH, OR, NHCOCH or NHCOR; another embodiment, the AR-positive breast cancer is ER R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF. negative PR-negative and HER2 negative. In another CF, CFCF, aryl, phenyl, halogen, alkenyl or OH: embodiment, the AR-positive breast cancer is ER-negative R is CH, CHF, CHF, CF, CHCH, or CFCF: PR-negative and HER2 positive. In another embodiment, the R is H, F, Cl, Br, I, CH, CF, OH, CN, NO, NHCOCH, 35 AR-positive breast cancer ER-negative is PR-positive and NHCOCF, NHCOR, alkyl, arylalkyl, OR, NH, NHR, HER2 negative. In another embodiment, the AR-positive N(R), SR; breast cancer is AR-positive, PR-positive and HER2 posi R is H, F, Cl, Br, I, CN, NO, COR, COOH, CONHR, CF, tive. In another embodiment, the AR-positive breast cancer Sn(R), or R together with the benzene ring to which it is ER positive PR-negative and HER2 positive. In another is attached forms a fused ring system represented by the 40 embodiment, the AR-positive breast cancer is ER-positive, Structure: PR-positive and HER2 negative. In another embodiment, the metastatic or advanced AR-positive breast cancer is ER positive, PR-positive and HER2 negative. In another embodiment, the refractory AR-positive breast cancer is 45 ER-positive, PR-positive and HER2 negative. One embodiment of this invention is treating, preventing, Suppressing or inhibiting metastasis in a subject Suffering M O M from breast cancer. Another embodiment is prolonging z1K / z-K / progression-free Survival of a Subject Suffering from breast CaCC. Y Y 50 In another embodiment the breast cancer of this invention is ER-positive metastatic breast cancer; ER-positive refrac Z is NO, CN, COR, COOH, or CONHR: tory breast cancer; AR-positive ER-positive breast cancer; Y is CF, F, Br, Cl, I, CN, or Sn(R): ER positive PR positive HER2 negative breast cancer; Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, AR-positive ER-positive refractory breast cancer; AR-posi NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, 55 tive ER-positive metastatic breast cancer; triple positive NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, breast cancer; advanced ER-positive breast cancer; AR OR, COR, OCOR, OSOR, SOR or SR: or Q together positive and/or ER-positive breast cancer that has failed with the benzene ring to which it is attached is a fused ring selective estrogen receptor modulator (tamoxifen, tore system represented by structure A, B or C: mifene), aromatase inhibitor, trastuzumab (Herceptin, ado 60 trastuzumab emtansine), pertuzumab (Perjeta), lapatinib, exemestane (Aromasin), bevacizumab (Avastin), and/or full VeStrant treatmentS. NH O 21 BRIEF DESCRIPTION OF THE DRAWINGS 65 N The Subject matter regarded as the invention is particu larly pointed out and distinctly claimed in the concluding US 9,622,992 B2 5 6 portion of the specification. The invention, however, both as R-enantiomer of formula IX (ICso 1689 nM); and open to organization and method of operation, together with triangles (A) correspond to RU486 (ICso 0.048 nM). objects, features, and advantages thereof, may best be under FIG. 10 demonstrates that SARM (formula VIII) inhibits stood by reference to the following detailed description MDA-MB-231-AR tumor growth. Body weight (10A) and when read with the accompanying drawings in which: 5 tumor size (10B) were measured for 35 days in intact female FIG. 1 illustrates that DHT and a compound of Formula nude mice having 150-200 mm tumors from MDA-MB IX inhibit MDA-MB-231 triple negative breast cancer cell 231-AR triple negative breast cancer cells and then orally growth. FIG. 1A shows MDA-MB-231 cell expression of administered vehicle (*) or 30 mg/kg of formula VIII (O). AR following transfection. FIG. 1B shows the ICs in AR FIG. 11 demonstrates that SARM (formula VIII) inhibits positive MDA-MB-231 cells. FIGS. 1C, 1D, 1E, 1F, 1G, 1H, 10 MDA-MB-231-AR tumor growth. Tumor size in mm (11A) 1I and 1J show the effects of DHT, Formula IX, bicaluta and % change in tumor size (11B), as well as tumor weight mide and the (R) enantiomer of Formula IX on percent (%) (11C) were measured after 35 days in intact female nude cell survival. (FIGS. 1C, 1E, 1G and 1 Icells were treated in mice having 150-200 mm tumors from MDA-MB-231-AR charcoal stripped FBS. FIGS. 1D, 1F, 1H and 1J cells were triple negative breast cancer cells and then receiving oral treated in full serum). O MDA-MB-231 with lacz: O 15 administration of vehicle or 30 mg/kg of formula VIII. MDA-MB-231 with AR 200 uL: A MDA-MB-231 with AR FIG. 12 demonstrates the morphology of MDA-MB-231 500 uL. breast cancer cells stably transfected with AR (MDA-MB FIG. 2 illustrates that DHT and Formula IX inhibit 231-AR cells). The results indicate that AR agonists, DHT, HCC-38 triple negative breast cancer cell growth. FIG. 2A formula IX, and formula VIII altered the morphology into a shows HCC-38 cell expression of AR following transfec more anchored phenotype compared to vehicle, bicaluta tion. FIG. 2B shows the ICs in AR positive HCC-38 cells. mide or an inactive isomer of formula IX. This may be FIGS. 2C, 2D, 2E, 2F, 2G and 2H show the effects of DHT, indicative of a less metastatic breast cancer phenotype. Formula IX and Bicalutamide on percent (%) cell survival. FIG. 13 demonstrates binding and transactivation of the (FIGS. 2C, 2E and 2G cells were treated in charcoal stripped indicated ligands to HEK-293 (13A) or MDA-MB-231 (13B FBS. FIGS. 2D, 2F and 2H cells were treated in full serum). 25 & 13C) cells. DHT, formula IX and formula VIII are O HCC-38 with lacZ: O HCC-38 with AR 200 uL: A agonists of AR in breast cancer cells. (Example 16) HCC-38 with AR 500 uL. FIG. 14 demonstrates anti-proliferative activity of DHT FIG. 3 illustrates that the effect of DHT and Formula IX and SARMs in MDA-MB-231 breast cancer cells stably on MDA-MB-231 cells was reversed by bicalutamide. transfected with AR. MDA-MB-231 cells stably transfected FIGS. 3A, 3B, 3C and 3D show the effects of DHT or 30 with AR using lentivirus were treated with the indicated Formula IX in the presence or absence of bicalutamide, on ligands for 6 days and the number of cells counted using percent (%) cell survival. (FIGS. 3A and 3C cells were coulter counter. DHT and SARMs, but not the AR antago treated in charcoal stripped FBS. FIGS. 3B and 3D cells nist, bicalutamide, inhibited the proliferation of MDA-MB were treated in full serum). O lacz and with 10 uM 231 triple negative breast cancer cells stably transfected with bicalutamide: O lacZ: A AR with 10 uM bicalutamide: A 35 AR. AR. FIG. 3E shows ICs values in AR positive cells in the FIG. 15 presents micro-array results showing that acti presence or absence of pretreatment with bicalutamide. vated AR (AR activated by compound of formula VIII) FIG. 4 illustrates that AR agonists inhibit triple negative Suppressed the expression of more genes than it induced in breast cancer cell growth. FIGS. 4A, 4B, 4E, 4F, 4G, 4H. MDA-MB-231-AR xenograft breast cancer cells. 4K, 4L, 4M, 4N, 4O and 4P show effect of AR agonists on 40 FIG. 16 depicts validation of micro-array results. percent (%) cell survival. FIGS. 4C and 4D show the effect FIG. 17 illustrates that compound VIII inhibited the of AR antagonist on percent (%) cell survival. FIGS. 4I and growth of MCF-7-AR triple positive xenograft. 4J show the effect of AR non-binder on percent (%) cell FIG. 18 presents inhibition of uterus weight gain in survival. FIGS. 4A, 4C, 4E, 4G, 4I, 4M and 4O cells were estrogen Supplemented animals treated with Compound treated in charcoal stripped FBS. FIGS. 4B, 4D, 4F, 4H, 4J, 45 VIII, demonstrating the ability of a SARM to counteract 4L, 4N and 4P cells were treated in full serum. FIG. 4Q estrogenic stimuli in vivo. shows ECs and ICso values in AR positive cells. FIG. 19 shows that the AR expression pattern in response FIG. 5 illustrates that growth inhibitory ligands are AR to an AR-agonist (compound VIII) is similar to that observed agonists in MDA-MB-231 cells. in prostate cancer cells. FIG. 6 illustrates that growth inhibitory effects in MDA 50 FIG. 20 depicts validation of micro-array results. MB-231 cells are selective to AR. FIGS. 6A and 6B show FIG. 21 demonstrates up-regulation of JNK phosphory the expression of ERC. or ERB in MDA-MB-231 cells lation in MCF7-AR Tumors using Compound VIII. following transfection, respectively. FIGS. 6C, 6D and 6E FIG. 22 shows inhibition of triple negative breast cancer show the effects of (E2) or ICI 182,780 (ICI) on (TNBC) growth using compounds VIII and IX. Compound percent (%) cell survival. (FIG. 6C cells were treated in 55 VIII and compound IX demonstrated -85%. TGI at all doses charcoal stripped serum. FIGS. 6D and 6E cells were treated tried (5, 10 mg per kg for compound VIII; 5, 10, 30 mg per in full serum). kg for compound IX) in the TNBC model using MDA-MB FIG. 7 shows DHT alters the morphology of MDA-MB 231-AR cells in nude mice. 231 cells. FIG. 23 demonstrates inhibition of triple negative breast FIG. 8 illustrates the effect of Formula VIII on 60 cancer using compounds VIII and IX. The tumor weights receptor transactivation (agonist mode). were likewise reduced for all doses of compound VIII and FIG. 9 depicts a dose response curve of PR activity compound IX. Spleen enlargement (680 mg vs. 200-300 mg (antagonist mode) for compound of formula VIII, formula for normal mice) was seen only in vehicle treated mice, IX, R-enantiomer of formula IX and RU486. The closed possibly indicative of prevention by the SARMs of tumor circles (O) correspond to formula VIII data points 65 metastasis to the spleen. (ICso 17.05 nM); open circles (O) correspond to formula FIG. 24 shows increase of body weight by the SARMs at IX (ICso 162.9 nM); closed triangles (V) correspond to all doses of compound VIII and compound IX, indicative of US 9,622,992 B2 7 8 healthy growth and a lack of toxicity. By comparison, the N-oxide, crystal, polymorph, prodrug or any combination vehicle treated animal did not grow as robustly. thereof, in an amount effective to treat metastatic breast FIGS. 25A to 25E depict antagonism by SARM regarding cancer in the Subject. In one embodiment, the Subject is a the ability of estradiol to activate ER target genes in MCF female Subject. In another embodiment, the Subject is a male 7-AR cells. FIGS. 25B and 25D show that adding AR (as 5 Subject. opposed to Green Fluorescent Protein (GFP) as seen in In another embodiment of the present invention, a method FIGS. 25A and 25C) to MCF-7-AR cells increases the is provided for treating a subject Suffering from refractory effects of estradiol (when unopposed) on the ER target genes breast cancer, comprising the step of administering to the PR and PS2, respectively. Adding AR to MCF-7-AR cells subject a compound of formulae I-XIV of this invention suppressed the activation of these ER targets in the presence 10 and/or its analog, derivative, isomer, metabolite, pharma of SARM alone or SARM--estradiol (E2) as compared to ceutically acceptable salt, pharmaceutical product, hydrate, GFP transfected cells (i.e. no AR: FIGS. 25A and 25C). FIG. N-oxide, crystal, polymorph, prodrug or any combination 25E shows that AR target genes are enhanced by SARM thereof, in an amount effective to treat refractory breast even in the presence of estradiol. cancer in the Subject. In one embodiment, the Subject is a 15 female Subject. In another embodiment, the Subject is a male DETAILED DESCRIPTION OF THE Subject. INVENTION In another embodiment of the present invention, a method is provided for treating a subject suffering from AR-positive In one embodiment, this invention relates to the treatment breast cancer, comprising the step of administering to the of androgen receptor-positive breast cancer in a subject. 20 subject a compound of formulae I-XIV of this invention Accordingly, this invention provides methods of: a) treating and/or its analog, derivative, isomer, metabolite, pharma a subject Suffering from breast cancer; b) treating a subject ceutically acceptable salt, pharmaceutical product, hydrate, Suffering from metastatic breast cancer; c) treating a subject N-oxide, crystal, polymorph, prodrug or any combination Suffering from refractory breast cancer; d) treating a subject thereof, in an amount effective to treat AR-positive breast Suffering from AR-positive breast cancer; e) treating a 25 cancer in the Subject. In one embodiment, the Subject is a subject suffering from AR-positive refractory breast cancer; female Subject. In another embodiment, the Subject is a male f) treating a subject Suffering from AR-positive metastatic Subject. breast cancer, g) treating a Subject suffering from AR In one embodiment, the AR-positive breast cancer is ER, positive and ER-positive breast cancer, h) treating a subject PR and HER2 positive. In another embodiment, the AR suffering from AR-positive breast cancer with or without 30 positive breast cancer is ER, PR and HER2 negative. In one expression of ER, PR, and/or HER2: i) treating a subject embodiment, the AR-positive breast cancer is ER positive, suffering from triple negative breast cancer; ) treating a and PR and HER2 negative. In another embodiment, the Subject Suffering from advanced breast cancer, k) treating a AR-positive breast cancer is ER and PR positive, and HER2 subject suffering from breast cancer that has failed SERM negative. In yet another embodiment, the AR-positive breast (tamoxifen, toremifene), aromatase inhibitor, trastuzumab 35 cancer is ER and HER2 positive, and PR negative. In still (Herceptin, ado-trastuzumab emtansine), pertuzumab (Per another embodiment, the AR-positive breast cancer is ER jeta), lapatinib, exemestane (Aromasin), bevacizumab negative, and PR and HER2 positive. In a further embodi (Avastin), and/or fulvestrant treatment: 1) treating a subject ment, the AR-positive breast cancer is ER and PR negative, Suffering from ER positive breast cancer; m) treating, pre and HER2 positive. In still a further embodiment, the venting, Suppressing or inhibiting metastasis in a subject 40 AR-positive breast cancer is ER and HER2 negative, and PR Suffering from breast cancer, n) prolonging Survival of a positive. In one embodiment, the AR-positive breast cancer Subject with breast cancer, o) slowing the progression of is ER-negative. In another embodiment, the AR-positive breast cancer in a subject; and/orp) prolonging progression breast cancer is ER-positive. free survival of a subject with breast cancer; by administer In another embodiment of the present invention, a method ing to the Subject a therapeutically effective amount of a 45 is provided for treating a subject suffering from AR-positive compound of formulae I-XIV of this invention and/or its refractory breast cancer, comprising the step of administer analog, derivative, isomer, metabolite, pharmaceutically ing to the subject a compound of formulae I-XIV of this acceptable salt, pharmaceutical product, hydrate, N-oxide, invention and/or its analog, derivative, isomer, metabolite, crystal, polymorph, prodrug or any combination thereof, as pharmaceutically acceptable salt, pharmaceutical product, described herein. In one embodiment, the subject is a male. 50 hydrate, N-oxide, crystal, polymorph, prodrug or any com In one embodiment, the Subject is a female. bination thereof, in an amount effective to treat AR-positive In one embodiment of the present invention, a method is refractory breast cancer in the Subject. In one embodiment, provided for treating a Subject Suffering from breast cancer, the subject is a female subject. In another embodiment, the comprising the step of administering to the Subject a com Subject is a male Subject. pound of formulae I-XIV of this invention and/or its analog, 55 In another embodiment of the present invention, a method derivative, isomer, metabolite, pharmaceutically acceptable is provided for treating a subject suffering from AR-positive salt, pharmaceutical product, hydrate, N-oxide, crystal, metastatic breast cancer, comprising the step of administer polymorph, prodrug or any combination thereof, in an ing to the subject a compound of formulae I-XIV of this amount effective to treat breast cancer in the subject. In one invention and/or its analog, derivative, isomer, metabolite, embodiment, the Subject is a female Subject. In another 60 pharmaceutically acceptable salt, pharmaceutical product, embodiment, the Subject is a male Subject. hydrate, N-oxide, crystal, polymorph, prodrug or any com In another embodiment of the present invention, a method bination thereof, in an amount effective to treat AR-positive is provided for treating a Subject Suffering from metastatic metastatic breast cancer in the Subject. In one embodiment, breast cancer, comprising the step of administering to the the subject is a female subject. In another embodiment, the subject a compound of formulae I-XIV of this invention 65 Subject is a male Subject. and/or its analog, derivative, isomer, metabolite, pharma In another embodiment of the present invention, a method ceutically acceptable salt, pharmaceutical product, hydrate, is provided for treating a subject suffering from AR-positive US 9,622,992 B2 10 and ER-positive breast cancer, comprising the step of As used herein, in one embodiment the term “treating administering to the subject a compound of formulae I-XIV may refer to treating, preventing, delaying the progression, of this invention and/or its analog, derivative, isomer, preventing the recurrence or treating the recurrence. In one metabolite, pharmaceutically acceptable salt, pharmaceuti embodiment, the term “treating refers to a reduction in cal product, hydrate, N-oxide, crystal, polymorph, prodrug morbidity, mortality, or a combination thereof, in association or any combination thereof, in an amount effective to treat with breast cancer. AR-positive metastatic breast cancer in the Subject. In one As used herein, the term “breast cancer may refer to embodiment, the Subject is a female Subject. In another breast cancer, advanced breast cancer, metastatic breast embodiment, the Subject is a male Subject. cancer, AR-positive breast cancer; ER-positive breast can 10 cer; AR-positive breast cancer with or without expression of In another embodiment of the present invention, a method ER, PR and/or HER2; triple-positive breast cancer (ER, PR is provided for treating a subject suffering from ER-positive and HER2 positive), AR-positive breast cancer with or breast cancer, comprising the step of administering to the without expression of ER; ER-positive breast cancer with or subject a compound of formulae I-XIV of this invention without expression of AR; AR-positive and ER-positive and/or its analog, derivative, isomer, metabolite, pharma 15 breast cancer; refractory breast cancer; AR-positive refrac ceutically acceptable salt, pharmaceutical product, hydrate, tory breast cancer; ER-positive refractory breast cancer; N-oxide, crystal, polymorph, prodrug or any combination AR-positive metastatic breast cancer; ER-positive meta thereof, in an amount effective to treat ER-positive breast static breast cancer, breast cancer that has failed SERM cancer in the Subject. In one embodiment, the Subject is a (tamoxifen, toremifene), aromatase inhibitor, trastuzumab female Subject. In another embodiment, the Subject is a male (Herceptin, ado-trastuzumab emtansine), pertuzumab (Per Subject. jeta), lapatinib, exemestane (Aromasin), bevacizumab In one embodiment, the ER-positive breast cancer is (Avastin), and/or fulvestrant treatments; or triple negative AR-positive. In another embodiment, the ER-positive breast breast cancer, or any combination thereof. cancer is AR-negative. In one embodiment, ER-positive In one embodiment, the term “breast cancer' refers to a breast cancer is triple positive (ER, PR, HER2) breast 25 condition characterized by anomalous rapid proliferation of cancer. In another embodiment, ER-positive breast cancer is abnormal cells in one or both breasts of a subject. The not triple positive breast cancer. 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 is provided for treating a subject Suffering from triple that can form a solid tumor. The term “tumor, in some negative breast cancer, comprising the step of administering 30 embodiments, refers to an abnormal mass or population of to the subject a compound of formulae I-XIV of this cells (i.e. two or more cells) that result from excessive or invention and/or its analog, derivative, isomer, metabolite, abnormal cell division, whether malignant or benign, and pharmaceutically acceptable salt, pharmaceutical product, pre-cancerous and cancerous cells. Malignant tumors are hydrate, N-oxide, crystal, polymorph, prodrug or any com distinguished from benign growths or tumors in that, in bination thereof, in an amount effective to treat triple nega 35 addition to uncontrolled cellular proliferation, they can tive breast cancer in the subject. In one embodiment, the invade Surrounding tissues and can metastasize. Subject is a female Subject. In another embodiment, the In breast cancer, neoplastic cells may be identified in one Subject is a male Subject. or both breasts only and not in another tissue or organ, in one In another embodiment of the present invention, a method or both breasts and one or more adjacent tissues or organs is provided for treating a subject suffering from advanced 40 (e.g. lymph node), or in a breast and one or more non breast cancer, comprising the step of administering to the adjacent tissues or organs to which the breast cancer cells subject a compound of formulae I-XIV of this invention have metastasized. and/or its analog, derivative, isomer, metabolite, pharma The term “metastasis', in some embodiments, refers to a ceutically acceptable salt, pharmaceutical product, hydrate, process in which cancer cells travel from one organ or tissue N-oxide, crystal, polymorph, prodrug or any combination 45 to another non-adjacent organ or tissue. Cancer cells in the thereof, in an amount effective to treat advanced breast breast(s) can spread to tissues and organs of a Subject, and cancer in the Subject. In one embodiment, the Subject is a conversely, cancer cells from other organs or tissue can female Subject. In another embodiment, the Subject is a male invade or metastasize to a breast. Cancerous cells from the Subject. breast(s) may invade or metastasize to any other organ or In another embodiment of the present invention, a method 50 tissue of the body. Breast cancer cells often invade lymph is provided for treating a subject Suffering from breast cancer node cells and/or metastasize to the liver, brain and/or bone that has failed (SERM) (tamoxifen, toremifene), aromatase and spread cancer in these tissues and organs. The term inhibitor, trastuzumab (Herceptin, ado-trastuzumab “invasion', in some embodiments, refers to the spread of emtansine), pertuzumab (Perjeta), lapatinib, exemestane cancerous cells to adjacent Surrounding tissues. (Aromasin), bevacizumab (Avastin), and/or fulvestrant 55 As used herein, the term “advanced breast cancer” refers treatments, comprising the step of administering to the to cancer that has spread to other places in the body and subject a compound of formulae I-XIV of this invention usually cannot be cured or controlled with current treatment. and/or its analog, derivative, isomer, metabolite, pharma As used herein, the term “AR-positive breast cancer may ceutically acceptable salt, pharmaceutical product, hydrate, refer to breast cancer wherein at least a portion of the cancer N-oxide, crystal, polymorph, prodrug or any combination 60 cells express at least the androgen receptor (AR). thereof, in an amount effective to treat breast cancer that has As used herein, the term “ER-positive breast cancer may failed SERM (tamoxifen, toremifene), aromatase inhibitor, refer to breast cancer wherein at last a portion of the cancer trastuzumab (Herceptin, ado-trastuzumab emtansine), per cells express at least the estrogen receptor (ER). tuZumab (Perjeta), lapatinib, exemestane (Aromasin), beva As used herein, the term “triple negative breast cancer' cizumab (Avastin), and/or fulvestrant treatments in the Sub 65 may refer to breast cancer cells that do not have estrogen ject. In one embodiment, the Subject is a female Subject. In receptors (ER), progesterone receptors (PR), or large another embodiment, the Subject is a male Subject. amounts of HER2/neu protein. “Triple negative breast can US 9,622,992 B2 11 12 cer may also be referred to herein as “ER-negative PR 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 5 cer; and in another embodiment to breast cancer that has HER2/neu (HER2) protein. “Triple positive breast cancer' 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 10 or fulvestrant treatments. cancer that does not respond to treatment. The breast cancer may be resistant at the beginning of treatment or it may In another embodiment of the present invention, a method become resistant during treatment. "Refractory breast can is provided for lowering biomarker levels in a subject with cer may also be referred to herein as “resistant cancer. breast cancer comprising the step of administering to the In another embodiment of the present invention, a method 15 subject a compound of formulae I-XIV of this invention is provided for treating, preventing, Suppressing or inhibit and/or its analog, derivative, isomer, metabolite, pharma ing metastasis in a Subject Suffering from breast cancer, ceutically acceptable salt, pharmaceutical product, hydrate, comprising the step of administering to the Subject a com N-oxide, crystal, polymorph, prodrug or any combination pound of formulae I-XIV of this invention and/or its analog, thereof, in an amount effective to lower the biomarker level derivative, isomer, metabolite, pharmaceutically acceptable in said subject. In another embodiment, the method com salt, pharmaceutical product, hydrate, N-oxide, crystal, prises administering a compound of formulae I-XIV of this polymorph, prodrug or any combination thereof, in an invention. amount effective to treat, prevent, Suppress or inhibit metas As used herein, the term “biomarker” may refer to a tasis in the Subject. In one embodiment, the Subject is a Substance used as an indicator of a process, event, or female Subject. In another embodiment, the Subject is a male 25 condition. A biomarker can be a biomolecule Such as a Subject. nucleic acid molecule (e.g. microRNA genomic DNA, etc.), In another embodiment of the present invention, a method a protein, a polysaccharide, and the like. Biomarkers include is provided for prolonging the survival of a subject with tumor antigens and tumor markers. In one embodiment, a breast cancer, comprising the step of administering to the biomarker indicates the presence of cancer, e.g., breast subject a compound of formulae I-XIV of this invention 30 cancer. In one embodiment, a biomarker may be used to and/or its analog, derivative, isomer, metabolite, pharma determine the efficacy of treatment. In one embodiment, a ceutically acceptable salt, pharmaceutical product, hydrate, biomarker may be used to determine the progression of a N-oxide, crystal, polymorph, prodrug or any combination condition, e.g., breast cancer. thereof, in an amount effective to prolong the survival of a The MUC-1 associated antigen, or CA 27.29, is a cancer subject with breast cancer. In one embodiment, the subject 35 antigen highly associated with breast cancer. As used herein, is a female Subject. In another embodiment, the Subject is a the term “CA27.29 biomarker refers to a biomarker for male Subject. breast cancer. In one embodiment, CA27.29 is a biomarker In another embodiment of the present invention, a method for advanced breast cancer. is provided for slowing the progression of breast cancer in “PSA (prostate-specific antigen) biomarker' is used as a a Subject, comprising the step of administering to the Subject 40 biomarker for prostate cancer, however PSA was also found a compound of formulae I-XIV of this invention and/or its in the blood of women with breast cancer at higher levels analog, derivative, isomer, metabolite, pharmaceutically compared to women without breast cancer. PSA is useful acceptable salt, pharmaceutical product, hydrate, N-oxide, also as a biomarker for breast cancer. crystal, polymorph, prodrug or any combination thereof, in “CTX biomarker and “NTX biomarker are the C-telo an amount effective to slow the progression of breast cancer 45 peptide and N-telopeptide of collagen type I, respectively, in the Subject. In one embodiment, the Subject is a female which are used as biomarkers of bone turnover. NTX and Subject. In another embodiment, the Subject is a male CTX biomarkers may be sensitive indicators of the presence Subject. of bone metastases in breast cancer patients. In another embodiment of the present invention, a method In one embodiment, a method of this invention lowers is provided for prolonging progression-free Survival of a 50 CA27.29 biomarker is a subject. In one embodiment, a Subject with breast cancer, comprising the step of adminis method of this invention lowers PSA in a subject. In one tering to the subject a compound of formulae I-XIV of this embodiment, a method of this invention lowers CTX bio invention and/or its analog, derivative, isomer, metabolite, marker in a Subject. In one embodiment of this invention, a pharmaceutically acceptable salt, pharmaceutical product, method of this invention lowers NTX biomarker in a subject. hydrate, N-oxide, crystal, polymorph, prodrug or any com 55 In another embodiment, a method of this invention main bination thereof, in an amount effective to prolong progres tains the level of CA27.29 in a subject. In another embodi sion-free survival of a subject with breast cancer. In one ment, a method of this invention maintains the level of PSA embodiment, the Subject is a female Subject. In another in a subject. In another embodiment, a method of this embodiment, the Subject is a male Subject. invention maintains the level of CTX biomarker in a subject. In one embodiment, breast cancer of this invention refers 60 In another embodiment, a method of this invention main to in one embodiment to ER-positive metastatic breast tains the level of NTX biomarker. In one embodiment, the cancer; In another embodiment to ER-positive refractory Subject has breast cancer. In one embodiment, the Subject breast cancer. In another embodiment to ER positive PR has advanced breast cancer. In another embodiment, the positive HER2 negative breast cancer; In another embodi Subject has refractory breast cancer. In yet another embodi ment to AR-positive ER-positive breast cancer. In another 65 ment, the subject has AR-positive breast cancer. In still embodiment to AR-positive ER-positive refractory breast another embodiment, the subject has ER-positive breast cancer; In another embodiment to AR-positive ER-positive CaCC. US 9,622,992 B2 13 14 In one embodiment, the compound of this invention is an isomer, metabolite, derivative, pharmaceutically acceptable antagonist. In another embodiment, the compound of this salt, pharmaceutical product, polymorph, crystal, impurity, invention is an agonist. In yet another embodiment, the N-oxide, hydrate or any combination thereof, for: a) treating compound of this invention is a partial agonist/partial a bone related disorder; b) preventing a bone related disor antagonist. In one embodiment, a compound of this inven 5 der; c) suppressing a bone related disorder; d) inhibiting a tion is an AR agonist. In another embodiment, a compound bone related disorder; e) increasing a strength of a bone of is an AR antagonist. In yet another embodiment, a com a Subject: f) increasing a bone mass in a Subject, g) use for pound is a partial AR agonist and AR antagonist. In one osteoclastogenesis inhibition. embodiment, a compound of this invention is a PR agonist. In one embodiment, this invention provides for the use of In another embodiment, a compound is a PR antagonist. In 10 a compound as herein described, or its prodrug, analog, yet another embodiment, a compound is a partial PR agonist isomer, metabolite, derivative, pharmaceutically acceptable and PR antagonist. salt, pharmaceutical product, polymorph, crystal, impurity, In one embodiment, a compound of this invention is an N-oxide, hydrate or any combination thereof, for: a) accel AR agonist and a PR antagonist. erating bone repair; b) treating bone disorders; c) treating The SARM compounds of this invention may be useful, 15 bone density loss; d) treating low bone mineral density in some embodiments, for: a) treatment, prevention, delay (BMD); e) treating reduced bone mass: f) treating metabolic ing onset of increasing time to first skeletal related event bone disease; g) promoting bone growth or regrowth; h) (SRE), suppression or inhibition of, or the reduction of the promoting bone restoration: i) promoting bone fracture risk of developing a skeletal-related event (SRE), such as repair, j) promoting bone remodeling, k) treating bone pathological bone fractures, Surgery of the bone, radiation of damage following reconstructive Surgery including of the the bone, spinal cord compression, new bone metastasis, face, hip, or joints; 1) enhancing of bone strength and and/or bone loss in a Subject; b) treatment, prevention, function; m) increasing cortical bone mass; and/or n) suppression or inhibition of, or the reduction of the risk of increasing trabecular connectivity. developing a variety of hormone-related conditions in a In one embodiment, the bone related disorder is a genetic Subject, for example for increasing libido; and/or for c) 25 disorder, or in another embodiment, is induced as a result of improving quality of life in a Subject. a treatment regimen for a given disease. For example, and in Osteoporosis is a systemic skeletal disease, characterized one embodiment, the compounds as herein described are by low bone mass and deterioration of bone tissue, with a useful in treating a bone-related disorder that arises as a consequent increase in bone fragility and Susceptibility to result of cancer metastasis to bone, or in another embodi fracture. In the U.S., the condition affects more than 25 30 ment, as a result of androgen-deprivation therapy, for million people and causes more than 1.3 million fractures example, given in response to prostate carcinogenesis in the each year, including 500,000 spine, 250,000 hip and 240,000 subject. wrist fractures annually. Hip fractures are the most serious As used herein, “Estrogen-deprivation therapy” may refer consequence of osteoporosis, with 5-20% of patients dying to therapy which is given in response to breast cancer in a within one year, and over 50% of survivors being incapaci 35 subject. Known treatments include treatment with SERMs. tated. The elderly are at greatest risk of osteoporosis, and the SERDs, or aromatase inhibitors (AI). For example, and in problem is therefore predicted to increase significantly with one embodiment, the compounds as herein described are the aging of the population. Worldwide fracture incidence is useful in treating a bone-related disorder that arises as a forecasted to increase three-fold over the next 60 years, and result of cancer metastasis to bone, or in another embodi one study estimated that there will be 4.5 million hip 40 ment, as a result of estrogen-deprivation therapy, for fractures worldwide in 2050. example, given in response to breast cancer in the Subject. Women are at greater risk of osteoporosis than men. In one embodiment, the bone-related disorder is a loss of Women experience a sharp acceleration of bone loss during bone mineral density (BMD). In another embodiment, the the five years following menopause. Other factors that bone-related disorder is osteoporosis. In another embodi increase the risk include Smoking, alcohol abuse, a sedentary 45 ment, the bone-related disorder is osteopenia. In another lifestyle and low intake. However, osteoporosis also embodiment, the bone-related disorder is increased bone occurs frequently in males. It is well established that the resorption. In another embodiment, the bone-related disor bone mineral density of males decreases with age. der is bone fracture. In another embodiment, the bone Decreased amounts of bone mineral content and density related disorder is bone frailty. In another embodiment, the correlates with decreased bone strength, and predisposes to 50 bone-related disorder is any combination of osteoporosis, fracture. The molecular mechanisms underlying the pleio osteopenia, increased bone resorption, bone fracture, bone tropic effects of sex-hormones in non-reproductive tissues frailty and loss of BMD. Each disorder represents a separate are only beginning to be understood, but it is clear that embodiment of the present invention. physiologic concentrations of androgens and estrogens play “Osteoporosis' refers, in one embodiment, to a thinning an important role in maintaining bone homeostasis through 55 of the bones with reduction in bone mass due to depletion of out the life-cycle. Consequently, when androgen or estrogen calcium and bone protein. In another embodiment, osteo deprivation occurs there is a resultant increase in the rate of porosis is a systemic skeletal disease, characterized by low bone remodeling that tilts the balance of resorption and bone mass and deterioration of bone tissue, with a conse formation to the favor of resorption that contributes to the quent increase in bone fragility and Susceptibility to fracture. overall loss of bone mass. In males, the natural decline in 60 In osteoporotic patients, bone strength is abnormal, in one sex-hormones at maturity (direct decline in androgens as embodiment, with a resulting increase in the risk of fracture. well as lower levels of estrogens derived from peripheral In another embodiment, osteoporosis depletes both the cal aromatization of androgens) is associated with the frailty of cium and the protein collagen normally found in the bone, bones. This effect is also observed in males who have been in one embodiment, resulting in either abnormal bone qual castrated. 65 ity or decreased bone density. In another embodiment, bones In one embodiment, this invention provides for the use of that are affected by osteoporosis can fracture with only a a compound as herein described, or its prodrug, analog, minor fall or injury that normally would not cause a bone US 9,622,992 B2 15 16 fracture. The fracture can be, in one embodiment, either in 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 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 10 follows androgen deprivation. In another embodiment, the using the methods provided herein and/or utilizing the osteoporosis results from estrogen-deprivation therapy. In compositions provided herein, are fractures, which in one another embodiment, the osteoporosis follows estrogen embodiment, are pathological fractures, non-traumatic frac deprivation therapy. In another embodiment, the osteoporo tures, vertebral fracture, non-vertebral fractures, morpho sis is primary osteoporosis. In another embodiment, the 15 metric fractures, or a combination thereof. In some embodi osteoporosis is secondary osteoporosis. In another embodi ments, fractures may be simple, compound, transverse, ment, the osteoporosis is postmenopausal osteoporosis. In greenstick, or comminuted fractures. In one embodiment, another embodiment, the osteoporosis is juvenile osteopo fractures may be to any bone in the body, which in one rosis. In another embodiment, the osteoporosis is idiopathic embodiment, is a fracture in any one or more bones of the osteoporosis. In another embodiment, the osteoporosis is arm, wrist, hand, finger, leg, ankle, foot, toe, hip, collar senile osteoporosis. bone, or a combination thereof. In another embodiment, the primary osteoporosis is Type In another embodiment, the methods and/or compositions I primary osteoporosis. In another embodiment, the primary provided herein, are effective in treatment, prevention, Sup osteoporosis is Type II primary osteoporosis. Each type of pression, inhibition or reduction of the risk of skeletal osteoporosis represents a separate embodiment of the pres 25 related events such as pathologic fractures, spinal cord ent invention. compression, hypercalcemia, bone-related pain, or their According to this aspect of the invention and in one combination. embodiment, the bone-related disorder is treated with a In another embodiment, the skeletal-related events sought compound as herein described, or a combination thereof. In to be treated using the methods provided herein and/or another embodiment, other bone-stimulating compounds 30 utilizing the compositions provided herein, comprise the can be provided to the subject, prior to, concurrent with or necessity for bone Surgery and/or bone radiation, which in following administration of a compound or compounds as some embodiments, is for the treatment of pain resulting in herein described. In one embodiment, Such a bone stimu one embodiment from bone damage, or nerve compression. lating compound may comprise natural or synthetic mate In another embodiment, the skeletal-related events sought to rials. 35 be treated using the methods provided herein and/or utilizing In one embodiment, the bone stimulating compound may the compositions provided herein, comprise spinal cord comprise a bone morphogenetic protein (BMP), a growth compression, or the necessity for changes in antineoplastic factor, such as epidermal growth factor (EGF), a fibroblast therapy, including changes in hormonal therapy, in a Subject. growth factor (FGF), a transforming growth factor (TGF, an In some embodiments, skeletal-related events sought to be insulin growth factor (IGF), a platelet-derived growth factor 40 treated using the methods provided herein and/or utilizing (PDGF) hedgehog proteins such as Sonic, indian and desert the compositions provided herein, comprise treating, Sup hedgehog, a hormone Such as follicle stimulating hormone, pressing, preventing, reducing the incidence of, or delaying parathyroid hormone, parathyroid hormone related peptide, progression or severity of bone metastases, or bone loss. In activins, inhibins, follistatin, frizzled, frzb or frazzled pro one embodiment, bone loss may comprise osteoporosis, teins, BMP binding proteins such as chordin and fetuin, a 45 osteopenia, or a combination thereof. In one embodiment, cytokine such as IL-3, IL-7, GM-CSF, a chemokine, such as skeletal-related events may comprise any combination of the eotaxin, a collagen, , osteonectin and others, as embodiments listed herein. will be appreciated by one skilled in the art. In one embodiment, the methods provided herein and/or In another embodiment, the compositions for use in utilizing the compositions provided herein, are effective in treating a bone disorder of this invention may comprise a 50 reducing metastases to the bone, such as in terms of number compound or compounds as herein described, an additional of foci, the size of foci, or a combination thereof. According bone stimulating compound, or compounds, and osteogenic to this aspect of the invention and in one embodiment, cells. In one embodiment, an osteogenic cell may be a stem provided herein is a method of preventing or inhibiting cell or progenitor cell, which may be induced to differentiate cancer metastasis to bone in a subject, comprising the step into an osteoblast. In another embodiment, the cell may be 55 of administering to the Subject a composition comprising an osteoblast. In another embodiment, nucleic acids which toremifene, raloxifene, tamoxifen or an analogue, functional encode bone-stimulating compounds may be administered derivative, metabolite or a combination thereof, or a phar to the subject, which is to be considered as part of this maceutically acceptable salt thereof. In one embodiment, invention. Such metabolites may comprise ospennifene, fispennifene or In one embodiment, this invention provides for the treat 60 their combination. In one embodiment, the cancer is prostate ment, prevention, Suppression or inhibition of, or the reduc cancer. In one embodiment, the cancer is breast cancer. tion of the risk of developing a skeletal-related event (SRE), In one embodiment, the skeletal-related events area result Such as bone fractures, Surgery of the bone, radiation of the of cancer therapy. In one embodiment, the skeletal-related bone, spinal cord compression, new bone metastasis, bone events are a result of hormone deprivation therapy, while in loss, or a combination thereof in a Subject with cancer, 65 another embodiment, they are a product of androgen depri comprising administering a compound as herein described vation therapy (ADT), and in another embodiment they are and/or its analog, derivative, isomer, metabolite, pharma a product of estrogen-deprivation therapy US 9,622,992 B2 17 18 As used herein, the term “libido’, may refer to sexual T is OH, OR, NHCOCH or NHCOR; desire, or as defined in Example 9. R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, As used herein, the term "quality of life' may refer to the CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl or focuses on the health and life of a subject suffering from a OH: condition or disease, for example Suffering from breast R is CH, CHF, CHF, CF, CHCH, or CFCF: cancer, post treatment until the end of life. It covers the R is H, F, Cl, Br, I, CH, CF, OH, CN, NO, NHCOCH, physical, psychosocial, and economic issues faced by the NHCOCF, NHCOR, alkyl, arylalkyl, OR, NH, NHR, Subject, beyond the diagnosis and treatment phases. The N(R), SR; term "quality of life' may also be referred to herein as R is H, F, Cl, Br, I, CN, NO, COR, COOH, CONHR, “survivorship’. In one embodiment, survivorship includes 10 CF, Sn(R), or R 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. 15 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 described herein may be useful for treating either males or M O \ females, females may respond more advantageously to z1K / z &V / administration of certain compounds, for certain methods. In Y Y other embodiments, while the methods as described herein may be useful for treating either males or females, males Z is NO, CN, COR, COOH, or CONHR: may respond more advantageously to administration of 25 Y is CF, F, Br, Cl, I, CN, or Sn(R): certain compounds, for certain methods. Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, Selective Androgen Receptor Modulator (SARM) Com NHCOR, NHCONHR, NHCOOR, OCONHR, pounds CONHR, NHCSCH NHCSCF, NHCSR, In one embodiment, the compound of this invention NHSOCH, NHSOR, OR, COR, OCOR, OSOR, which is effective at: a) treating a subject suffering from 30 SOR or SR; breast cancer; b) treating a Subject suffering from metastatic or Q together with the benzene ring to which it is attached breast cancer; c) treating a subject suffering from refractory is a fused ring system represented by structure A, B or breast cancer; d) 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-positive metastatic breast cancer, g) 35 treating a Subject Suffering from AR-positive and ER-posi 21 NH O A 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 ls negative breast cancer, j) treating a Subject Suffering from 40 advanced breast cancer, k) treating a subject Suffering from 21 NH O B breast cancer that has failed SERM (tamoxifen, toremifene), aromatase inhibitor, trastuzumab (Herceptin, ado-trastu ls 21 Zumab emtansine), pertuzumab (Perjeta), lapatinib, exemes 45 tane (Aromasin), bevacizumab (Avastin), and/or fulvestrant 21 NH C treatment: 1) treating a subject suffering from ER positive breast cancer; m) treating, preventing, Suppressing or inhib iting metastasis in a subject Suffering from breast cancer, n) Y prolonging Survival of a subject with breast cancer, o) slowing the progression of breast cancer in a subject; and/or 50 p) prolonging progression-free Survival of a subject with n is an integer of 1-4; and breast cancer, is a compound represented by a structure of m is an integer of 1-3. formula I, and/or its analog, derivative, isomer, metabolite, In one embodiment, this invention relates to the treatment pharmaceutically acceptable salt, pharmaceutical product, of androgen receptor-positive breast cancer in a Subject, for 55 example a female Subject. Accordingly, this invention pro hydrate, N-oxide, crystal, polymorph, prodrug or any com vides methods for: a) treating AR-positive breast cancer in bination thereof: a subject; b) treating metastatic AR-positive breast cancer, or advanced AR-positive breast cancer; c) treating refractory (R3) y AR-positive breast cancer; d) treating, preventing, Suppress 60 ing or inhibiting metastasis in a subject Suffering from breast cancer; e) prolonging progression-free Survival of a subject t-Cl G 21 3-(R) Suffering from breast cancer, f) treating a Subject Suffering y-4 S from ER-positive breast cancer, g) treating a subject Suffer ing from metastatic ER-positive breast cancer; h) treating a 65 subject suffering from refractory ER-positive breast cancer; X is a bond, O, CH, NH, S, Se, PR, NO or NR; i) treating a subject suffering from AR-positive ER-positive G is O or S; breast cancer, j) treating a subject Suffering from AR US 9,622,992 B2 19 20 positive ER-positive refractory breast cancer, k) treating a subject suffering from AR-positive ER-positive metastatic breast cancer; 1) treating a Subject Suffering from AR 21 NH O A positive and ER-positive breast cancer; m) treating a subject suffering from AR-positive ER-positive breast cancer with 5 or without expression of PR, and/or HER2; n) treating a ln subject suffering from advanced ER-positive breast cancer; o) treating a subject suffering from ER-positive breast 21 NH O B cancer that has failed SERM (tamoxifen, toremifene), aro matase inhibitor, trastuzumab (Herceptin, ado-trastuzumab 10 l' 21 emtansine), pertuzumab (Perjeta), lapatinib, exemestane (Aromasin), bevacizumab (Avastin), and/or fulvestrant 21 NH C 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 15 tul / breast cancer, r) slowing the progression of ER-positive breast cancer in a subject; and/or S) prolonging progression n is an integer of 1-4; and free survival of a subject with ER-positive breast cancer; m is an integer of 1-3: comprising administering to the Subject a therapeutically and/or its analog, derivative, isomer, metabolite, pharma effective amount of a selective androgen receptor modulator ceutically acceptable salt, pharmaceutical product, hydrate, (SARM) compound represented by a compound of formula N-oxide, crystal, polymorph, prodrug or any combination I: thereof, as described herein. In one embodiment, the subject is a female Subject. In one embodiment, the Subject is a male 25 Subject. (R3) Q I In one embodiment, G in formula I is O. In another embodiment, X in formula I is O. In another embodiment, T in formula I is OH. In another embodiment, R in formula I 1-ClA-4 G N21 (R2), is CH. In another embodiment, Z in formula I is NO. In 30 another embodiment, Z in formula I is CN. In another embodiment, Y in formula I is CF. In another embodiment, Y in formula I is Cl. In another embodiment, Q in formula X is a bond, O, CH, NH, S, Se, PR, NO or NR; 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, NHCOCH or NHCOR; 35 embodiment, Q in formula I is C1. In another embodiment, R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, Q in formula I is NHCOCH. In another embodiment, Q in CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl or formula I is CN and R is F. In another embodiment, Q in OH: formula I is C1 and R is F. In another embodiment, Q in R is CH, CHF, CHF, CF, CHCH, or CFCF: formula I is in the para position. In another embodiment, Z R is H, F, Cl, Br, I, CH, CF, OH, CN, NO, NHCOCH, 40 in formula I is in the para position. In another embodiment, NHCOCF, NHCOR, alkyl, arylalkyl, OR, NH, NHR, Y in formula I is in the meta position. N(R), SR; The substituents Z. Yand R can be in any position of the R is H, F, Cl, Br, I, CN, NO, COR, COOH, CONHR, ring carrying these Substituents (hereinafter "A ring'). In one CF, Sn(R), or R together with the benzene ring to embodiment, the substituent Z is in the para position of the 45 A ring. In another embodiment, the substituent Y is in the which it is attached forms a fused ring system repre meta position of the A ring. In another embodiment, the sented by the structure: Substituent Z is in the para position of the A ring and substituent Y is in the meta position of the A ring. The substituents Q and R can be in any position of the 50 ring carrying these Substituents (hereinafter “Bring'). 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 z-KM / O z1KM / substituent Q is CN and is in the para position of the Bring. 55 As contemplated herein, when the integers m and n are Y Y greater than one, the substituents R and R are not limited to one particular substituent, and can be any combination of Z is NO, CN, COR, COOH, or CONHR: the substituents listed above. Y is CF, F, Br, Cl, I, CN, or Sn(R): In another embodiment, the compound of this invention Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, 60 which is effective at: a) treating a subject suffering from NHCOR, NHCONHR, NHCOOR, OCONHR, breast cancer; b) treating a Subject suffering from metastatic CONHR, NHCSCH, NHCSCF, NHCSR, breast cancer; c) treating a Subject Suffering from refractory NHSOCH, NHSOR, OR, COR, OCOR, OSOR, breast cancer; d) treating a Subject suffering from AR SOR or SR; positive breast cancer; e) treating a subject Suffering from or Q together with the benzene ring to which it is attached 65 AR-positive refractory breast cancer, f) treating a subject is a fused ring system represented by structure A, B or Suffering from AR-positive metastatic breast cancer, g) C: treating a subject Suffering from AR-positive and ER-posi US 9,622,992 B2 21 22 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, 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 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 10 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) breast cancer, j) treating a subject Suffering from AR prolonging Survival of a subject with breast cancer, o) positive ER-positive refractory breast cancer, k) treating a slowing the progression of breast cancer in a subject; and/or 15 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, 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 matase inhibitor, trastuzumab (Herceptin, ado-trastuzumab II emtansine), pertuzumab (Perjeta), lapatinib, exemestane 25 (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 30 breast cancer in a subject; and/or S) prolonging progression wherein X is a bond, O, CH, NH, Se, PR, or NR; free survival of a subject with ER-positive breast cancer, G is O or S; comprising administering to the Subject a therapeutically T is OH, OR, NHCOCH or NHCOR; effective amount of a selective androgen receptor modulator Z is NO, CN, COR, COOH or CONHR: 35 (SARM) compound represented by a compound of formula Y is I, CF, Br, Cl, or Sn(R): II: Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, II

NHSOCH, NHSOR, OR, COR, OCOR, OSOR, 40 SOR 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: 45 wherein X is a bond, O, CH, NH, Se, PR, or NR; 21 NH O A G is O or S; T is OH, OR, NHCOCH, or NHCOR; l' 50 Z is NO, CN, COR, COOH or CONHR: Y is I, CF, Br, Cl, or Sn(R): 21 NH O B Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, ln 21 55 NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOR or SR; 21 NH C or Q together with the benzene ring to which it is attached is a fused ring system tul / represented by structure A, B or C: 60 R is a C-C alkyl, aryl, phenyl, alkenyl, hydroxyl, a C-C haloalkyl, halogen, or haloalkenyl; and NH O R is CH, CF, CHCH, or CFCF. 21 In one embodiment, this invention relates to the treatment 65 of androgen receptor-positive breast cancer in a Subject, for N example a female Subject. Accordingly, this invention pro US 9,622,992 B2 23 24 -continued aromatase inhibitor, trastuzumab (Herceptin, ado-trastu B Zumab emtansine), pertuzumab (Perjeta), lapatinib, exemes 21 NH O tane (Aromasin), bevacizumab (Avastin), and/or fulvestrant treatment: 1) treating a subject suffering from ER positive is 21 breast cancer; m) treating, preventing, Suppressing or inhib C iting metastasis in a subject Suffering from breast cancer, n) NH prolonging Survival of a Subject with breast cancer, o) 21 slowing the progression of breast cancer in a Subject; and/or p) prolonging progression-free Survival of a Subject with ls 10 breast cancer, is a compound represented by a structure of formula III, and/or its analog, derivative, isomer, metabolite, R is a C-C alkyl, aryl, phenyl, alkenyl, hydroxyl, a pharmaceutically acceptable salt, pharmaceutical product, C-C haloalkyl, halogen, or haloalkenyl; and hydrate, N-oxide, crystal, polymorph, prodrug or any com bination thereof: R is CH, CF, CHCH, or CFCF: 15 and/or its analog, derivative, isomer, metabolite, pharma ceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug or any combination III thereof, as described herein. In one embodiment, the subject

is a female Subject. In one embodiment, the Subject is a male Subject. e In one embodiment, G in formula II is O. In another 2. embodiment, X in formula II is O. In another embodiment, O T informula II is OH. In another embodiment, R in formula II is CH. In another embodiment, Z in formula II is NO. 25 wherein In another embodiment, Z in formula II is CN. In another Z is NO, CN, COOH, COR, NHCOR or CONHR: embodiment, Yin formula II is CF. In another embodiment, Y is CF, F, I, Br, C1, CN, C(R) or Sn(R): Y in formula II is halogen. In another embodiment, Y in Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, formula II is C1. In another embodiment, Q in formula II is NHCOR, NHCONHR, NHCOOR, OCONHR, CN. In another embodiment, Q in formula II is halogen. In 30 CONHR, NHCSCH, NHCSCF, NHCSR, another embodiment, Q in formula II is C1. In another NHSOCH, NHSOR, OR, COR, OCOR, OSOR, embodiment, Q in formula II is F. In another embodiment, SOR or SR; Q in formula II is NHCOCH. In another embodiment, Qin or Q together with the benzene ring to which it is attached formula II is in the para position. In another embodiment, Z is a fused ring system represented by structure A, B or in formula II is in the para position. In another embodiment, 35 Y in formula II is in the meta position. In another embodi ment, G in formula II is O. T is OH, R is CH, X is O. Z is CN, Y is CF or halogen and Q is CN or F. In another embodiment, G in formula II is O. T is OH, R is CH, X is 21 NH O A O, Z is NO, Y is CF, and Q is NHCOCH, F or C1. 40 The substituents Z and Y can be in any position of the ring carrying these substituents (hereinafter “A ring). In one in embodiment, the substituent Z is in the para position of the 21 NH O B A ring. In another embodiment, the substituent Y is in the meta position of the A ring. In another embodiment, the 45 Substituent Z is in the para position of the A ring and ls 21 substituent Y is in the meta position of the A ring. The Substituent Q can be in any position of the ring 21 NH C carrying this substituent (hereinafter “B ring'). In one embodiment, the substituent Q is in the para position of the 50 is / Bring. In another embodiment, the substituent Q is CN and is in the para position of the Bring. In another embodiment, the compound of this invention and which is effective at: a) treating a subject suffering from R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, breast cancer; b) treating a Subject suffering from metastatic 55 CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl or breast cancer; c) treating a Subject Suffering from refractory OH. breast cancer; d) treating a Subject suffering from AR In one embodiment, this invention relates to the treatment positive breast cancer; e) treating a subject Suffering from of androgen receptor-positive breast cancer in a Subject, for AR-positive refractory breast cancer, f) treating a subject example a female Subject. Accordingly, this invention pro Suffering from AR-positive metastatic breast cancer, g) 60 vides methods for: a) treating AR-positive breast cancer in treating a Subject Suffering from AR-positive and ER-posi a subject; b) treating metastatic AR-positive breast cancer, or tive breast cancer, h) treating a subject Suffering from advanced AR-positive breast cancer; c) treating refractory AR-positive breast cancer with or without expression of ER, AR-positive breast cancer; d) treating, preventing, Suppress PR, and/or HER2: i) treating a subject suffering from triple ing or inhibiting metastasis in a subject Suffering from breast negative breast cancer, j) treating a Subject Suffering from 65 cancer; e) prolonging progression-free Survival of a subject advanced breast cancer, k) treating a subject Suffering from Suffering from breast cancer, f) treating a Subject Suffering breast cancer that has failed SERM (tamoxifen, toremifene), from ER-positive breast cancer, g) treating a subject Suffer US 9,622,992 B2 25 26 ing from metastatic ER-positive breast cancer, h) treating a 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 positive ER-positive refractory breast cancer, k) treating a combination thereof, as described herein. In one subject suffering from AR-positive ER-positive metastatic embodiment, the Subject is a female Subject. In one breast cancer; 1) treating a Subject Suffering from AR embodiment, the Subject is a male Subject. positive and ER-positive breast cancer; m) treating a subject In one embodiment, Z in formula III is NO. In another suffering from AR-positive ER-positive breast cancer with embodiment, Zinformula III is CN. In another embodiment, or without expression of PR, and/or HER2; n) treating a 10 Y in formula III is CF. In another embodiment, Y in subject suffering from advanced ER-positive breast cancer; formula III is Cl. In another embodiment, Y in formula III o) treating a subject suffering from ER-positive breast is halogen. In another embodiment, Q in formula III is CN. cancer that has failed SERM (tamoxifen, toremifene), aro matase inhibitor, trastuzumab (Herceptin, ado-trastuzumab In another embodiment, Q in formula III is halogen. In emtansine), pertuzumab (Perjeta), lapatinib, exemestane another embodiment, Q in formula III is F. In another (Aromasin), bevacizumab (Avastin), and/or fulvestrant 15 embodiment, Q in formula III is C1. In another embodiment, treatments; p) treating, preventing, Suppressing or inhibiting Q in formula III is NHCOCH. In another embodiment, Z is metastasis in a subject suffering from ER-positive breast CN, Y is CF or halogen, and Q is CN or F. In another cancer, q) prolonging Survival of a Subject with ER-positive embodiment, Z is NO, Y is CF, and Q is NHCOCH, For breast cancer, r) slowing the progression of ER-positive C1. breast cancer in a subject; and/or S) prolonging progression In another embodiment, the compound of this invention free survival of a subject with ER-positive breast cancer; which is effective at: a) treating a subject suffering from comprising administering to the Subject a therapeutically breast cancer; b) treating a Subject suffering from metastatic effective amount of a selective androgen receptor modulator breast cancer; c) treating a Subject Suffering from refractory (SARM) compound represented by a compound of formula 25 breast cancer; d) treating a Subject suffering from AR III: 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) III treating a subject Suffering from AR-positive and ER-posi 30 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 2. Y negative breast cancer, j) treating a Subject Suffering from O advanced breast cancer, k) treating a subject Suffering from 35 breast cancer that has failed SERM (tamoxifen, toremifene), wherein aromatase inhibitor, trastuzumab (Herceptin, ado-trastu Z is NO, CN, COOH, COR, NHCOR or CONHR: Zumab emtansine), pertuzumab (Perjeta), lapatinib, exemes Y is CF, F, I, Br, C1, CN, C(R) or Sn(R): tane (Aromasin), bevacizumab (Avastin), and/or fulvestrant Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, treatment: 1) treating a subject suffering from ER positive NHCOR, NHCONHR, NHCOOR, OCONHR, 40 breast cancer; m) treating, preventing, Suppressing or inhib CONHR, NHCSCH, NHCSCF, NHCSR, iting metastasis in a subject Suffering from breast cancer, n) NHSOCH, NHSOR, OR, COR, OCOR, OSOR, prolonging Survival of a Subject with breast cancer, o) SOR or SR; slowing the progression of breast cancer in a Subject; and/or or Q together with the benzene ring to which it is attached p) prolonging progression-free Survival of a Subject with is a fused ring system represented by structure A, B or 45 breast cancer, is a compound represented by a structure of formula IV, and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug or any com bination thereof: 21 NH O A 50

ls IV

21 NH O B 55 2. S. 21 T 21 NH C 60 wherein X is a bond, O, CH, NH, S, Se, PR, NO or NR; len / G is O or S; R is CH, CHF, CHF, CF, CHCH, or CFCF: and T is OH, OR, NHCOCH or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, 65 R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl or CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl or OH: OH: US 9,622,992 B2 27 28 A is a ring selected from: 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 4N-HY 4N-HY 4N-HY positive ER-positive refractory breast cancer, k) treating a subject suffering from AR-positive ER-positive metastatic ZS- S4Z ZSA-N breast cancer; 1) treating a subject Suffering from AR positive and ER-positive breast cancer; m) treating a subject 4. 21 W suffering from AR-positive ER-positive breast cancer with -HY +-Y X or without expression of PR, and/or HER2; n) treating a y- y- 47 ya 10 subject suffering from advanced ER-positive breast cancer; W o) treating a subject suffering from ER-positive breast cancer that has failed SERM (tamoxifen, toremifene), aro X matase inhibitor, trastuzumab (Herceptin, ado-trastuzumab Ajšy emtansine), pertuzumab (Perjeta), lapatinib, exemestane Z 15 (Aromasin), bevacizumab (Avastin), and/or fulvestrant treatments; p) treating, preventing, Suppressing or inhibiting B is a ring selected from: metastasis in a subject suffering from ER-positive breast cancer, q) prolonging Survival of a Subject with ER-positive 21 21 NN 21 breast cancer, r) slowing the progression of ER-positive +-Q, Q breast cancer in a subject; and/or S) prolonging progression SAS SAS Sás free survival of a subject with ER-positive breast cancer; ^X. A comprising administering to the Subject a therapeutically 2 21 4N effective amount of a selective androgen receptor modulator (SARM) compound represented by a compound of formula j jo t-Q IV: ySAS S4As Q2Sá1 25 W W IV

7-/YQ, and "/.. wo, Q1 Q1 30 2. T wherein A and B cannot simultaneously be a benzene ring; wherein X is a bond, O, CH, NH, S, Se, PR, NO or NR; Z is NO, CN, COOH, COR, NHCOR or CONHR: G is O or S; Y is CF, F, I, Br, C1, CN, C(R) or Sn(R): 35 R is CH, CHF, CHF, CF, CHCH, or CFCF: Q and Q are independently hydrogen, alkyl, halogen, T is OH, OR, NHCOCH or NHCOR; CF, CN, C(R), Sn(R), N(R), NHCOCH, R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, NHCOCF, NHCOR, NHCONHR, NHCOOR, CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl or OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, OH: NHSOCH, NHSOR, OR, COR, OCOR, OSOR, 40 A is a ring selected from: SOR, SR, 4N 4N 4N S--HY Sá -HY SA-N-HY rtyW ryW Z Z Z Q’so O 7. wif Q, 45 Q3 Q4 4. 21 W Q and Q are independently of each other a hydrogen, -HY +-Y X alkyl, halogen, CF, CN, C(R), Sn(R), N(R), ZS- ZS4- Z7-7 Y and NHCOCH, NHCOCF, NHCOR, NHCONHR, 50 W NHCOOR, OCONHR, CONHR, NHCSCH, NHC SCF, NHCSR, NHSOCH, NHSOR, OR, COR, AjšyX OCOR, OSOR, SOR or SR; Z W is O, NH, NR, NO or S; and W, is N or NO. 55 B is a ring selected from: 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 21 21 21 vides methods for: a) treating AR-positive breast cancer in +-Q, --Q, a subject; b) treating metastatic AR-positive breast cancer, or 60 advanced AR-positive breast cancer; c) treating refractory Sás-X S- SÁ-N AR-positive breast cancer; d) treating, preventing, Suppress Q2 Q1 Q2 Q2 ing or inhibiting metastasis in a subject Suffering from breast 2 21 4N cancer; e) prolonging progression-free Survival of a subject --Q, HQ, --Q, Suffering from breast cancer, f) treating a subject Suffering 65 S- S4- SS-N from ER-positive breast cancer, g) treating a subject Suffer Q2 Q2 Q2 ing from metastatic ER-positive breast cancer, h) treating a US 9,622,992 B2 29 30 -continued tion of the Bring and the substituent is Q is H. In another embodiment, the substituent Q is CN and is in the para position of the B ring, and the Substituent is Q is H. X X As contemplated herein, other specific embodiments of Q’o, and "/ WSo, compounds included within the scope of the present inven tion, and which are useful in: a) treating a Subject suffering from breast cancer; b) treating a subject Suffering from wherein metastatic breast cancer; c) treating a subject suffering from refractory breast cancer, d) treating a Subject Suffering from A and B cannot simultaneously be a benzene ring; AR-positive breast cancer; e) treating a Subject Suffering Z is NO, CN, COOH, COR, NHCOR or CONHR: 10 from AR-positive refractory breast cancer, f) treating a Y is CF, F, I, Br, C1, CN, C(R) or Sn(R): Subject Suffering from AR-positive metastatic breast cancer, Q and Q are independently hydrogen, alkyl, halogen, g) treating a Subject Suffering from AR-positive and ER CF, CN, C(R), Sn(R), N(R), NHCOCH, positive breast cancer; h) treating a Subject Suffering from NHCOCF, NHCOR, NHCONHR, NHCOOR, AR-positive breast cancer with or without expression of ER, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, 15 PR, and/or HER2: i) treating a subject suffering from triple NHSOCH, NHSOR, OR, COR, OCOR, OSOR, negative breast cancer, j) treating a Subject Suffering from SOR, SR, advanced breast cancer, k) treating a subject Suffering from breast cancer that has failed SERM (tamoxifen, toremifene), HN aromatase inhibitor, trastuzumab (Herceptin, ado-trastu Zumab emtansine), pertuzumab (Perjeta), lapatinib, exemes X tane (Aromasin), bevacizumab (Avastin), and/or fulvestrant Q4 or / woX treatment: 1) treating a subject suffering from ER positive Q4 breast cancer; m) treating, preventing, Suppressing or inhib iting metastasis in a subject Suffering from breast cancer, n) Q and Q are independently of each other a hydrogen, 25 prolonging Survival of a Subject with breast cancer, o) alkyl, halogen, CF, CN, C(R) Sn(R), N(R), slowing the progression of breast cancer in a Subject; and/or NHCOCH, NHCOCF, NHCOR, NHCONHR, p) prolonging progression-free Survival of a Subject with NHCOOR, OCONHR, CONHR, NHCSCH, NHC breast cancer; are formulas V or VI. It is understood that SCF, NHCSR, NHSOCH, NHSOR, OR, COR, included within the scope of the present invention are OCOR, OSOR, SOR or SR; 30 analogs, derivatives, metabolites, isomers, pharmaceutically W is O, NH, NR, NO or S; and acceptable salts, pharmaceutical products, hydrates, N-ox W, is N or NO; ides, polymorphs, crystals, prodrugs or combinations thereof and/or its analog, derivative, isomer, metabolite, pharma of these compounds: ceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug or any combination 35 thereof, as described herein. In one embodiment, the subject is a female Subject. In one embodiment, the Subject is a male Subject In one embodiment, G in formula IV is O. In another embodiment, X in formula IV is O. In another embodiment, 40 T in formula IV is OH. In another embodiment, R in VI formula IV is CH. 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 CF. In another embodiment, Yin formula IV is halogen. In another embodi 45 ment, Y in formula IV is C1. In another embodiment, Q in formula II is CN. In another embodiment, Q, in formula IV is F. In another embodiment, Q in formula IV is C1. In another embodiment, Q, in formula II is NHCOCH. In wherein Q is CN, alkyl, halogen, N(R), NHCOCH, another embodiment, Q in Formula IV is in the para 50 NHCOCF, NHCOR, NHCONHR, NHCOOR, position. In another embodiment, Z in formula IV is in the OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, para position. In another embodiment, Y in formula IV is in NHSOCH, NHSOR, OR, COR, OCOR, OSOR, the meta position. In another embodiment, G in formula IV SOR or SR; is O, T is OH, R is CH, X is O, Z is NO, or CN, Y is CF, or Q together with the benzene ring to which it is attached or halogen and Q is CN, F, Cl, or NHCOCH. 55 is a fused ring system represented by structure A, B or 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 A ring. In another embodiment, the substituent Y is in the 21 NH O A meta position of the A ring. In another embodiment, the 60 Substituent Z is in the para position of the A ring and in substituent Y is in the meta position of the A ring. The substituents Q and Q can be in any position of the 21 NH O B ring carrying these Substituents (hereinafter “Bring'). In one embodiment, the Substituent Q is in the para position of the 65 Bring. In another embodiment, the substituent is Q is H. In ls 21 another embodiment, the Substituent Q is in the para posi US 9,622,992 B2 31 32 -continued OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, NH SOR or SR; or Q together with the benzene ring to which it is attached Nr is a fused ring system represented by structure A, B or C: and R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, A CHF, CF, CFCF, aryl, phenyl, halogen, alkenyl or 10 21 NH O OH. In one embodiment, this invention relates to the treatment of androgen receptor-positive breast cancer in a Subject, for N example a female Subject. Accordingly, this invention pro NH O B vides methods for: a) treating AR-positive breast cancer in 15 a subject; b) treating metastatic AR-positive breast cancer, or advanced AR-positive breast cancer; c) treating refractory rN 21 AR-positive breast cancer; d) treating, preventing, Suppress ing or inhibiting metastasis in a subject Suffering from breast C cancer; e) prolonging progression-free Survival of a subject 21 NH Suffering from breast cancer, f) treating a subject Suffering from ER-positive breast cancer, g) treating a subject Suffer in / ing from metastatic ER-positive breast cancer, h) treating a subject suffering from refractory ER-positive breast cancer; and i) treating a subject suffering from AR-positive ER-positive 25 R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF. breast cancer, j) treating a Subject Suffering from AR positive ER-positive refractory breast cancer, k) treating a CF, CFCF, aryl, phenyl, halogen, alkenyl or OH: subject suffering from AR-positive ER-positive metastatic 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 30 N-oxide, crystal, polymorph, prodrug or any combination suffering from AR-positive ER-positive breast cancer with thereof, as described herein. In one embodiment, the subject or without expression of PR, and/or HER2; n) treating a is a female subject. In one embodiment, the subject is a male subject suffering from advanced ER-positive breast cancer; Subject. o) treating a subject suffering from ER-positive breast In one embodiment, Q in formula V or VI is CN. In one cancer that has failed SERM (tamoxifen, toremifene), aro 35 embodiment, Q in Formula V or VI is halogen. In one matase inhibitor, trastuzumab (Herceptin, ado-trastuzumab embodiment, Q in formula V or VI is F. In one embodiment, emtansine), pertuzumab (Perjeta), lapatinib, exemestane Q in formula V or VI is C1. In one embodiment, Q in formula (Aromasin), bevacizumab (Avastin), and/or fulvestrant V or VI is NHCOCH. treatments; p) treating, preventing, Suppressing or inhibiting In another embodiment, the compound of this invention metastasis in a subject suffering from ER-positive breast 40 which is effective at: a) treating a subject suffering from cancer, q) prolonging Survival of a Subject with ER-positive breast cancer; b) treating a Subject suffering from metastatic breast cancer, r) slowing the progression of ER-positive breast cancer; c) treating a Subject Suffering from refractory breast cancer in a subject; and/or S) prolonging progression breast cancer; d) treating a Subject suffering from AR free survival of a subject with ER-positive breast cancer; positive breast cancer; e) treating a subject Suffering from comprising administering to the Subject a therapeutically 45 AR-positive refractory breast cancer, f) treating a subject effective amount of a selective androgen receptor modulator Suffering from AR-positive metastatic breast cancer, g) (SARM) compound represented by the following structures treating a subject Suffering from AR-positive and ER-posi of formula V or VI: tive breast cancer; h) treating a subject suffering from AR-positive breast cancer with or without expression of ER, 50 PR, and/or HER2: i) treating a subject suffering from triple 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), aromatase inhibitor, trastuzumab (Herceptin, ado-trastu 55 Zumab emtansine), pertuzumab (Perjeta), lapatinib, exemes tane (Aromasin), bevacizumab (Avastin), and/or fulvestrant treatment: 1) treating a subject suffering from ER positive VI breast cancer; m) treating, preventing, Suppressing or inhib iting metastasis in a subject Suffering from breast cancer, n) 60 prolonging Survival of a Subject with breast cancer, o) slowing the progression of breast cancer in a Subject; and/or p) prolonging progression-free Survival of a Subject with breast cancer, is a compound represented by a structure of formula VII, and/or its analog, derivative, isomer, metabo 65 lite, pharmaceutically acceptable salt, pharmaceutical prod wherein Q is CN, alkyl, halogen, N(R), NHCOCH, uct, hydrate, N-oxide, crystal, polymorph, prodrug or any NHCOCF, NHCOR, NHCONHR, NHCOOR, combination thereof: US 9,622,992 B2 34 treating a Subject Suffering from refractory breast cancer; d) VII treating a subject Suffering from AR-positive breast cancer, NC CN e) treating a subject Suffering from AR-positive refractory O breast cancer, f) treating a subject Suffering from AR positive metastatic breast cancer, g) treating a subject Suf Z NH e O fering from AR-positive and ER-positive breast cancer; h) Hd OH 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 can wherein Z is C1 or CF. 10 cer, j) treating a subject Suffering from advanced breast In one embodiment, this invention relates to the treatment of androgen receptor-positive breast cancer in a Subject, for cancer, k) treating a Subject suffering from breast cancer that has failed SERM (tamoxifen, toremifene), aromatase inhibi example a female Subject. Accordingly, this invention pro tor, trastuzumab (Herceptin, ado-trastuzumab emtansine), vides methods for: a) treating AR-positive breast cancer in pertuzumab (Perjeta), lapatinib, exemestane (Aromasin), a subject; b) treating metastatic AR-positive breast cancer, or 15 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 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/orp) 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 structure of formula VIII, i) 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 25 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 positive and ER-positive breast cancer; m) treating a subject suffering from AR-positive ER-positive breast cancer with 30 VIII or without expression of PR, and/or HER2; n) treating a subject suffering from advanced ER-positive breast cancer; NC CN. o) treating a subject suffering from ER-positive breast cancer that has failed SERM (tamoxifen, toremifene), aro matase inhibitor, trastuzumab (Herceptin, ado-trastuzumab 35 C NH O emtansine), pertuzumab (Perjeta), lapatinib, exemestane Hd OH (Aromasin), bevacizumab (Avastin), and/or fulvestrant treatments; p) treating, preventing, Suppressing or inhibiting metastasis in a subject suffering from ER-positive breast In another embodiment, the compound which is effective cancer, q) prolonging Survival of a Subject with ER-positive 40 at: a) treating a Subject Suffering from breast cancer; b) breast cancer, r) slowing the progression of ER-positive treating a subject suffering from metastatic breast cancer; c) breast cancer in a subject; and/or S) prolonging progression treating a Subject Suffering from refractory breast cancer; d) free survival of a subject with ER-positive breast cancer; treating a subject Suffering from AR-positive breast cancer, comprising administering to the Subject a therapeutically e) treating a subject Suffering from AR-positive refractory effective amount of a selective androgen receptor modulator 45 breast cancer, f) treating a subject Suffering from AR (SARM) compound represented by the following structures positive metastatic breast cancer, g) treating a subject Suf of formula VII: fering from AR-positive and ER-positive breast cancer; h) treating a subject Suffering from AR-positive breast cancer with or without expression of ER, PR, and/or HER2: i) VII 50 treating a subject Suffering from triple negative breast can NC CN cer, j) treating a subject Suffering from advanced breast cancer, k) treating a Subject suffering from breast cancer that has failed SERM (tamoxifen, toremifene), aromatase inhibi Z NH O tor, trastuzumab (Herceptin, ado-trastuzumab emtansine), 55 pertuzumab (Perjeta), lapatinib, exemestane (Aromasin), Hd oH bevacizumab (Avastin), and/or fulvestrant treatment: 1) treating a Subject Suffering from ER positive breast cancer, wherein Z is C1 or CF; m) treating, preventing, Suppressing or inhibiting metastasis and/or its analog, derivative, isomer, metabolite, pharma in a Subject Suffering from breast cancer, n) prolonging ceutically acceptable salt, pharmaceutical product, hydrate, 60 survival of a subject with breast cancer; o) slowing the N-oxide, crystal, polymorph, prodrug or any combination progression of breast cancer in a Subject; and/orp) prolong thereof, as described herein. In one embodiment, the subject ing progression-free Survival of a subject with breast cancer, is a female Subject. In one embodiment, the Subject is a male is a compound represented by a structure of formula IX, Subject. and/or its analog, derivative, isomer, metabolite, pharma In another embodiment, the compound which is effective 65 ceutically acceptable salt, pharmaceutical product, hydrate, at: a) treating a subject Suffering from breast cancer; b) N-oxide, crystal, polymorph, prodrug or any combination treating a subject suffering from metastatic breast cancer; c) thereof: US 9,622,992 B2 35 36 m) treating, preventing, Suppressing or inhibiting metastasis IX in a Subject Suffering from breast cancer, n) prolonging NC CN. survival of a subject with breast cancer; o) slowing the progression of breast cancer in a Subject; and/orp) prolong ing progression-free Survival of a subject with breast cancer, FC NH O is a compound represented by a structure of formula XI. Hd OH and/or its analog, derivative, isomer, metabolite, pharma ceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, crystal, polymorph, prodrug or any combination In another embodiment, the compound which is effective 10 at: a) treating a subject Suffering from breast cancer; b) thereof: treating a subject suffering from metastatic breast cancer; c) treating a subject Suffering from refractory breast cancer; d) XI treating a subject Suffering from AR-positive breast cancer, NC C. e) treating a subject Suffering from AR-positive refractory 15

breast cancer, f) treating a subject Suffering from AR positive metastatic breast cancer, g) treating a subject Suf FC NH fering from AR-positive and ER-positive breast cancer; h) treating a subject Suffering from AR-positive breast cancer HC OH with or without expression of ER, PR, and/or HER2: i) treating a subject Suffering from triple negative breast can In another embodiment, the compound which is effective cer, j) treating a subject Suffering from advanced breast at: a) treating a Subject Suffering from breast cancer; b) cancer, k) treating a subject suffering from breast cancer that treating a subject suffering from metastatic breast cancer; c) has failed SERM (tamoxifen, toremifene), aromatase inhibi treating a Subject Suffering from refractory breast cancer; d) tor, trastuzumab (Herceptin, ado-trastuzumab emtansine), 25 treating a subject Suffering from AR-positive breast cancer, pertuZumab (Perjeta), lapatinib, exemestane (Aromasin), e) treating a subject Suffering from AR-positive refractory bevacizumab (Avastin), and/or fulvestrant treatment: 1) breast cancer, f) treating a subject Suffering from AR treating a subject Suffering from ER positive breast cancer, positive metastatic breast cancer, g) treating a subject Suf m) treating, preventing, Suppressing or inhibiting metastasis fering from AR-positive and ER-positive breast cancer; h) in a Subject Suffering from breast cancer, n) prolonging 30 treating a subject Suffering from AR-positive breast cancer survival of a subject with breast cancer; o) slowing the with or without expression of ER, PR, and/or HER2: i) progression of breast cancer in a subject; and/or p) prolong treating a subject Suffering from triple negative breast can ing progression-free Survival of a subject with breast cancer, cer, j) treating a subject Suffering from advanced breast is a compound represented by a structure of formula X, cancer, k) treating a Subject suffering from breast cancer that and/or its analog, derivative, isomer, metabolite, pharma 35 has failed SERM (tamoxifen, toremifene), aromatase inhibi ceutically acceptable salt, pharmaceutical product, hydrate, tor, trastuzumab (Herceptin, ado-trastuzumab emtansine), N-oxide, crystal, polymorph, prodrug or any combination pertuzumab (Perjeta), lapatinib, exemestane (Aromasin), thereof: bevacizumab (Avastin), and/or fulvestrant treatment: 1) treating a Subject Suffering from ER positive breast cancer, 40 m) treating, preventing, Suppressing or inhibiting metastasis in a Subject Suffering from breast cancer, n) prolonging NC F. survival of a subject with breast cancer; o) slowing the progression of breast cancer in a Subject; and/orp) prolong ing progression-free Survival of a subject with breast cancer, FC NH O 45 is a compound represented by a structure of formula XII. Hd oH and/or its analog, derivative, isomer, metabolite, pharma ceutically acceptable salt, pharmaceutical product, hydrate, 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) 50 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, XII e) treating a subject Suffering from AR-positive refractory ON NHCOCH. breast cancer, f) treating a subject Suffering from AR 55 positive metastatic breast cancer, g) treating a subject Suf fering from AR-positive and ER-positive breast cancer; h) NH s O treating a subject Suffering from AR-positive breast cancer with or without expression of ER, PR, and/or HER2: i) Hd OH treating a subject Suffering from triple negative breast can 60 cer, j) treating a subject Suffering from advanced breast In another embodiment, the compound which is effective cancer, k) treating a subject suffering from breast cancer that at: a) treating a Subject Suffering from breast cancer; b) has failed SERM (tamoxifen, toremifene), aromatase inhibi treating a subject suffering from metastatic breast cancer; c) tor, trastuzumab (Herceptin, ado-trastuzumab emtansine), treating a Subject Suffering from refractory breast cancer; d) pertuZumab (Perjeta), lapatinib, exemestane (Aromasin), 65 treating a subject Suffering from AR-positive breast cancer, bevacizumab (Avastin), and/or fulvestrant treatment: 1) e) treating a subject Suffering from AR-positive refractory treating a subject Suffering from ER positive breast cancer, breast cancer, f) treating a subject Suffering from AR US 9,622,992 B2 37 38 positive metastatic breast cancer, g) treating a subject Suf In one embodiment, this invention relates to the treatment fering from AR-positive and ER-positive breast cancer; h) of androgen receptor-positive breast cancer in a Subject, for treating a subject Suffering from AR-positive breast cancer example a female Subject. Accordingly, this invention pro with or without expression of ER, PR, and/or HER2: i) treating a subject Suffering from triple negative breast can vides methods for: a) treating AR-positive breast cancer in cer, j) treating a subject Suffering from advanced breast a subject; b) treating metastatic AR-positive breast cancer, or cancer, k) treating a subject suffering from breast cancer that advanced AR-positive breast cancer; c) treating refractory has failed SERM (tamoxifen, toremifene), aromatase inhibi AR-positive breast cancer; d) treating, preventing, Suppress tor, trastuzumab (Herceptin, ado-trastuzumab emtansine), ing or inhibiting metastasis in a subject Suffering from breast pertuZumab (Perjeta), lapatinib, exemestane (Aromasin), cancer; e) prolonging progression-free Survival of a subject bevacizumab (Avastin), and/or fulvestrant treatment: 1) 10 Suffering from breast cancer, f) treating a Subject Suffering treating a subject Suffering from ER positive breast cancer, from ER-positive breast cancer, g) treating a subject Suffer m) treating, preventing, Suppressing or inhibiting metastasis ing from metastatic ER-positive breast cancer; h) treating a in a Subject Suffering from breast cancer, n) prolonging subject suffering from refractory ER-positive breast cancer; survival of a subject with breast cancer; o) slowing the i) treating a subject suffering from AR-positive ER-positive progression of breast cancer in a subject; and/or p) prolong 15 ing progression-free Survival of a subject with breast cancer, breast cancer, j) treating a subject Suffering from AR is a compound represented by a compound of formula XIII, positive ER-positive refractory breast cancer, k) treating a and/or its analog, derivative, isomer, metabolite, pharma subject suffering from AR-positive ER-positive metastatic ceutically acceptable salt, pharmaceutical product, hydrate, breast cancer; 1) treating a subject Suffering from AR N-oxide, crystal, polymorph, prodrug or any combination positive and ER-positive breast cancer; m) treating a subject thereof: suffering from AR-positive ER-positive breast cancer with or without expression of PR, and/or HER2; n) treating a XIII subject suffering from advanced ER-positive breast cancer; NC CN. o) treating a subject suffering from ER-positive breast 25 cancer that has failed SERM (tamoxifen, toremifene), aro

matase inhibitor, trastuzumab (Herceptin, ado-trastuzumab FC NH emtansine), pertuzumab (Perjeta), lapatinib, exemestane (Aromasin), bevacizumab (Avastin), and/or fulvestrant HC OH treatments; p) treating, preventing, Suppressing or inhibiting 30 metastasis in a subject suffering from ER-positive breast In another embodiment, the compound which is effective cancer, q) prolonging Survival of a subject with ER-positive at: a) treating a subject Suffering from breast cancer; b) breast cancer, r) slowing the progression of ER-positive treating a subject suffering from metastatic breast cancer; c) treating a subject Suffering from refractory breast cancer; d) breast cancer in a subject; and/or S) prolonging progression treating a subject Suffering from AR-positive breast cancer, 35 free survival of a subject with ER-positive breast cancer; e) treating a subject Suffering from AR-positive refractory comprising administering to the Subject a therapeutically breast cancer, f) treating a subject Suffering from AR effective amount of a selective androgen receptor modulator positive metastatic breast cancer, g) treating a subject Suf (SARM) compound represented by the following structures fering from AR-positive and ER-positive breast cancer; h) of formula VIII, IX, X, XI, XII, XIII or XIV: treating a subject Suffering from AR-positive breast cancer 40 with or without expression of ER, PR, and/or HER2: i) VIII treating a subject Suffering from triple negative breast can NC CN: cer, j) treating a subject Suffering from advanced breast cancer, k) treating a subject suffering from breast cancer that Cl O O has failed SERM (tamoxifen, toremifene), aromatase inhibi 45 C sis tor, trastuzumab (Herceptin, ado-trastuzumab emtansine), HC OH pertuZumab (Perjeta), lapatinib, exemestane (Aromasin), IX bevacizumab (Avastin), and/or fulvestrant treatment: 1) treating a subject Suffering from ER positive breast cancer, NC CN: m) treating, preventing, Suppressing or inhibiting metastasis 50 in a Subject Suffering from breast cancer, n) prolonging survival of a subject with breast cancer; o) slowing the FC NH --> progression of breast cancer in a subject; and/or p) prolong He oH ing progression-free Survival of a subject with breast cancer, X is a compound represented by a structure of formula XIV. 55 NC F; and/or its analog, derivative, isomer, metabolite, pharma ceutically acceptable salt, pharmaceutical product, hydrate, O O N-oxide, crystal, polymorph, prodrug or any combination FC NH --> thereof: He oH 60 XIV XI NC C. NC Cl; O O 65 FC stsHd oH US 9,622,992 B2 40 -continued embodiment, the methods of the present invention comprise XII administering a combination of any of an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, phar ON NHCOCH: maceutical product, hydrate, N-oxide, polymorph, crystal or prodrug of the compound of formula I-XIV. O O In one embodiment, the methods of this invention com prise administering a compound of Formula I-XIV. In FC sisHd oH another embodiment, the methods of this invention comprise XIII administering a compound of Formula I. In another embodi 10 ment, the methods of this invention comprise administering NC CN; or a compound of Formula II. In another embodiment, the methods of this invention comprise administering a com pound of Formula III. In another embodiment, the methods FC F of this invention comprise administering a compound of 15 Formula IV. In another embodiment, the methods of this XIV invention comprise administering a compound of Formula NC C. V. In another embodiment, the methods of this invention comprise administering a compound of Formula VI. In another embodiment, the methods of this invention comprise O O administering a compound of Formula VII. In another FC sis F embodiment, the methods of this invention comprise admin HC OH istering a compound of Formula VIII. In another embodi ment, the methods of this invention comprise administering and/or its analog, derivative, isomer, metabolite, pharma a compound of Formula IX. In another embodiment, the ceutically acceptable salt, pharmaceutical product, hydrate, 25 methods of this invention comprise administering a com N-oxide, crystal, polymorph, prodrug or any combination pound of Formula X. In another embodiment, the methods thereof, as described herein. In one embodiment, the subject of this invention comprise administering a compound of is a female Subject. In one embodiment, the Subject is a male Formula XI. In another embodiment, the methods of this Subject. invention comprise administering a compound of Formula 30 XII. In another embodiment, the methods of this invention In one embodiment, the methods of this invention make comprise administering a compound of Formula XIII In use of a compound of formula VIII. In one embodiment, the another embodiment, the methods of this invention comprise methods of this invention make use of a compound of administering a compound of Formula XIV. formula IX. In one embodiment, the methods of this inven The compounds of the present invention, either alone or tion make use of a compound of formula X. In one embodi 35 as a pharmaceutical composition, are useful for: a) treating ment, the methods of this invention make use of a compound a subject Suffering from breast cancer; b) treating a subject of formula XI. In one embodiment, the methods of this Suffering from metastatic breast cancer; c) treating a subject invention make use of a compound of formula XII. In one Suffering from refractory breast cancer; d) treating a subject embodiment, the methods of this invention make use of a Suffering from AR-positive breast cancer; e) treating a compound of formula XIII. In one embodiment, the methods 40 subject suffering from AR-positive refractory breast cancer; of this invention make use of a compound of formula XIV. f) treating a subject Suffering from AR-positive metastatic In one embodiment, the methods of the present invention breast cancer, g) treating a Subject suffering from AR comprise administering an analog of the compound of positive and ER-positive breast cancer; h) treating a subject formula I-XIV. In another embodiment, the methods of the suffering from AR-positive breast cancer with or without present invention comprise administering a derivative of the 45 expression of ER, PR, and/or HER2: i) treating a subject compound of formula I-XIV. In another embodiment, the Suffering from triple negative breast cancer, j) treating a methods of the present invention comprise administering an Subject Suffering from advanced breast cancer, k) treating a isomer of the compound of formula I-XIV. In another subject suffering from breast cancer that has failed SERM embodiment, the methods of the present invention comprise (tamoxifen, toremifene), aromatase inhibitor, trastuzumab administering a metabolite of the compound of formula 50 (Herceptin, ado-trastuzumab emtansine), pertuzumab (Per I-XIV. In another embodiment, the methods of the present jeta), lapatinib, exemestane (Aromasin), bevacizumab invention comprise administering a pharmaceutically (Avastin), and/or fulvestrant treatment: 1) treating a subject acceptable salt of the compound of formula I-XIV. In Suffering from ER positive breast cancer, m) treating, pre another embodiment, the methods of the present invention venting, Suppressing or inhibiting metastasis in a subject comprise administering a pharmaceutical product of the 55 Suffering from breast cancer, n) prolonging Survival of a compound of formula I-XIV. In another embodiment, the Subject with breast cancer, o) slowing the progression of methods of the present invention comprise administering a breast cancer in a subject; and/orp) prolonging progression hydrate of the compound of formula I-XIV. In another free survival of a subject with breast cancer. embodiment, the methods of the present invention comprise The compounds of the present invention offer a significant administering an N-oxide of the compound of formula 60 advance over steroidal androgen treatment since treatment I-XIV. In another embodiment, the methods of the present of breast cancer with these compounds will not be accom invention comprise administering a polymorph of the com panied by serious side effects, inconvenient modes of admin pound of formula I-XIV. In another embodiment, the meth istration, or high costs and still have the advantages of oral ods of the present invention comprise administering a crystal bioavailability, lack of cross-reactivity with other steroid of the compound of formula I-XIV. In another embodiment, 65 receptors, and long biological half-lives. the methods of the present invention comprise administering In one embodiment, this invention relates to the treatment a prodrug of the compound of formula I-XIV. In another of androgen receptor-positive breast cancer in a Subject. US 9,622,992 B2 41 42 Accordingly, this invention provides methods of: a) treating The invention includes pharmaceutically acceptable salts a subject Suffering from breast cancer; b) treating a subject of amino-Substituted compounds with organic and inorganic Suffering from metastatic breast cancer; c) treating a subject acids, for example, citric acid and hydrochloric acid. The Suffering from refractory breast cancer; d) treating a subject invention also includes N-oxides of the amino substituents Suffering from AR-positive breast cancer; e) treating a of the compounds described herein. Pharmaceutically subject suffering from AR-positive refractory breast cancer; acceptable salts can also be prepared from the phenolic f) treating a subject Suffering from AR-positive metastatic compounds by treatment with inorganic bases, for example, breast cancer, g) treating a Subject suffering from AR Sodium hydroxide. Also, esters of the phenolic compounds positive and ER-positive breast cancer, h) treating a subject can be made with aliphatic and aromatic carboxylic acids, 10 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 pounds of Formula 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 15 tion are bisulfates, borates, bromides, chlorides, hemisul (tamoxifen, toremifene), aromatase inhibitor, trastuzumab fates, hydrobromates, hydrochlorates, 2-hydroxyethylsul (Herceptin, ado-trastuzumab emtansine), pertuzumab (Per 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 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/orp) prolonging progression cycloaliphatic, aromatic, araliphatic, heterocyclic, carbox free survival of a subject with breast cancer; by administer 25 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 receptor modulator of formulas I-XIV of 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 30 camphorates, camphorsulfonates, cyclohexylsulfamates, combination thereof, as described herein. cyclopentanepropionates, calcium edetates, camsylates, car As defined herein, the term "isomer' includes, but is not 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 like. As used herein, the term "isomer may also be referred 35 lates, esylates, fumarates, formates, fluorides, galacturonates to herein as an “enantiomer having all of the qualities and gluconates, glutamates, glycolates, glucorate, glucoheptano properties of an "isomer'. ates, glycerophosphates, gluceptates, glycolylarsanilates, In one embodiment, this invention encompasses the use of glutarates, glutamate, heptanoates, hexanoates, hydroxy various optical isomers of the selective androgen receptor maleates, hydroxycarboxlic acids, hexylresorcinates, modulator. It will be appreciated by those skilled in the art 40 hydroxybenzoates, hydroxynaphthoate, hydrofluorate, lac that the selective androgen receptor modulators of the pres tates, lactobionates, laurates, malates, maleates, methylen ent invention contain at least one chiral center. Accordingly, ebis(beta-oxynaphthoate), malonates, mandelates, mesy the selective androgen receptor modulators used in the lates, methane Sulfonates, methylbromides, methylnitrates, methods of the present invention may exist in, and be methylsulfonates, monopotassium maleates, mucates, isolated in, optically-active or racemic forms. Some com 45 monocarboxylates, mitrates, naphthalenesulfonates, 2-naph pounds may also exhibit polymorphism. It is to be under thalenesulfonates, nicotinates, napsylates, N-methylglu stood that the present invention encompasses any racemic, camines, oxalates, octanoates, oleates, pamoates, phenylac optically-active, polymorphic, or stereoisomeric form, or etates, picrates, phenylbenzoates, pivalates, propionates, any combination thereof, which form possesses properties phthalates, phenylacetate, pectinates, phenylpropionates, useful in the treatment of androgen-related conditions 50 palmitates, pantothenates, polygalacturates, pyruvates, qui described herein. In one embodiment, the selective androgen nates, Salicylates, succinates, Stearates, Sulfanilate, Subac receptor modulators are the pure (R)-isomers. In another etates, tartrates, theophyllineacetates, p-toluenesulfonates embodiment, the selective androgen receptor modulators are (tosylates), trifluoroacetates, terephthalates, tannates, teo the pure (S)-isomers. In another embodiment, the selective clates, trihaloacetates, triethiodide, tricarboxylates, unde androgen receptor modulators are a mixture of the (R) and 55 canoates and Valerates. the (S) isomers. In another embodiment, the selective andro In one embodiment, the salts may be formed by conven gen receptor modulators are a racemic mixture comprising tional means, such as by reacting the free base or free acid an equal amount of the (R) and the (S) isomers. It is well form of the product with one or more equivalents of the known in the art how to prepare optically-active forms (for appropriate acid or base in a solvent or medium in which the example, by resolution of the racemic form by recrystalli 60 salt is insoluble or in a solvent such as water, which is Zation techniques, by Synthesis from optically-active starting removed in vacuo or by freeze drying or by exchanging the materials, by chiral synthesis, or by chromatographic sepa of a existing salt for another ion or Suitable ion ration using a chiral stationary phase). exchange resin. The invention includes “pharmaceutically acceptable This invention further includes derivatives of the selective salts' of the compounds of this invention, which may be 65 androgen receptor modulators. The term "derivatives' produced, by reaction of a compound of this invention with includes but is not limited to ether derivatives, acid deriva an acid or base. tives, amide derivatives, ester derivatives and the like. In US 9,622,992 B2 43 44 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' 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 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 10 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 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 15 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, 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 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 formulas I-XIV of this invention and/or its analog, deriva properties such as X-ray diffraction, IR spectra, melting 25 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 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 formulas I-XIV of this 30 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, 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 receptor modulator of in the Subject. In one embodiment, the Subject is a female 35 formulas I-XIV of this invention and/or its analog, deriva Subject. In another embodiment, the Subject is a male tive, isomer, metabolite, pharmaceutically acceptable salt, Subject. pharmaceutical product, hydrate, N-oxide, crystal, poly In another embodiment of the present invention, a method morph, prodrug or any combination thereof, in an amount is provided for treating a Subject Suffering from metastatic effective to treat AR-positive metastatic breast cancer in the breast cancer, comprising the step of administering to the 40 Subject. In one embodiment, the Subject is a female Subject. Subject a selective androgen receptor modulator of formulas In another embodiment, the Subject is a male Subject. I-XIV of this invention and/or its analog, derivative, isomer, In another embodiment of the present invention, a method metabolite, pharmaceutically acceptable salt, pharmaceuti is provided for treating a subject suffering from ER-positive cal product, hydrate, N-oxide, crystal, polymorph, prodrug breast cancer, comprising the step of administering to the or any combination thereof, in an amount effective to treat 45 Subject a selective androgen receptor modulator of formulas metastatic breast cancer in the Subject. In one embodiment, I-XIV of this invention and/or its analog, derivative, isomer, the subject is a female subject. In another embodiment, the metabolite, pharmaceutically acceptable salt, pharmaceuti Subject is a male Subject. cal product, hydrate, N-oxide, crystal, polymorph, prodrug In another embodiment of the present invention, a method or any combination thereof, in an amount effective to treat is provided for treating a subject Suffering from refractory 50 ER-positive breast cancer in the subject. In one embodiment, breast cancer, comprising the step of administering to the the subject is a female subject. In another embodiment, the Subject a selective androgen receptor modulator of formulas Subject is a male Subject. I-XIV of this invention and/or its analog, derivative, isomer, In another embodiment of the present invention, a method metabolite, pharmaceutically acceptable salt, pharmaceuti is provided for treating a subject suffering from AR-positive cal product, hydrate, N-oxide, crystal, polymorph, prodrug 55 and ER-positive breast cancer, comprising the step of or any combination thereof, in an amount effective to treat administering to the Subject a selective androgen receptor refractory breast cancer in the Subject. In one embodiment, modulator of formulas I-XIV of this invention and/or its the subject is a female subject. In another embodiment, the analog, derivative, isomer, metabolite, pharmaceutically Subject is a male Subject. acceptable salt, pharmaceutical product, hydrate, N-oxide, In another embodiment of the present invention, a method 60 crystal, polymorph, prodrug or any combination thereof, in is provided for treating a subject suffering from AR-positive an amount effective to treat AR-positive metastatic breast breast cancer, comprising the step of administering to the cancer in the Subject. In one embodiment, the Subject is a Subject a selective androgen receptor modulator of formulas female Subject. In another embodiment, the Subject is a male I-XIV of this invention and/or its analog, derivative, isomer, Subject. metabolite, pharmaceutically acceptable salt, pharmaceuti 65 In another embodiment of the present invention, a method cal product, hydrate, N-oxide, crystal, polymorph, prodrug is provided for treating a subject suffering from ER-positive or any combination thereof, in an amount effective to treat refractory breast cancer, comprising the step of administer US 9,622,992 B2 45 46 ing to the Subject a selective androgen receptor modulator of In one embodiment, the Subject is a female Subject. In formulas 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 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 10 Subject a selective androgen receptor modulator of formulas metastatic breast cancer, comprising the step of administer I-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 formulas I-XIV of this invention and/or its analog, deriva cal product, hydrate, N-oxide, crystal, polymorph, prodrug tive, isomer, metabolite, pharmaceutically acceptable salt, 15 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 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 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 25 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 formulas tive androgen receptor modulator of formulas 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 30 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, 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. In another embodiment of the present invention, a method 35 In another embodiment of the present invention, a method is provided for treating a subject suffering from AR-positive is provided for treating and/or preventing skeletal related and ER-positive breast cancer, comprising the step of events in a Subject Suffering, comprising the step of admin administering to the Subject a selective androgen receptor istering to the Subject a selective androgen receptor modu modulator of formulas I-XIV of this invention and/or its lator of formulas I-XIV of this invention and/or its analog, analog, derivative, isomer, metabolite, pharmaceutically 40 derivative, isomer, metabolite, pharmaceutically acceptable acceptable salt, pharmaceutical product, hydrate, N-oxide, salt, pharmaceutical product, hydrate, N-oxide, crystal, crystal, polymorph, prodrug or any combination thereof, in polymorph, prodrug or any combination thereof, in an an amount effective to treat AR-positive and ER-positive amount effective to treat and/or prevent skeletal related refractory breast cancer in the Subject. In one embodiment, events in the Subject. In one embodiment, the Subject is a the subject is a female subject. In another embodiment, the 45 female Subject. In another embodiment, the Subject is a male Subject is a male Subject. Subject. In another embodiment of the present invention, a method In another embodiment of the present invention, a method is provided for treating a subject suffering from AR-positive is provided for improving libido in a subject, comprising the and ER-negative breast cancer, comprising the step of step of administering to the Subject a selective androgen administering to the Subject a selective androgen receptor 50 receptor modulator of formulas I-XIV of this invention modulator of formulas I-XIV of this invention and/or its and/or its analog, derivative, isomer, metabolite, pharma analog, derivative, isomer, metabolite, pharmaceutically ceutically acceptable salt, pharmaceutical product, hydrate, acceptable salt, pharmaceutical product, hydrate, N-oxide, N-oxide, crystal, polymorph, prodrug or any combination crystal, polymorph, prodrug or any combination thereof, in thereof, in an amount effective to improve libido in the an amount effective to treat AR-positive and ER-negative 55 Subject. In one embodiment, the Subject is a female Subject. metastatic breast cancer in the Subject. In one embodiment, In another embodiment, the Subject is a male Subject. the subject is a female subject. In another embodiment, the In another embodiment of the present invention, a method Subject is a male Subject. is provided for improving quality of life in a Subject, In another embodiment of the present invention, a method comprising the step of administering to the Subject a selec is provided for treating a subject Suffering from triple 60 tive androgen receptor modulator of formulas I-XIV of this negative breast cancer, comprising the step of administering invention and/or its analog, derivative, isomer, metabolite, to the Subject a selective androgen receptor modulator of pharmaceutically acceptable salt, pharmaceutical product, formulas I-XIV of this invention and/or its analog, deriva hydrate, N-oxide, crystal, polymorph, prodrug or any com tive, isomer, metabolite, pharmaceutically acceptable salt, bination thereof, in an amount effective to quality of life in pharmaceutical product, hydrate, N-oxide, crystal, poly 65 the subject. In one embodiment, the subject is a female morph, prodrug or any combination thereof, in an amount Subject. In another embodiment, the Subject is a male effective to treat triple negative breast cancer in the subject. Subject. US 9,622,992 B2 47 48 In another embodiment of the present invention, a method a subject suffering from AR-positive and ER-positive breast is provided for treating, preventing, Suppressing or inhibit cancer; h) treating a Subject Suffering from AR-positive ing metastasis in a Subject Suffering from breast cancer, breast cancer with or without expression of ER, PR, and/or comprising the step of administering to the Subject a selec HER2: i) treating a subject suffering from triple negative tive androgen receptor modulator of formulas I-XIV of this 5 breast cancer, j) treating a subject Suffering from advanced invention and/or its analog, derivative, isomer, metabolite, breast cancer, k) treating a Subject Suffering from breast pharmaceutically acceptable salt, pharmaceutical product, cancer that has failed SERM (tamoxifen, toremifene), aro hydrate, N-oxide, crystal, polymorph, prodrug or any com matase inhibitor, trastuzumab (Herceptin, ado-trastuzumab bination thereof, in an amount effective to treat, prevent, emtansine), pertuzumab (Perjeta), lapatinib, exemestane Suppress or inhibit metastasis in the Subject. In one embodi- 10 ment, the Subject is a female Subject. In another embodi (Aromasin), bevacizumab (Avastin), and/or fulvestrant ment, the Subject is a male Subject. 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, CHF, CHF, CF, CFCF: aryl, iting metastasis in a subject Suffering from breast cancer, n) phenyl, halogen, alkenyl, or hydroxyl (OH). 15 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 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 20 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 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- 25 ment with anthracyclines, taxanes, capecitabine, ixabepi alkyl. lone, SERM (tamoxifen, toremifene), aromatase inhibitor, A "haloalkyl group refers to an alkyl group as defined 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, Cl, Br or I. cizumab (Avastin), fulvestrant or any combination thereof. An “aryl group refers to an aromatic group having at 30 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 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, alkoxy carbonyl, amido, alkylamido, dialky 15% of all types of breast cancer. This subtype of breast lamido, nitro, amino, alkylamino, dialkylamino, carboxy or 35 cancer is clinically characterized as more aggressive and less thio or thioalkyl. Nonlimiting examples of aryl rings are responsive to standard treatment and associated with poorer phenyl, naphthyl, pyranyl, pyrrolyl pyrazinyl, pyrimidinyl, overall patient prognosis. pyrazolyl pyridinyl, furanyl, thiophenyl, thiazolyl, imida In one embodiment, the methods of this invention are Zolyl, isoxazolyl, and the like. directed to treating a subject Suffering from AR-positive A “hydroxyl group refers to an OH group. An “alkenyl' 40 breast cancer, regardless of grade, stage or prior treatments. group refers to a group having at least one carbon to carbon In one embodiment, the methods of this invention are double bond. A halo group refers to F, Cl, Br or I. first, second, third, or fourth line therapies for breast cancer. An “arylalkyl group refers to an alkyl bound to an aryl, A first line therapy refers to a medical therapy recommended wherein alkyl and aryl are as defined above. An example of for the initial treatment of a disease, sign or symptom. A an aralkyl group is a benzyl group. 45 second line therapy is given when initial treatment (first-line Biological Activity of Selective Androgen Receptor Modu therapy) does not work, or stops working. Third line therapy lators is given when both initial treatment (first-line therapy) and The selective androgen receptor modulators provided Subsequent treatment (second-line therapy) does not work, herein are a new class of compounds, which Suppress growth or stop working, etc. of AR-positive breast cancers. The compounds of this inven- 50 As used herein, "kinases’ are a group of enzymes that tion have a tissue-selective myoanabolic activity profile of a catalyze the transfer of a phosphate group from a donor. Such nonsteroidal ligand for the androgen receptor. Furthermore as ADP or ATP to an acceptor. In one embodiment, phos compounds of the present invention are non-aromatizable, phorylation results in a functional change of the target non-virilizing, and are not commonly cross-reactive with ER protein (Substrate) by changing enzyme activity, cellular and PR. In addition, in one embodiment, the selective 55 location, or association with other proteins kinases. Kinases androgen receptor modulators (SARMs) of the present regulate the majority of cellular pathways, especially those invention are beneficial to refractory breast cancer patients involved in signal transduction. In one embodiment, deregu undergoing chemotherapy due to anabolism. lated kinase activity is a frequent cause of disease, in As contemplated herein, the appropriately substituted particular cancer, wherein kinases regulate many aspects selective androgen receptor modulators of the present inven- 60 that control cell growth, movement and death. In one tion are useful for: a) treating a subject Suffering from breast embodiment, drugs that inhibit specific kinases are used to cancer; b) treating a subject Suffering from metastatic breast treat kinase-related diseases, including cancer. In one cancer; c) treating a subject Suffering from refractory breast embodiment, HER2 positive breast cancers are susceptible cancer; d) treating a Subject Suffering from AR-positive to HER2 kinase inhibitors (e.g., trastuzumab and lapatinib) breast cancer; e) treating a Subject Suffering from AR- 65 and are generally used in metastatic disease. However, some positive refractory breast cancer, f) treating a Subject Suf breast cancers are refractory to HER2 kinase inhibitor fering from AR-positive metastatic breast cancer, g) treating treatment. US 9,622,992 B2 49 50 As used herein, receptors for extracellular signaling mol Assays to determine whether the compounds of the pres ecules are collectively referred to as “cell signaling recep ent invention are AR agonists or antagonists are well known tors'. Many cell signaling receptors are transmembrane to a person skilled in the art. For example, AR agonistic proteins on a cell surface; when they bind an extracellular activity can be determined by monitoring the ability of the signaling molecule (i.e., a ligand), they become activated So 5 selective androgen receptor modulators to maintain and/or as to generate a cascade of intracellular signals that alter the stimulate the growth of AR containing androgenic tissue behavior of the cell. In contrast, in Some cases, the receptors Such as prostate and seminal vesicles, as measured by are inside the cell and the signaling ligand has to enter the weight, in castrated animals. AR antagonistic activity can be cell to activate them; these signaling molecules therefore determined by monitoring the ability of the selective andro must be sufficiently small and hydrophobic to diffuse across 10 gen receptor modulators to inhibit the growth of AR con the plasma membrane of the cell. taining tissue in intact animals or counter the effects of Steroid hormones are one example of small hydrophobic testosterone in castrated animals. molecules that diffuse directly across the plasma membrane Anandrogen receptor (AR) is an androgen receptor of any of target cells and bind to intracellular cell signaling recep species, for example a mammal. In one embodiment, the tors. These receptors are structurally related and constitute 15 androgen receptor is an androgen receptor of a human. Thus, the intracellular receptor superfamily (or steroid-hormone in another embodiment, the selective androgen receptor receptor superfamily). Steroid hormone receptors include modulators bind reversibly to an androgen receptor of a but are not limited to progesterone receptors, estrogen human. In another embodiment, the selective androgen receptors, androgen receptors, glucocorticoid receptors, and receptor modulators bind reversibly to an androgen receptor mineralocorticoid receptors. In one embodiment, the present 20 of a mammal. invention is directed to androgen receptors. In one embodi As contemplated herein, the term “selective androgen ment, the present invention is directed to androgen receptor receptor modulator” (SARM) refers to, in one embodiment, agonists. In one embodiment, the present invention is a molecule that exhibits in vivo tissue selectivity, activating directed to progesterone receptors. In one embodiment, the signaling activity of the Androgen Receptor in anabolic present invention is directed to progesterone receptor 25 (muscle, bone, etc.) tissues to a greater extent than in the 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 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 30 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 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 35 effects on the androgen receptor in a tissue-dependent man the binding site more frequently. Once bound, signals may ner. In one embodiment, a SARM of this invention will have be sent through the receptor into the cells, causing the cell an ICso or ECso with respect to AR, as determined using AR to respond in Some fashion. This is called activation. On transactivation assays, as known in the art, or, in other activation, the activated receptor then directly regulates the embodiments, as described herein. transcription of specific genes. But the Substance and the 40 The term “ICs” refers, in some embodiments, to a receptor may have certain attributes, other than affinity, in concentration of the SARM which reduces the activity of a order to activate the cell. Chemical bonds between atoms of target (e.g., AR) to half-maximal level. the Substance and the atoms of the receptors may form. In The term “ECso refers, in some embodiments, to a Some cases, this leads to a change in the configuration of the concentration of the SARM that produces a half-maximal receptor, which is enough to begin the activation process 45 effect. (called signal transduction). For example, utilizing transactivation assays, FIG. 5 In one embodiment, the compounds of this invention shows that compounds of this invention exhibit AR agonist inhibit the intratumoral expression of genes and pathways activity in MDA-MB-231 cells transfected with AR. that promote breast cancer development through their As defined herein, “contacting means that the selective actions on the AR. In one embodiment, a compound of this 50 androgen receptor modulators of the present invention are invention inhibits intratumoral expression of Muc1, SLUG, introduced into a sample containing the receptor in a test VCAM1, SPARC or MMP2, or any combination thereof. In tube, flask, tissue culture, chip, array, plate, microplate, another embodiment, Compound VIII inhibits gene expres capillary, or the like, and incubated at a temperature and time sion that promotes breast cancer. Sufficient to permit binding of the selective androgen recep In one embodiment, a receptor antagonist is a Substance 55 tor modulators to the receptor. Methods for contacting the which binds receptors and inactivates them. In one embodi samples with the selective androgen receptor modulators or ment, a selective androgen receptor modulator is a molecule other specific binding components are known to those that exhibits in vivo tissue selectivity, activating signaling skilled in the art and may be selected depending on the type activity of the androgen receptor (AR) in anabolic (muscle, of assay protocol to be run. Incubation methods are also bone, etc.) tissues to a greater extent than in the androgenic 60 standard and are known to those skilled in the art. tissues. Thus, in one embodiment, the selective androgen In another embodiment, the term "contacting means that receptor modulators of the present invention are useful in the selective androgen receptor modulators of the present binding to and activating steroidal hormone receptors. In invention are introduced into a subject receiving treatment, one embodiment, the SARM compound of the present and the selective androgen receptor modulator is allowed to invention is an agonist which binds the androgen receptor. In 65 come in contact with the androgen receptor in vivo. another embodiment, the compound has high affinity for the As used herein, the term “treating includes preventative androgen receptor. as well as disorder remitative treatment. As used herein, the US 9,622,992 B2 51 52 terms “reducing”, “suppressing and “inhibiting have their limited to: selective estrogen receptor modulators (SERM), commonly understood meaning of lessening or decreasing. 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, inhibitors (exemestane, anastroZole, letrozole, Vorozole, holding up or setting back. As used herein, the term “metas , 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 10 estrogen receptors, estrogens, progestins, PDES 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 (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 15 Additional therapeutic agents that may 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 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 (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 25 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 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 30 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 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 As used herein, the term “administering refers to bring 35 (methotrexate), Neosar (cyclophosphamide), Nolvadex (ta ing a subject in contact with a compound of the present moxifen citrate), paclitaxel, paclitaxel albumin-stabilized invention. As used herein, administration can be accom nanop article formulation, Perjeta (pertuzumab), pertu plished in vitro, i.e. in a test tube, or in Vivo, i.e. in cells or Zumab, yamoxifen citrate, Taxol (paclitaxel), Taxotere (doc tissues of living organisms, for example humans. In one etaxel), trastuzumab, toremifene, Tykerb (lapatinib ditosy embodiment, the present invention encompasses adminis 40 late), Xeloda (capecitabine). tering the compounds of the present invention to a Subject. Thus, in one embodiment, the methods of the present In one embodiment, a compound of the present invention invention comprise administering the selective androgen is administered to a Subject once a week. In another embodi receptor modulator, in combination with a selective estrogen ment, a compound of the present invention is administered receptor modulator. Thus, in one embodiment, the methods to a subject twice a week. In another embodiment, a com 45 of the present invention comprise administering the selective pound of the present invention is administered to a subject androgen receptor modulator, in combination with a selec three times a week. In another embodiment, a compound of tive estrogen receptor degrader (fulvestrant). Thus, in one the present invention is administered to a subject four times embodiment, the methods of the present invention comprise a week. In another embodiment, a compound of the present administering the selective androgen receptor modulator, in invention is administered to a subject five times a week. In 50 combination with a HER2 inhibitor (lapatinib, trastuzumab). another embodiment, a compound of the present invention is Thus, in one embodiment, the methods of the present administered to a subject daily. In another embodiment, a invention comprise administering the selective androgen compound of the present invention is administered to a receptor modulator, in combination with a VEGF-A inhibi Subject weekly. In another embodiment, a compound of the tor (bevacizumab). Thus, in one embodiment, the methods present invention is administered to a Subject bi-weekly. In 55 of the present invention comprise administering the selective another embodiment, a compound of the present invention is androgen receptor modulator, in combination with a che administered to a subject monthly. motherapeutic agent. In one embodiment, the chemothera In one embodiment, the methods of the present invention peutic agent is a taxane. In another embodiment, the che comprise administering a selective androgen receptor modu motherapeutic agent is an anthracycline. In one lator as the sole active ingredient. However, also encom 60 embodiment, the chemotherapeutic agent is an epothilone passed within the scope of the present invention are methods (ixabepilone). Thus, in one embodiment, the methods of the for hormone therapy, for treating breast cancer, for delaying present invention comprise administering the selective the progression of breast cancer, and for preventing and androgen receptor modulator, in combination with an LHRH treating the recurrence of breast cancer and/or breast cancer analog. In another embodiment, the methods of the present metastasis, which comprise administering the selective 65 invention comprise administering a selective androgen androgen receptor modulators in combination with one or receptor modulator, in combination with a reversible anti more therapeutic agents. These agents include, but are not androgen. In another embodiment, the methods of the pres US 9,622,992 B2 53 54 ent invention comprise administering a selective androgen lator of this invention, in combination with Afinitor (everoli receptor modulator, in combination with an antiestrogen. In 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 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 10 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 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 15 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 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 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 25 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 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 30 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 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 methods of the present invention comprise administering a 35 of the present invention comprise administering a selective selective androgen receptor modulator of this invention, in androgen receptor modulator of this invention, in combina combination with a bisphosphonate. In another embodiment, tion with Ellence (epirubicin hydrochloride). In another the methods of the present invention comprise administering embodiment, the methods of the present invention comprise a selective androgen receptor modulator of this invention, in administering a selective androgen receptor modulator of combination with a growth factor inhibitor. In another 40 this invention, in combination with epirubicin hydrochlo embodiment, the methods of the present invention comprise ride. In another embodiment, the methods of the present administering a selective androgen receptor modulator of invention comprise administering a selective androgen this invention, in combination with one or more additional receptor modulator of this invention, in combination with selective androgen receptor modulators (SARMs). everolimus. In another embodiment, the methods of the In another embodiment, the methods of the present inven 45 present invention comprise administering a selective andro tion comprise administering a selective androgen receptor gen receptor modulator of this invention, in combination modulator of this invention, in combination with Abitrexate with exemestane. In another embodiment, the methods of (methotrexate). In another embodiment, the methods of the the present invention comprise administering a selective present invention comprise administering a selective andro androgen receptor modulator of this invention, in combina gen receptor modulator of this invention, in combination 50 tion with Fareston (toremifene). In another embodiment, the with Abraxane (paclitaxel albumin-stabilized nanoparticle methods of the present invention comprise administering a formulation). 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 with ado-trastuzumab emtansine. In another embodiment, 55 istering a selective androgen receptor modulator of this the methods of the present invention comprise administering invention, in combination with Femara (letrozole). In a selective androgen receptor modulator of this invention, in another embodiment, the methods of the present invention combination with Adriamycin PFS (doxorubicin hydrochlo comprise administering a selective androgen receptor modu ride). In another embodiment, the methods of the present lator of this invention, in combination with Fluoroplex invention comprise administering a selective androgen 60 (fluorouracil). In another embodiment, the methods of the receptor modulator of this invention, in combination with present invention comprise administering a selective andro Adriamycin RDF (doxorubicin hydrochloride). In another gen receptor modulator of this invention, in combination embodiment, the methods of the present invention comprise with fluorouracil. In another embodiment, the methods of administering a selective androgen receptor modulator of the present invention comprise administering a selective this invention, in combination with Adrucil (fluorouracil). In 65 androgen receptor modulator of this invention, in combina another embodiment, the methods of the present invention tion with Folex (methotrexate). In another embodiment, the comprise administering a selective androgen receptor modu methods of the present invention comprise administering a US 9,622,992 B2 55 56 selective androgen receptor modulator of this invention, in ment, the methods of the present invention comprise admin combination with Folex PFS (methotrexate). In another 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 5 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 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 oremifene. In invention comprise administering a selective androgen 10 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 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 15 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 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 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 25 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 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 30 “therapeutically effective amount’ as used herein refers to tion with methotrexate. In another embodiment, the methods that amount which provides a therapeutic effect for a given of the present invention comprise administering a selective 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 embodiment, the methods of the present invention comprise 35 HCI., acetate, phosphate), pH and ionic strength, additives administering a selective androgen receptor modulator of Such as albumin or gelatin to prevent absorption to surfaces, this invention, in combination with Mexate (methotrexate). detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile In another embodiment, the methods of the present inven acid salts), solubilizing agents (e.g., glycerol, polyethylene tion comprise administering a selective androgen receptor glycerol), anti-oxidants (e.g., ascorbic acid, Sodium meta modulator of this invention, in combination with Mexate 40 bisulfite), preservatives (e.g., Thimerosal, benzyl alcohol, AQ (methotrexate). In another embodiment, the methods of parabens), bulking Substances or tonicity modifiers (e.g., the present invention comprise administering a selective lactose, mannitol), covalent attachment of polymers such as androgen receptor modulator of this invention, in combina polyethylene glycol to the protein, complexation with metal tion with Neosar (cyclophosphamide). In another embodi ions, or incorporation of the material into or onto particulate ment, the methods of the present invention comprise admin 45 preparations of polymeric compounds such as polylactic istering a selective androgen receptor modulator of this acid, polyglycolic acid, hydrogels, etc, or onto liposomes, invention, in combination with Nolvadex (tamoxifen cit microemulsions, micelles, unilamellar or multilamellar rate). In another embodiment, the methods of the present vesicles, erythrocyte ghosts, or spheroplasts). Such compo invention comprise administering a selective androgen sitions will influence the physical state, solubility, stability, receptor modulator of this invention, in combination with 50 rate of in Vivo release, and rate of in vivo clearance. paclitaxel. In another embodiment, the methods of the Controlled or Sustained release compositions include for present invention comprise administering a selective andro mulation in lipophilic depots (e.g., fatty acids, waxes, oils). gen receptor modulator of this invention, in combination Also comprehended by the invention are particulate com with paclitaxel albumin-stabilized nanoparticle formulation. positions coated with polymers (e.g., poloxamers or poloX In another embodiment, the methods of the present inven 55 amines). Other embodiments of the compositions of the tion comprise administering a selective androgen receptor invention incorporate particulate forms protective coatings, modulator of this invention, in combination with Perjeta protease inhibitors or permeation enhancers for various (pertuzumab). In another embodiment, the methods of the routes of administration, including parenteral, pulmonary, present invention comprise administering a selective andro nasal and oral. In one embodiment the pharmaceutical gen receptor modulator of this invention, in combination 60 composition is administered parenterally, paracancerally, with pertuzumab. In another embodiment, the methods of transmucosally, transdermally, intramuscularly, intrave the present invention comprise administering a selective nously, intradermally, Subcutaneously, intraperitoneally, androgen receptor modulator of this invention, in combina intraventricularly, intravaginally, intracranially and intratu tion with tamoxifen citrate. In another embodiment, the morally. methods of the present invention comprise administering a 65 Further, as used herein “pharmaceutically acceptable car selective androgen receptor modulator of this invention, in riers' are well known to those skilled in the art and include, combination with Taxol (paclitaxel). In another embodi but are not limited to, 0.01-0.1 M and preferably 0.05 M US 9,622,992 B2 57 58 phosphate buffer or about 0.8% saline. Additionally, such gums, starches, Sugars, cellulosic materials, and mixtures pharmaceutically acceptable carriers may be acqueous 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 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 Parenteral vehicles include sodium chloride solution, tion of a liquid preparation, oral administration of a liquid or Ringer's dextrose, dextrose and sodium chloride, lactated 10 Solid preparation, or by topical application. Administration Ringer's and fixed oils. Intravenous vehicles include fluid can also be accomplished by use of a rectal Suppository or and nutrient replenishers, electrolyte replenishers such as a urethral Suppository. those based on Ringer's dextrose, and the like. Preservatives The pharmaceutical preparations of the invention can be and other additives may also be present, such as, for prepared by known dissolving, mixing, granulating, or tab example, antimicrobials, antioxidants, collating agents, inert 15 let-forming processes. For oral administration, the selective gases and the like. androgen receptor modulators or their physiologically tol Controlled or Sustained release compositions include for erated derivatives such as salts, esters, N-oxides, and the like mulation in lipophilic depots (e.g. fatty acids, waxes, oils). are mixed with additives customary for this purpose. Such as Also comprehended by the invention are particulate com vehicles, stabilizers, or inert diluents, and converted by positions coated with polymers (e.g. poloxamers or poloX customary methods into Suitable forms for administration, amines) and the compound coupled to antibodies directed Such as tablets, coated tablets, hard or soft gelatin capsules, against tissue-specific receptors, ligands or antigens or aqueous, alcoholic or oily Solutions. Examples of Suitable coupled to ligands of tissue-specific receptors. inert vehicles are conventional tablet bases such as lactose, Other embodiments of the compositions of the invention Sucrose, or cornstarch in combination with binders such as incorporate particulate forms, protective coatings, protease 25 acacia, cornstarch, gelatin, with disintegrating agents such inhibitors or permeation enhancers for various routes of as cornstarch, potato starch, alginic acid, or with a lubricant administration, including parenteral, pulmonary, nasal and Such as Stearic acid or Stearate. oral. Examples of suitable oily vehicles or solvents are veg Compounds modified by the covalent attachment of etable or animal oils such as sunflower oil or fish-liver oil. water-soluble polymers such as polyethylene glycol, copo 30 Preparations can be effected both as dry and as wet granules. lymers of polyethylene glycol and polypropylene glycol, For parenteral administration (Subcutaneous, intravenous, carboxymethyl cellulose, dextran, polyvinyl alcohol, poly intraarterial, or intramuscular injection), the selective andro vinylpyrrolidone or polyproline are known to exhibit sub gen receptor modulators or their physiologically tolerated stantially longer half-lives in blood following intravenous derivatives such as salts, esters, N-oxides, and the like are injection than do the corresponding unmodified compounds 35 converted into a solution, Suspension, or emulsion, if desired (Abuchowski et al., 1981; Newmark et al., 1982; and Katre with the Substances customary and Suitable for this purpose, et al., 1987). Such modifications may also increase the for example, solubilizers or other auxiliaries. Examples are compounds solubility in aqueous solution, eliminate aggre sterile liquids such as water and oils, with or without the gation, enhance the physical and chemical stability of the addition of a surfactant and other pharmaceutically accept compound, and greatly reduce the immunogenicity and 40 able adjuvants. Illustrative oils are those of petroleum, reactivity of the compound. As a result, the desired in vivo animal, vegetable, or synthetic origin, for example, peanut biological activity may be achieved by the administration of oil, soybean oil, or mineral oil. In general, water, Saline, Such polymer-compound abducts less frequently or in lower aqueous dextrose and related Sugar Solutions, and glycols doses than with the unmodified compound. Such as propylene glycols or polyethylene glycol are pre In yet another embodiment, the pharmaceutical compo 45 ferred liquid carriers, particularly for injectable solutions. sition can be delivered in a controlled release system. For The preparation of pharmaceutical compositions which example, the agent may be administered using intravenous contain an active component is well understood in the art. infusion, an implantable osmotic pump, a transdermal patch, Such compositions can be prepared as aerosols of the active liposomes, or other modes of administration. In one embodi component delivered to the nasopharynx or as injectables, ment, a pump may be used (see Langer, Supra; Sefton, CRC 50 either as liquid solutions or Suspensions; however, Solid Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., forms suitable for Solution in, or Suspension in, liquid prior Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. to injection can also be prepared. The preparation can also 321:574 (1989). In another embodiment, polymeric materi be emulsified. The active therapeutic ingredient is often als can be used. In yet another embodiment, a controlled mixed with excipients which are pharmaceutically accept release system can be placed in proximity to the therapeutic 55 able and compatible with the active ingredient. Suitable target, i.e., the brain, thus requiring only a fraction of the excipients are, for example, water, saline, dextrose, glycerol, systemic dose (see, e.g., Goodson, in Medical Applications ethanol, or the like or any combination thereof. of Controlled Release, supra, Vol. 2, pp. 115-138 (1984). In addition, the composition can contain minor amounts Other controlled release systems are discussed in the review of auxiliary Substances such as wetting or emulsifying by Langer (Science 249:1527-1533 (1990). 60 agents, pH buffering agents which enhance the effectiveness The pharmaceutical preparation can comprise the selec of the active ingredient. tive androgen receptor modulator alone, or can further An active component can be formulated into the compo include a pharmaceutically acceptable carrier, and can be in sition as neutralized pharmaceutically acceptable salt forms. Solid or liquid form Such as tablets, powders, capsules, Pharmaceutically acceptable salts include the acid addition pellets, solutions, Suspensions, elixirs, emulsions, gels, 65 salts (formed with the free amino groups of the polypeptide creams, or suppositories, including rectal and urethral Sup or antibody molecule), which are formed with inorganic positories. Pharmaceutically acceptable carriers include acids such as, for example, hydrochloric or phosphoric US 9,622,992 B2 59 60 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, 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 For topical administration to body Surfaces using, for not excluding others which may be optional. By the phrase example, creams, gels, drops, and the like, the selective “consisting essentially of it is meant a method that includes androgen receptor modulators or their physiologically tol 10 erated derivatives such as salts, esters, N-oxides, and the like the recited elements but exclude other elements that may are prepared and applied as solutions, Suspensions, or emul have an essential significant effect on the performance of the sions in a physiologically acceptable diluent with or without method. "Consisting of shall thus mean excluding more a pharmaceutical carrier. than traces of other elements. Embodiments defined by each In another embodiment, the active compound can be 15 of these transition terms are within the scope of this inven delivered in a vesicle, in particular a liposome (see Langer, tion. Science 249:1527-1533 (1990); Treat et al., in Liposomes in In one embodiment, the present invention provides com the Therapy of Infectious Disease and Cancer, Lopez-Ber bined preparations. In one embodiment, the term "a com estein and Fidler (eds.), Liss, New York, pp. 353–365 (1989); bined preparation' defines especially a “kit of parts” in the Lopez-Berestein, ibid., pp. 317-327; see generally ibid). sense that the combination partners as defined above can be For use in medicine, the salts of the selective androgen dosed independently or by use of different fixed combina receptor modulator will be pharmaceutically acceptable tions with distinguished amounts of the combination part salts. Other salts may, however, be useful in the preparation ners i.e., simultaneously, concurrently, separately or sequen of the compounds of the invention or of their pharmaceuti tially. In some embodiments, the parts of the kit of parts can cally acceptable salts. Suitable pharmaceutically acceptable 25 then, e.g., be administered simultaneously or chronologi salts of the compounds of this invention include acid addi cally staggered, that is at different time points and with equal tion salts which may, for example, be formed by mixing a or different time intervals for any part of the kit of parts. The solution of the compound of the invention with a solution of ratio of the total amounts of the combination partners, in a pharmaceutically acceptable acid Such as hydrochloric Some embodiments, can be administered in the combined acid, Sulphuric acid, methaneSulphonic acid, fumaric acid, 30 preparation. In one embodiment, the combined preparation maleic acid. Succinic acid, acetic acid, benzoic acid, oxalic can be varied, e.g., in order to cope with the needs of a acid, citric acid, tartaric acid, carbonic acid or phosphoric patient subpopulation to be treated or the needs of the single acid. patient which different needs can be due to a particular In one embodiment, the term “about’, refers to a deviance disease, severity of a disease, age, sex, or body weight as can of between 0.0001-5% from the indicated number or range 35 be readily made by a person skilled in the art. of numbers. In one embodiment, the term “about’, refers to In one embodiment, the term “a” or 'one' or “an refers a deviance of between 1-10% from the indicated number or to at least one. In one embodiment the phrase “two or more’ range of numbers. In one embodiment, the term “about', may be of any denomination, which will Suit a particular refers to a deviance of up to 25% from the indicated number purpose. In one embodiment, “about may comprise a or range of numbers. 40 deviance from the indicated term of +1%, or in some In some embodiments, the term "comprise' or grammati embodiments.-1%, or in some embodiments, t2.5%, or in cal forms thereof, refers to the inclusion of the indicated some embodiments, t5%, or in some embodiments, +7.5%, active agent, Such as the compound of this invention, as well or in some embodiments, it 10%, or in Some embodiments, as inclusion of other active agents, and pharmaceutically +15%, or in some embodiments, t20%, or in some embodi acceptable carriers, excipients, emollients, stabilizers, etc., 45 ments, t25%. as are known in the pharmaceutical industry. In some The following examples are presented in order to more embodiments, the term “consisting essentially of refers to fully illustrate the preferred embodiments of the invention. a composition, whose only active ingredient is the indicated They should in no way be construed, however, as limiting active ingredient, however, other compounds may be the broad scope of the invention. included which are for stabilizing, preserving, etc. the for 50 mulation, but are not involved directly in the therapeutic EXPERIMENTAL DETAILS SECTION effect of the indicated active ingredient. In some embodi ments, the term “consisting essentially of may refer to General Experimental Methods components, which exert a therapeutic effect via a mecha nism distinct from that of the indicated active ingredient. In 55 Cell Growth Conditions Some embodiments, the term "consisting essentially of may HCC 1937, HCC 1954, HCC 38, T47D-Kbluc, MDA refer to components, which exert a therapeutic effect and MB-453, and MDA-MB-231 cells were grown in RPMI belong to a class of compounds distinct from that of the 1640 medium containing 2 mM L-glutamine Supplemented indicated active ingredient. In some embodiments, the term with 10% fetal bovine serum (FBS). Cells were maintained “consisting essentially of may refer to components, which 60 in a 5% CO/95% air humidified atmosphere at 37° C. exert atherapeutic effect and belong to a class of compounds MCF-7 cells were grown in Minimum Essential Medium distinct from that of the indicated active ingredient, by supplemented with 10% FBS. acting via a different mechanism of action, for example, and Breast cancer tumors typically express AR 70-90% of the representing an embodiment of this invention, polypeptides time, however breast cancer cell lines typically do not comprising T cell epitopes present in a composition may be 65 express AR. This makes development of a preclinical model specifically combined with polypeptides comprising B cell for the study of androgen effects on breast cancer very epitopes. In some embodiments, the term "consisting essen difficult. Consequently, the AR has been introduced by US 9,622,992 B2 61 62 adenoviral infection (stably incorporated into the genome) of AR (compare w/lacZ and w/AR). ICso values in AR into some breast cancer cell lines used in the studies below. positive cells for DHT and Formula IX are presented in FIG. Sulforhodamine B (SRB) Assay 1B and FIG. 2B. The SRB Assay was used to determine cell number during cytotoxocity experiments. The following protocol was used: EXAMPLE 2 1. Cells were detached with 0.25% trypsin. 2. Experimental cultures were cultured in 96-well microtiter Reversal of Effect of Formula IX on Growth plates (200 uL growth medium per well: 1,000-200,000 cells per well). Materials and Methods 3. Cultures were fixed with 50 uL 50%TCA (4° C.). (see cell 10 fixation protocol for details). To determine if the growth inhibition observed with DHT 4. Fixed cells were stained with 50 uL 0.4% (wt/vol). SRB and Formula IX in AR positive cells is AR dependent, in 1% acetic acid for 10 minutes. MDA-MB-231 cells were infected with adenovirus contain 5. SRB was removed and the cultures were quickly rinsed 15 ing Lacz (negative control) or AR and were treated with AR 5 times with 1% acetic acid to remove unbound dye.** agonists, DHT or Formula IX, in the presence or absence of 6. Cultures were air-dried overnight until there was no the AR antagonist, bicalutamide. Cells were treated in visible moisture. charcoal stripped FBS (FIGS. 3A and 3C) or full serum 7. The cellular protein-bound SRB was dissolved with 200 (FIGS. 3B and 3D) for 3 days, fixed and stained with uL unbuffered Tris base (10 mM, pH 10.5) for 30 minutes sulforhodamine blue (SRB) to measure cell viability. ICso on a rocking platform shaker. values were calculated. 8. Absorbance was read at 540 nm. * quickly performing rinsing process was to prevent Results desorption of protein-bound SRB ** completely removed residual wash solution by sharply 25 Both DHT and Formula IX required AR to inhibit MDA flicking plates over sink. MB-231 cell growth, as demonstrated by the weakened Fixation of Cells Attached to the Plastic Substratum growth inhibitory effects in the presence of bicalutamide The following protocol was used for fixing cells: (FIG.3A, 3B, 3C, 3D). ICs values for DHT and Formula IX a. 50 uI of 50% TCA (4°C.) was gently layered on the top in AR positive cells pretreated with or without bicalutamide of growth medium in each well to make a final TCA 30 are presented in FIG. 3E. concentration of 10%. b. Cultures were incubated at 4°C. for 1 hour. EXAMPLE 3 c. Cultures were washed 5 times with tap water to remove TCA, growth medium, low-molecular-weight metabo lites, and serum protein. 35 Effect of AR Ligands on Breast Cancer Cell d. Plates were air-dried until there was no visible moisture. Growth

EXAMPLE 1. Materials and Methods Effect of Formula IX on Growth in Different Breast 40 To determine if all AR ligands inhibit the growth of triple Cancers Cell Lines Expressing Androgen Receptor negative breast cancer cells, MDA-MB-231 cells were infected with adenovirus containing Lacz or AR and were Materials and Methods treated with various AR ligands (agonists: DHT, Formula VIII, Formula IX, Formula X, Formula XIII, Formula XIV: MDA-MB-231 and HCC-38 triple negative breast cancer 45 antagonist: bicalutamide) and a non-AR-binder: cells were used to analyze growth effects of various com R-enantiomer of Formula IX. Cells were treated in charcoal pounds. stripped FBS (FIGS. 4A, 4C, 4E, 4G, 4I, 4K, 4M and 4O) MDA-MB-231 and HCC-38 triple negative breast cancer or full serum (4B, 4D, 4F, 4H, 4J, 4L, 4N and 4P) for 3 days, cells were infected with 200 uL or 500 u, adenovirus fixed and stained with sulforhodamine blue (SRB) to mea containing Lac Z (negative control) or AR, and were treated 50 sure cell viability. Anti-proliferative ICs values were cal with various AR ligands (agonists: DHT and Formula IX, culated in breast cancer cells and compared to transactiva and antagonist: bicalutamide) or a non-AR binder that is tion Values, i.e., ECso (agonists) and ICso (antagonists) structurally similar to Formula IX, R-enantiomer of Formula values, generated in HEK-293 cells. The growth regulatory IX. Cells were treated in charcoal stripped FBS (FIGS. 1C, properties in breast cancer cells of these molecules in breast 1E, 1G and 1I; 2C, 2E and 2G) or full serum (FIGS. 1D, 1F, 55 cancer cells are comparable to the transactivation values 1H and 1.J: 2D, 2F and 2H) for 3 days, fixed and stained with obtained in HEK-293 cells. sulforhodamine blue (SRB) to measure cell viability. ICso values were calculated Results Results 60 Only AR agonists inhibited the growth of MDA-MB-231 Expression of AR in cells infected with AR or Lacz was cells (FIGS. 4A-4B, 4E-4H, and 4K-4P) and the growth evaluated using Western blotting (FIG. 1A and FIG. 2A). inhibitory potential of these ligands rank order with their Only the AR agonists, DHT and Formula IX, inhibited agonistic activity observed in HEK-293 cells (FIG. 4Q). MDA-MB-231 and HCC-38 triple negative breast cancer 65 Example 14 demonstrates as well that AR agonists inhib cell growth (FIGS. 1C, 1D, 1E, 1F and FIGS. 2C, 2D, 2E ited the proliferation of MDA-MB-231 cells stably trans and 2F). This inhibition was observed only in the presence fected with AR. US 9,622,992 B2 63 64 EXAMPLE 4 for 3 days with the indicated concentrations of DHT or bicalutamide. Live cells were visualized using a light AR Transactivation Assays in Breast Cancer Cells microscope and photographed. The cells were imaged at the same magnification and under the same microscopic condi Materials and Methods tions. To ensure that the ligands that elicited growth inhibitory properties are agonists in MDA-MB-231 cells, AR transac Results tivation assays were performed in MDA-MB-231 cells. Though AR transactivation assay was performed in HEK FIG. 7 shows that DHT altered the morphology of MDA 293 cells, the ability of ligands to function as agonists or 10 MB-231 cells into more anchorage dependent and differen antagonists depends on cellular microenvironment. Hence, tiated cells, indicating that agonist-bound AR expressing MDA-MB-231 cells were transfected using lipofectamine breast cancer cells will have less invasive and migratory with AR, GRE-LUC and CMV-LUC as normalization con properties (e.g., less likely to metastasize). trol. The cells were treated 24 h after transfection and DHT and SARMs alter the morphology of AR-positive luciferase assay performed 48 h after transfection. 15 MDA-MB-231 cells. MDA-MB-231 cells were stably trans fected with AR using lentivirus and were treated with Results vehicle or AR agonists at the indicated concentrations. At the end of 3 days of incubation, the cells were imaged under a FIG. 5 shows that all AR ligands that elicited anti microscope (40x). proliferative activity are agonists in MDA-MB-231 cells DHT and SARMs, but not the AR antagonist, bicaluta transfected with AR and their agonist and growth inhibitory mide (data not shown), or the inactive isomer of formula IX, properties compare well. In other words, growth inhibitory altered the morphology of the cells into a more anchorage ligands are AR agonists in MDA-MB-231 cells transfected dependent phenotype. (FIG. 12). with AR. 25 EXAMPLE 7 EXAMPLE 5 Cross-Reactivity of Formula VIII with Other Analysis of Growth Inhibitory Effects in Breast Nuclear Hormone Receptors Cancer Cells Expressing Estrogen Receptor 30 In order to determine whether compounds of this inven Materials and Methods tion affected other nuclear hormone receptor signaling, the ability of a compound represented by formula VIII to To ensure that growth inhibitory effects in MDA-MB-231 stimulate (agonist) or inhibit (antagonist) ERC.-, ERB-, GR-. cells are selective to AR, and to determine if the ligand PR-, or MR-mediated transcriptional activation, was ana dependent-growth-inhibitory effects are exclusive to AR and 35 lyzed. 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-C. or ER-Badenovirus constructs and were treated with ER agonist: estradiol (E2) or ER antago Transient Transfection nist: ICI 182,780 (ICI) in charcoal stripped serum (FIG. 6C) 40 Rat GR, MR, PR, ER-C. and ER-B were individually or full serum (FIGS. 6D and 6E) for 3 days. Cells were fixed cloned into a pCR3.1 vector backbone. Sequencing was and stained with sulforhodamine blue (SRB) to measure cell performed to verify the absence of any mutations. HEK-293 viability. Expression of ER in infected cells was evaluated cells were plated at 90,000 cells per well of a 24 well plate using Western blotting. in Dulbecco's Minimal Essential Media supplemented with 45 5% charcoal-stripped FBS. The cells were transfected using Results Lipofectamine (Invitrogen, Carlsbad, Calif.) with 0.25 ug GRE-LUC for GR, MR and PR and ERE-LUC for ER-O. and FIGS. 6A-6B show the presence or absence of ERC. or ER-B, 0.5 ng CMV-LUC (renilla luciferase) and 12.5-25 ng ERB in MDA-MB-231 cells following transfection. These of the respective expression vector for each receptor. The results show that the anti-proliferative effects observed with 50 cells were treated 24 h after transfection with formula VIII androgens is unique to ligand activated AR and not an in the absence (agonist mode) and presence (antagonist artifact of adenovirus. FIGS. 6C-6E show that over-expres mode) of known agonists (estradiol for ER; dexamethasone sion of ER-O. or ER-B in MDA-MB-231 cells failed to for GR: aldosterone for MR; progesterone for PR) as con promote growth inhibition either in the presence of ER trols. Luciferase assays were performed 48 h after transfec agonists or antagonists. Thus, the observed growth inhibi 55 tion. Transcriptional activation values are represented as tory effects in MDA-MB-231 cells are selective to the firefly luciferase normalized to renilla luciferase. presence of the AR and AR agonists. Results EXAMPLE 6 60 The agonist effects of formula VIII on ER-B, ER-O, GR, Effect of AR Agonist on Morphology of Breast PR and MR were tested and compared to the activities of the Cancer Cells known ligands, as well (FIG. 8). A compound of formula VIII failed to activate ER-B or ER-C. even at the highest Materials and Methods tested concentration (1 uM) whereas 1 nM estradiol induced 65 ERC- and ERB-mediated transactivation by 3- and 5-fold, MDA-MB-231 cells were stably transfected with AR respectively. A compound of formula VIII failed to activate using lentivirus. Following transfection, cells were treated GR- or MR-mediated transactivation. A compound of for US 9,622,992 B2 65 66 mula VIII at all the tested concentrations did not induce GR and compound IX, indicative of healthy growth and a lack or MR-mediated transactivation, whereas the known ligands of toxicity. By comparison, the vehicle treated animal did (dexamethasone and aldosterone) induced the activities of not grow as robustly. GR or MR by 70- and 60-fold, respectively, at a concentra In summary, the formula VIII SARM is extremely effec tion of 1 nM. However, a compound of formula VIII tive in regressing the growth of AR expressing triple nega increased the transactivation of PR at 1 uM and 10 uM by tive breast cancer Xenografts in mice, and is likely to be 3 and 8 fold, respectively. Progesterone activated PR by 23 effective in a wide variety of AR-positive breast cancers in fold at a 1 nM concentration, indicating that a compound of humans, as described Supra and infra. formula VIII is greater than 10,000-fold weaker than the endogenous agonist for PR. 10 EXAMPLE 9 The ability of a compound of formula VIII to inhibit the effects of a known agonist for each of the above mentioned Effect of Formula IX in Women with Metastatic or receptors was tested as well. Er and/or AR Positive Refractory Breast Cancer Co-incubation of HEK 293 cells with the indicated con centrations of formula VIII failed to alter the estradiol 15 This clinical trial assessed the safety and efficacy of 9 mg induced ER-B or ER-C. activity, dexamethasone-induced of the compound represented by the structure of Formula IX GR-mediated transactivation or aldosterone-induced MR (Formula IX), in 22 post-menopausal women who have mediated transactivation. estrogen receptor (ER) positive metastatic breast cancer, and A dose response curve for a compound of formula VIII in who have responded previously to adjuvant and/or salvage antagonist mode demonstrated potent partial inhibition of endocrine therapy. The goal of this study was to determine PR activity (FIG. 9). In comparison to formula IX, formula the importance of the AR status as a therapeutic target in VIII is was 10-times more potent, and 100-times more women with ER positive metastatic breast cancer (MBC) potent than R-enantiomer of formula IX. In comparison to that had previously responded to hormone therapy. The RU486, formula VIII was about 1,000 fold weaker as a PR treatment was continued until disease progression (PD). antagonist, than RU486. 25 Primary endpoint was clinical benefit response (CBR) by Compounds of formula VIII and IX are specific for the 6 months (iii) defined as patients having a complete response AR and do not stimulate or inhibit receptor-mediated trans (CR), partial response (PR), or stable disease (SD). CBR activation of ERO, ERB, GR, or MR. Unexpectedly, formula will be correlated with AR status of metastatic tumor biopsy. VIII exhibited moderate potency partial agonist activity for Serum prostate specific antigen (PSA) was evaluated as a PR, and potent PR partial antagonism (see FIG. 9). Com 30 biomarker of AR activity. bined AR-agonism and PR-antagonism will be beneficial in Results: Formula IX was well-tolerated, with no drug certain breast cancers (e.g., PR-positive breast cancers). related serious adverse events and none exceeding Grade 3. Conclusions: Formula IX demonstrated promise as a novel EXAMPLE 8 targeted therapy for AR positive MBC. The primary end 35 point has been achieved, with 6/17 AR+ patients meeting Formula VIII and Compound IX Inhibits Triple statistical threshold for success, as outline in the Table Negative Breast Cancer Cell Tumor Growth in herein below. Serum PSA appeared to be a surrogate marker Mice for AR activity and disease response.

Materials and Methods 40 Materials and Methods MDA-MB-231-AR triple negative breast cancer cells (2 Subject Population million cells/mouse; MDA-MB-231 cells stably transfected Female subjects with ER positive metastatic breast cancer with AR using lentivirus) were mixed with matrigel (1:1) who have previously been treated with up to 3 prior hor and injected Subcutaneously into the flanks of intact female 45 monal therapies for the treatment of breast cancer. Subjects nude mice (n=5/group). When the tumors reached 150-200 must have been treated with and responded to previous mm, the animals were separated into two groups, one adjuvant therapy for 23 years or hormonal therapy for receiving vehicle and the other receiving 30 mg/kg formula metastatic disease for 26 months prior to progression. VIII orally. Tumor volume was measured thrice weekly and Details of subject selection criteria are presented below: % tumor growth inhibition (TGI) was calculated. At the end 50 To be eligible for participation in this study, subjects must of 35 days of treatment, the animals were sacrificed, tumors meet all of the following criteria, including give Voluntary, excised, weighed, and collected for various analyses. Blood signed informed consent in accordance with institutional was collected and serum separated for drug concentration policies; be a woman that has been diagnosed with ER measurement. positive metastatic breast cancer, and be clinically con 55 firmed as postmenopausal. Subjects must have undergone Results the onset of spontaneous, medical or Surgical menopause prior to the start of this study. (Spontaneous menopause is Formula VIII significantly reduced the tumor growth with defined as the natural cessation of ovarian function as TGI of -7.5% (FIG. 10B). Tumor weights were also reduced indicated by being amenorrheic for at least 12 months. If the by more than 50% by Formula VIII treatment (FIG. 11C) as 60 subject has been amenorrheic for >6 months but <12 months were tumor size (FIGS. 11A-B). Formula VIII elicited these they must have a serum FSH concentration of 50 m IU/mL results without any associated toxicity or changes in body and an estradiol concentration of s25 pg/mL, medical meno weight (FIG. 10A). Uterus weight also increased in response pause is defined as treatment with a luteinizing hormone to formula VIII treatment (not shown), indicative of in vivo receptor hormone agonist; and Surgical menopause is androgenic response. 65 defined as bilateral oophorectomy). The results presented in FIG. 24 shows the increase of Additional requirement that Subjects must meet include body weight by the SARMs at all doses of compound VIII that they have been treated and responded to previous US 9,622,992 B2 67 68 adjuvant hormonal therapy for 23 years or previous hor secondary and tertiary endpoints in Subsets based on AR monal therapy for metastatic disease for 26 months prior to status (i.e., all subjects, AR positive subjects, and AR negative subjects). disease progression; that they have not had radiation therapy At the time of this writing, patient demographics were: for breast cancer within 2 weeks of randomization in this mean age 63.7 years, mean time from diagnosis 11.0 years, study and are not planned to have radiation therapy during 72.7% prior chemotherapy, 89% (17/19) AR+, 41% detect participation in this study. Subjects must be willing to able baseline PSA and 86.4% previous radiation. provide tissue sample from a biopsy of a metastatic tumor The baseline characteristic by response was as follows: lesion(s) for determination of AR and ER status. Tissue samples from a biopsy of a primary tumor lesion will also be 10 provided if available. Further subjects must have ECOG Clinical Benefit at Clinical Benefit at Progressive Disease at score s2 and be age 218 years. Best Response 6 Months 6 Months or Prior Subjects with any of the following exclusion criteria will N = 9 N = 7 N = 12 NOT be eligible for enrollment in this study: have triple Mean age 65.5 Mean age 64.6 Mean age 60.5 negative breast cancer, have, in the judgment of the Inves AR status 7.7 AR+ AR status 66 AR+ AR status 8.10 AR+ tigator, a clinically significant concurrent illness or psycho 15 Years from Years from Years from logical, familial, sociological, geographical or other con Diagnosis (DX) Diagnosis (DX) Diagnosis (DX) Mean 13.7 Mean 157 Mean 8.6 comitant condition that would not permit adequate follow Median 11.4 Median 15.0 Median 7.8 up and compliance with the study protocol; have (5.1-27.2) (8.5-27.2) (1.9-22.8) uncontrolled hypertension, congestive heart failure or Years from Dx to Years from Dx to Years from Dx to Metastasis (Mets) Metastasis (Mets) Metastasis (Mets) angina; have Stage 4 chronic obstructive pulmonary disease Mean 8.6 Mean 9.8 Mean 4.4 (COPD); have positive screen for Hepatitis B consisting of Median 9.3 (0-15.8) Median 9.8 (0-15.8) Median 4.1 (0-17.2) HBS Ag (Hepatitis B Surface Antigen), unless subject was Chemotherapy Chemotherapy Chemotherapy diagnosed D10 years prior to enrollment and no evidence of (NA+A): 6/9 (NA+A): 5/7 (NA+A): 9/12 active liver disease; have ALT/SGOT or AST/SGPT above Everolimus: 0.9 Everolimus: 0.7 Everolimus: 4f12 25 Bone only Bone only Bone only 1.5 times the upper limit of normal (ULN); have positive disease: 49 disease: 47 disease: 112 screen for hepatitis A antibody IgM or HIV; have received Visceral only Visceral only Visceral only chemotherapy for metastatic breast cancer within the 3 disease: 29 disease: 27 disease: 212 months prior to enrollment in the study or be expected to receive chemotherapy for metastatic breast cancer during the study; be currently taking testosterone, , 30 (OxandrinR), , , flu Table of Subjects Assessed as (Halotestin R), testosterone-like agents (such Having Clinical Benefit as Best Response as (DHEA), , and other androgenic compounds, including herbals), or antian Time 35 Time Time (y) (y) From Number of drogens; previous therapy with testosterone and testoster (y) From Metastatic Lines of one-like agents is acceptable with a 30-day washout (if From Dx to Dx to Previous previous testosteronetherapy was long term depot within the Sub- Initial Metastatic Enroll- Hormonal Metas past 6 months, the site should contact the medical monitor ject Age AR BC DX Disease ment Therapy 8Se:S for this study to determine appropriate washout period); 22 739 - 8.7 8.5 O.2 2 Lymph have untreated or uncontrolled brain metastasis; have been 40 Nodes, Bone diagnosed with or treated for cancer within the previous two O7 64.1 S.1 O S.1 2 Perito years, other than breast cancer or non-melanoma carcinoma neum, of the skin Bone Androgen receptor (AR) status was assessed in all Sub O8 S2.5 - 11.4 9.8 1.6 2 Bone 45 14 656 - 27.2 13.5 13.7 5 Liver, jects from primary and/or metastatic lesions after enroll Bone ment. It was observed that the majority (17/19) of subjects 16 80.1 - 21.6 12.5 9.1 3 Lung, with ER positive breast cancer also expressed AR) in their Chest primary tumor samples, which correlated well with previous Wall, literature which predicted 70-95% would be AR-positive Skin 50 19 676 -- 9.5 8 1.5 4 Bone (Niemeier LA, et. al. Androgen receptor in breast cancer: 18 54.4 + 15 9.3 5.7 4 Bone expression in estrogen receptor-positive tumors and in estro O3 62.8 - 16.6 15.8 O.8 1 Bone gen-negative tumors with apocrine differentiation. Modern 11 69 8.5 O 8.5 2 Liver Pathology 23:205-212, 2010; Narita D, et al. Immunohis tochemical expression of androgen receptor and prostate specific antigen in breast cancer. Folia Histochemica Et 55 Cytobiologica 44.165-172, 2006). High percentages (72 Table of Subjects Assessed as Having Clinical Benefit at 6 Months 84%) of metastatic lesions obtained from women with advanced breast cancer have also been found to be AR Time positive (Lea OA. et al. Improved measurement of androgen Time (y) (y) From Number 60 Time From Meta- of receptors in human breast cancer. Cancer Research 49:7162 (y) Dx to static Lines of 7167, 1989). From Meta- Dx to Previous As 70% or greater of the women with ER positive breast Sub- Initial static Enroll- Hormonal Metas cancer were expected to have tumors that are AR positive, ject Age AR BC DX Disease ment Therapy tases the study was designed to enroll approximately 27 Subjects O8 S2.5 - 11.4 9.8 1.6 2 Bone (of 40 originally intended to be enrolled) with AR positive 65 14 656 - 27.2 13.5 13.7 5 Liver, breast cancer in each dose arm, enabling assessment of the Bone primary endpoint in AR positive Subjects, as well as the US 9,622,992 B2 69 70 -continued Response Evaluation Criteria In Solid Tumors (RECIST 1.1) classification over the course of this study (described in Table of Subjects Assessed as Having Clinical Benefit at 6 Months detail below). Time Study Duration Time (y) (y) From Number Each subject enrolled into this study received intervention Time From Meta- of until a progression free survival (PFS) endpoint has been (y) Dx to static Lines of reached (tumor progression or death). Subjects will be From Meta- Dx to Previous followed after treatment has been discontinued for vital Sub- Initial static Enroll- Hormonal Metas status only. ject Age AR BC DX Disease ment Therapy tases 10 Efficacy Endpoints 16 80.1 - 21.6 12.5 9.1 3 Lung, The primary efficacy analysis was the clinical benefit in Chest subjects with AR positive breast cancer at 6 months as Wall, Skin measured by a modified Response Evaluation Criteria In 19 676 -- 9.5 8 1.5 4 Bone 15 Solid Tumors (RECIST 1.1) classification. Key secondary 18 54.4 + 15 9.3 5.7 4 Bone endpoints of clinical benefit in all subjects and AR negative O3 62.8 - 16.6 15.8 O.8 1 Bone Subjects, as well as objective response rate, progression free 11 69 8.5 O 8.5 2 Liver Survival, time to progression, duration of response, inci dence of SREs, and time to first SRE in subsets based on AR status (i.e., all subjects, AR positive subjects, and AR negative subjects) was also assessed. Effects on CA 27-29, Table of Subjects Assessed as Having PSA, bone turnover markers, QOL, and libido were assessed Progressive Disease at 6 Months or Prior as tertiary endpoints. Time Number Primary Endpoint Time (y) of 25 Clinical benefit in a subject is defined as a complete Time (y) From Lines of (y) From Meta- Pre response ICR), a partial response PR or stable disease ISD From Dx to static vious as measured by modified RECIST 1.1, which is described in Initial Meta- Dx to Hor detail below. (Eisenhauer EA et al. New response evaluation Sub- BC static Enroll- monal criteria in solid tumors: revised RECIST guideline (version ject Age AR DX Disease ment Therapy Metastases 30 1.1). European Journal of Cancer 45:228-247, 2009). 2O 66.9 - 1.9 O.1 1.8 5 Lymph For Subjects with non-measurable (non-target) disease Nodes, only at baseline, SD was defined as those with non-CR/non Bone PD combined response. The primary endpoint of the study O7 64.1 S.1 O S.1 2 Perito neum, was to assess the proportion of subjects with clinical benefit Bone 35 (PCB) at 6 months (CR+PR+SD) in subjects with AR O6 49.1 - 7.6 S.1 2.5 3 Pleura, positive breast cancer. Liver, Secondary Endpoints Lymph Nodes The secondary efficacy endpoints include: O9 67.3 + 7.9 4 3.9 3 Lymph To assess the clinical benefit in all subjects with breast Nodes, 40 cancer treated with Formula IX. The clinical benefit is Liver, defined as the proportion of subjects with complete Bone 12 485 14.4 4.1 10.3 5 Lung, response CR+partial response PR+stable disease Liver, ISD as measured by modified RECIST 1.1 (Eisen Bone hauer E A et al. New response evaluation criteria in 13 63.5 - 5.8 O 5.8 3 Abd Wall, 45 solid tumors: revised RECIST guideline (Version 1.1). Lung, Bone, European Journal of Cancer 45:228-247, 2009). Skin For Subjects with non-measurable (non-target) disease 21 S63 - 3.7 O 3.7 2 Liver, only at baseline, SD was defined as those with non Bone CR/non-PD combined response. O1 67.3 + 3.7 2 Lung, Liver, 50 To assess objective response rate (ORR) in subjects with Bone breast cancer treated with Formula IX. Objective O2 62.1 - 8.3 5.3 3 4 Bone, response rate is defined as the proportion of Subjects Adrenal Nodule with a CR or PR at 6 months as measured by modified O4 45.7 - 5.3 O 5.3 6 Bone RECIST 1.1. For subjects with non-measurable (non 17 84.7 - 22.8 17.2 S.6 4 Bone, 55 target) disease only at baseline, ORR is defined as the Pleura proportion of subjects with a CR at 6 months as 1O SO.8 - 16 12.7 3.3 3 Lymph measured by modified RECIST 1.1. Nodes, Neck To assess progression free survival (PFS) in subjects with breast cancer treated with Formula IX. PFS is defined 60 as the time elapsed between treatment initiation and Treatment tumor progression as measured by modified RECIST Subjects received 9 mg daily dose of Formula IX, with 1.1 OR death. baseline and regular on study assessments of safety and To assess time to progression (TTP) in subjects with efficacy. breast cancer treated with Formula IX. Time to tumor 65 progression is defined as the time elapsed between Measurable and non-measurable lesions (primary and/or treatment initiation and tumor progression as measured metastatic) will be identified and assessed by a modified by modified RECIST 1.1. US 9,622,992 B2 71 72 To assess duration of response in Subjects with breast PSA. 1 has yet to reach 6 m and no CR or PR has been cancer treated with Formula IX. observed. Formula IX was well-tolerated, with no drug related serious adverse events and none exceeding To assess incidence of skeletal related events (SREs) in Grade 3. subjects treated with Formula IX. No useful trends were seen with the biomarkers of bone To assess time to first skeletal related event (SRE) in 5 turnover: bone specific alkaline phosphatase, C-telopep subjects treated with Formula IX. tides, N-telopeptides, and osteocalcin. Likewise breast can Tertiary Endpoints cer biomarker CA 27-29 did not demonstrate any useful To assess serum CA 27-29 changes in subjects with breast trends. cancer treated with Formula IX. PSA levels appeared to increase in response to Formula To assess serum PSA changes in subjects with breast 10 IX treatment as was observed in 20 of the 22 patients cancer treated with Formula IX measured, but correlation with clinical benefit or disease To assess changes in bone turnover markers (serum progression is not yet evident. osteocalcin, serum collagen type I cross linked C-telo- The following non serous adverse events were observed: peptide CTX., serum collagen type I cross linked A-fib(1); anxiety/emotional changes (5), arthralgia (6), N-telopeptide NTX), serum bone specific alkaline 15 bloating (2), bruising (1), cellulitis (1), chills (1), constipa phosphatase, and urinary NTX in subjects treated with tion (2), cough (1), dehydration (1), diarrhea (3), dizziness Formula IX. (2), dysgeusia (1), dyspepsia (1), dyspnea (3), edema (2), To assess the effect of Formula IX on quality of life fatigue (14), fever (1), flatulence (1), glaucoma (1), head (QOL) as measured by FACIT-F questionnaire in sub- ache (4), hot flash night Sweats (7), hypertension (2), infec jects treated with Formula IX. tion (1), insomnia (2), myalgia (5), nail discoloration (1), To assess the effect of Formula IX on libido as measured nausea (11), pain (22), paresthesia (1), pleural effusion (1), by female sexual function index (FSFI) questionnaire polyuria (1), post menopausal bleeding (3), rash/acne (3), in subjects treated with Formula IX. stiffness (1), tendonitis (1), vision changes (3), vomiting (2), To explore the relationship of various levels of AR weight gain (2), and weight loss (2). expression as determined by immunohistochemistry The liver enzymes (ALT, AST and bilirubin) returned to with primary, secondary and tertiary objectives. * baseline with no interruption of therapy and no increase in Results: total bilirubin. After a median follow-up of 81 days (d) (range 7-304 d). Conclusions: Compound IX demonstrated promise as a preliminary results of the 22 patients were as follows: novel targeted therapy for AR-positive MBC. The primary 9 SD was observed as best response, median duration endpoint was achieved, with 6/17 AR-positive patients 212 d. Current disposition of all patients: 15 PD after 30 meeting statistical threshold for success. Serum PSA a median 80 d (range 15-304 d), 4 SD, and 3 early appeared to be a Surrogate marker for AR activity and discontinuations (d 7, 28, 255), Among patients who disease response. reached 6 m, six are AR-positive with SD and increased AR Status and Patient Disposition

Primary Metastatic Days Lesion Lesion MAX Patient Day 84 Day 168 Current Oil H ER ER PSA PSA i RECIST RECIST Disposition Study Score % H. Score % Day 0 F/U O1 PD NA Deceased 100 245 40 270 90 O.220 O.046 O2 PD NA PD 91 200 SO O O <0.007 O.O92 O3 SD SD D.C 2SS 260 80 26S 90 O.O10 2.430 O4 PD NA PD 105 O 20 O 60 <0.007 O.OS8 OS DfC SAE NA D.C 7 3OO 100 300 1OO <0.007 O.OO8 D2 O6 , 3. NA Deceased 18 55 70 <0.007 <0.007 (D15) O7 SD PD PD 158 <0.007 O.078 O8 SD SD PD 3O8 120 95 O.104 O.217 09 PD SAE NA Deceased 52 150 70 O.OO9 9.610 (D52) 10 PD NA PD 63 195 40 <0.007 O.4SO 11 SD SD PD 23O 3OO 100 O.104 3.540 12 PD NA PD 84 <0.007 O.238 13 PD NA PD 84 210 1OO O.O23 8.18O 14 SD SD PD 252 95 1 <0.007 O.S48 (D56) (D140) 15 D.C NA Deceased 28 160 95 <0.007 O.062 16 SD SD SD 239 240 95 <0.007 O.O24 17 PD NA PD 86 70 30 2.850 13.160 18 SD SD SD 2O2 285 90 <0.007 O.069 19 SD SD SD 190 110 <0.007 O.O31 2O PD NA PD 99 300 1OO O.O8O 0.795 21 PD NA PD 84 160 1OO O.298 O.301 22 SD SD 137 285 90 <0.007 O.O28 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 9,622,992 B2 73 74 Modified RECIST 1.1 at baseline and for which a follow-up scan is performed for The modified RECIST 1.1 definitions described below clinical Suspicion of new disease. New lymph nodes need to was applied: have a minimum size of 10 mm in their shortest axis. New Measurable Lesions non-nodal lesions need not to be measurable or to have a A measurable lesion is defined as one lesion whose minimum size. Measurements of new lesions may be per longest diameter (LD) can be accurately measured as a 10 formed. mm CT or MRI technique by using a 5 mm contiguous Response Criteria Definitions reconstruction algorithm. The following response criteria will be applied for target Measurable lesions must be at least 2 times the slice and non-target lesions: thickness or at least two times the size of the CT scan 10 Target Lesion Response Criteria interval cut. Complete Response (CR): Disappearance of all target Lesions seen on chest X-ray but not confirmed by CT or lesions. Target lymph node lesions that become <10 mm in MRI scan are not acceptable as measurable lesions for this their shortest diameter will be considered to be normal study. (non-pathologic) and their actual measurement will be To be considered pathologically enlarged and measurable, 15 recorded. Thus, it follows that if all target node lesions have a lymph node must be >15 mm in short axis when assessed become < 10 mm, and all other non-nodal lesions have by CT scan (CT scan slice thickness recommended to be no disappeared (whether target or non-target type), the overall greater than 5 mm). At baseline and in follow-up, only the response will be considered to be a CR. short axis will be measured and followed. Partial Response (PR): At least a 30% decrease in the sum Measurable disease is defined as the presence of at least of diameters of target lesions, taking as reference the base one measurable lesion. line sum of the diameters. All measurements will be taken and recorded in millime Stable Disease (SD): Neither sufficient shrinkage to ters using an electronic measurement method. qualify for PR nor sufficient increase to qualify for PD Non-Measurable Lesions taking as reference the Smallest Sum of diameters (nadir). Non-measurable lesions are defined as any lesion(s) that 25 Progressive Disease (PD): At least a 20% increase in the are smaller than the criteria for measurable lesions stated Sum of the diameters of target lesions taking as reference the above (non-nodal lesions with longest diameter <10 mm or Smallest Sum of diameters (nadir) recorded since the treat pathological lymph nodes with a 10 mm to <15 mm in short ment started. In addition to the relative increase of 20%, the axis) or truly non measurable lesions (or sites of disease). Sum of diameters must also demonstrate an absolute increase Lesions considered to be truly non-measurable are bone 30 of at least 5 mm. lesions (lytic lesions or mixed lytic-blastic lesions without Not evaluable (NE): NE can be applied if repeated identifiable soft tissue components, and blastic lesions), measurements cannot be assessed for reasons such as inad leptomeningeal disease, ascites, pleural/pericardial effu equate or missing imaging. sions, lymphangitis cutis/pulmonis, inflammatory breast dis Non-Target Lesion Response Criteria ease, abdominal masses not confirmed by imaging tech 35 Complete Response (CR): Disappearance of all non niques, and cystic lesions. target lesions. All lymph nodes must be non-pathological in 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 40 lesions. Stability, decrease, or mild increase in uptake of organs, will be selected/confirmed as target lesions, recorded 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 45 Sion. For bone Scintigraphy, at least two new lesions are niques and be most representative of the Subjects tumor 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 dimension by the radiography, CT or MRI. size estimation of their diameter. A sum of the diameters Not Evaluable (NE): NE can be applied if repeated (longest for non-nodal lesions and shortest for nodal lesions) 50 evaluations cannot be assessed for reasons such as inad for all target lesions will be calculated and reported for each equate or missing imaging. time point. The baseline sum of diameters will be used as Definitions of Combined Response at Each Time Point reference to further characterize the objective tumor Determination of an overall response for each time point response of the measurable dimension of the disease. is based on the combination of responses for target, non Non-Target Lesions 55 target, and the presence or absence of new lesions using the All other lesions (or sites of disease) and any measurable algorithm outlined on tables C1 and C2 below. lesions that were not selected as target lesions) should be identified as non-target lesions and indicated as present at TABLE C1 baseline. 60 Summary of Definitions of Response for Patients with Measurements of the non-target lesions may be per Measurable (Target) Disease at Baseline formed, however the continued presence or absence as well Response of Combined Lesion Types as the disappearance or progression status of these lesions will be noted throughout follow-up assessments. Target Non-Target New Combined New Lesions Lesions Lesions Lesions Response New lesions will be called at follow-up visits regardless 65 CR CR No CR of whether they occur in anatomic regions that were rou CR Non-CR non-PD or NE No PR tinely Subjected to follow-up, or in regions without disease US 9,622,992 B2 75 76 TABLE C1-continued desired compound as colorless crystals: mp 102-103°C.; the NMR spectrum of this compound demonstrated the exis Summary of Definitions of Response for Patients with Measurable (Target) Disease at Baseline tence of two rotamers of the title compound. 'H NMR (300 Response of Combined Lesion Types MHz, DMSO-d) & 5.28 (s) and 5.15 (s) for the first rotamer, 5 5.15 (s) and 5.03 (s) for the second rotamer (totally 2H for Target Non-Target New Combined both rotamers, vinyl CH), 4.48-4.44 for the first rotamer, Lesions Lesions Lesions Response 4.24-4.20 (m) for the second rotamer (totally 1H for both PR CR, non-CR/non-PD, No PR rotamers, CH at the chiral canter), 3.57-3.38 (m. 2H, CH), or NE 2.27-2.12 (1H, CH), 1.97-1.72 (m, 6H, CH, CH, Me); 'C SD CR, non-CR/non-PD, No SD 10 or NE NMR (75 MHz, DMSO-d) & for major rotamer 173.3, PD Any Yes or No PD 169.1, 140.9, 116.4, 58.3, 48.7, 28.9, 24.7, 19.5: for minor Any PD Yes or No PD rotamer 174.0, 170.0, 141.6, 115.2, 60.3, 45.9, 31.0, 22.3, Any Any Yes PD 19.7: IR (KBr) 3437 (OH), 1737 (C–O), 1647 (CO, NE Non-PD No NE COOH), 1584, 1508, 1459, 1369, 1348, 1178 cm; c. Non-PD Non-PD NE NE 15 +80.8° (c=1, MeOH); Anal. Calcd. for CHNO: C, 59.00: H, 7.15; N, 7.65. Found: C, 59.13; H, 7.19; N, 7.61.

TABLE C2 Summary of Definitions of Response for Patients with Non-Measurable (Non-Target) Disease only at Baseline s' O Response of Combined Lesion Types N H NBSDMF N RT Non-Target Lesions New Lesions Combined Response O O O v CR No CR Br Non-CR non-PD No Non-CR non-PD 25 H3C NE No NE PD Yes or No PD Any Yes PD (3R,8aR)-3-Bromomethyl-3-methyl-tetrahydro-pyrrolo 2.1-c. 14 oxazine-1,4-dione. A solution of NBS (23.5 g. 0.132 mol) in 100 mL of DMF was added dropwise to a 30 stirred solution of the (methyl-acryloyl)-pyrrolidine (16.1 g, EXAMPLE 10 88 mmol) in 70 mL of DMF under argon at room tempera ture, and the resulting mixture was stirred 3 days. The Synthesis of (S) Enantiomer of Formula VIII Solvent was removed in vacuo, and a yellow solid was precipitated. The Solid was suspended in water, stirred 35 overnight at room temperature, filtered, and dried to give 18.6 g (81%) (smaller weight when dried -34%) of the title C compound as a yellow solid: mp 152-154°C.; H NMR (300 -- CO2H 2NNaOHacetone MHz, DMSO-d) & 4.69 (dd, J=9.6 Hz, J=6.7 Hz, 1H, CH at O H O-5° C.RT 3 hrs N 40 the chiral center), 4.02 (d. J=11.4 Hz, 1H, CHH), 3.86 (d. H 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); C NMR (75 MHz, DMSO-d) & 167.3, 163.1, 83.9, N H 57.2, 45.4, 37.8, 29.0, 22.9, 21.6; IR (KBr) 3474, 1745 (C=O), 1687 (C=O), 1448, 1377, 1360, 1308, 1227, 1159, 45 1062 cm; C+124.5° (c=1.3, chloroform); Anal. Calcd. for CHBrNO: C, 41.24; H, 4.61; N, 5.34. Found: C, 41.46; H, 4.64; N, 5.32.

(2R)-1-Methacryloylpyrrolidin-2-carboxylic Aci. D-Pro 50 line, 14.93 g, 0.13 mol) was dissolved in 71 mL of 2 N H NaOH and cooled in an ice bath; the resulting alkaline O N 24% HBir HO solution was diluted with acetone (71 mL). An acetone He solution (71 mL) of methacryloyl chloride (13.56 g., 0.13 O Reflux HC OH mol) and 2 N NaOH solution (71 mL) were simultaneously 55 O v added over 40 minto the aqueous solution of D-proline in Br (R)-3-bromo-2-hydroxy-2- an ice bath. The pH of the mixture was kept at 10-11° C. HC methylpropanoic acid during the addition of the methacryloyl chloride. After stirring (3h, room temperature), the mixture was evaporated (2R)-3-Bromo-2-hydroxy-2-methylpropanoic Acid. A in vacuo at a temperature at 35-45° C. to remove acetone. 60 mixture of bromolactone (18.5 g. 71 mmol) in 300 mL of The resulting solution was washed with ethyl ether and was 24% HBr was heated at reflux for 1 h. The resulting solution acidified to pH 2 with concentrated HC1. The acidic mixture was diluted with brine (200 mL), and was extracted with was saturated with NaCl and was extracted with EtOAc (100 ethyl acetate (100 mLx4). The combined extracts were mLX3). The combined extracts were dried over NaSO, washed with saturated NaHCO (100 mLX4). The aqueous filtered through Celite, and evaporated in vacuo to give the 65 solution was acidified with concentrated HCl to pH=1, crude product as a colorless oil. Recrystallization of the oil which, in turn, was extracted with ethyl acetate (100 mLx4). from ethyl ether and hexanes afforded 16.2 g (68%) of the The combined organic solution was dried over NaSO, US 9,622,992 B2 77 filtered through Celite, and evaporated in vacuo to dryness. -continued Recrystallization from toluene afforded 10.2 g (86%) of the CN desired compound as colorless crystals: mp 107-109° C.; H K2CO3 -e- NMR (300 MHz, DMSO-d) & 3.63 (d. J=10.1 Hz, 1H, 2-propanol CHH), 3.52 (d. J=10.1 Hz, 1H, CHH), 1.35 (s, 3H, Me): HO IR (KBr) 3434 (OH), 3300-2500 (COOH), 1730 (C=O), NC CN 1449, 1421, 1380, 1292, 1193, 1085 cm; C+10.5° O (c=2.6, MeOH); Anal. Calcd. for CHBrO: C, 26.25; H, 3.86. Found: C, 26.28; H, 3.75. C NH O 10 Hd OH Synthesis of (S) N-(3-chloro-4-cyanophenyl)-3-(4-cya SOCI THF/O-5°C. nophenoxy)-2-hydroxy-2-methylpropanamide. A mixture of bromoamine (2.0 g. 6.3 mmol), anhydrous KCO (2.6 g. 15 18.9 mmol) in 50 mL of acetone was heated to reflux for 2 (R)-3-bromo-2-hydroxy-2- h and then concentrated under reduced pressure to give a methylpropanoic acid solid. The resulting solid was treated with 4-cyanophenol R-18 (1.1 g, 9.5 mmol) and anhydrous KCO (1.7g, 12.6 mmol) O in 50 mL of 2-propanol was heated to reflux for 3 hand then concentrated under reduced pressure to give a solid. The C Br residue was treated with 100 mL of HO and then extracted with EtOAc (2x100 mL). The combined EtOAc extracts Hd OH were washed with 10% NaOH (4x100 mL) and brine, NC Successively. The organic layer was dried over MgSO and EtN/RT 25 -- -e- then concentrated under reduced pressure to give an oil which was purified by column chromatography using C NH2 EtOAc/hexane (50:50) to give a solid. The solid was recrys NC tallized from CHC1/hexane to give 1.4 g (61.6%) of O (S)-N-(3-chloro-4-cyanophenyl)-3-(4-cyanophenoxy)-2- 30 hydroxy-2-methylpropanamide as a colorless Solid. C NH s Br H NMR (CDC1/TMS) & 1.61 (s, 3H, CH), 3.25 (s, Hd oH 1H-OH), 4.06 (d. J=9.15 Hz, 1H, CH), 4.50 (d. J=9.15 Hz, 1H, CH), 6.97-6.99 (m, 2H, ArH), 7.53-7.59 (m, 4H, ArH), 35 7.97 (d. J–2.01 Hz, 1H, ArH), 8.96 (s, 1H, NH). Calculated Synthesis of (2R)-3-bromo-N-(3-chloro-4-cyanophenyl)- Mass: 355.1, M+Na378.0. Mp: 103-105° C. 2-hydroxy-2-methylpropanamide. Thionyl chloride (7.8 g. 65.5 mmol) was added dropwise to a cooled solution (less EXAMPLE 11 than 4° C.) of (R)-3-bromo-2-hydroxy-2-methylpropanoic acid (9.0 g, 49.2 mol) in 50 mL of THF under an argon Synthesis of (S) Enantiomer of Formula IX atmosphere. The resulting mixture was stirred for 3 hunder 40 the same condition. To this was added EtN (6.6 g. 65.5 mol) and stirred for 20 min under the same condition. After 20 min, 4-amino-2-chlorobenzonitrile (5.0 g, 32.8 mmol) and 100 mL of THF were added and then the mixture was allowed to stir overnight at room temperature. The solvent 45 SOCI THF/O-5°C. was removed under reduced pressure to give a solid which was treated with 100 mL of H2O, extracted with EtOAc HC (2x150 mL). The combined organic extracts were washed (R)-3-bromo-2-hydroxy-2- methylpropanoic acid with saturated NaHCO, solution (2x100 mL) and brine (300 50 mL). Successively. The organic layer was dried over MgSO and concentrated under reduced pressure to give a solid which was purified from column chromatography using C Br EtOAc/hexane (50:50) to give 7.7 g (49.4%) of target Hd OH compound as a brown solid. 55 "H NMR (CDC1/TMS) & 1.7 (s, 3H, CH), 3.0 (s, 1H, FC NH2 OH), 3.7 (d. 1H, CH), 4.0 (d. 1H, CH), 7.5 (d. 1H, ArH), 7.7 EtN/RT (d. 1H, ArH), 8.0 (s, 1H, ArH), 8.8 (s, 1H, NH). MS: 342.1 -- His (M+23). Mp 129° C. NC NC 60 NC

FC C 65 Synthesis of (2R)-3-Bromo-N-4-cyano-3-(trifluorom ethyl)phenyl-2-hydroxy-2-methylpropanamide. Thionyl US 9,622,992 B2 79 80 chloride (46.02 g, 0.39 mol) was added dropwise to a cooled concentrated under reduced pressure to give an oil. This oil solution (less than 4° C.) of (R)-3-bromo-2-hydroxy-2- was purified by column chromatography using CH-Cl/ methylpropanoic acid (51.13 g, 0.28 mol) in 300 mL of THF EtOAc (80:20) to give an oil which was crystallized from under an argon atmosphere. (R)-3-bromo-2-hydroxy-2- CHC1/hexane to give 33.2 g (59.9%) of (S)-N-(4-cyano 3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy methylpropanoic acid was prepared as described in Example 2-methylpropanamide as a colorless Solid (a cotton type). 10. The resulting mixture was stirred for 3 hunder the same H NMR (CDC1/TMS) & 1.63 (s, 3H, CH), 3.35 (s, condition. To this was added EtN (39.14 g. 0.39 mol) and 1H-OH), 4.07 (d. J=9.04 Hz, 1H, CH), 4.51 (d. J=9.04 Hz, stirred for 20 min under the same condition. After 20 min, 1H, CH), 6.97-6.99 (m, 2H, ArH), 7.57-7.60 (m, 2H, ArH), 5-amino-2-cyanobenzotrifluoride (40.0 g, 0.21 mol), 400 7.81 (d. J=8.55 Hz, 1H, ArH), 7.97 (dd, J=1.95, 8.55 Hz, 1H, mL of THF were added and then the mixture was allowed to 10 ArH), 8.12 (d. J=1.95 Hz, 1H, ArH), 9.13 (bs, 1H, NH). stir overnight at room temperature. The solvent was Calculated Mass: 389.10, M-H 388.1. Mp: 92-94° C. removed under reduced pressure to give a solid which was treated with 300 mL of HO, extracted with EtOAc (2x400 EXAMPLE 12 mL). The combined organic extracts were washed with saturated NaHCO solution (2x300 mL) and brine (300 mL). 15 Synthesis of (R) Enantiomer of Formula IX The organic layer was dried over MgSO and concentrated under reduced pressure to give a solid which was purified from column chromatography using CH.Cl/EtOAc (80:20) to give a solid. This solid was recrystallized from CHCl/ hexane to give 55.8 g (73.9%) of (2R)-3-bromo-N-4-cyano 1. SOCl, O C. to 4°C./3 hrs 3-(trifluoromethyl)phenyl-2-hydroxy-2-methylpropana -e- mide as a light-yellow solid. "H NMR (CDC1/TMS) & 1.66 (s.3H, CH), 3.11 (s, 1H, 2. EtN, NC NH2 OH), 3.63 (d. J=10.8 Hz, 1H, CH,), 4.05 (d. J=10.8 Hz, 1H, 25 CH), 7.85 (d. J=8.4 Hz, 1H, ArH), 7.99 (dd, J=2.1, 8.4 Hz, FC 1H, ArH), 8.12 (d. J=2.1 Hz, 1H, ArH), 9.04 (bs, 1H, NH). NC

Calculated Mass: 349.99, M-H 349.0. M.p.: 124-126° C.

FC N Br NC 30 H CH,

FC Synthesis of (2S)-3-bromo-N-4-cyano-3-(trifluorom ethyl)phenyl-2-hydroxy-2-methylpropanamide (precursor 35 (2R)-3-bromo-N-4-cyano-3- to R-enantiomer of formula IX). Thionyl chloride (46.02 g, (trifluoromethyl)phenyl]-2-hydroxy-2- 0.39 mol) was added dropwise to a cooled solution (less than methylpropanamide 4° C.) of (S)-3-bromo-2-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 hunder 40 the same condition. To this was added EtN (39.14 g. 0.39 mol) and stirred for 20 min under the same condition. After 20 min, 5-amino-2-cyanobenzotrifluoride (40.0 g, 0.21 mol), 400 mL of THF were added and then the mixture was allowed to stir overnight at room temperature. The solvent 45 was removed under reduced pressure to give a solid which was treated with 300 mL of HO, extracted with EtOAc (2x400 mL). The combined organic extracts were washed HC with saturated NaHCO, solution (2x300 mL) and brine (300 (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4- mL). The organic layer was dried over MgSO and concen cyanophenoxy)-2-hydroxy-2-methylpropanamide trated under reduced pressure to give a solid which was 50 purified from column chromatography using CH2Cl2/EtOAc Synthesis of (S)-N-(4-Cyano-3-(trifluoromethyl)phe (80:20) to give a solid. This solid was recrystallized from nyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropana EtOAc/hexane to give 55.8 g (73.9%) of target compound as mide. A mixture of bromoamine (2R)-3-bromo-N-4- a light-yellow solid. cyano-3-(trifluoromethyl)phenyl-2-hydroxy-2- 55 "H NMR (CDC1/TMS) & 1.66 (s.3H, CH,), 3.11 (s, 1H, methylpropanamide, 50 g., 0.14 mol), anhydrous KCO OH), 3.63 (d. J=10.8 Hz, 1H, CH,), 4.05 (d. J=10.8 Hz, 1H, (59.04 g. 0.43 mol), 4-cyanophenol (25.44g, 0.21 mol) in CH), 7.85 (d. J=8.4 Hz, 1H, ArH), 7.99 (dd, J=2.1, 8.4 Hz, 500 mL of 2-propanol was heated to reflux for 3 hand then 1H, ArH), 8.12 (d. J=2.1 Hz, 1H, ArH), 9.04 (bs, 1H, NH). concentrated under reduced pressure to give a solid. The Calculated Mass: 349.99, M-H 349.0. Mp: 124-126° C. resulting residue was treated with 500 mL of H2O and then 60 extracted with EtOAc (2x300 mL). The combined EtOAc extracts were washed with 10% NaOH (4x200 mL) and NC brine. The organic layer was dried over MgSO and then concentrated under reduced pressure to give an oil which Ol O was treated with 300 mL of ethanol and an activated carbon. 65 FC ar The reaction mixture was heated to reflux for 1 h and then the hot mixture was filtered through Celite. The filtrate was US 9,622,992 B2 81 82 -continued sure to give a solid which was treated with 300 mL of HO, NC extracted with EtOAc (2x400 mL). The combined organic O extracts were washed with saturated NaHCO solution O CN (2x300 mL) and brine (300 mL). The organic layer was FC N dried over MgSO and concentrated under reduced pressure H 2. to give a solid which was purified by column chromatog HO CH, raphy using CH.Cl/EtOAc (80:20) to give a solid. This Solid was recrystallized from CH2Cl2/hexane to give a target compound (55.8 g. 73.9%) as a light-yellow solid. Synthesis of (R) N-(4-cyano-3-(trifluoromethyl)phe H NMR (CDC1/TMS) & 1.66 (s, 3H, CH), 3.11 (s, 1H, nyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide 10 OH), 3.63 (d. J=10.8 Hz, 1H, CH,), 4.05 (d. J=10.8 Hz, 1H, (R-enantiomer of formula IX). A mixture of bromoamine CH), 7.85 (d. J=8.4 Hz, 1H, ArH), 7.99 (dd, J=2.1, 8.4 Hz, (50.0 g, 0.14 mol), anhydrous KCO (59.04 g., 0.43 mol), 1H, ArH), 8.12 (d. J=2.1 Hz, 1H, ArH), 9.04 (bs, 1H, NH). 4-cyanophenol (25.44g, 0.21 mol) in 500 mL of 2-propanol Calculated Mass: 349.99, M-H 349.0. Mp: 124-126° C. was heated to reflux for 3 h and then concentrated under reduced pressure to give a solid. The resulting residue was 15 treated with 500 mL of HO and then extracted with EtOAc (2x300 mL). The combined EtOAc extracts were washed with 10% NaOH (4x200 mL) and brine. The organic layer was dried over MgSO and then concentrated under reduced Br K2CO3, 2-propanol pressure to give an oil which was treated with 300 mL of Hd OH ethanol and an activated carbon. The reaction mixture was NC heated to reflux for 1 h and then the hot mixture was filtered O through Celite. The filtrate was concentrated under reduced O F FC N pressure to give an oil. This oil was purified by column H chromatography using hexane/EtOAc (20:80) to give an oil 25 which was crystallized from EtOAc/hexane to give 33.2g HC OH (59.9%) of (R) N-(4-cyano-3-(trifluoromethyl)phenyl)-3- (4-cyanophenoxy)-2-hydroxy-2-methylpropanamide Synthesis of (S)-N-(4-cyano-3-(trifluoromethyl)phe (R-isomer of formula IX) as a colorless solid. nyl)-3-(4-fluorophenoxy)-2-hydroxy-2-methylpropanamide "H NMR (CDC1/TMS) & 1.63 (s, 3H, CH), 3.44 (s, 30 (Formula X). A mixture of bromoamine (10.0g, 28.5 mmol), anhydrous KCO (11.8 g. 85.4 mmol) in 150 mL of acetone 1H-OH), 4.07 (d. J=9.16 Hz, 1H, CH), 4.51 (d. J=9.16 Hz, was heated to reflux for 1 h and then concentrated under 1H, CH), 6.97-6.99 (m. 2H, ArH), 7.57-7.59 (m, 2H, ArH), reduced pressure to give a solid. The resulting residue was 7.81 (d. J=8.54 Hz, 1H, ArH), 7.97 (dd, J=2.07, 8.54 Hz, 1H, treated with 4-fluorophenol (4.8 g. 42.7 mmol), anhydrous ArH), 8.12 (d. J=2.07 Hz, 1H, ArH), 9.15 (bs, 1H, NH). KCO (7.9 g, 57.0 mmol), 150 mL of 2-propanol and then Calculated Mass: 389.10, M-H 388.1. Mp: 92-94° C. 35 heated to reflux for 2 h. The resulting mixture was concen trated under reduced pressure to give a solid. This solid was EXAMPLE 13 treated with 300 mL of HO and extracted with EtOAc (2x250 mL). The combined EtOAc extracts were washed Synthesis of (S) Enantiomer of Formula X with a saturated NaHCO solution (2x250 mL) and brine. The organic layer was dried over MgSO and then concen 40 trated under reduced pressure to give an oil which was

purified by column chromatography using CH.Cl/EtOAC (80:20) to give a solid. This solid was recrystallized from CHCl2/hexane to give (S) N-(4-cyano-3-(trifluorom 1. SOCl, O C. to 4°C./3 hrs ethyl)phenyl)-3-(4-fluorophenoxy)-2-hydroxy-2-methyl 45 propanamide (Formula X, 10.04 g. 92.2%) as a colorless 2. EtN, NC solid. H NMR (CDC1/TMS) & 1.59 (s.3H, CH), 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), NC 50 7.81 (d. J=8.45 Hz, 1H, ArH), 7.94-7.98 (m, 1H, ArH), 8.10 (d. J–1.79 HZ, 1H, ArH), 9.11 (s, 1H, NH). Calculated Mass: 382.31, M-H 380.9. Mp: 139-141° C. N Br Hd OH EXAMPLE 1.4 55 Synthesis of (S) Enantiomer of Formula XIII Synthesis of (2R)-3-bromo-N-4-cyano-3-(trifluorom ethyl)phenyl-2-hydroxy-2-methylpropanamide. Thionyl

chloride (46.02 g, 0.39 mol) was added dropwise to a cooled solution (less than 4° C.) of (R)-3-bromo-2-hydroxy-2- methylpropanoic acid (51.13 g, 0.28 mol) in 300 mL of THF 60 under an argon atmosphere. The resulting mixture was SOCI THF/O-5°C. stirred for 3 hunder the same condition. To this was added EtN (39.14 g., 0.39 mol) and stirred for 20 min under the same condition. After 20 min, 5-amino-2-cyanobenzotrif (R)-3-bromo-2-hydroxy-2- luoride (40.0 g, 0.21 mol), 400 mL of THF were added and 65 methylpropanoic acid then the mixture was allowed to stir overnight at room R-18 temperature. The solvent was removed under reduced pres US 9,622,992 B2 84 -continued panamide (Formula XIII). A mixture of bromoamide (2R)- O 3-bromo-N-4-cyano-3-(trifluoromethyl)phenyl-2- hydroxy-2-methylpropanamide, R-19 (2.0 g, 5.70 mmol), C Br anhydrous KCO (2.4g, 17.1 mmol) in 50 mL of acetone was heated to reflux for 2 h and then concentrated under

Hd oH reduced pressure to give a solid. The resulting Solid was FC NH2 treated with 2-fluoro-4-hydroxybenzonitrile (1.2 g, 8.5 EtN/RT mmol) and anhydrous KCO (1.6 g., 11.4 mmol) in 50 mL -- -- of 2-propanol was heated to reflux for 3 hand then concen 10 NC trated under reduced pressure to give a solid. The residue NC was treated with 100 mL of HO and then extracted with O EtOAc (2x100 mL). The combined EtOAc extracts were washed with 10% NaOH (4x100 mL) and brine, succes sively. The organic layer was dried over MgSO and then FC N Br H 2. 15 concentrated under reduced pressure to give an oil which H3C OH was crystallized from CHC1/hexane to give 0.5 g (23%) of R-19 (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyano-3- fluorophenoxy)-2-hydroxy-2-methylpropanamide as a col Synthesis of (2R)-3-Bromo-N-4-cyano-3-(trifluorom orless solid. ethyl)phenyl-2-hydroxy-2-methylpropanamide. Thionyl H NMR (CDC1/TMS) & 1.63 (s, 3H, CH), 3.34 (bs, chloride (46.02 g, 0.39 mol) was added dropwise to a cooled 1H-OH), 4.08 (d. J=9.17 Hz, 1H, CH), 4.50 (d. J=9.17 Hz, solution (less than 4°C.) of R-18 (51.13 g, 0.28 mol) in 300 1H, CH), 6.74-6.82 (m, 2H, ArH), 7.50-7.55 (m, 1H, ArH), mL of THF under an argon atmosphere. R-18 is (R)-3- 7.81 (d. J=8.50 Hz, 1H, ArH), 7.97 (q, J=2.03, 8.50 Hz, 1H, bromo-2-hydroxy-2-methylpropanoic acid was prepared as ArH), 8.11 (d. J=2.03 Hz, 1H, ArH), 9.12 (s, 1H, NH). described in Example 10. The resulting mixture was stirred 25 Calculated Mass: 407.1, M+Na"430.0. Mp: 124-125° C. for 3 hunder the same condition. To this was added EtsN (39.14 g. 0.39 mol) and stirred for 20 min under the same EXAMPLE 1.5 condition. After 20 min, 5-amino-2-cyanobenzotrifluoride (40.0g, 0.21 mol), 400 mL of THF were added and then the Synthesis of (S) Enantiomer of Formula XIV mixture was allowed to stir overnight at room temperature. 30 The solvent was removed under reduced pressure to give a solid which was treated with 300 mL of HO, extracted with EtOAc (2x400 mL). The combined organic extracts were washed with saturated NaHCO solution (2x300 mL) and SOCI THF/O-5°C. brine (300 mL). The organic layer was dried over MgSO 35 and concentrated under reduced pressure to give a solid HC which was purified from column chromatography using (R)-3-bromo-2-hydroxy-2- CHCl/EtOAc (80:20) to give a solid. This solid was methylpropanoic acid R-18 recrystallized from CHC1/hexane to give 55.8 g (73.9%) of 40 (2R)-3-bromo-N-4-cyano-3-(trifluoromethyl)phenyl-2- hydroxy-2-methylpropanamide (R-19) as a light-yellow solid. C Br "H NMR (CDC1/TMS) & 1.66 (s.3H, CH), 3.11 (s, 1H, Hd OH OH), 3.63 (d. J=10.8 Hz, 1H, CH,), 4.05 (d. J=10.8 Hz, 1H, 45 CH), 7.85 (d. J=8.4 Hz, 1H, ArH), 7.99 (dd, J=2.1, 8.4 Hz, FC NH2 1H, ArH), 8.12 (d. J=2.1 Hz, 1H, ArH), 9.04 (bs, 1H, NH). EtN/RT Calculated Mass: 349.99, M-H 349.0. M.p.: 124-126° C. -- -e- NC NC

50 NC O -- FC FC N Br H e HC OH R-19 55 CN R-19 K2CO3 He 2-propanol Synthesis of (2R)-3-Bromo-N-4-cyano-3-(trifluorom HO F ethyl)phenyl-2-hydroxy-2-methylpropanamide. Thionyl NC CN 60 chloride (46.02 g, 0.39 mol) was added dropwise to a cooled O solution (less than 4°C.) of R-18 (51.13 g, 0.28 mol) in 300 mL of THF under an argon atmosphere. R-18 is (R)-3- FC NH a O F bromo-2-hydroxy-2-methylpropanoic acid was prepared as Hd oH described in Example 10. The resulting mixture was stirred 65 for 3 hunder the same condition. To this was added EtN Synthesis of (S) N-(4-cyano-3-(trifluoromethyl)phe (39.14 g., 0.39 mol) and stirred for 20 min under the same nyl)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methylpro condition. After 20 min, 5-amino-2-cyanobenzotrifluoride US 9,622,992 B2 85 86 (40.0g, 0.21 mol), 400 mL of THF were added and then the EXAMPLE 16 mixture was allowed to stir overnight at room temperature. The solvent was removed under reduced pressure to give a Binding and Transactivation of SARMs in Breast solid which was treated with 300 mL of HO, extracted with Cancer Cells EtOAc (2x400 mL). The combined organic extracts were 5 washed with saturated NaHCO solution (2x300 mL) and In order to determine whether compounds of this inven brine (300 mL). The organic layer was dried over MgSO tion are agonists in breast cancer cells, HEK-293 or MDA and concentrated under reduced pressure to give a solid, MB-231 cells were transfected with 0.25 ug GRE-LUC, 10 which was purified from column chromatography using ng CMV-renilla LUC, and 25 ng CMV-haR using lipo CHCl/EtOAc (80:20) to give a solid. This solid was 10 fectamine. Twenty four hours after transfection, the cells recrystallized from CHC1/hexane to give 55.8 g (73.9%) of were treated with DHT, compound of formula VIII and (2R)-3-bromo-N-4-cyano-3-(trifluoromethyl)phenyl-2- compound of formula IX and luciferase assay performed 48 hydroxy-2-methylpropanamide (R-19) as a light-yellow hrs after transfection. Competitive binding of DHT, com solid. pound of formula VIII and compound of formula IX were 15 measured using an in vitro competitive radioligand binding "H NMR (CDC1/TMS) & 1.66 (s.3H, CH), 3.11 (s, 1H, assay with 17O-methyl-3H- (3HMIB), a OH), 3.63 (d. J=10.8 Hz, 1H, CH,), 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, known steroidal and high affinity AR ligand, and purified 1H, ArH), 8.12 (d. J=2.1 Hz, 1H, ArH), 9.04 (bs, 1H, NH). AR-LBD protein. Calculated Mass: 349.99, M-H 349.0. M.p.: 124-126° C. 2O Results

NC DHT, compound of formula VIII and formula IX are agonists of AR in breast cancer cells as presented in FIG. 13 (HEK-293 cells in FIG. 13A and MDA-MB-231 cells in -- 25 FIGS. 13B-13C). The relative binding affinities (RBAs) for FC NH Br AR of DHT, formula IX, formula VIII, and bicalutamide were 1.0, 0.330, 0.314, and 0.016, respectively, demonstrat R-19 ing high affinity AR binding for the SARM compounds of C this invention (data not shown). K2CO3 30 Her 2-propanol EXAMPLE 17 HO F NC C Inhibition of Intratumoral Gene Expression O 35 AR agonists differentially regulate genes in AR-positive

FC NH s O F and AR-negative breast cancer cells. MDA-MB-231 and MCF-7 cells infected with AR or GFP containing adenovirus Hd OH were maintained in charcoal stripped serum containing medium for 3 days and were treated with DHT or Compound Synthesis of (S)-3-(4-chloro-3-fluorophenoxy)-N-(4- 40 VIII. After overnight treatment, the cells were harvested, cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpro RNA isolated and real-time PCR for the indicated genes panamide (Formula XIV). A mixture of bromoamide (2R)- were performed. The expression of various genes in 3-bromo-N-4-cyano-3-(trifluoromethyl)phenyl-2- response to either DHT or Compound VIII were measured and normalized to GAPDH, and are presented as composite hydroxy-2-methylpropanamide, (R-19) 2.0 g, 5.70 mmol), data (same effects for DHT and Compound VIII) in Table 2. anhydrous KCO (2.4 g 17.1 mmol) was heated to reflux 45 for 2 hand then concentrated under reduced pressure to give a solid. The resulting solid was treated with 4-chloro-3- TABLE 2 fluorophenol (1.3 g 8.5 mmol) and anhydrous KCO (1.6 Differential Regulation of Gene Expression by AR Ligands in ER g, 11.4 mmol) in 50 mL of 2-propanol was heated to reflux Positive (MCF7) and ER-Negative (MDA-MB-231) Breast Cancers for 3 hand then concentrated under reduced pressure to give 50 a solid. The residue was treated with 100 mL of HO and AR PSA Muc1 SLUG VCAM1 SPARC MMP2 then extracted with EtOAc (2x100 mL). The combined MDA-MB 231 (GFP EtOAc extracts were washed with 10% NaOH (4x100 mL) MDA-MB and brine, successively. The organic layer was dried over 231 AR MgSO and then concentrated under reduced pressure to 55 MDA-MB give an oil which was purified by column chromatography 231 AR using EtOAc/hexane (50:50) to give a solid which was cS FBS MCF7 (GFP O O recrystallized from CHCl/hexane to give 1.7 g (70.5%) of MCF7 AR O O (S)-3-(4-chloro-3-fluorophenoxy)-N-(4-cyano-3-(trifluo MCF7 AR O O romethyl)phenyl)-2-hydroxy-2-methylpropanamide as a 60 cS FBS colorless solid. WCAM1—Vascular cell adhesion protein-1-Important for anchorage-dependent growth "H NMR (CDC1/TMS) & 1.60 (s.3H, CH), 3.28 (s, 1H, of cells and also is a chemoattractant, SPARC-Secreted protein acidic and rich in cysteine (aka Osteonectin)—extracellular OH), 3.98 (d. J=9.05 Hz, 1H, CH), 6.64-6.76 (m, 2H, ArH), glycoprotein important for angiogenesis, MUC1—Mucin1—Extracellular glycoprotein associated with cancers—Its promoter has a 7.30 (d. J=8.67 Hz, 1H, ArH), 7.81 (d. J=8.52 Hz, 1H, ArH), strong ARE. 7.96 (q, J=2.07, 8.52 Hz, 1H, ArH), 8.10 (d. J=2.07 Hz, 1H, 65 SLUG- finger transcription factor—Its promoter has a strong ARE, ArH), 9.10 (s, 1H, NH). Calculated Mass: M-H 414.9. MMP2-matrix metalloproteinase-2–gene that is activated by cell-cell clustering, Mp: 132-134° C. US 9,622,992 B2 87 88 EXAMPLE 1.8 incubated with phospho MAPK array to determine the effect of compound of formula VIII on phosphorylation of various Gene Expression Array of MDA-MB-231-AR kinases. Xenograft Results RNA was extracted from MDA-MB-231-AR tumors (n=5/group) treated with vehicle or compound of formula VIII. RNA was pooled and Affymetrix microarray was The results presented in FIG. 21 show that JNK phos performed to determine the change in expression of gene phorylation is upregulated in MCF-7-AR tumors by treat 10 ment with compound VIII. JNK plays a critical role in death signature. receptor-mediated intrinsic and extrinsic apoptotic path ways. JNK activates apoptotic signaling by up-regulating Results pro-apoptotic genes. The observed phosphorylation of the pro-apoptotic kinase, JNK, may be suggestive of a possible The results presented in FIG. 15 show that activation of mechanistic explanation of the anti-proliferation. AR in MDA-MB-231-AR xenografts suppressed the expres 15 sion of more genes than it induced in these tumors. This pattern is unique in breast cancer cells and is different from EXAMPLE 21 gene expression results observed in prostate cancer cells, where more genes are induced than repressed (data not Gene Expression Analysis of MDA-M-231-AR and shown). MCF-7-AR Xenografts Following Treatment with The results presented in FIG. 16 validate the micro-array Compound VIII and Compound IX results presented in FIG. 15 by analyzing selected genes using realtime PCR TaqMan primers and probe in ABI 7900. Microarray Analysis was performed on RNA from MDA 25 MB-231-AR and MCF-7-AR tumors in order to identify and EXAMPLE 19 compare changes in gene expression in ER-negative (MDA MB-231-AR: triple negative) an ER-positive (MCF-7-AR; Compound VIII Inhibits the Growth of MCF-7-AR triple positive) breast cancer tumors treated with a com Xenograft pound of formula VIII (30 mg/kg/day p.o. for 4 weeks). 30 Affymetrix analysis of the Xenografts was done on pooled MCF-7 cells stably transfected with AR using lentivirus samples of the xenografts. The analysis included ~70,000 were implanted (2 million cells/mouse, n=5) in nude mice sequences with ~30,000 genes and variations thereof repre that were ovariectomized and supplemented with estradiol sented, as well as microRNAs. RNA was isolated and (50 ug/day). Once tumors reached 100-200 mm, the ani expression of genes was evaluated using microarray (Alf mals were randomized and treated with vehicle or 30 mg/kg 35 fymetrix Human Gene ST 2.0 array). Expression of genes in per day of compound VIII. Tumor volumes and body compound VIII-treated samples was compared with the weights were measured thrice weekly. At the end of 5 weeks expression in vehicle-treated Samples. Genes that were up of treatment, the animals were sacrificed, tumors weighed or down-regulated by more than 2 fold were considered and stored for RNA and protein isolation and histology. * differentially regulated by compound VIII. significance at PK0.05. 40 In addition, uterus weights were measured in these Xeno Results graft studies, and Western blot from MCF-7 tumor xeno grafts were probed for AR. Table 3 below presents the sum totals of up-regulated and 45 down-regulated genes in MDA-MB-231-AR and MCF-7- Results AR tumors.

The graph presented in FIG. 17 demonstrates inhibition of TABLE 3 Triple-Positive Breast Cancer (ER, PR, and HER2) using Compound VIII. The results show that compound VIII 50 Type Up Down Total inhibited the growth of MCF-7 breast cancer cell xenografts MCF-7-AR 566 981 1547 by greater than 50%. MDA-ME-231-AR 720 816 1536 The results presented in FIG. 18 show compound VIII inhibited uterus weight in these estrogen Supplemented animals. 55 Of particular interest was that of the 1547 regulated genes The results presented in FIG. 19 demonstrate that the AR identified in MCF-7-AR tumors and the 1536 regulated expression pattern in response to agonist (compound VIII) is genes identified in MDA-MB-231-AR tumors, the subset of similar to that observed in prostate cancer cells (data not overlapping genes was only 245 genes. This result indicated shown). that compound VIII regulated distinct sets of genes in 60 MCF-7-AR (ER-positive; triple positive) and MDA-MB EXAMPLE 20 231-AR (ER-negative; triple negative) breast cancer cells. Tables 4 and 5 below presents genes involved in mam Compound VIII Up-Regulates JNK mary tumorigenesis that were differentially regulated (by at Phosphorylation in MCF7-ARTumors least 2 fold) by compound VIII in MDA-MB-231-AR 65 tumors (Table 4) and MCF-7-AR tumors (Table 5). Indica Protein from MCF-7-AR tumors that were treated with tions of up-regulation or down-regulation are presented in vehicle or compound of formula VIII were extracted and the right-most column US 9,622,992 B2 89 90 TABLE 4 (note: plot is log of fold change; follow-up RT-PCR dem onstrated 10-20-fold changes). Well known androgen-de Breast cancer relevant genes modulated pendent genes (e.g. FKP5 and MUC 1: See Table 6 below) in MDA-MB-231-AR tumors were elevated, showing SARM penetration into the tumor. Also 29/36 known breast cancer-related genes were shown Compound to be decreased, Supporting a rational basis for the anti Gene Function VIII proliferation activity of compound VIII in ER-negative NQO1 Anti-proliferative, reduces oxidative increased breast cancer. stress of cells, regulates p53-dependent apoptosis Further analysis of the results in MDA-MB-231-AR B- increases proliferation and metastasis Decrease 10 tumors showed that compound VIII induced known andro Adrenoceptor2 of breast cancer, increases inflammation gen-responsive genes (Table 6 below). Thus, breast cancer Aurora increase proliferation of breast cancer Decrease relevant genes such as beta2-adrenergic receptor and PARP1 kinase and aurora kinase inhibitors are effec were suppressed by compound VIII; whereas ARE-depen ive preclinically BUB1 expression correlates with tumor status, Decrease dent genes were induced by treatment of compound VIIII. ST kinase node- and distant-metastasis, and histo ogical grade in BC 15 TABLE 6 CENPE Promotes breast cancer growth, Small Decrease molecule inhibitors of CENPE inhibit Gene Fold Function BC cell growth EHMT2 Up-regulated in variety of cancers, Decrease TFP2 4.76 Tumor suppressor, protease inhibitor family including breast F3 6.94 Coagulation factor ERCC1 Expressed in 70% TNBCs and its expres- Decrease Carboxipeptidase 3.25 Androgen responsive gene Sion leads to resistance to chemotherapy SNAI2, SLUG 2.10 Androgen responsive gene IGFBP3 increases proliferative disease, higher Decrease ASAM 3.27 GFBP3 in serum correlates with higher DUSP1 4.14 Inactivates MAPK, androgen responsive grade disease gene ITGA2 Cancer development and metastasis Decrease Col12a1 5.93 PARP1 PARP inhibitors are currently under Decrease 25 Amphiregulin 4.47 Regulated by androgens and estrogens development for breast cancer Protein S 3.69 Regulated by estrogen (down) and POLD1 Associated with multiple cancers, Decrease progestin (up) including breast cancer PDLIM1 2.06 PR regulated gene PTPRT Tumor Suppressor increased FBXO32 6.62 Very interesting gene. Androgens inhibit SERPINE1 Tumor Suppressor and inhibitor of angio- Increased in muscle, Promotes muscle atrophy, genesis, invasion and metastasis 30 ubiquitin, Mixed functions in cancer RASD1 18.62 GC-stimulated gene, Down-regulated in GC-resistant melanoma RS2 4.40 FKBP51 o Androgen and GC stimulated gene TABLE 5 MUC1 9 Androgen and estrogen stimulated gene DUSP23 7.35 Androgen stimulated Breast cancer relevant genes modulated in MCF-7-AR tumors 35 PTGS2 14 Androgen stimulated Compound RHOB 7.92 Androgen regulated Gene Function VIII MTR increases breast cancer risk Decreased The results presented in Tables 3 and 5 show that com FACGD2 inhibition increases the sensitivity Decreased pound VIII did not have as strong of a gene Suppressive tone o cancer therapeutics 40 in MCF-7-AR triple positive (ER-positive) tumors as in TIMP3 Silenced in several aggressive cancers increased due to promoter methylation triple negative (ER-negative) tumors. Interestingly though, XRCC1 High XRCC1 leads to poor Survival of Decreased the MCF-7-AR analysis showed that androgen-dependent cancer patients genes were up regulated and estrogen-dependent genes were AHR increases sensitivity to anti-cancer increased suppressed (Table 7 below), as validated by RT-PCR. agents, good prognostic marker, 45 agonists are used for cancers Catalase nversely correlates with breast cancer increased TABLE 7 risk, good marker, prevents DNA damage CDT1 Promotes replication, increases cancer Decreased Androgen Target Estrogen Target incidence ER-O. Promotes breast cancer proliferation Decreased 50 KLK3 (PSA) PR EHMT1 Tumor Suppressor complex protein increased SNAI2 ER ERCC2 Promotes breast cancer and other cancers Decreased MUC1 IGFBP4 hrough DNA damage IRS2 pS2 IRS1 Highly expressed in breast cancer, over- Decreased FKBP5 DUSP23 expression in mice increases breast miR21 cancer incidence 55 KLK3 KLK3 (PSA) increase is highly correlative Increased of positive breast cancer outcome; good prognostic marker The results presented in FIG. 20 validate the micro-array PR increases proliferation of breast cancer Decreased results presented in the above analyses, by analyzing PON2 Anti-oxidative properties; cells over- increased selected genes using realtime PCR TaqMan primers and expressing PON2 have reduced oxidative 60 stress; anti-cancer probe in ABI 7900. NPAS2 Tumor Suppressor gene increased The results presented in FIG.22 shows inhibition of triple negative breast cancer growth using compounds VIII and IX. Compound VIII and compound IX demonstrated -85% The results presented in Tables 3 and 4 show that SARM TGI at all doses tried (5, 10 mg per kg for compound VIII; treatment (compound VIII) caused net down-regulation of 65 5, 10, 30 mg per kg for compound IX) in the triple negative genes in MDA-MB-231-AR tumors (N=1042 suppressed; breast cancer model using MDA-MB-231-AR cells in nude N=640 induced; threshold of 2-2.5-fold increase or decrease 1CC. US 9,622,992 B2 91 92 The results presented in FIG. 23 demonstrate inhibition of triple negative breast cancer using compounds VIII and IX. XIII NC CN Tumor weights were likewise reduced for all doses of compound VIII and compound IX. Spleen enlargement (680 mg vs. 200-300 mg for normal mice) was seen only in 5 vehicle treated mice, possibly indicative of prevention by . NH O1 the SARMs of tumor metastasis to the spleen. The in vitro data shown in MCF-7 cells with and without AR (FIGS. 25A-25E) support that SARM-activated AR may sequester the co-factors that are used by ER. Adding AR to 10 or formula XIV: the MCF-7 cells increased the effect of estradiol (when unopposed) on the ER target genes PR and PS2, but the antagonism caused by SARM alone or SARM--estradiol (E2) was enhanced in this setting (FIGS. 25B and 25D) as XIV compared to GFP (i.e. no AR: FIGS. 25A and 25C). FIG. 15 25E shows that AR target genes are enhanced by SARM even in the presence of estradiol. While certain features of the invention have been illus O tF trated and described herein, many modifications, Substitu tions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifi 3. The method of claim 1, wherein said SARM compound cations and changes as fall within the true spirit of the is represented by a structure of formula II: invention. 25

What is claimed is: II

1. A method of treating, reducing, Suppressing the severity of or inhibiting AR-positive breast cancer in a subject with AR-positive breast cancer, comprising administering to said subject a selective androgen receptor modulator (SARM) 30 compound represented by a structure of formula I:

35 wherein X is O: G is O: T is OH, OR, NHCOCH or NHCOR; Z is NO, CN, COR, COOH or CONHR: 40 Y is I, CF, Br, Cl, or Sn(R): Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, X is O: NHCOR, NHCONHR, NHCOOR, OCONHR, G is O: CONHR, NHCSCH, NHCSCF, NHCSR, T is OH, OR, NHCOCH, or NHCOR: 45 NHSOCH, NHSOR, OR, COR, OCOR, OSOR, R is alkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, SOR or SR; CFCF, aryl, alkenyl or OH: R is a C-C alkyl, aryl, alkenyl, or hydroxyl; and R is CH, CHF, CHF, CF, CHCH, or CFCF: R is CH, CF, CHCH, or CFCF. R is H, F, Cl, Br, I, CH, CF, OH, CN, NO, NHCOCH, NHCOCF, NHCOR, alkyl, arylalkyl, OR, NH, NHR, 50 4. The method of claim 3, wherein said SARM compound N(R), or SR; is represented by a structure of formula: R is H, F, Cl, Br, I, CN, NO, COR, COOH, CONHR, CF, or Sn(R): IX Z is NO, CN, COR, COOH, or CONHR: 55 CN, Y is CF, F, Br, Cl, I, CN, or Sn(R): Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, 60 NHSOCH, NHSOR, OR, COR, OCOR, OSOR, VIII SOR or SR; n is an integer of 1-4; and m is an integer of 1-3, wherein said treating does not include preventing. 65 2. The method of claim 1, wherein said SARM compound is represented by a structure of formula XIII: US 9,622,992 B2 93 94 -continued 7. The method of claim 6, wherein said SARM compound is represented by a structure of formula XIII.

XIII NC CN

FC F

or formula XIV:

XII

XIV NC C. O 2O FC NH O F Hd OH 5. The method of claim 1, wherein said breast cancer is a breast cancer that has failed selective estrogen receptor modulator (tamoxifen, toremifene), aromatase inhibitor, 25 8. The method of claim 6, wherein said SARM compound trastuzumab, ado-trastuzumab emtansine, pertuzumab, lapa is represented by a structure of formula II: tinib, exemestane, bevacizumab, and/or fulvestrant treat mentS. II

6. A method of treating, reducing, Suppressing the severity 30 Z of or inhibiting metastatic or advanced AR-positive breast 2xa cancer in a subject with metastatic AR-positive breast cancer or advanced AR-positive breast cancer, comprising admin- SS istering to said subject a selective androgen receptor modu- Y lator (SARM) compound represented by a structure of 35 formula I: wherein X is O: G is O: T is OH, OR, NHCOCH or NHCOR; 40 Z is NO, CN, COR, COOH or CONHR: Z- Y is I, CF, Br, Cl, or Sn(R): U Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, Y NHCOR, NHCONHR, NHCOOR, OCONHR, 45 CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, s SOR or SR; is U. R is a C-C alkyl, aryl, phenyl, alkenyl, or hydroxyl; and T is OH, OR, NHCOCH, O NHCOR; R is CH, CF, CHCH O CFCF. R is alkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CFs 50 9. The method of claim 8, wherein said SARM compound CFCF, aryl, alkenyl or OH: is represented by a structure of formula: R is CH, CHF, CHF, CF, CHCH, or CFCF: R is H, F, Cl, Br, I, CH, CF, OH, CN, NO, NHCOCH,

NHCOCF, NHCOR, alkyl, arylalkyl, OR, NH, NHR, IX N(R), or SR; 55 CN, R is H, F, Cl, Br, I, CN, NO, COR, COOH, CONHR, CF, or Sn(R): Z is NO, CN, COR, COOH, or CONHR: Y is CF, F, Br, Cl, I, CN, or Sn(R): Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, 60 NHCOR, NHCONHR, NHCOOR, OCONHR, VIII CONHR, NHCSCH, NHCSCF, NHCSR, NHSOCH, NHSOR, OR, COR, OCOR, OSOR, SOR or SR; n is an integer of 1-4; and 65 m is an integer of 1-3, wherein said treating does not include preventing. US 9,622,992 B2 95 96 -continued XIII

or formula XIV:

XIV

13. The method of claim 11, wherein said SARM com 10. The method of claim 6, wherein said metastatic or pound is represented by a structure of formula II: advanced breast cancer is AR-positive ER-positive meta 25 static or advanced breast cancer. II 11. A method of treating, reducing, Suppressing the sever Z ity of, or inhibiting refractory AR-positive breast cancer in x1 G N a Subject with refractory AR-positive breast cancer, com 30 C --Q prising administering to said Subject a selective androgen Sás NH s X 21 receptor modulator (SARM) compound represented by a Y structure of formula I: R 1.

35 wherein X is O:

G is O: T is OH, OR, NHCOCH, or NHCOR;

40 Z is NO, CN, COR, COOH or CONHR: Y is I, CF, Br, Cl, or Sn(R): Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, X is O: CONHR, NHCSCH, NHCSCF, NHCSR, G is O: 45 NHSOCH, NHSOR, OR, COR, OCOR, OSOR, T is OH, OR, NHCOCH or NHCOR; SOR or SR; R is alkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, R is a C-C alkyl, aryl, phenyl, alkenyl, or hydroxyl; and CFCF, aryl, alkenyl or OH: R is CH, CHF, CHF, CF, CHCH, or CFCF: R is CH, CF, CHCH, or CFCF. R is H, F, Cl, Br, I, CH, CF, OH, CN, NO, NHCOCH, 50 14. The method of claim 13, wherein said SARM com NHCOCF, NHCOR, alkyl, arylalkyl, OR, NH, NHR, pound is represented by a structure of formula: N(R), or SR; R is H, F, Cl, Br, I, CN, NO, COR, COOH, CONHR,

IX CF, or Sn(R), 55 CN, Z is NO, CN, COR, COOH, or CONHR: Y is CF, F, Br, C1, I, CN, or Sn(R): Q is CN, alkyl, halogen, N(R), NHCOCH, NHCOCF, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH, NHCSCF, NHCSR, 60 NHSOCH, NHSOR, OR, COR, OCOR, OSOR, VIII SOR or SR; n is an integer of 1-4; and m is an integer of 1-3, wherein said treating does not include preventing. 65 12. The method of claim 11, wherein said SARM com pound is represented by a structure of formula XIII: US 9,622,992 B2 97 98 -continued 21. The method of claim 1, wherein said AR-positive breast cancer is ER-positive, PR-negative and HER2-posi tive. 22. The method of claim 1, wherein said AR-positive breast cancer is ER-positive, PR-positive and HER2-nega tive. 23. The method of claim 6, wherein said AR-positive breast cancer is ER-positive, PR-positive and HER2-nega tive. 24. The method of claim 11, wherein said AR-positive breast cancer is ER-positive, PR-positive and HER2-nega tive. 25. The method of claim 1, comprising administering a racemic mixture of said SARM compound, or an isomer, a metabolite, pharmaceutically acceptable salt, pharmaceuti XII cal product, hydrate, N-oxide, or crystal of said selective androgen receptor modulator, or any combination thereof. 26. The method of claim 25, wherein said administering comprises intravenously, intraarterially, or intramuscularly injecting to said subject said pharmaceutical product in liquid form; Subcutaneously implanting in said Subject a pellet containing said pharmaceutical product; orally admin istering to said Subject said pharmaceutical product in a 15. The method of claim 11, wherein said refractory liquid or Solid form; or topically applying to said subject said AR-positive breast cancer is AR-positive ER-positive 25 pharmaceutical product. refractory breast cancer. 27. The method of claim 26, wherein said pharmaceutical 16. The method of claim 1, wherein said AR-positive product is a pellet, a tablet, a capsule, a solution, a Suspen breast cancer is AR-positive ER-positive breast cancer. Sion, an emulsion, an elixir, a gel, a cream, a Suppository or 17. The method of claim 1, wherein said AR-positive a parenteral formulation. breast cancer is ER-negative PR-negative and HER2-nega 30 28. The method of claim 6, comprising administering a tive. racemic mixture of said SARM compound, or an isomer, a 18. The method of claim 1, wherein said AR-positive metabolite, pharmaceutically acceptable salt, pharmaceuti breast cancer is ER-negative PR-negative and HER2-posi cal product, hydrate, N-oxide, or crystal of said selective tive. androgen receptor modulator, or any combination thereof. 19. The method of claim 1, wherein said AR-positive 35 29. The method of claim 11, comprising administering a breast cancer is ER-negative PR-positive and HER2-nega racemic mixture of said SARM compound, or an isomer, a tive. metabolite, pharmaceutically acceptable salt, pharmaceuti 20. The method of claim 1, wherein said AR-positive cal product, hydrate, N-oxide, or crystal of said selective breast cancer is ER-positive, PR-positive and HER2-posi androgen receptor modulator, or any combination thereof. tive. k k k k k