WO2012145328A1

WO2012145328A1 - Dibenzylphenyl compounds and methods for their use

Info

Publication number: WO2012145328A1
Application number: PCT/US2012/033957
Authority: WO
Inventors: Raymond John ANDERSEN; Javier Garcia FERNANDEZ; Marianne Dorothy Sadar; Nasrin MAWJI; Carmen Adriana BANUELOS; Jun Wang
Original assignee: The University Of British Columbia; British Columbia Cancer Agency Branch
Priority date: 2011-04-18
Filing date: 2012-04-17
Publication date: 2012-10-26

Abstract

Compounds having a structure of Formula I: or a pharmaceutically acceptable salt thereof, wherein Z¹, Z², R¹ and R² are as defined herein are provided. Uses of such compounds for treatment of various indications, including prostate cancer as well as methods of treatment involving such compounds are also provided.

Description

DIBENZYLPHENYL COMPOUNDS AND METHODS FOR THEIR USE

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 61/476,729 filed 18 April 2011, where this provisional application is incorporated herein by reference in its entirety.

FIELD OF INVENTION

This invention relates to therapeutics, their uses and methods for the treatment of various indications, including various cancers. In particular the invention relates to therapies and methods of treatment for cancers such as prostate cancer, including all stages and androgen dependent, androgen-sensitive and castration-resistant (also referred to as hormone refractory, androgen-independent, androgen deprivation resistant, androgen ablation resistant, androgen depletion-independent, castration-recurrent, anti-androgen-recurrent) .

BACKGROUND OF THE INVENTION

Androgens mediate their effects through the androgen receptor (AR). Androgens play a role in a wide range of developmental and physiological responses and are involved in male sexual differentiation, maintenance of spermatogenesis, and male gonadotropin regulation (R. K. Ross, G. A. Coetzee, C. L. Pearce, J. K. Reichardt, P. Bretsky, L. N. Kolonel, B. E. Henderson, E. Lander, D. Altshuler & G. Daley, Eur Urol 35, 355-361 (1999); A. A. Thomson, Reproduction 121, 187-195 (2001); N. Tanji, K. Aoki & M. Yokoyama, Arch Androl 47, 1-7 (2001)). Several lines of evidence show that androgens are associated with the development of prostate carcinogenesis. Firstly, androgens induce prostatic carcinogenesis in rodent models (R. L. Noble, Cancer Res 37, 1929-1933 (1977); R. L. Noble, Oncology 34, 138-141 (1977)) and men receiving androgens in the form of anabolic steroids have a higher incidence of prostate cancer (J. T. Roberts & D. M. Essenhigh, Lancet 2, 742 (1986); J. A. Jackson, J. Waxman & A. M. Spiekerman, Arch Intern Med 149, 2365-2366 (1989); P. D. Guinan, W. Sadoughi, H. Alsheik, R. J. Ablin, D. Alrenga & I. M. Bush, Am J Surg 131, 599-600 (1976)). Secondly, prostate cancer does not develop if humans or dogs are castrated before puberty (J. D. Wilson & C. Roehrborn, J Clin Endocrinol Metab 84, 4324-4331 (1999); G. Wilding, Cancer Surv 14, 113-130 (1992)). Castration of adult males causes involution of the prostate and apoptosis of prostatic epithelium while eliciting no effect on other male external genitalia (E. M. Bruckheimer & N. Kyprianou, Cell Tissue Res 301, 153-162 (2000); J. T. Isaacs, Prostate 5, 545-557 (1984)). This dependency on androgens provides the underlying rationale for treating prostate cancer with chemical or surgical castration (androgen ablation).

Androgens also play a role in female cancers. One example is ovarian cancer where elevated levels of androgens are associated with an increased risk of developing ovarian cancer (K. J. Helzlsouer, A. J. Alberg, G. B. Gordon, C. Longcope, T. L. Bush, S. C. Hoffman & G. W. Comstock, JAMA 274, 1926-1930 (1995); R. J. Edmondson, J. M. Monaghan & B. R. Davies, Br J Cancer 86, 879-885 (2002)). The AR has been detected in a majority of ovarian cancers (H. A. Risch, J Natl Cancer Inst 90, 1774-1786 (1998); B. R. Rao & B. J. Slotman, Endocr Rev 12, 14-26 (1991); G. M. Clinton & W. Hua, Crit Rev Oncol Hematol 25, 1-9 (1997)), whereas estrogen receptor-alpha (ERa) and the progesterone receptor are detected in less than 50% of ovarian tumors.

The only effective treatment available for advanced prostate cancer is the withdrawal of androgens which are essential for the survival of prostate epithelial cells. Androgen ablation therapy causes a temporary reduction in tumor burden concomitant with a decrease in serum prostate-specific antigen (PSA). Unfortunately prostate cancer can eventually grow again in the absence of testicular androgens (castration-resistant disease) (Huber et al 1987 Scand J. Urol Nephrol. 104, 33-39). Castration-resistant prostate cancer is biochemically characterized before the onset of symptoms by a rising titre of serum PSA (Miller et al 1992 J. Urol. 147, 956-961). Once the disease becomes castration-resistant most patients succumb to their disease within two years.

The AR has distinct functional domains that include the carboxy-terminal ligand-binding domain (LBD), a DNA-binding domain (DBD) comprising two zinc finger motifs, and an N-terminus domain (NTD) that contains one or more transcriptional activation domains. Binding of androgen (ligand) to the LBD of the AR results in its activation such that the receptor can effectively bind to its specific DNA consensus site, termed the androgen response element (ARE), on the promoter and enhancer regions of "normally" androgen regulated genes, such as PSA, to initiate transcription. The AR can be activated in the absence of androgen by stimulation of the cAMP-dependent protein kinase (PKA) pathway, with interleukin-6 (IL-6) and by various growth factors (Culig et al 1994 Cancer Res. 54, 5474-5478; Nazareth et al 1996 J. Biol. Chem. 271, 19900-19907; Sadar 1999 J. Biol. Chem. 274, 7777-7783; Ueda et al 2002 A J. Biol. Chem. 211, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 211, 38087-38094). The mechanism of ligand-independent transformation of the AR has been shown to involve: 1) increased nuclear AR protein suggesting nuclear translocation; 2) increased AR/ARE complex formation; and 3) the AR-NTD (Sadar 1999 J. Biol. Chem. 21 A, 1111-11%Ί; Ueda et al 2002 A J. Biol. Chem. 211, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 211, 38087-38094). The AR may be activated in the absence of testicular androgens by alternative signal transduction pathways in castration-resistant disease, which is consistent with the finding that nuclear AR protein is present in secondary prostate cancer tumors (Kim et al 2002 Am. J. Pathol. 160, 219-226; and van der Kwast et al 1991 Inter. J. Cancer 48, 189-193).

Available inhibitors of the AR include nonsteroidal antiandrogens such as bicalutamide (Casodex™), nilutamide, flutamide, investigational drugs MDV3100 and ARN-509, and the steroidal antiandrogen, cyproterone acetate. These antiandrogens target the LBD of the AR and predominantly fail presumably due to poor affinity and mutations that lead to activation of the AR by these same antiandrogens (Taplin, M.E., Bubley, G.J., Kom Y.J., Small E.J., Uptonm M., Rajeshkumarm B., Balkm S.P., Cancer Res., 59, 2511-2515 (1999)). These antiandrogens would also have no effect on the recently discovered AR splice variants that lack the ligand-binding domain (LBD) to result in a constitutively active receptor which promotes progression of androgen- independent prostate cancer (Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ., Cancer Res 68, 5469-77, 2008; Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J, Tepper CG, Kung HJ, Brodie AM, Edwards J, Qiu Y., Cancer Res. 69, 2305-13, 2009; Hu et al 2009 Cancer Res. 69, 16-22; Sun et al 2010 J Clin Invest. 2010 120, 2715-30).

Conventional therapy has concentrated on androgen-dependent activation of the AR through its C-terminal domain. Recent studies developing antagonists to the AR have concentrated on the C-terminus and specifically: 1) the allosteric pocket and AF-2 activity (Estebanez-Perpina et al 2007, PNAS 104, 16074-16079); 2) in silico "drug repurposing" procedure for identification of nonsteroidal antagonists (Bisson et al 2007, PNAS 104, 11927 - 11932); and coactivator or corepressor interactions (Chang et al 2005, Mol Endocrinology 19, 2478-2490; Hur et al 2004, PLoS Biol 2, E274; Estebanez-Perpina et al 2005, JBC 280, 8060-8068; He et al 2004, Mol Cell 16, 425-438).

The AR-NTD is also a target for drug development (e.g. WO 2000/001813), since the NTD contains Activation-Function- 1 (AF l) which is the essential region required for AR transcriptional activity (Jenster et al 1991. Mol Endocrinol. 5, 1396- 404). The AR-NTD importantly plays a role in activation of the AR in the absence of androgens (Sadar, M.D. 1999 J. Biol. Chem. 21 A, 7777-7783; Sadar MD et al 1999 Endocr Relat Cancer. 6, 487-502; Ueda et al 2002 J. Biol. Chem. 277, 7076-7085; Ueda 2002 J. Biol. Chem. 277, 38087-38094; Blaszczyk et al 2004 Clin Cancer Res. 10, 1860-9; Dehm et al 2006 J Biol Chem. 28, 27882-93; Gregory et al 2004 J Biol Chem. 279, 7119-30). The AR-NTD is important in hormonal progression of prostate cancer as shown by application of decoy molecules (Quayle et al 2007, Proc Natl Acad Sci USA. 104,1331-1336).

While the crystal structure has been resolved for the AR C-terminus LBD, this has not been the case for the NTD due to its high flexibility and intrinisic disorder in solution (Reid et al 2002 J. Biol. Chem. 277, 20079-20086) thereby hampering virtual docking drug discovery approaches.

Recent advances in the development of compounds that modulate AR include the bis-phenol compounds disclosed in published PCT WO 2010/000066 to the British Columbia Cancer Agency Branch and The University of British Columbia. While such compounds appear promising, there remains a need in the art for additional and/or improved compounds that modulate the AR, and which provide treatment for conditions that benefit from such modulation.

BRIEF SUMMARY

The compounds described herein may be used for in vivo or in vitro research uses (i.e. non-clinical) to investigate the mechanisms of orphan and nuclear receptors (including steroid receptors such as the androgen receptor). Furthermore, these compounds may be used individually or as part of a kit for in vivo or in vitro research to investigate signal transduction pathways and/or the activation of orphan and nuclear receptors using recombinant proteins, cells maintained in culture, and/or animal models.

This invention is also based in part on the surprising discovery that the compounds described herein, may also be used to modulate AR activity either in vivo or in vitro for both research and therapeutic uses. The compounds may be used in an effective amount so that androgen receptor activity may be modulated. The AR may be mammalian. Alternatively, the androgen receptor may be human. In particular, the compounds may be used to inhibit the AR. The compounds modulatory activity may be used in either an in vivo or an in vitro model for the study of at least one of the following indications: prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, endometrial cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty (testoxicosis), spinal and bulbar muscular atrophy (SBMA, Kennedy's disease), and age-related macular degeneration. Furthermore, the compounds modulatory activity may be used for the treatment of at least one of the following indications: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration. The indication for treatment may be prostate cancer. The prostate cancer may be castration-resistant prostate cancer. The prostate cancer may be androgen-dependent prostate cancer. In other examples the indication is Kennedy's disease.

In accordance with one embodiment, there is provided a compound having a structure of Formula I:

I

or a pharmaceutically acceptable salt or tautomer thereof, wherein Z¹, Z² R¹ and R² are as defined herein.

In other embodiments, the present disclosure provides the use of a compound of Formula I, for modulating androgen receptor (AR) activity. Methods for modulating AR, as well as pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable excipient are also provided. In addition, the present disclosure provides combination therapy treatments for any of the disease states disclosed herein, for example prostate cancer or Kennedy's disease. The disclosed therapies include use of a pharmaceutical composition comprising a compound of Formula I, an additional therapeutic agent and a pharmaceutically acceptable excipient. Methods and compositions related to the same are also provided.

These and other aspects of the invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and/or compositions, and are each hereby incorporated by reference in their entirety.

DETAILED DESCRIPTION

As used herein, the phrase "C_x-C_y alkyl" is used as it is normally understood to a person of skill in the art and often refers to a chemical entity that has a carbon skeleton or main carbon chain comprising a number from x to y (with all individual integers within the range included, including integers x and y) of carbon atoms. For example a "Ci-Cio alkyl" is a chemical entity that has 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atom(s) in its carbon skeleton or main chain. Non- limiting examples of saturated Ci-Cio alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl and n-penty, n-hexyl, n-heptane, and the like. Non-limiting examples of C₂-Ci₀ alkenyl include vinyl, allyl, isopropenyl, l-propene-2-yl, 1-butene- 1-yl, l-butene-2-yl, l-butene-3-yl, 2-butene-l-yl, 2-butene-2-yl, penteneyl , hexeneyl, and the like. Non-limiting examples of C₂-Cio alkynyl include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted (i.e., a hydrogen atom in the alkyl group may be replaced with an optional substituent).

As used herein, the term "cyclic C_x-C_y alkyl" is used as it is normally understood to a person of skill in the art and often refers to a compound or a chemical entity in which at least a portion of the carbon skeleton or main chain of the chemical entity is bonded in such a way so as to form a 'loop', circle or ring of atoms that are bonded together. The atoms do not have to all be directly bonded to each other, but rather may be directly bonded to as few as two other atoms in the 'loop' . Non- limiting examples of cyclic alkyls include benzene, toluene, cyclopentane, bisphenol and 1 -chloro-3-ethylcyclohexane.

As used herein, the term "branched" is used as it is normally understood to a person of skill in the art and often refers to a chemical entity that comprises a skeleton or main chain that splits off into more than one contiguous chain. The portions of the skeleton or main chain that split off in more than one direction may be linear, cyclic or any combination thereof. Non-limiting examples of a branched alkyl are tert-butyl and isopropyl.

As used herein, the term "unbranched" is used as it is normally understood to a person of skill in the art and often refers to a chemical entity that comprises a skeleton or main chain that does not split off into more that one contiguous chain. Non-limiting examples of unbranched alkyls are methyl, ethyl, n-propyl, and n-butyl.

"Aryl" refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For purposes of this invention, the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, 5-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals that are optionally substituted.

"Aralkyl" refers to a radical of the formula -R_b-R_c where R_b is an alkylene chain as defined above and R_c is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group may be optionally substituted.

As used herein, the term "substituted" is used as it is normally understood to a person of skill in the art and often refers to a chemical entity that has one chemical group replaced with a different chemical group that contains one or more heteroatoms. Unless otherwise specified, a substituted alkyl is an alkyl in which one or more hydrogen atom(s) is/are replaced with one or more atom(s) that is/are not hydrogen(s). For example, chloromethyl is a non-limiting example of a substituted alkyl, more particularly an example of a substituted methyl. Aminoethyl is another non-limiting example of a substituted alkyl, more particularly it is a substituted ethyl.

As used herein, the term "unsubstituted" is used as it is normally understood to a person of skill in the art and often refers to a chemical entity that is a hydrocarbon and/or does not contain a heteroatom. Non-limiting examples of unsubstituted alkyls include methyl, ethyl, tert-butyl, and pentyl.

As used herein, the term "saturated" when referring to a chemical entity is used as it is normally understood to a person of skill in the art and often refers to a chemical entity that comprises only single bonds. Non-limiting examples of saturated chemical entities include ethane, tert-butyl, and N⁺¾.

As used herein, Ci-Cio alkyl may include, for example, and without limitation, saturated Ci-Cio alkyl, C₂-Cio alkenyl and C₂-Cio alkynyl. Non-limiting examples of saturated Ci-Cio alkyl may include methyl, ethyl, n-propyl, i-propyl, sec- propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, sec-pentyl, t-pentyl, n- hexyl, i-hexyl, 1 ,2-dimethylpropyl, 2-ethylpropyl, l-methyl-2-ethylpropyl, l-ethyl-2- methylpropyl, 1,1,2-trimethylpropyl, 1 , 1 ,2-triethylpropyl, 1,1-dimethylbutyl, 2,2- dimethylbutyl, 2-ethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, sec- hexyl, t-hexyl, n-heptyl, i-heptyl, sec-heptyl, t-heptyl, n-octyl, i-octyl, sec-octyl, t-octyl, n-nonyl, i-nonyl, sec-nonyl, t-nonyl, n-decyl, i-decyl, sec-decyl and t-decyl. Non- limiting examples of C₂-Cio alkenyl may include vinyl, allyl, isopropenyl, l-propene-2- yl, 1-butene-l-yl, l-butene-2-yl, l-butene-3-yl, 2-butene-l-yl, 2-butene-2-yl, octenyl and decenyl. Non- limiting examples of C₂-Cio alkynyl may include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl. Saturated Ci-Cio alkyl, C₂-Cio alkenyl or C₂-Cio alkynyl may be, for example, and without limitation, interrupted by one or more heteroatoms which are independently nitrogen, sulfur or oxygen.

As used herein, cyclic C3-C10 alkyl may include, for example, and without limitation, saturated C3-C10 cycloalkyl, C3-C10 cycloalkenyl, C3-C10 cycloalkynyl, C₆_io aryl, C₆_9 aryl-Ci_₄ alkyl, C₆_8 aryl-C₂_₄ alkenyl, C₆_8 aryl-C₂_₄ alkynyl, a 4- to 10-membered non-aromatic heterocyclic group containing one or more heteroatoms which are independently nitrogen, sulfur or oxygen, and a 5- to 10- membered aromatic heterocyclic group containing one or more heteroatoms which are independently nitrogen, sulfur or oxygen. Non-limiting examples of the saturated C3- Cio cycloalkyl group may include cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, cyclooctanyl, cyclononanyl and cyclodecanyl. Non- limiting examples of the C3-C10 cycloalkenyl group may include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononanenyl and cyclodecanenyl. Non- limiting examples of the C₆-Cio aryl group may include phenyl (Ph), pentalenyl, indenyl, naphthyl, and azulenyl. The C₆-9 aryl-Ci_4 alkyl group may be, for example, and without limitation, a Ci_₄ alkyl group as defined anywhere above having a C₆_9 aryl group as defined anywhere above as a substituent. The C₆-8 aryl-C₂-4 alkenyl group may be, for example, and without limitation, a C₂_₄ alkenyl as defined anywhere above having a C₆-8 aryl group as defined anywhere above as a substituent. The C₆-8 aryl-C₂_₄ alkynyl group may be, for example, and without limitation, a C₂_₄ alkynyl group as defined anywhere above having a C₆_8 aryl group as defined anywhere above as a substituent. Non- limiting examples of the 4- to 10- membered non-aromatic heterocyclic group containing one or more heteroatoms which are independently nitrogen, sulfur or oxygen may include pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, imidazolinyl, pyrazolidinyl, imidazolydinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, oxathiolanyl, phthalimide and succinimide. Non-limiting examples of the 5- to 10-membered aromatic heterocyclic group containing one or more heteroatoms which are independently nitrogen, sulfur or oxygen may include pyrrolyl, pyridinyl, pyridazinyl, pyrimidinyl, pirazinyl, imidazolyl, thiazolyl and oxazolyl.

Non-limiting examples of one to ten carbon substituted or unsubstituted acyl include acetyl, propionyl, butanoyl and pentanoyl. Non-limiting examples of Ci- C10 alkoxy include methoxy, ethoxy, propoxy and butoxy.

As used herein, the symbol "

" (hereinafter may be referred to as

"a point of attachment bond") denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment

XY-§- bond. For example, " " indicates that the chemical entity "XY" is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity ma be specified by inference.

For example, the compound

CH₃-R³, wherein R³ is H or " " infers that when R³ is "XY", the point of attachment bond is the same bond as the bond by which R³ is depicted as being bonded to CH₃.

"Halo" refers to fluoro (F), chloro (CI), bromo (Br) or iodo (I). Radioisotopes are included witin the definition of halo. Accordingly, compounds comprising fluoro , chloro , bromo or iodo may also comprise radioisotopes of the same.

As noted above, the present disclosure provides a compound having a structure of Formula I:

armaceutically acceptable salt or tautomer thereof, wherein:

at least one Z¹ is independently C-Q;

at least one Z² is independently C-W, wherein W is

at least one Z³ is independently C-T, CH, CCH₃, CF, CCl, CBr, CI, COH, CG¹, COG¹, CNH₂, CNHG¹, CNG^, COS0₃H, COP0₃H₂, CSG¹, CSOG¹, or each remaining Z¹, Z² and Z³ is, at each occurrence, independently C-T, N, CH, CCH₃, CF, CCl, CBr, CI, COH, CG¹, COG¹, CNH₂, CNHG¹, CNG^, COS0₃H, COP0₃H₂, CSG¹, CSOG¹, or CSOzG¹;

R¹, R², R³ and R⁴ are each independently H or a linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C10 alkyl, or R¹ and R², or R³ and R⁴ may independently together form a substituted or unsubstituted, saturated or unsaturated cyclic C₃-Cio alkyl or R¹ and R², or R³ and R⁴ may independently together form =CR"R"', wherein R" and R'" are each independently a linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl, aryl or aralkyl;

Q is ;

J is G¹, O, CH₂, CHG¹, CG^, S, NH, NG¹, SO, S0₂, or NR; M is H, F, CI, Br, CH₂OH, CH₂OD, CH₂OG¹, CH₂F, CH₂C1, CHC1₂, CC1₃, CH₂Br, CHBr₂, CBr₃ or C≡CH;

L is H or A-D;

A is O, S, NH, NG¹, N⁺H₂ or N⁺HG¹;

D is, at each occurrence, in ¹, R,

.OR

Ό

or a moiety from TABLE 1 ;

each of q, r and t may independently be 0, 1, 2, 3, 4, 5, 6 or 7;

n is 0, 1, 2, 3, 4, 5, 6, 7 or 8:

T is, at each occurrence, independently

J is, at each occurrence, independentl

S, NH, NG¹, SO, S0₂, or NR;

M² is, at each occurrence, independently H, CH₃, F, CI, Br, CH₂F , CH₂C1, CHC1₂, CC1₃, CH₂Br, CHBr₂, CBr₃, CH₂OH, CH₂OD², CH₂OJ", G

CH₂OR,

CHjSG¹, CH₂NH₂,

CH^G^, or C≡CH;

L² is, at each occurrence, independently H or A²-D²;

A² is, at each occurrence, independently O, S, SO, S02, NH, NG¹, N⁺H₂, or N⁺HG¹; D² is, at each occurrence, independently H, G¹, R,

or a moiety selected from TABLE 1 ;

each of u, y and j are, at each occurrence, independently 0, 1, 2, 3, 4, 5, 6 or 7;

m is, at each occurrence, independently 0, 1, 2, 3, 4, 5, 6, 7 or 8;

J" and J'" are, at each occurrence, independently a moiety selected from

TABLE 1;

G¹, G¹' and G¹" are, at each occurrence, independently a linear or branched, aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated Ci-Ci₀ alkyl, wherein the optional substituents for the Ci-Ci₀ alkyl are oxo, CH₂C0₂R', OJ'", COOH, R¹, OH, OR¹, F, CI, Br, I, NH₂, NHR¹, N(R¹)₂, CN, SH, SR¹, SO3H, SO3R¹, SO2R¹, OSO3R¹, OR², CO2R¹, CONH2, CONHR¹, CONHR², CON(R¹)₂, NHR², OPO3H3, CON^R², NR^JR² or N0₂;

each R' is independently H, linear or branched, aromatic cyclic or non- aromatic cyclic, substituted or unsubstituted, saturated or unsaturated C₁-C₁₀ alkyl or a metal counter ion, wherein the metal counter ion is Li, Na, K, Mg or Ca;

each R¹ is independently unsubstituted C₁-C₁₀ alkyl; and each R and R² are independently C₁-C₁₀ acyl. For example, in some embodiments at least one Z³ is independently C-T.

In other embodiments, the compound has a structure of Formula II or III:

II III

In some other examples, the compound has a structure of Formula IV or

V:

V

In yet other embodiments, the compound has a structure of Formula VI or VII:

VI

VII

wherein:

R⁷, R⁸, R⁹, R¹⁰. R¹¹ and R¹² are each independently hydrogen, halo, or linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl.

In still other embodiments, the compound has a structure of Formula

VIII or IX:

VIII

IX

In yet other embodiments, the compound has a structure of Formula X or

For example in some embodiments, the compound has a structure of Formula Xa, Xb, Xc, Xd, XIa, Xlb, XIc or Xld:

L²

Xld

In certain embodiments of any of the foregoing, R¹, R², R³ and R⁴ are each independently H or a linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl, or R¹ and R², or R³ and R⁴ may independently together form a substituted or unsubstituted, saturated or unsaturated cyclic C3-C10 alkyl.

In certain embodiments of any of the foregoing, R¹, R², R³ and R⁴ are each independently H or a linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C10 alkyl. In other embodiments, R¹ and R², or R³ and R⁴ may independently together form a substituted or unsubstituted, saturated or unsaturated cyclic C3-C10 alkyl.

In other embodiments, R¹ and R², or R³ and R⁴ may independently together form an alkene goup, which is represented herein by the following structure:

=CR"R"'

wherein R" and R'" are each independently a linear or branched, substituted or unsubstituted, saturated or unsaturated C₁-C₁₀ alkyl, aryl or aralkyl.

In other embodiments of the foregoing compound, J is G¹, O, CH₂, CHG¹, CG^, NH, SO, or NR. For example in some embodiments, J is O.

In other embodiments, M is CI, Br, CH₂OH, CH₂OD, CH₂OG¹, CH₂F, CH₂C1, CHC1₂, CCI₃, CH₂Br, CHBr₂, CBr₃, or C≡CH. In still other embodiments, M is CH₂OH, CH₂F, C≡CH, CH₂OCH₂C≡CH, CH₂0- i-butyl, or CH₂OD, wherein D is

. For example in some embodiments, M is CH₂OH, and in other embodiments, M is H.

In other embodiments, L is H, and in other embodiments, L is A-D.

In yet other embodiments, A is O while in other embodiments D is H, R,

moiety from TABLE 1; and each of q, r and t is independently 0, 1, 2, 3, 4, 5, 6 or 7. For example in some embodiments, D is H, and in other embodiments D is R.

In certain embodiments, D is a moiety selected from TABLE 1. For

exam le in some embodiments, the moiety from TABLE 1 is or

In other embodiments, n is 0, and in some other embodiments n is 1, 2, 3, 4, or 5. For example in some embodiments, n is 1.

In certain embodiments, J² is G¹, O, CH₂, CHG¹, CG^, NH, SO, or NR. For example in some embodiments, J² is O.

In other embodiments, M² is H, CH₂F, CH₂C1, CH₂Br, CH₂OH, CH₂OJ", or C≡CH. For example in some embodiments, M² is C¾F. In other embodiments, M² is CH₂CI. In still other embodiments, M² is C¾Br. In yet other embodiments, M² is CH₂OH, and in some embodiments M² is H. In other embodiments, M² is C≡CH.

In still other embodiments, L² is H, and in other examples L² is A²-D².

In certain embodiments A² is O, and in other certain embodiments D² is

a moiety from TABLE 1; and each of u, y and j is independently 0, 1, 2, 3, 4, 5, 6 or 7. For example, in some embodiments D² is H, and in other embodiments D² is R. In still other embodiments, D² is a moiety from TABLE 1. For exam le in some

embodiments, the moiety from TABLE 1 is

In other embodiments of the foregoing compound, m is 0. In still other embodiments, m is 1, 2, 3, 4, or 5. For example in some embodiments, m is 1.

In other examples, M is CH₂OH and L is OH. In still other examples, M² is CH₂C1 and L is OH. In even further examples, M is CH₂OH, M² is CH₂C1, L is OH and L² is OH. In even further examples, M is CH₂F, M² is CH₂C1, L is OH and L² is OH.

In other embodiments, n and m are each 1.

In still other embodiments, at least one of R¹, R², R³ or R⁴ is methyl. For example in some embodiments, each of R¹, R², R³ and R⁴ is methyl.

In other embodiments, at least one of R¹, R², R³ or R⁴ is hydrogen. For example in some embodiments, each of R¹, R², R³ and R⁴ is hydrogen.

In other examples, R¹ and R² or R³ and R⁴ join to form substituted or unsubstituted cyclohexyl. For example in some embodiments, each of R¹ and R² and R³ and R⁴ join to form substituted or unsubstituted cyclohexyl.

In still other embodiments, at least one of R⁷, R⁸, R⁹, R¹⁰, R¹¹ or R¹² is

7 8 9 10 11 12 hydrogen. For example in some embodiments, each of R , R , R , R , R and R are hydrogen.

In certain other embodiments,at least one of R 7 , R 8 , R 9 , R 10 , R 11 or R 12 is

7 8 9 10 11 12

methyl. For example, each of R , R , R , R , R and R are methyl in some embodiments. In other embodiments, each of R⁷, R⁸, R⁹, and R¹² are methyl. In still other embodiments, at least one of R⁷, R⁸, R⁹, R¹⁰, R¹¹ or R¹² is

7 8 9 10 11 12 fluoro. For example in some embodiments, each of R , R , R , R , R and R are fluoro. In certain futher embodiments, each of R⁷, R⁸, R⁹, and R¹² are fluoro.

7 8 9 10 11 12

In other aspects, at least one of R , R , R , R , R or R is chloro. For

7 8 9 10 11 12

example in some embodiments, each of R', R°, R", R , R and R are chloro, while in other examples each of R⁷, R⁸, R⁹, and R¹² are chloro.

7 8 9 10 11 12

In other embodiments, at least one of R , R , R , R , R or R is

7 8 9 10 11 12 bromo. For example in some embodiments, each of R , R , R , R , R and R are bromo, and in other embodiments each of R⁷, R⁸, R⁹, and R¹² are bromo.

In other embodiments of the fore oing compound, Q

independently 0, 1, 2, 3, 4, 5, 6 or 7; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; each of u, j and y is independently 0, 1, 2, 3, 4, 5, 6 or 7 and each G¹ is independently linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl, wherein the optional substituents are selected from oxo, OJ'", COOH, OH, F, CI, Br, I, NH₂, CN, SH, S0₃H, CONH₂, OP0₃H₃ and N0₂.

In still other embodiments Q is

; n is 0, 1, 2, 3, 4, 5, 6, 7 or 8; each of q, r, and t is independently 0,

1, 2, 3, 4, 5, 6 or 7; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; each of u, j and y is independently 0, 1, 2, 3, 4, 5, 6 or 7 and each G¹ is independently linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl, wherein the optional substituents are selected from oxo, OJ'", COOH, OH, F, CI, Br, I, NH₂, CN, SH, S0₃H, CONH₂, OP0₃H₃, and N0₂.

In other embodiments Q is

4, 5, 6, 7 or 8; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and each G¹ is independently linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Ci₀ alkyl, wherein the optional substituents are selected from oxo, OJ'", COOH, OH, F, CI, Br, I, NH₂, CN, SH, S0₃H, CONH2, OPO3H3, and N0₂.

In still other embodiments Q is

nis 0, 1,2, 3,4, 5, 6, 7 or 8; q is 0, 1,2,3,4, 5, 6 or 7; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; u is 0, 1, 2, 3, 4, 5, 6 or 7; and each G¹ is independently linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl, wherein the optional substituents are selected from oxo, OJ'", COOH, OH, F, CI, Br, I, NH₂, CN, SH, S0₃H, CONH₂, OP0₃H₃, and N0₂.

In ot er em o ments

n certain other embodiments of the foregoing compound, T is

0- ci

; and n, m and q are each independently 0, 1 , 2, 3, 4, 5, or 8.

In certain further embodiments Q is

or and T is

In other embodiments, each remaining Z¹, Z² and Z³ is, at each occurrence, independently CCH₃; CH; CF, CC1 or CBr. For example in some embodiments, each remaining Z Z² and Z³ is CH.

In some other embodiments, one or more of the OH groups of any one of the foregoing compounds of Formula I is substituted to replace the H with a moiety from TABLE 1. For exam le in some embodiments, the moiety from TABLE 1 is

In another embodiment, the present disclosure provides a compound having one of the following structures:

For example, in some other embodiments, one or more of the OH groups of the foregoing compounds is substituted to replace the H with a moiet from TABLE 1. For example in some embodiments, the

moiety from TABLE 1 is

In another embodiment, the present disclosure provides the use of any one of the foregoing compounds for modulating androgen receptor (AR) activity. For example in some embodiments, modulating androgen receptor (AR) activity is in a mammalian cell.

In other embodiments, modulating androgen receptor (AR) activity is for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration. For example in some embodiments,the indication is prostate cancer. In other embodiments, the prostate cancer is castration resistant prostate cancer. While in other embodiments, the prostate cancer is androgen-dependent prostate cancer. In other embodiments, the spinal and bulbar muscular atrophy is Kennedy's disease.

In other embodiments, the present disclosure provides a method of modulating androgen receptor (AR) activity, the method comprising administering any one of the foregoing compounds, or pharmaceutically acceptable salt thereof to a subject in need thereof. In other further embodiments of the foregoing method, modulating androgen receptor (AR) activity is for the treatment of one or more of the following: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration. For example in some embodiments, the prostate cancer is castration resistant prostate cancer. In other embodiments, the prostate cancer is androgen-dependent prostate cancer, and in other embodiments, the spinal and bulbar muscular atrophy is Kennedy's disease.

In some other embodiments, the present disclosure provides a pharmaceutical composition comprising any one of the foregoing compounds and a pharmaceutically acceptable carrier.

In yet another embodiment, the present disclosure provides a pharmaceutical composition comprising any one of the foregoing compounds, an additional therapeutic agent and a pharmaceutically acceptable carrier. For example, in some embodiments, the additional therapeutic agent is for treating prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy or age-related macular degeneration.

In other embodiments, the additional therapeutic agent is MDV3100 , TOK 001, TOK 001; ARN-509; abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab (Avastin), QSU-HDAC42, VITAXIN, sunitumib, ZD-4054, VN/I24-L Cabazitaxel (XRP-6258), MDX-G10 (Ipilimumab), OGX 427, OGX Oi l, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF 105,111 or a related compound thereof.

In another embodiment, the present disclosure provides the use of any one of the foregoing pharmaceutical compositions for modulating androgen receptor (AR) activity. For example in some embodiments, modulating androgen receptor (AR) activity is in a mammalian cell.

In other embodiments, modulating androgen receptor (AR) activity is for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration. For example in some embodiments, the indication is prostate cancer. For example, in some embodiments, the prostate cancer is castration resistant prostate cancer, and in other embodiments the prostate cancer is androgen-dependent prostate cancer. In still other embodiments, the spinal and bulbar muscular atrophy is Kennedy's disease.

In yet another embodiment, the present disclosure provides a method of modulating androgen receptor (AR) activity, the method comprising administering any one of the foregoing pharmaceutical compositions to a subject in need thereof. For example in some embodiments, modulating androgen receptor (AR) activity is for the treatment of one or more of the following: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration. In other embodiments, the spinal and bulbar muscular atrophy is Kennedy's disease. In still other embodiments, the indication is prostate cancer. For example, in some embodiments, the prostate cancer is castration resistant prostate cancer, while in other embodiments, the prostate cancer is androgen-dependent prostate cancer.

Each J may independently be G¹, O, CH₂, CHG¹, CG^, S, NH, NG¹, SO, S0₂, or NR. Each J may independently be G¹, O, CH₂, CHG¹, CG^, S, NH, or NG¹. Each J may independently be O, S, NH, NG¹, SO, S0₂, or NR. Each J may independently be O, S, SO, or S0₂. Each J may independently be O, NH, NG¹, or NR. Each J may independently be S, NH, NG¹, SO, S0₂, or NR. Each J may independently be S, SO, or S0₂. Each J may independently be NH, NG¹, or NR. Each J may independently be G¹, CH₂, CHG¹, or CG^. Each J may independently be O, CH₂, S, or NH. Each J may independently be O, CH₂, or NH. Each J may independently be O, or CH₂. Each J may independently be G¹, O, CHG¹, or NH. Each J may independently be G¹, O, or CHG¹. Each J may independently be G¹, or O. Each J may independently be O, or S. Each J may independently be G¹. Each J may independently be CH₂. Each J may be CHG¹. Each J may be CG^. Each J may be NR. Each J may be S0₂. Each J may be SO. Each J may be NG¹. Each J may be NH. Each J may be S. Each J may be O.

Each M may independently be H, CI, Br, CH₂OH, CH₂OD,

CH₂F, CH₂C1, CHC1₂, CC1₃, CH₂Br, CHBr₂, CBr₃, or C≡CH. Each M may independently be CI, Br, CH₂OH, CH₂OD, CH₂OG¹, CH₂F, CH₂C1, CHC1₂, CC1₃, CH₂Br, CHBr₂, or CBr₃. Each M may independently be CI, CH₂C1, CHC1₂, or CC1₃. Each M may independently be Br, CH₂Br, CHBr₂, or CBr₃. Each M may independently be CI, or Br. Each M may independently be CH₂C1, or CH₂Br. Each M may independently be CHC1₂, or CHBr₂. Each M may independently be CC1₃, or CBr₃. Each M may independently be CH₂C1, CHC1₂, or CC1₃. Each M may independently be CH₂Br, CHBr₂, or CBr₃. Each M may independently be CI, CH₂C1, or CHC1₂. Each M may independently be Br, CH₂Br, or CHBr₂. Each M may independently be CH₂C1, or CHC1₂. Each M may independently be CH₂Br, or CHBr₂. Each M may independently be CI, or CC1₃. Each M may independently be Br, or CBr₃. Each M may be H. Each M may be CI. Each M may be Br. Each M may be CHC1₂. Each M may be CC1₃. Each M may be CH₂Br. Each M may be CHBr₂. Each M may be CBr₃. Each M may be C≡CH. Each M may be CH₂C1. Each M may be CH₂F. Each M may be CH₂OH. Each M may be CH₂OD. Each M may be CF^OG¹.

Each L may independently be H or A-D. Each L may be H. Each L may be A-D.

Each A may independently be O, S, NH, NG1, N+H2, or N+HG1. Each A may independently be O, NH, or N⁺H₂. Each A may independently be O, S, NH, or N H₂. Each A may independently be O, S, or NH. Each A may independently be O, or NH. Each A may independently be O, or S. Each A may be S. Each A may be NH. Each A may be NG¹. Each A may be N⁺H₂. Each A may be N HG¹. Each A may be O.

.OH

Each D may inde endently be H, G¹, R, ^ ^¾

, or a moiety selected from

TABLE 1. Each D may independently be H, G¹, or R. Each D may independently be H, or R. Each D may independently be G¹, or R. Each D may independently be H, or G¹.

, or a moiet selected from TABLE 1. Each D may independently be

Eac D may n epen ent y e

moiety selected from TABLE 1. Each D may independently be

, or a moiety selected from TABLE 1. Each

D ma be H. Each D may be G¹. Each D ma be R. Each D may be . Each D may be

. Each D may be a moiety selected from TABLE 1.

Each J² may independently be G¹, O, CH₂, CHG¹, CG^, S, NH, NG¹, SO, S0₂, or NR. Each J² may independently be G¹, O, CH₂, CHG¹, CG^, S, NH, or NG¹. Each J² may independently be O, S, NH, NG¹, SO, S0₂, or NR. Each J² may independently be O, S, SO, or S0₂. Each J² may independently be O, NH, NG¹, or NR.

2 1 2

Each J may independently be S, NH, NG , SO, S0₂, or NR. Each J may independently be S, SO, or S0₂. Each J² may independently be NH, NG¹, or NR. Each J² may independently be G¹, CH₂, CHG¹, or CG^. Each J² may independently be O,

2 2

CH₂, S, or NH. Each J may independently be O, CH₂, or NH. Each J may independently be O, or CH₂. Each J² may independently be G¹, O, CHG¹, or NH. Each J² may independently be G¹, O, or CHG¹. Each J² may independently be G¹, or O. Each

2 2 1 2

J may independently be O, or S. Each J may independently be G . Each J may independently be CH₂. Each J² may be CHG¹. Each J² may be CG^. Each J² may be

2 2 2 l 2

NR. Each J may be S0₂. Each J may be SO. Each J may be NG . Each J may be

2 2

NH. Each J may be S. Each J may be O. Each M² may independently be H, CH₃, CI, Br, CH₂F, CH₂C1, CHC1₂, CC1₃, CH₂Br, CHBr₂, CBr₃, CH₂OH, CH₂OJ", G¹,

CH₂OR, CH₂OG¹OG¹',

may independently be H, CH₃, CH₂C1, CH₂Br, CH₂OJ"', CH₂OG, CH₂OGOG', GOG', GOG'OG", CH₂SG, CH₂NH₂, CH₂NHG, or CH₂NG₂. Each M² may independently be H, CH₃, CH₂C1, CH₂Br, CH₂OJ"', CH₂OG, or CH₂OGOG'. Each M² may independently be CH₂C1, CH₂Br, CH₂OH, CH₂OCH₃, CH₂0(isopropyl), or CH₂OC₂H₄OC₄H₉. Each M² may independently be H, CH₃, CH₃OCH₃, CH₃OCH₂CH₃, CH₂C1, or CH₂Br. Each M² may independently be CH₃, CH₃OCH₂CH₃, CH₂C1, CH₂Br, CH₂OH, CH₂OCH₃, or CH₂0(isopropyl). Each M² may independently be CH₃, CH₂C1, CH₂Br, CH₂OH, CH₃OCH₂CH₃, or CH₂OCH₃. Each M² may independently be CH₃, CH₂C1, CH₂Br, CH₂OH, or CH₂OCH₃. Each M² may independently be CH₃, CH₂OH, CH₂OCH₃, or CH₂OCH₂CH₃. Each M² may independently be CH₂C1, or CH₂Br. Each M² may independently be H, CI, Br, CH₂C1, CHC1₂, CC1₃, CH₂Br, CHBr₂, CBr₃, or C≡CH. Each

M² may independently be CI, Br, CH₂C1, CHC1₂, CC1₃, CH₂Br, CHBr₂, or CBr₃. Each

2 2

M may independently be CI, CH₂C1, CHC1₂, or CC1₃. Each M may independently be

2 2 Br, CH₂Br, CHBr₂, or CBr₃. Each M may independently be CI, or Br. Each M may

₂

independently be CH₂C1, or CH₂Br. Each M may independently be CHC1₂, or CHBr₂.

2 2

Each M may independently be CC1₃, or CBr₃. Each M may independently be CH₂C1,

CHC1₂, or CC1₃. Each M² may independently be CH₂Br, CHBr₂, or CBr₃. Each M² may

₂

independently be CI, CH₂C1, or CHC1₂. Each M may independently be Br, CH₂Br, or

2 2

CHBr₂. Each M may independently be CH₂C1, or CHC1₂. Each M may independently

2 2 be CH₂Br, or CHBr₂. Each M may independently be CI, or CC1₃. Each M may independently be Br, or CBr₃. Each M² may be H. Each M² may be CH₃. Each M² may be CI. Each M² may be Br. Each M² may be CH₂C1. Each M² may be CHC1₂. Each M² may be CC1₃. Each M² may be CH₂Br. Each M² may be CHBr₂. Each M² may be CBr₃.

Each M² may be CH₂OH. Each M² may be CH₂OJ". Each M² may be G¹. Each M² may be CH₂0G¹. Each M² may be CH₂OR. Each M² may be CH₂OG¹OG¹'. Each M² may be

G^G¹'. Each M² may be G^G^OG¹". Each M² may be CH₂SG¹. Each M² may be

CH₂NH₂. Each M² may be CH₂ HG¹. Each M² may be CF^NG^. Each M² may be

C≡CH. Each M² may be CH₂F. Each L 2 may independently be H or A 2 -D 2. Each L 2 may be H. Each L 2 may be A²-D².

Each A² may independently be O, S, SO, S0₂, NH, NG¹, N⁺H₂, or N⁺HG\ Each A² may independently be O, S, SO, or S0₂. Each A² may independently be O, NH, NG¹, N⁺H₂, or N⁺HG\ Each A² may independently be S, SO, S0₂, NH, NG¹, N⁺H₂, or N⁺HG\ Each A² may independently be O, S, SO, S0₂, NH, or N⁺H₂. Each A² may independently be S, SO, or S0₂. Each A² may independently be NH, NG¹, N⁺H₂, or N⁺HG\ Each A² may independently be NH, or N H₂. Each A may independently be O, S, NH, NG¹, N⁺H₂, or N⁺HG\ Each A² may independently be O,

+ 2 + 2

NH, or N H₂. Each A may independently be O, S, NH, or N H₂. Each A may

2 2 independently be O, S, or NH. Each A may independently be O, or NH. Each A may independently be O, or S. Each A² may be S. Each A² may be SO. Each A² may be S0₂. Each A² may be NH. Each A² may be NG¹. Each A² may be N⁺H₂. Each A² may be N⁺HG\ Each A² may be O.

Each D² ma independently be H, G¹, R,

, or a moiety selected from TABLE

1. Each D² may independently be H, G¹, or R. Each D² may independently be H, or R. Each D² may independently be G¹ or R. Each D² may independently be H, or G¹. Each

D² ma independently

or a moiety selected from TABLE 1. Each D² may independently be

or

. Each D² may independently be OR OH

O

or J . Each D² may independently be cr , or

Each D may independently be

. or a moiety selected from TABLE 1. Each D may

OH

independently be ^ l^u , or a moiety selected from TABLE 1. Each

D² may be H. Each D² may be G¹. Each D² may be R. Each D² may be

.OH OG¹ cr O

. Each D may be . Each D may be

Each D² may be a moiety selected from TABLE 1.

Each may inde endently be

o OH

X, cr XI O " xi OH

51

in

de endently be

Each ma inde endentl be or

Each may independently be

inde endently be

Each Q may independently

Each may independently be

. Each Q

independently be Each may independently be

. Each Q may

independently Each Q may independently be

. Each Q may independently be . Each Q may

independently

Each Q may independently be

. Each Q may

independently be Each Q may independently be . Each Q

may independently be Each Q may independently be

. Each Q

may independently be Each Q may independently be

Each Q may independently be . Each Q

may independently be Each Q may independently be

Each may independently be . Each Q may

inde endently Each may independently be

. Each Q may

inde endently be Each Q may independently be

Each Q may O" ^"Br

inde endently OR Each Q may independently be

Each Q

may independently be Each Q may independently be

. Each Q

may independently be Each may independently be

Each Q

ma independently be

Each Q may independently be

Br

O CI ^ O" Br O-V £ Br

Each Q may independently be

may independently be

.Br

O CI Ό ^"Br

. Each Q may independently be X,

Each Q may independently

Each may independently be

ΥΊ ¹¹ CI be X, . Each Q may independently be ¹¹ . Each Q

.B

may be X, o" r

Q may be X, ^"Br

. Each . Each Q may

independently be . Each Q ma be . Each Q may be . Each Q may be

Each may independently be

Each Q may independently be

Each Q may independently be

Each Q may ind OH Each Q may independently ach Q may independently be . Each Q may

independently be

Each T ma inde endently

inde endently be

e

independently be

independently be

6R Each T may independently be

, or . Each T ma independently

independently be

or

Each T may independently be

E

a h T may

or Each T may independently be

Each T may independently be

or 0H Each T ma independently be

. Each T may independently be i

Each T ma independently be or

independently be or

Each T ma independently be

in

dependently be

or OGⁱ Each T ma independently be

Each T may independently

inde endently be or

endently

independently be or

Each T may independently be

inde endently be

or

independently be

Each T may independently be

Each T ma independently

inde endently be Each T ma independently be

Each T ma independently be . Each T may independently be

Each T may independently be . Each T may

ndependently be Each T may independently be

. Each T may

independently be Each T may independently be

. Each T may endently be

. Each T may

inde endently be Each T may independently be

. Each T may

independently be Each T may independently be

inde endently

Each T may independently be

. Each T may

inde endently Each T may independently be

Each T may

inde endently be Each T may independently be i

nde endently be Each T may independently

. Each T

independently be Each T may independently

independently be Each T may independently be

Each T may independently be Each T ma independently be

Each T ma independently be

. Each T ma independently be . Each T

may independently be Each T may independently be

Each T

ma independently be Each T ma independently be

. Each T may independently be . Each T ma independently be

Each T may independently be

. Each T

may independently be Each T may independently be

Each T

may independently be Each T may independently be

Each T may independently be Each T

ma inde endentl be Each T may independently be

Each T may independently be Each T

may independently be Each T may independently be

independently be Each T ma independently be

. Each T may independently be . Each T

ma independently be . Each T may independently be

Each T

independently be Each T may independently be

Each T may independently

Each T may independently be . Each T

ma independently be

Each T ma independently be

. Each T ma independently be . Each T

ma independently be Each T ma independently be

Each T may independently be . Each T o" γ ^{^}OG^I

may independently be 6R Each T may independently be

Each T

may independently be Each T may independently be

. Each T

may independently be . Each T may independently be . Each T

m

ay independently be Each T may independently be

Each T may independently be Each T may

independently be . Each T may independently be

. Each T may independently be may independently be X₀^^^cl , CI

Each T may independently

X, .Br X

T may independently be O" . o' -Br * O^ ^ ¾ .OH

0 Br O

or Each T may independently be .OG¹ .OR

O^' or X cr Each T may independently be

or Each T ma independently be

Ό CI

independently be Each T may independently be

. Each T may

O Br

independently be Each T may independently be O XI

Each T may independently be , ¾r

Each T may independently be .OH OG¹

O Each T may independently be O Each T may independently be X, .OR

T ma independently

Each T may independently be

. Each T may independently

Each T may independently be

Each q may independently be 0, 1, 2, 3, 4, 5, 6 or 7. Each q may independently be 0 to 1, 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, or 0 to 7. Each q may independently be 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, or 1 to 7. Each q may independently be 2 to 3, 2 to 4, 2 to 5, 2 to 6, or 2 to 7. Each q may independently be 3 to 4, 3 to 5, 3 to 6, or 3 to 7. Each q may be 0. Each q may be 1. Each q may be 2. Each q may be 3. Each q may be 4. Each q may be 5. Each q may be 6. Each q may be 7.

Each r may independently be 0, 1, 2, 3, 4, 5, 6 or 7. Each r may independently be 0 to 1, 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, 0 to 7. Each r may independently be 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, or 1 to 7. Each r may independently be 2 to 3, 2 to 4, 2 to 5, 2 to 6, or 2 to 7. Each r may independently be 3 to 4, 3 to 5, 3 to 6, or 3 to 7. Each r may be 0. Each r may be 1. Each r may be 2. Each r may be 3. Each r may be 4. Each r may be 5. Each r may be 6. Each r may be 7.

Each t may independently be 0, 1, 2, 3, 4, 5, 6 or 7. Each t may independently be 0 to 1, 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, or 0 to 7. Each t may independently be 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, or 1 to 7. Each t may independently be 2 to 3, 2 to 4, 2 to 5, 2 to 6, or 2 to 7. Each t may independently be 3 to 4, 3 to 5, 3 to 6, or 3 to 7. Each t may be 0. Each t may be 1. Each t may be 2. Each t may be 3. Each t may be 4. Each t may be 5. Each t may be 6. Each t may be 7.

Each n may independently be 0, 1, 2, 3, 4, 5, 6, 7 or 8. Each n may independently be 0 to 1 , 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, 0 to 7, or 0 to 8. Each n may independently be 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, or 1 to 8. Each n may independently be 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, or 2 to 8. Each n may independently be 3 to 4, 3 to 5, 3 to 6, 3 to 7, or 3 to 8. Each n may be 0. Each n may be 1. Each n may be 2. Each n may be 3. Each n may be 4. Each n may be 5. Each n may be 6. Each n may be 7. Each n may be 8.

Each u may independently be 0, 1, 2, 3, 4, 5, 6 or 7. Each u may independently be 0 to 1, 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, 0 to 7. Each u may independently be 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, or 1 to 7. Each u may independently be 2 to 3, 2 to 4, 2 to 5, 2 to 6, or 2 to 7. Each u may independently be 3 to 4, 3 to 5, 3 to 6, or 3 to 7. Each u may be 0. Each u may be 1. Each u may be 2. Each u may be 3. Each u may be 4. Each u may be 5. Each u may be 6. Each u may be 7.

Each y may independently be 0, 1, 2, 3, 4, 5, 6 or 7. Each y may independently be 0 to 1, 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, or 0 to 7. Each y may independently be 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, or 1 to 7. Each y may independently be 2 to 3, 2 to 4, 2 to 5, 2 to 6, or 2 to 7. Each y may independently be 3 to 4, 3 to 5, 3 to 6, or 3 to 7. Each y may be 0. Each y may be 1. Each y may be 2. Each y may be 3. Each y may be 4. Each y may be 5. Each y may be 6. Each y may be 7.

Each j may independently be 0, 1, 2, 3, 4, 5, 6 or 7. Each j may independently be 0 to 1, 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, or 0 to 7. Each j may independently be 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, or 1 to 7. Each j may independently be 2 to 3, 2 to 4, 2 to 5, 2 to 6, or 2 to 7. Each j may independently be 3 to 4, 3 to 5, 3 to 6, or 3 to 7. Each j may be 0. Each j may be 1. Each j may be 2. Each j may be 3. Each j may be 4. Each j may be 5. Each j may be 6. Each j may be 7.

Each m may independently be 0, 1, 2, 3, 4, 5, 6, 7 or 8. Each m may independently be 0 to 1, 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, 0 to 7, or 0 to 8. Each m may independently be 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, or 1 to 8. Each m may independently be 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, or 2 to 8. Each m may independently be 3 to 4, 3 to 5, 3 to 6, 3 to 7, or 3 to 8. Each m may be 0. Each m may be 1. Each m may be 2. Each m may be 3. Each m may be 4. Each m may be 5. Each m may be 6. Each m may be 7. Each m may be 8.

At least one Z¹ is C-Q, at least one Z² is C-W, at least one Z³ is C-T, CH, CCH₃, CF, CC1, CBr, CI, COH, CG¹, COG¹, CNH₂, CNHG¹, CNG^, COS0₃H, COP0₃H₂, CSG¹, CSOG¹, or

and each remaining Z¹, Z² and Z³ is, at each occurrence, independently C-T, N, CH, CCH₃, CF, CC1, CBr, CI, COH, CG¹, COG¹, CNH₂, CNHG¹, CNG^, COS0₃H, COP0₃H₂, CSG¹, CSOG¹, or CSOzG¹ or at least one Z³ may independently be C-T, and each remaining Z¹, Z² and Z³ may, at each occurrence, independently be N, CH, CF, CC1, CBr, CI, CG¹, or COH. At least one Z¹ may independently be C-Q, at least one Z² or Z³ may independently be COH, and each remaining Z¹, Z² and Z³ may, at each occurrence, independently be N, CH, CF, CC1, CBr, CI, CG¹, or COH. At least one Z¹ may, at each occurrence, independently be C-Q, at least one Z² or Z³ may, at each occurrence, independently be C-T, and each remaining Z¹, Z² and Z³ may, at each occurrence, independently be N, CH, CF, CC1, CBr, CI, or COH. At least one Z¹ may independently be C-Q, at least one Z² or Z³ may independently be COH, and each remaining Z¹, Z² and Z³ may, at each occurrence, independently be N, CH, CF, CC1, CBr, CI, or COH. At least one Z¹ may independently be C-Q, at least one Z² or Z³ may independently be C-T, and each remaining Z¹, Z² and Z³ may, at each occurrence, independently be CH. At least one Z¹ may independently be C-Q, at least one Z² or Z³ may independently be COH, and each remaining Z¹, Z² and Z³ may, at each occurrence, independently be CH. In any of the foregoing embodiments, each remaining Z¹, Z² and Z³ may, at each occurrence, independently be N, CH, CF, CCl, CBr, CI, COH, CCH₃, CNH₂, COS0₃H, or COP0₃H₂, each remaining Z¹, Z² and Z³ may, at each occurrence, independently be N, CH, CF, CCl, CBr, CI, COH, CNH₂, COSO₃H, or COP0₃H₂, each remaining Z¹, Z² and Z³ may, at each occurrence, independently be N, CH, CF, CCl, CBr, CI, or COH, each remaining Z¹, Z² and Z³ may, at each occurrence, independently be CH, CF, CCl, CBr, or CI, each remaining Z¹, Z² and Z³ may, at each occurrence, independently be CH, CCl, or CBr or each remaining Z¹, Z² and Z³ may, at each occurrence, be CH.

Each of J" and J'" may independently be a moiety selected from TABLE 1. Each of J", and V" may independently be an amino acid based moiety or a polyethylene glycol based moiety selected from TABLE 1. Alternatively, each of J", and V" may independently an amino acid based moiety selected from TABLE 1. Each J", and J'" may be

Each G¹ G¹' and G¹" may independently be linear or branched, or aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated C₁-C₁₀ alkyl. Each G¹, G¹' and G¹" may independently be a branched, linear, or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated C₁-C₁₀ alkyl. Each G¹, G¹' and G¹" may independently be a branched, linear, or non- aromatic cyclic, substituted or saturated or unsaturated C₁-C₁₀ alkyl. Each G¹, G¹' and G¹" may independently be a branched, unbranched, or aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated C₁-C9 alkyl. Each G¹, G¹' and G¹" may independently be a branched, unbranched, or aromatic cyclic or non- aromatic cyclic, substituted or unsubstituted, saturated or unsaturated Ci-C₈ alkyl. Each G , G ' and G " may independently be a branched, unbranched, or aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated C₁-C7 alkyl. Each G , G ' and G " may independently be a branched, unbranched, or aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated Ci-C₆ alkyl. Each G , G ' and G " may independently be a branched, unbranched, or aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated C₁-C5 alkyl. Each G¹, G¹' and G¹" may independently be a branched, unbranched, or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated C₁-C4 alkyl. Each G , G ' and G " may independently be a branched, unbranched, or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated C₁-C3 alkyl. Each G¹, G¹' and G¹" may independently be a substituted or unsubstituted, saturated or unsaturated C1-C2 alkyl.

Each G¹ may independently be a non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated cyclopropyl. Each G¹ may independently be a non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated cyclobutyl. Each G¹ may independently be an aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated cyclobutyl. Each G¹ may independently be an aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated cyclopentyl. Each G¹ may independently be an aromatic cyclic or non- aromatic cyclic, substituted or unsubstituted, saturated or unsaturated cyclohexyl. Each G¹ may independently be an aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated cycloheptyl. Each G¹ may independently be an aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated cyclooctyl. Each G¹ may independently be cyclohexyl.

Each G¹ may independently be substituted or unsubstituted methyl. Each G¹ may independently be substituted or unsubstituted, saturated or unsaturated ethyl. Each G¹ may independently be a branched, unbranched, substituted or unsubstituted, saturated or unsaturated propyl. Each G¹ may be isopropyl. Each G¹ may independently be a branched, unbranched, substituted or unsubstituted, saturated or unsaturated butyl. Each G¹ may be n-butyl. Each G¹ may independently be a branched, unbranched, substituted or unsubstituted, saturated or unsaturated pentyl. Each G¹ may independently be a branched, unbranched, substituted or unsubstituted, saturated or unsaturated hexyl. Each G¹ may independently be a branched, unbranched, substituted or unsubstituted, saturated or unsaturated heptyl. Each G¹ may independently be a branched, unbranched, substituted or unsubstituted, saturated or unsaturated octyl. Each G¹ may be propargyl (CH₂C≡CH).

An optional substituent may be selected from the group consisting of oxo, OJ'", COOH, R⁴, OH, OR⁴, F, CI, Br, I, NH₂, NHR⁴, NR⁴ ₂, CN, SH, SR⁴, S0₃H, S0₃R⁴, S0₂R⁴, OS0₃R⁴, OR⁵, C0₂R⁴, CONH₂, CONHR⁴, CONHR⁵, CONR⁴ ₂, NHR⁵, OP0₃H₃, CONR⁴R⁵, NR⁴R⁵, and N0₂. An optional substituent may be selected from the group consisting of: oxo (i.e. =0), OJ'", COOH, R⁴, OH, OR⁴, F, CI, Br, I, NH₂, NHR⁴, NR⁴2, CN, SH, SR⁴, S0₃H, S0₃R⁴, S0₂R⁴, OS0₃R⁴, and N0₂. An optional substituent

4 4 may be selected from the group consisting of: oxo (i.e. =0), OJ'", COOH, R , OH, OR , F, CI, Br, I, NH₂, NHR⁴, NR⁴ ₂, S0₃H, S0₃R⁴, S0₂R⁴, and N0₂. An optional substituent may be selected from the group consisting of: oxo (i.e. =0), OJ'", COOH,

4 4

R , OH, OR , F, CI, Br, I, NH₂, and N0₂. An optional substituent may be selected from the group consisting of: oxo (i.e. =0), OJ'", COOH, R⁴, OH, OR⁴, F, CI, Br, and I. An optional substituent may be selected from the group consisting of: oxo (i.e. =0), OJ'", COOH, OH, F, CI, Br, and I. An optional substituent may be selected from the group consisting of: oxo (i.e. =0), OJ'", COOH, OH, F, and CI. Each linear or branched, or aromatic cyclic or non-aromatic cyclic, saturated or unsaturated Ci-Cio alkyl may be substituted with, for example, 1, 2, 3, 4, 5, or 6 substituents.

Each R may independently be a non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated cyclopropyl. Each R may independently be a non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated cyclobutyl. Each R may independently be an aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated cyclobutyl. Each R may independently be an aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated cyclopentyl. Each R may independently be an aromatic cyclic or non- aromatic cyclic, substituted or unsubstituted, saturated or unsaturated cyclohexyl. Each R may independently be an aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated cycloheptyl. Each R may independently be an aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated cyclooctyl. Each R may independently be substituted or unsubstituted methyl. Each R may independently be substituted or unsubstituted, saturated or unsaturated ethyl. Each R may independently be a branched, unbranched, substituted or unsubstituted, saturated or unsaturated propyl. Each R may be isopropyl. Each R may independently be a branched, unbranched, substituted or unsubstituted, saturated or unsaturated butyl. Each R may be n-butyl. Each R may independently be a branched, unbranched, substituted or unsubstituted, saturated or unsaturated pentyl. Each R may independently be a branched, unbranched, substituted or unsubstituted, saturated or unsaturated hexyl. Each R may independently be a branched, unbranched, substituted or unsubstituted, saturated or unsaturated heptyl. Each R may independently be a branched, unbranched, substituted or unsubstituted, saturated or unsaturated octyl.

Each R may independently be H. Each R may independently be Li. Each R may independently be Na. Each R may independently be K. Each R may independently be Mg. Each R may independently be Ca.

Each R may independently be Ci-Cio acyl. Each R may independently be C₁-C₉ acyl. Each R may independently be Ci-Cg acyl. Each R may independently be Ci- C₇ acyl. Each R may independently be Ci-C₆ acyl. Each R may independently be C₁-C5 acyl. Each R may independently be C₁-C4 acyl. Each R may independently be C₁-C₃ acyl. Each R may independently be C₁-C₂ acyl. Each R may independently be Ci acyl. Each R may independently be C₂ acyl. Each R may independently be C₃ acyl. Each R may independently be C₄ acyl. Each R may independently be C₅ acyl. Each R may independently be C₆ acyl. Each R may independently be C₇ acyl. Each R may independently be Cg acyl. Each R may independently be C₉ acyl. Each R may independently be Ci₀ acyl.

Each of R¹, R², R³ and R⁴ may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C₁-C₁₀ alkyl, or R¹ and R² or R³ and R⁴ may independently together form a substituted or unsubstituted, saturated or unsaturated cyclic C₃-C₁₀ alkyl. Each of R¹, R², R³ and R⁴ may independently be branched or unbranched, substituted or unsubstituted, saturated or unsaturated C₁-C₁₀ alkyl. Each of R¹, R², R³ and R⁴ may independently be branched or unbranched, substituted or unsubstituted, saturated or unsaturated C₁-C₉ alkyl. Each of R¹, R², R³ and R⁴ may independently be branched or unbranched, substituted or unsubstituted, saturated or unsaturated Ci-Cs alkyl. Each of R¹, R², R³ and R⁴ may independently be branched or unbranched, substituted or unsubstituted, saturated or unsaturated C₁-C₇ alkyl. Each of R¹, R², R³ and R⁴ may independently be branched or unbranched, substituted or unsubstituted, saturated or unsaturated Ci-C₆ alkyl. Each of R¹, R², R³ and R⁴ may independently be branched or unbranched, substituted or unsubstituted, saturated or unsaturated C₁-C₅ alkyl. Each of R¹, R², R³ and R⁴ may independently be branched or unbranched, substituted or unsubstituted, saturated or unsaturated C₁-C₄ alkyl. Each of R¹, R², R³ and R⁴ may independently be branched or unbranched, substituted or unsubstituted, saturated or unsaturated C₁-C₃ alkyl. Each of R¹, R², R³ and R⁴ may independently be branched or unbranched, substituted or unsubstituted, saturated or unsaturated C₁-C₂ alkyl. Each of R¹, R², R³ and R⁴ may be CH₃. R¹ and R² together may form a substituted or unsubstituted, saturated or unsaturated cyclic C₃-C₁₀ alkyl. R¹ and R² together may form an unsubstituted, saturated cyclic C₆ alkyl. R³ and R⁴ together may form a substituted or unsubstituted, saturated or unsaturated cyclic C₃-C₁₀ alkyl. R³ and R⁴ together may form an unsubstituted, saturated cyclic C₆ alkyl. Each of R¹ and R² and R³ and R⁴ may together form a substituted or unsubstituted, saturated or unsaturated cyclic C₃-C₁₀ alkyl. Each of R¹ and R² and R³ and R⁴ may together form an unsubstituted, saturated cyclic C₆ alkyl.

Each R⁵ may independently be unsubstituted C₁-C₁₀ alkyl. Each R⁵ may independently be unsubstituted C₁-C₉ alkyl. Each R⁵ may independently be unsubstituted Ci-C₈ alkyl. Each R⁵ may independently be unsubstituted C₁-C₇ alkyl. Each R⁵ may independently be unsubstituted Ci-C₆ alkyl. Each R⁵ may independently be unsubstituted C₁-C₅ alkyl. Each R⁵ may independently be unsubstituted C₁-C₄ alkyl. Each R⁵ may independently be unsubstituted C₁-C₃ alkyl. Each R⁵ may independently be unsubstituted Ci-C₂ alkyl. Each R⁵ may independently be unsubstituted Ci alkyl. Each R⁵ may independently be unsubstituted C₂ alkyl. Each R⁵ may independently be unsubstituted C₃ alkyl. Each R⁵ may independently be unsubstituted C₄ alkyl. Each R⁵ may independently be unsubstituted C₅ alkyl. Each R⁵ may independently be unsubstituted C₆ alkyl. Each R⁵ may independently be unsubstituted C₇ alkyl. Each R⁵ may independently be unsubstituted Cg alkyl. Each R⁵ may independently be unsubstituted C₉ alkyl. Each R⁵ may independently be unsubstituted C₁₀ alkyl.

Each R⁶ may independently be C₁-C₁₀ acyl. Each R⁶ may independently be C₁-C₉ acyl. Each R⁶ may independently be Ci-Cg acyl. Each R⁶ may independently be C₁-C7 acyl. Each R⁶ may independently be Ci-C₆ acyl. Each R⁶ may independently be C₁-C5 acyl. Each R⁶ may independently be C₁-C4 acyl. Each R⁶ may independently be C₁-C₃ acyl. Each R⁶ may independently be C₁-C₂ acyl. Each R⁶ may independently be Ci acyl. Each R⁶ may independently be C₂ acyl. Each R⁶ may independently be C₃ acyl. Each R⁶ may independently be C₄ acyl. Each R⁶ may independently be C₅ acyl. Each R⁶ may independently be C₆ acyl. Each R⁶ may independently be C₇ acyl. Each R⁶ may independently be Cs acyl. Each R⁶ may independently be C9 acyl. Each R⁶ may independently be Ci₀ acyl.

7 8 9 10 11 12

R , R , R , R . R and R are each independently hydrogen, halo, or linear or branched, substituted or unsubstituted, saturated or unsaturated C₁-C₁₀ alkyl. R⁷, R⁸, R⁹, R¹⁰. R¹¹ and R¹² are each independently hydrogen. At least one of R⁷, R⁸, R⁹, R¹⁰. R¹¹ or R¹² is independently hydrogen. R⁷, R⁸, R⁹, R¹⁰. R¹¹ and R¹² are each independently fiuoro. At least one of 7 8 9 10 11 12

R', R°, R R . R or R is independently fiuoro. R⁷, R⁸, R⁹, R¹⁰. R¹¹ and R¹² are each independently chloro. At least one of R⁷, R⁸, R⁹, R¹⁰. R¹¹ or R¹² is independently chloro. R⁷, R⁸, R⁹, R¹⁰. R¹¹ and R¹² are each independently bromo. At least one of 7 8 9 10 11 12

R', R°, R R . R or R is independently bromo. 7 8 9 10 11 12 least one of 7 R', R°, R", R . R and R are each independently methyl. At R , R⁸, R⁹, R¹⁰. R¹¹ or R¹² is independently methyl. R⁷, R⁸, R⁹, R¹⁰. R¹¹ and R¹² are each independently ethyl. At least one of 7 8 9 10 11 12

R', R°, R R . R or R is independently ethyl. R⁷, R⁸, R⁹, R¹⁰. R¹¹ and R¹² are each independently C₃ alkyl. At least one of R⁷, R⁸, R⁹, R¹⁰. R¹¹ or R¹² is independently C₃ alkyl. R⁷, R⁸, R⁹, R¹⁰. R¹¹ and R¹² are each independently C₄ alkyl. At least one of R⁷, R⁸, R⁹, R¹⁰. R¹¹ or R¹² is independently C₄ alkyl. R⁷, R⁸, R⁹, R¹⁰. R¹¹ and R¹² are each independently C₅ alkyl. At least one of R⁷, R⁸, R⁹, R¹⁰. R¹¹ or R¹² is independently C₅ alkyl. R⁷, R⁸, R⁹, R¹⁰. R¹¹ and R¹² are each independently C₆ alkyl. At least one of R⁷, R⁸, R⁹, R¹⁰. R¹¹ or R¹² is independently C₆ alkyl. R⁷, R⁸, R⁹, R¹⁰. R¹¹ and R¹² are each independently C₇ alkyl. At least one of R⁷, R⁸, R⁹, R¹⁰. R¹¹ or R¹² is independently C₇ alkyl. R⁷, R⁸, R⁹, R¹⁰. R¹¹ and R¹² are each independently C₈ alkyl. At least one of R⁷, R⁸, R⁹, R¹⁰. R¹¹ or R¹² is independently C₈ alkyl. R⁷, R⁸, R⁹, R¹⁰. R¹¹ and R¹² are each independently C₉ alkyl. At least one of R⁷, R⁸, R⁹, R¹⁰. R¹¹ or R¹² is independently C₉ alkyl. R⁷, R⁸, R⁹, R¹⁰. R¹¹ and R¹² are each independently C₁₀ alkyl. At least one of R⁷, R⁸, R⁹, R¹⁰. R¹¹ or R¹² is independently C₁₀ alkyl. The compounds described herein are meant to include all racemic mixtures and all individual enantiomers or combinations thereof, whether or not they are specifically depicted herein. Alternatively, one or more of the OH groups on the above compounds may be substituted to replace the H with a moiety selected from TABLE 1.

In yet other embodiments, the present disclosure provide the use of any of the compounds disclosed herein for modulating androgen receptor (AR) activity. For example, in certain embodiments modulating androgen receptor (AR) activity is in a mammalian cell.

In other examples, modulating androgen receptor (AR) activity is for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration. For example, in certain embodiments the indication is prostate cancer, for example, castration resistant prostate cancer. In other examples, the prostate cancer is androgen-dependent prostate cancer. In other further embodiments, the spinal and bulbar muscular atrophy is Kennedy's disease.

The present disclosure also provides a method of modulating androgen receptor (AR) activity, the method comprising administering any of the compounds disclosed herein, or pharmaceutically acceptable salt thereof, to a subject in need thereof. For example, in certain specific embodiments modulating androgen receptor (AR) activity is for the treatment of one or more of the following: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration. In certain embodiments, the spinal and bulbar muscular atrophy is Kennedy's disease.

The present disclosure also provides a pharmaceutical composition comprising any one or more of the compounds disclosed herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may be for treating one or more of the following: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration.

In accordance with another embodiment, there is provided a use of the compounds of Formula (I) as described anywhere herein for preparation of a medicament for modulating androgen receptor (AR).

In accordance with a further embodiment, there is provided a method of screening for androgen receptor modulating compounds, wherein the compounds screened are selected from the compounds as described anywhere herein.

The modulating of the androgen receptor (AR) activity may be in a mammalian cell. The modulating of the androgen receptor (AR) activity may be in a mammal. The mammal may be a human.

Alternatively, the administering may be to a mammal. The administering may be to a mammal in need thereof and in an effective amount for the treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy (e.g., Kennedy's disease), and age-related macular degeneration.

The mammalian cell may be a human cell. The modulating AR activity may be for inhibiting AR N-terminal domain activity. The modulating AR activity may be for inhibiting AR activity. The modulating may be in vivo. The modulating AR activity may be for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy (e.g., Kennedy's disease), and age-related macular degeneration. The indication may be prostate cancer. The prostate cancer may be castration-resistant prostate cancer. The prostate cancer may be androgen-dependent prostate cancer. TABLE 1. Amino Acid, Polyethylene Glycol, and Phosphate Based Moieties

Moieties from TABLE 1 may be, for example, and without limitation, subdivided into three groups: 1) amino acid based moieties; 2) polyethylene glycol based moieties; and 3) phosphate based moieties. In the Moieties Table 1 above, the first four moieties are amino acid based moieties, the fifth and sixth are polyethylene glycol based moieties and the remaining moieties are phosphate based moieties.

The amino acid side chains of naturally occurring amino acids (as often denoted herein using "(aa)") are well known to a person of skill in the art and may be found in a variety of text books such as "Molecular Cell Biology" by James Darnell et al. Third Edition, published by Scientific American Books in 1995. Often the naturally occurring amino acids are represented by the formula (NH₂)C(COOH)(H)(R), where the chemical groups in brackets are each bonded to the carbon not in brackets. R represents the side chains in this particular formula.

Those skilled in the art will appreciate that the point of covalent attachment of the moiety to the compounds as described herein may be, for example, and without limitation, cleaved under specified conditions. Specified conditions may include, for example, and without limitation, in vivo enzymatic or non-enzymatic means. Cleavage of the moiety may occur, for example, and without limitation, spontaneously, or it may be catalyzed, induced by another agent, or a change in a physical parameter or environmental parameter, for example, an enzyme, light, acid, temperature or pH. The moiety may be, for example, and without limitation, a protecting group that acts to mask a functional group, a group that acts as a substrate for one or more active or passive transport mechanisms, or a group that acts to impart or enhance a property of the compound, for example, solubility, bioavailability or localization.

In other particular embodiments of the compounds as described anywhere herein, the following compounds in Table 2 are provided.

TABLE 2. Re resentative Compounds

Prodrugs are also included within the scope of the present disclosure. For example, in one embodiment the hydrogen atom of one or more hydroxyl groups of any of the compounds of Formula I may be replaced with a moiety from Table 1. Non- limiting examples of such prodrugs include glycine esters and salts thereof as shown below.

In some embodiments, the compounds as described herein or acceptable salts thereof above may be used for systemic treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration. In some embodiments, the compounds as described herein or acceptable salts thereof above may be used in the preparation of a medicament or a composition for systemic treatment of an indication described herein. In some embodiments, methods of systemically treating any of the indications described herein are also provided. Some aspects of this invention, make use of compositions comprising a compound described herein and a pharmaceutically acceptable excipients or carrier. In some embodiments, the prostate cancer is castration-resistant prostate cancer (also referred to as hormone refractory, androgen-independent, androgen deprivation resistant, androgen ablation resistant, androgen depletion-independent, castration- recurrent, anti-androgen-recurrent). In some embodiments the prostate cancer is androgen-dependent or androgen-sensitive. Methods of treating any of the indications described herein are also provided. Such methods may include administering a compound as described herein or a composition of a compound as described herein, or an effective amount of a compound as described herein or composition of a compound as described herein to a subject in need thereof.

Compounds as described herein may be in the free form or in the form of a salt thereof. In some embodiments, compounds as described herein may be in the form of a pharmaceutically acceptable salt, which are known in the art (Berge et al., J. Pharm. Sci. 1977, 66, 1). Pharmaceutically acceptable salt as used herein includes, for example, salts that have the desired pharmacological activity of the parent compound (salts which retain the biological effectiveness and/or properties of the parent compound and which are not biologically and/or otherwise undesirable). Compounds as described herein having one or more functional groups capable of forming a salt may be, for example, formed as a pharmaceutically acceptable salt. Compounds containing one or more basic functional groups may be capable of forming a pharmaceutically acceptable salt with, for example, a pharmaceutically acceptable organic or inorganic acid. Pharmaceutically acceptable salts may be derived from, for example, and without limitation, acetic acid, adipic acid, alginic acid, aspartic acid, ascorbic acid, benzoic acid, benzenesulfonic acid, butyric acid, cinnamic acid, citric acid, camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid, diethylacetic acid, digluconic acid, dodecylsulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, glucoheptanoic acid, gluconic acid, glycerophosphoric acid, glycolic acid, hemisulfonic acid, heptanoic acid, hexanoic acid, hydrochloric acid, hydrobromic acid, hydriodic acid, 2- hydroxyethanesulfonic acid, isonicotinic acid, lactic acid, malic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-napthalenesulfonic acid, naphthalenedisulphonic acid, p-toluenesulfonic acid, nicotinic acid, nitric acid, oxalic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, phosphoric acid, picric acid, pimelic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, succinic acid, sulfuric acid, sulfamic acid, tartaric acid, thiocyanic acid or undecanoic acid. Compounds containing one or more acidic functional groups may be capable of forming pharmaceutically acceptable salts with a pharmaceutically acceptable base, for example, and without limitation, inorganic bases based on alkaline metals or alkaline earth metals or organic bases such as primary amine compounds, secondary amine compounds, tertiary amine compounds, quaternary amine compounds, substituted amines, naturally occurring substituted amines, cyclic amines or basic ion-exchange resins. Pharmaceutically acceptable salts may be derived from, for example, and without limitation, a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation such as ammonium, sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese or aluminum, ammonia, benzathine, meglumine, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2- dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine, procaine, N- ethylpiperidine, theobromine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, Ν,Ν-dimethylaniline, N-methylpiperidine, morpholine, N- methylmorpholine, N-ethylmorpholine, dicyclohexylamine, dibenzylamine, N,N- dibenzylphenethylamine, 1-ephenamine, Ν,Ν'-dibenzylethylenediamine or polyamine resins. In some embodiments, compounds as described herein may contain both acidic and basic groups and may be in the form of inner salts or zwitterions, for example, and without limitation, betaines. Salts as described herein may be prepared by conventional processes known to a person skilled in the art, for example, and without limitation, by reacting the free form with an organic acid or inorganic acid or base, or by anion exchange or cation exchange from other salts. Those skilled in the art will appreciate that preparation of salts may occur in situ during isolation and purification of the compounds or preparation of salts may occur by separately reacting an isolated and purified compound.

In some embodiments, compounds and all different forms thereof (e.g. free forms, salts, polymorphs, isomeric forms) as described herein may be in the solvent addition form, for example, solvates. Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent in physical association the compound or salt thereof. The solvent may be, for example, and without limitation, a pharmaceutically acceptable solvent. For example, hydrates are formed when the solvent is water or alcoholates are formed when the solvent is an alcohol.

In some embodiments, compounds and all different forms thereof (e.g. free forms, salts, solvates, isomeric forms) as described herein may include crystalline and amorphous forms, for example, polymorphs, pseudopolymorphs, conformational polymorphs, amorphous forms, or a combination thereof. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and/or solubility. Those skilled in the art will appreciate that various factors including recrystallization solvent, rate of crystallization and storage temperature may cause a single crystal form to dominate. In some embodiments, compounds and all different forms thereof (e.g. free forms, salts, solvates, polymorphs) as described herein include isomers such as geometrical isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomers, individual enantiomers, individual diastereomers, racemates, diastereomeric mixtures and combinations thereof, and are not limited by the description of the formula illustrated for the sake of convenience.

In some embodiments, pharmaceutical compositions in accordance with this invention may comprise a salt of such a compound, preferably a pharmaceutically or physiologically acceptable salt. Pharmaceutical preparations will typically comprise one or more carriers, excipients or diluents acceptable for the mode of administration of the preparation, be it by injection, inhalation, topical administration, lavage, or other modes suitable for the selected treatment. Suitable carriers, excipients or diluents are those known in the art for use in such modes of administration.

Suitable pharmaceutical compositions may be formulated by means known in the art and their mode of administration and dose determined by the skilled practitioner. For parenteral administration, a compound may be dissolved in sterile water or saline or a pharmaceutically acceptable vehicle used for administration of non-water soluble compounds such as those used for vitamin K. For enteral administration, the compound may be administered in a tablet, capsule or dissolved in liquid form. The tablet or capsule may be enteric coated, or in a formulation for sustained release. Many suitable formulations are known, including, polymeric or protein microparticles encapsulating a compound to be released, ointments, pastes, gels, hydrogels, or solutions which can be used topically or locally to administer a compound. A sustained release patch or implant may be employed to provide release over a prolonged period of time. Many techniques known to one of skill in the art are described in Remington: the Science & Practice of Pharmacy by Alfonso Gennaro, 20^th ed., Lippencott Williams & Wilkins, (2000). Formulations for parenteral administration may, for example, contain excipients, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxy ethylene -polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems for modulatory compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.

Compounds or pharmaceutical compositions in accordance with this invention or for use in this invention may be administered by means of a medical device or appliance such as an implant, graft, prosthesis, stent, etc. Also, implants may be devised which are intended to contain and release such compounds or compositions. An example would be an implant made of a polymeric material adapted to release the compound over a period of time.

An "effective amount" of a pharmaceutical composition according to the invention includes a therapeutically effective amount or a prophylactically effective amount. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as reduced tumor size, increased life span or increased life expectancy. A therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as smaller tumors, increased life span, increased life expectancy or prevention of the progression of prostate cancer to an androgen-independent form. Typically, a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount may be less than a therapeutically effective amount.

It is to be noted that dosage values may vary with the severity of the condition to be alleviated. For any particular subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgement of the person administering or supervising the administration of the compositions. Dosage ranges set forth herein are exemplary only and do not limit the dosage ranges that may be selected by medical practitioners. The amount of active compound(s) in the composition may vary according to factors such as the disease state, age, sex, and weight of the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.

In some embodiments, compounds and all different forms thereof as described herein may be used, for example, and without limitation, in combination with other treatment methods for at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration. For example, compounds and all their different forms as described herein may be used as neoadjuvant (prior), adjunctive (during), and/or adjuvant (after) therapy with surgery, radiation (brachytherapy or external beam), or other therapies (eg. HIFU), and in combination with chemotherapies, androgen ablation, antiandrogens or any other therapeutic approach.

With respect to combination therapies, one embodiment of the present disclosure provides a combination of any one or more of a compound of Formula I with one or more currently-used or experimental pharmacological therapies which are or may be utilized to treat any of the above disease states (e.g., androgen-independent prostate cancer or Kennedy's disease). Methods, uses and pharmaceutical compositions comprising the above combination are also provided. Combination therapies for such indications are disclosed in co-pending U.S. Provisional Application No. 61/384,628, which is hereby incorporated by reference in its entirety.

Surprisingly, it has been found that the disclosed compounds, which interfere with the AR principally through binding to the N-terminus of the AR, demonstrate beneficial synergistic therapeutic effects when used in concert with existing approved and in-development agents. That is, the biological impact of using the agents in concert with one another produces a biological and therapeutic effect which is greater than the simple additive effect of each of them separately.

Accordingly, one embodiment comprises the use of the disclosed compounds in combination therapy with one or more currently-used or experimental pharmacological therapies which are utilized for treating the above disease states irrespective of the biological mechanism of action of such pharmacological therapies, including without limitation pharmacological therapies which directly or indirectly inhibit the androgen receptor, pharmacological therapies which are cyto-toxic in nature, and pharmacological therapies which interfere with the biological production or function of androgen (hereinafter, the "Other Therapeutic Agents"). By "combination therapy" is meant the administration of any one or more of a coumpound of Formula I with one or more of another therapueitc agent to the same patient such that their pharmacological effects are contemporaneous with one another, or if not contemporaneous, that their effects are synergistic with one another even though dosed sequentially rather than contemporaneously.

Such administration includes without limitation dosing of one or more of a compound of Formula I and and one or more of the Other Therapeutic Agent(s) as separate agents without any comingling prior to dosing, as well as formulations which include one or more Other Androgen-Blocking Therapeutic Agents mixed with one or more compound of Formula I as a pre -mixed formulation. Administration of the compound(s) of Formula I in combination with Other Therapeutic Agents for treatment of the above disease states also includes dosing by any dosing method including without limitation, intravenous delivery, oral delivery, intra-peritoneal delivery, intramuscular delivery, or intra-tumoral delivery.

In another aspect of the present disclosure, the one or more of the Other Therapeutic Agent may be administered to the patient before administration of the compound(s) of Formula I. In another embodiment, the compound(s) of Formula I may be co-administered with one or more of the Other Therapeutic Agents. In yet another aspect, the one or more Other Therapeutic Agent may be administered to the patient after administration of the compound(s) of Formula I.

It is fully within the scope of the disclosure that the ratio of the doses of compound(s) of Formula I to that of the one or more Other Therapeutic Agents may or may not equal to one and may be varied accordingly to achieve the optimal therapeutic benefit.

For greater clarity the compound(s) of Formula I that are combined with the one or more Other Therapeutic Agents for improved treatment of the above disease states may comprise, but are not limited to any compound having a structure of Formula I, including those compounds shown in Table 2.

The Other Therapeutic Agents include without limitation any pharmacological agent which is currently approved by the FDA in the U.S. (or elsewhere by any other regulatory body) for use as pharmacological treatment of any of the above disease states, or which is currently being used experimentally as part of a clinical trial program that relates to the above disease states. Non-limiting examples of the Other Pharmacological Agents comprise, without limitation: the chemical entity known as MDV3100 (4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide) and related compounds, which appears to be a blocker of the AR LBD and is currently in development as a treatment for prostate cancer; the chemical entity known as TOK 001 and related compounds which appears to be a blocker of the AR LBD, and a CYP17 lyase inhibitor, and also appears to decrease overall androgen receptor levels in prostate cancer cells. TOK 001 is currently in development as a treatment for prostate cancer; the chemical entity known as ARN-509 and related compounds which appears to be a blocker of the AR LBD and is currently in development as a treatment for prostate cancer; the chemical entity known as abiraterone (or CB-7630; (3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17- (pyridin-3-yl) 2,3,4,7,8,9,10,11,12,13, 14,15-dodecahydro-lH- cyclopenta[a]phenanthren-3-ol), and related molecules, which appears to block the production of androgen and is currently in development for the treatment of prostate cancer; the chemical entity known as bicalutamide (N-[4-cyano-3- (trifluoromethyl)phenyl] -3 - [(4-fluorophenyl)sulfonyl] -2-hydroxy-2- methylpropanamide) and related compounds, which appears to be a blocker of the AR LBD and which is currently used to treat prostate cancer, the chemical entity known as nilutamide (5 ,5 -dimethyl-3 - [4-nitro-3 -(trifluoromethyl)phenyl] imidazolidine-2,4- dione) and related compounds, which appears to be a blocker of the AR LBD and which is currently used to treat prostate cancer, the chemical entity known as flutamide (2- methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide) and related compounds, which appears to be a blocker of the AR LBD and which is currently used to treat prostate cancer, the chemical entities know as cyproterone acetate (6-ΰΜθΓθ-1β,2β- dihydro- 17-hydroxy-3 'H-cyclopropa[ 1 ,2]pregna-4,6-diene-3 ,20-dione) and related compounds, which appears to be a blocker of the AR LBD and which is currently used to treat prostate cancer, the chemical entity known as docetaxel (Taxotere; 1,7β,10β- trihydroxy-9-oxo-5P,20-epoxytax-l l-ene-2a,4,13a-triyl 4-acetate 2-benzoate 13- {(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate}) and related compounds, which appears to be a cytotoxic antimicrotubule agent and is currently used in combination with prednisone to treat prostate cancer, the chemical entity known as Bevacizumab (Avastin), a monoclonal antibody that recognizes and blocks vascular endothelial growth factor A (VEGF-A) and may be used to treat prostate cancer, the chemical entity known as QSU-HDAC42 ((S)-( )~N-liydroxy-4-(3~n\ethyl-2- phenylbutyiylamiiioi-benzarnide), and related compounds, which appears to act as a histone deacetylase inhibitor, and is currently being developed as a treatment for prostate cancer, the chemical entity known as VITAXIN which appears to be a monoclonal antibody against the vascular integrin ανβ3 to prevent angiogenesis, and which may be used to treat prostate cancer, the chemical entity known as sunitumib (N- (2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-lH-indol-3-ylidene)methyl]-2,4- dimethyl-lH-pyrrole-3-carboxamide) and related compounds, which appears to inhibit multiple receptor tyrosine kinases (RTKs) and may be used for treatment of prostate cancer, the chemical entity known as ZD-4054 (N~(3~Methoxy~5-methylpyrazin~2-yl)- 2~[4~(1 ,4<>xadiazoi-2-y])phenyl]pyi^,iditi-3-suifotianiid) and related compounds, which appears to block the edta receptor and which may be used for treatment of prostate cancer, the chemical entity known as VN/ 124-1 (3 β-Hy droxy- i 7-( .1 H~benzimidazol~ 1 - yI)androsta-5 , 16~diene), and related compounds which appears to block the production of androgen (via inhibition of -hydroxylase/17,20 lyase) and is currently in development for the treatment of prostate cancer; the chemical entity known as Cabazitaxel (XRP-6258), and related compounds, which appears to be a cytotoxic microtubule inhibitor, and which is currently used to treat prostate cancer; the chemical entity known as MDX-01G (Ipilimumab), a fully human monoclonal antibody that binds to and blocks the activity of CTLA-4 which is currently in development as an immunotherapeutic agent for treatment of prostate cancer; the chemical entity known as OCX 427 which appears to target HSP27 as an antisense agent, and which is currently in development for treatment of prostate cancer; the chemical entity known as OGX Oi l which appears to target clusterin as an antisense agent, and which is currently in development as a treatment for prostate cancer; the chemical entity known as finasteride (Proscar, Propecia; N-(l , 1 -dimethylethyl)-3-oxo-(5 , 17P)-4-azaandrost- 1 -ene- 17- carboxamide), and related compounds, which appears to be a 5-alpha reductase inhibitor that reduces levels of dihydrotestosterone, and may be used to treat prostate cancer; the chemical entity known as dutasteride (Avodart; 5a, 17β)-Ν-{2,5 bis(trifluoromethyl) phenyl} -3-oxo-4-azaandrost-l-ene-17-carboxamide) and related molecules, which appears to be a 5-alpha reductase inhibitor that reduces levels of dihydrotestosterone, and may be used in the treatment of prostate cancer; the chemical entity known as turosteride ((4aR,4bS,6aS,7S,9aS,9bS,l laR)-l,4a,6a-trimethyl-2-oxo- N-(propan-2-yl)-N-(propan-2 ylcarbamoyl)hexadecahydro-lH-indeno[5,4-f]quinoline- 7-carboxamide), and related molecules, which appears to be a 5-alpha reductase inhibitor that reduces levels of dihydrotestosterone and may be used in the treatment of prostate cancer; the chemical entity known as bexlosteride (LY-191,704; (4aS,10bR)-8- chloro-4-methyl-l,2,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one), and related compounds, which appears to be a 5-alpha reductase inhibitor that reduces levels of dihydrotestosterone and may be used in the treatment of prostate cancer; the chemical entity known as izonsteride (LY-320,236; (4aR,10bR)-8-[(4-ethyl-l,3-benzothiazol-2- yl)sulfanyl]-4,10b-dimethyl-l ,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one) and related compounds, which appears to be a 5-alpha reductase inhibitor that reduces levels of dihydrotestosterone and may be used for the treatment of prostate cancer; the chemical entity known as FCE 28260 and related compounds, which appears to be a 5- alpha reductase inhibitor that reduces levels of dihydrotestosterone and may be used for the treatment of prostate cancer; the chemical entity known as SKF 105,111, and related compounds, which appears to be a 5-alpha reductase inhibitor that reduces levels of dihydrotestosterone and may be used for treatment of prostate cancer.

In general, compounds of the invention should be used without causing substantial toxicity. Toxicity of the compounds of the invention can be determined using standard techniques, for example, by testing in cell cultures or experimental animals and determining the therapeutic index, i.e.,, the ratio between the LD50 (the dose lethal to 50% of the population) and the LD100 (the dose lethal to 100% of the population). In some circumstances however, such as in severe disease conditions, it may be necessary to administer substantial excesses of the compositions. Some compounds of this invention may be toxic at some concentrations. Titration studies may be used to determine toxic and non-toxic concentrations. Toxicity may be evaluated by examining a particular compound's or composition's specificity across cell lines using PC3 cells as a negative control that do not express functional AR. Animal studies may be used to provide an indication if the compound has any effects on other tissues. Systemic therapy that targets the AR will not likely cause major problems to other tissues since antiandrogens and androgen insensitivity syndrome are not fatal.

Compounds as described herein may be administered to a subject. As used herein, a "subject" may be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat and the like. The subject may be suspected of having or at risk for having a cancer, such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, or endometrial cancer, or suspected of having or at risk for having acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration. Diagnostic methods for various cancers, such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, or endometrial cancer, and diagnostic methods for acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration and the clinical delineation of cancer, such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, or endometrial cancer, diagnoses and the clinical delineation of acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration are known to those of ordinary skill in the art.

Compounds described herein may be used for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration. Compounds described herein may be used for treatment of prostate cancer. Compounds described herein may be used for treatment of castration-resistant prostate cancer. Compounds described herein may be used for treatment of androgen-dependent prostate cancer. Compounds described herein may be used for preparation of a medicament for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration. Compounds described herein may be used for the preparation of a medicament for treatment of prostate cancer. Compounds described herein may be used for the preparation of a medicament for treatment of castration- resistant prostate cancer. Compounds described herein may be used for the preparation of a medicament for treatment of androgen-dependent prostate cancer. Compounds described herein may be used in a method for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration. The method may comprise administering to a subject in need thereof an effective amount of a compound described herein. Compounds described herein may be used in a method of treatment of prostate cancer, the method comprising administering to a subject in need thereof an effective amount of a compound described herein. Compounds described herein may be used in a method of treatment of castration resistant prostate cancer, the method comprising administering to a subject in need thereof an effective amount of a compound described herein. Compounds described herein may be used in a method of treatment of androgen-dependent prostate cancer, the method comprising administering to a subject in need thereof an effective amount of a compound described herein.

Compounds described herein may also be used in assays and for research purposes. Definitions used include ligand-dependent activation of the androgen receptor (AR) by androgens such as dihydrotestosterone (DHT) or the synthetic androgen (R1881) used for research purposes. Ligand-independent activation of the AR refers to transactivation of the AR in the absence of androgen (ligand) by, for example, stimulation of the cAMP-dependent protein kinase (PKA) pathway with forskolin (FSK). Some compounds and compositions of this invention may inhibit both FSK and androgen (e.g. R1881) induction of ARE-luciferase (ARE-luc). Constituative activity of the AR refers to splice variants lacking the AR ligand-binding domain. Such compounds may block a mechanism that is common to both ligand-dependent and ligand-independent activation of the AR, as well as constitutively active splice variants of the AR that lack ligand-binding domain. This could involve any step in activation of the AR including dissociation of heatshock proteins, essential posttranslational modifications (e.g., acetylation, phosphorylation), nuclear translocation, protein-protein interactions, formation of the transcriptional complex, release of co-repressors, and/or increased degradation. Some compounds and compositions of this invention may inhibit ligand-only activityand may interfere with a mechanism specific to ligand-dependent activation (e.g., accessibility of the ligand binding domain (LBD) to androgen). Numerous disorders in addition to prostate cancer involve the androgen axis (e.g., acne, hirsutism, alopecia, benign prostatic hyperplasia) and compounds interfering with this mechanism may be used to treat such conditions. Some compounds and compositions of this invention may only inhibit FSK induction and may be specific inhibitors to ligand-independent activation of the AR. These compounds and compositions may interfere with the cascade of events that normally occur with FSK and/or PKA activity or any downstream effects that may play a role on the AR (e.g. FSK increases MAPK activity which has a potent effect on AR activity). Examples may include an inhibitor of cAMP and or PKA or other kinases. Some compounds and compositions of this invention may induce basal levels of activity of the AR (no androgen or stimulation of the PKA pathway). Some compounds and compositions of this invention may increase induction by R1881 or FSK. Such compounds and compositions may stimulate transcription or transactivation of the AR. Some compounds and compositions of this invention may inhibit activity of the androgen receptor. Interleukin-6 (IL-6) also causes ligand-independent activation of the AR in LNCaP cells and can be used in addition to FSK.

Compounds for use in the present invention may be obtained from medical sources or modified using known methodologies from naturally occurring compounds. In addition, methods of preparing or synthesizing compounds of the present invention will be understood by a person of skill in the art having reference to known chemical synthesis principles. For example, Auzou et al 1974 European Journal of Medicinal Chemistry 9(5), 548-554 describes suitable synthetic procedures that may be considered and suitably adapted for preparing compounds of any one of the Formula I to XXI as set out above. Other references that may be helpful include: Debasish Das, Jyh-Fu Lee and Soofin Cheng "Sulfonic acid functionalized mesoporous MCM-41 silica as a convenient catalyst for Bisphenol-A synthesis" Chemical Communications, (2001) 2178-2179; US Patent 2571217 Davis, Orris L.; Knight, Horace S.; Skinner, John R. (Shell Development Co.) "Halohydrin ethers of phenols." (1951); and Rokicki, G.; Pawlicki, J.; Kuran, W. "Reactions of 4-chloromethyl-l ,3-dioxolan-2-one with phenols as a new route to polyols and cyclic carbonates." Journal fuer Praktische Chemie (Leipzig) (1985) 327, 718-722.

For example, compounds of the present invention which contain an ether moiety (e.g., compounds having Formulas X or XI) may be obtained with reference to the following general chemical synthetic Scheme I:

General Reaction Scheme

Referring to the above General Reaction Scheme, compounds of structure A, wherein R^J-R¹² are as defined herein, can be purchased or prepared according to methods known in the art. Reaction of A with acetonide B, wherein n is as defined herein and X is a suitable leaving group (e.g., chloro and the like), produces compounds of structure C. Subsequent reaction of C with D, wherein m is as defined herein and X is a suitable leaving group (e.g., chloro and the like), yields E. Finally, opening of the acetonide and/or epoxide rings of E by treatment with a sutiable reagent (e.g., CeCl₃, and the like) produces compounds of structure X or XII.

One skilled in the art will recognize that certain variations to the above general methodology are possible in order to prepare various embodiments of the present disclosure. For example, in one embodiment, a starting material comprising various Z¹, Z² and/or Z³ moieties may be used to produce different compounds of structure I. In addition, the order of reaction may be changed and/or bis acetonides or bis epoxides may prepared and opened according to the above methodolgy. Further, various embodiments may be prepared without the use of the epoxide and/or acetonide intermediates shown above. For example, certain embodiments may be prepared by reaction of A with a suitable alkylating reagent to produce any of the ether-containing compounds described herein.

Various alternative embodiments and examples of the invention are described herein. These embodiments and examples are illustrative and should not be construed as limiting the scope of the invention.

I l l EXAMPLES

All non-aqueous reactions were performed in flame-dried round bottomed flasks. The flasks were fitted with rubber septa and reactions were conducted under a positive pressure of argon unless otherwise specified. Stainless steel syringes were used to transfer air- and moisture-sensitive liquids. Flash column chromatography was performed as described by Still et al. (Still, W. C; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923) using 230-400 mesh silica gel. Thin-layer chromatography was performed using aluminium plates pre-coated with 0.25 mm 230-400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Thin-layer chromatography plates were visualized by exposure to ultraviolet light and a "Seebach" staining solution (700 mL water, 10.5 g Cerium (IV) sulphate tetrahydrate, 15.0 g molybdato phosphoric acid, 17.5 g sulphuric acid) followed by heating (~1 min) with a heating gun (-250 °C). Organic solutions were concentrated on Buchi R-114 rotatory evaporators at reduced pressure (15-30 torr, house vacuum) at 25-40 °C.

Commercial regents and solvents were used as received. All solvents used for extraction and chromatography were HPLC grade. Normal-phase Si gel Sep paks™ were purchased from waters, Inc. Thin-layer chromatography plates were Kieselgel 6OF254. All synthetic reagents were purchased from Sigma Aldrich and Fisher Scientific Canada.

Proton nuclear magnetic resonance (1H NMR) spectra were recorded at 25 °C using a Bruker 400 with inverse probe and Bruker 400 spectrometers, are reported in parts per million on the δ scale, and are referenced from the residual protium in the NMR solvent (DMSO-d₆: δ 2.50 (DMSO-d₅), CDC1₃: δ 7.24 (CHC1₃)). Carbon- 13 nuclear magnetic resonance (¹³C NMR) spectra were recorded with a Bruker 400 spectrometer, are reported in parts per million on the δ scale, and are referenced from the carbon resonances of the solvent (DMSO-d₆: δ 39.51, CDC1₃: δ 77.00). Spectral features are tabulated in the following order: chemical shift (δ, ppm); multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, br = broad); coupling constant (J, Hz, number of protons).

LNCaP cells were employed initially for all experiments because they are well-differentiated human prostate cancer cells in which ligand-independent activation of the AR by FSK has been characterized (Nazareth et al 1996 J. Biol. Chem. 271, 19900-19907; and Sadar 1999 J. Biol. Chem. 274, 7777-7783). LNCaP cells express endogenous AR and secrete prostate-specific antigen (PSA) (Horoszewicz et al 1983 Cancer Res. 43, 1809-1818). LNCaP cells can be grown either as monolayers in cell culture or as tumors in the well-characterized xenograft model that progresses to androgen independence in castrated hosts (Sato et al 1996 J. Steroid Biochem. Mol. Biol. 58, 139-146; Gleave et al 1991 Cancer Res. 51, 3753-3761; Sato et al 1997 Cancer Res. 57, 1584-1589; and Sadar et al 2002 Mol. Cancer Ther. 1(8), 629-637). R1881 was employed since it is stable and avoids problems associated with the labile physiological ligand dihydrotestosterone (DHT). Reporter specificity may be determined using several alternative reporter gene constructs. Some well characterized ARE-driven reporter gene constructs that have been used extensively are the PSA (6.1 kb) enhance/promoter which contains several AREs and is highly inducible by androgens as well as by FSK (Ueda et al 2002 A J. Biol. Chem. 277, 7076-7085) and the ARR3 -thymidine kinase (tk)-luciferase, which is an artificial reporter construct that contains three tandem repeats of the rat probasin AREl and ARE2 regions upstream of a luciferase reporter (Snoek et al 1996 J. Steroid Biochem. Mol. Biol. 59, 243-250).

EXAMPLE 1

SYNTHESIS OF 4-(2-(3-(2-(4-((2,2-DIMETHYL-1,3-DIOXOLAN-4- YL)METHOXY)PHENYL)P OPAN-2-YL)PHENYL)P OPAN-2-YL)PHENOL (3)

Sodium hydride (60% dispersion in mineral oil, 69 mg, 1.73 mmol, 1.2 equiv) was added slowly to a stirred solution of 4,4'-(l,3- Phenylenediisopropylidene)bisphenol 1 (500 mg, 1.44 mmol, 1 equiv) in anhydrous dimethyl formamide (8 mL), at room temperature, and the contents were stirred under an atmosphere of argon for 20 min. Racemic 4-chloromethyl-2,2-dimethyl-l,3- dioxolane 2 (245 μί, 1.73 mmol, 1.2 equiv) was added via syringe, and the mixture was allowed to react at 70-80 ⁰ C for 40 h. Next, the reaction was quenched by the addition of a saturated solution of ammonium chloride (4 mL), and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic layer was washed with deionized water (10 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 100% dichloromethane) to provide 3 (140 mg, 21%>) as a yellow foam. Note: The same reaction also yielded the bis ketal analogue of 3. H NMR (400 MHz, CDCI₃): δ 7.21-7.19 (m, 1H), 7.12 (d, J = 7.6, 2H), 7.08 (d, J = 8.8, 2H), 6.99 (d, J = 8.4, 2H), 6.85 (s, 1H), 6.78 (d, J = 8.8, 2H), 6.68 (d, J = 8.4, 2H), 6.10 (br, 1H), 4.57- 4.53 (m, 1H), 4.24-4.20 (m, 1H), 4.10-4.07 (m, 1H), 4.03-3.96 (m, 2H), 1.64-1.61 (m, 12H), 1.55 (s, 3H), 1.47 (s, 3H); ¹³C NMR (100 MHz, CDC1₃): δ 156.4, 153.8, 150.7, 150.6, 143.6, 142.7, 128.0, 127.9, 127.5, 126.9, 123.6, 123.4, 114.8, 113.9, 110.2 74.4, 68.7, 66.8, 42.5, 31.1, 31.0, 30.9, 30.9, 26.9, 25.6; HRMS (EI) (m/z): calc'd for C30H36O4: 460.26136, found: 460.26093. EXAMPLE 2

SYNTHESIS OF 2,2-DIMETHYL-4-((4-(2-(3-(2-(4-(OXIRAN-2- YLMETHOXY)PHENYL)P OPAN-2-YL)PHENYL)P OPAN-2-YL)PHENOXY)METHYL)-1,3-

DIOXOLANE (5)

Sodium hydride (60% dispersion in mineral oil, 18 mg, 0.45 mmol, 1.5 equiv) was added slowly to a stirred solution of 3 (137 mg, 0.30 mmol, 1 equiv) in anhydrous dimethyl formamide (1 mL) at room temperature, and the contents were stirred under an atmosphere of argon for 20 min. Racemic epichlorohydrin 4 (47 ί, 0.59 mmol, 2.0 equiv) was added via syringe, and the mixture was allowed to react at room temperature for 22 h. Next, the reaction was quenched by the addition of a saturated solution of ammonium chloride (0.5 mL), and the mixture was extracted with ethyl acetate (3 x 5 mL). The organic layer was washed with deionized water (5 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 40% ethyl acetate in hexane to 100% ethyl acetate) to provide 5 (127 mg, 83%) as a clear foam. H NMR (400 MHz, CDC1₃): δ 7.20-7.16 (m, 2H), 7.15-7.12 (dd, J = 8.8, 1.6, 4H), 7.06-7.04 (dd, J = 8.0, 1.6, 2H), 6.85-6.82 (dd, J = 8.4, 1.6, 4H), 4.52-4.49 (m, 1H), 4.23-4.15 (m, 2H), 4.10-4.06 (m, 1H), 3.99-3.91 (m, 3H), 3.38-3.35 (m, 1H), 2.91 (t, J = 4.8, 1H), 2.78-2.76 (dd, J = 4.8, 2.8, 1H), 1.65 (s, 12H), 1.55 (s, 3H), 1.47 (s, 3H); ¹³C NMR (100 MHz, CDC1₃): δ 156.5, 156.5, 150.4, 143.8, 143.7, 128.0, 127.9, 127.6, 125.5, 124.2, 114.1, 114.0, 109.8, 74.3, 69.0, 68.9, 67.1, 50.4, 44.9, 42.6, 31.1, 27.0, 25.6; HRMS (ESI) (m/z): calc'd for C₃₃H₄₀O₅Na [M+Na]⁺: 539.2773, found: 539.2776. EXAMPLE 3

SYNTHESIS OF 3-(4-(2-(3-(2-(4-(3-CHLORO-2-HYDROXYPROPOXY)PHENYL)PROPAN-2- YL)PHENYL)PROPAN-2-YL)PHENOXY)PROPANE- 1 ,2-DIOL (6)

To a solution of racemic 5 (127 mg, 0.24 mmol, 1 equiv) in acetonitrile (2 mL) was added CeCl₃-7H₂0 (227 mg, 0.61 mmol, 2.5 equiv), and the mixture was refluxed for 22 h. The resulting white paste was filtered and washed with ethyl acetate, and the clear suspension was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 5% methanol in dichloromethane to 10% methanol) to provide 6 (65 mg, 52%) as a white foamy solid. H NMR (400 MHz, CDC1₃): δ 7.26-7.22 (m, 1H), 7.14-7.09 (m, 6H), 6.98 (m, 1H), 6.82-6.79 (dd, J = 8.8, 2.0, 4H), 4.28-4.23 (m, 1H), 4.18-4.13 (m, 1H), 4.11-4.10 (m, 2H), 4.06 (d, J= 5.2, 2H), 3.90-3.87 (dd, J= 11.6, 3.6, 1H), 3.84-3.74 (m, 3H), 1.65 (s, 12H); ¹³C NMR (100 MHz, CDC1₃): δ 156.3, 156.1, 150.5, 150.4, 144.0, 143.9, 128.0, 128.0, 127.6, 126.6, 123.8, 114.0, 114.0, 70.7, 70.1, 69.4, 68.9, 68.8, 63.9, 46.1, 42.6, 31.1; HRMS (ESI) (m/z): calc'd for C₃₀H₃₇O₅NaCl [M+Na]⁺: 535.2227, found: 535.2235.

EXAMPLE 4

SYNTHESIS OF 4-(2-(4-(2-(4-((2,2-DIMETHYL-1,3-DIOXOLAN-4- YL)METHOXY)PHENYL)PROPAN-2-YL)PHENYL)PROPAN-2-YL)PHENOL (8)

Sodium hydride (60%> dispersion in mineral oil, 173 mg, 4.33 mmol, 1.5 added slowly to a stirred solution of 4,4'-(l,4- Phenylenediisopropylidene)bisphenol 7 (1000 mg, 2.88 mmol, 1 equiv) in anhydrous dimethyl formamide (10 mL) at room temperature, and the contents were stirred under an atmosphere of argon for 20 min. Racemic 4-chloromethyl-2,2-dimethyl-l,3- dioxolane 2 (613 μί, 4.33 mmol, 1.5 equiv) was added via syringe, and the mixture was allowed to react at 70-80 °C for 21 h. Then, the reaction was quenched by the addition of a saturated solution of ammonium chloride (5 mL), and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic layer was washed with deionized water (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 100% dichloromethane) to provide 8 (271 mg, 20%) as a colourless foam. Note: The same reaction yielded the bis ketal analogue of 8 as well. H NMR (400 MHz, CDCls): δ 7.21-7.19 (m, 2H), 7.15-7.12 (m, 6H), 6.87- 6.84 (m, 2H), 6.77-

6.75 (m, 2H), 5.78 (s, 1H), 4.55-4.52 (m, 1H), 4.24-4.20 (dd, J = 8.8, 6.8, 1H), 4.11- 4.08 (dd, J = 9.6, 5.6, 1H), 3.99-3.94 (m, 2H), 1.68 (d, J = 4.0, 12H), 1.53 (s, 3H), 1.47 (s, 3H); ¹³C NMR (100 MHz, CDC1₃): δ 156.5, 153.7, 148.1, 148.0, 143.7, 143.0, 128.1, 128.0, 126.4, 126.4, 114.9, 114.1, 110.1, 74.3, 68.9, 67.1, 42.1, 42.0, 31.1, 31.1, 27.0, 25.6; HRMS (ESI) (m/z): calc'd for CsoHseC^Na [M+Na]⁺: 483.2511, found: 483.2503.

EXAMPLE 5

SYNTHESIS OF 2,2-DIMETHYL-4-((4-(2-(4-(2-(4-(OXIRAN-2- YLMETHOXY)PHENYL)P OPAN-2-YL)PHENYL)P OPAN-2-YL)PHENOXY)METHYL)-1,3-

DIOXOLANE (9)

Sodium hydride (60%> dispersion in mineral oil, 25 mg, 0.62 mmol, 1.5 equiv) was added slowly to a stirred solution of derivative 8 (191 mg, 0.41 mmol, 1 equiv) in anhydrous dimethyl formamide (1 mL) at room temperature, and the contents were stirred under an atmosphere of argon for 20 min. Racemic epichlorohydrin 4 (64 μί, 0.82 mmol, 2.0 equiv) was added via syringe, and the mixture was allowed to react at room temperature for 22 h. Then, the reaction was quenched by the addition of a saturated solution of ammonium chloride (0.5 mL), and the mixture was extracted with ethyl acetate (3 x 5 mL). The organic layer was washed with deionized water (5 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 40% ethyl acetate in hexane to 50% ethyl acetate) to provide 9 (203 mg, 95%) as a white foam. H NMR (400 MHz, CDC1₃): δ 7.24-7.22 (m, 4H), 7.18 (br, 4H), 6.91-6.88 (m, 4H), 4.55-4.52 (m, 1H), 4.25-4.20 (m, 2H), 4.13-4.09 (dd, J = 9.6, 5.2, 1H), 4.02-3.94 (m, 3H), 3.39-3.38 (m, 1H), 2.94-2.92 (dd, J = 4.8, 4.4, 1H), 2.80-

2.78 (dd, J = 4.8, 2.8, 1H), 1.68 (s, 12H), 1.53 (s, 3H), 1.47 (s, 3H); ¹³C NMR (100 MHz, CDC1₃): δ 156.6, 156.6, 148.1, 148.0, 143.7, 143.6, 128.0, 128.0, 126.4, 114.2, 114.1, 109.9, 74.3, 69.0, 69.0, 67.2, 50.4, 44.9, 42.1, 31.1, 27.1, 25.6; HRMS (ESI) (m/z): calc'd for C₃₃H₄₀O₅Na [M+Na]⁺: 539.2773, found: 539.2784.

EXAMPLE 6

SYNTHESIS OF 3-(4-(2-(4-(2-(4-(3-CHLORO-2-HYDROXYPROPOXY)PHENYL)PROPAN-2- YL)PHENYL)PROPAN-2-YL)PHENOXY)PROPANE-1 ,2-DIOL (10)

To a solution of racemic 9 (203 mg, 0.39 mmol, 1 equiv) in acetonitrile (3 mL) was added CeCl₃-7H₂0 (366 mg, 0.98 mmol, 2.5 equiv), and the mixture was refluxed for 19 h. The resulting white paste was filtered and washed with ethyl acetate, and the clear suspension was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 5%> methanol in dichloromethane to 10% methanol) to provide 10 (144 mg, 71%) as a white solid. H NMR (400 MHz, CDC1₃): δ 7.19-7.15 (m, 4H), 7.12 (br, 4H), 6.85-6.81 (m, 4H), 4.22-4.18 (m, 1H), 4.11-4.05 (m, 3H), 4.00 (d, J = 5.6, 2H), 3.84-3.80 (dd, J = 11.6, 3.6, 1H), 3.78-3.69 (m, 3H), 3.07 (m, 3H), 1.66 (d, J = 2.0, 12H); ¹³C NMR (100 MHz, CDCls): δ 156.4, 156.2, 148.0, 147.9, 144.0, 143.8, 128.1, 128.1, 126.4, 114.1, 114.1, 70.7, 70.1, 69.2, 68.7, 63.9, 46.1, 42.1, 31.0, HRMS (ESI) (m/z): calc'd for CsoHsvOsNaCl [M+Na]⁺: 535.2227, found: 535.2222.

EXAMPLE 7

IN VITRO ACTIVITY OF SELECT COMPOUNDS

LNCaP cells were transiently cotransfected with PSA (6.1 kb)-luciferase (0.25 μ§Λνε11) in 24-well plates for 24 h prior to pre-treatment with compounds for 1 hour before the addition of synthetic androgen, R1881 (1 11M) to induce PSA

production or vehicle. The total amount of plasmid DNA transfected was normalized to 0.75 μ§Λνε11 by the addition of the empty vector. After 48 h of incubation with R1881, the cells were harvested, and relative luciferase activity was determined. Test compounds were added to the cells at various concentrations and activity for each treatment was normalized to the predicted maximal activity induction (in the absence of test compounds, vehicle only). Plotting of sigmoidal curves (Boltzmann Function) and IC50 calculations were done using OriginPro 8.1 Sofware (Northampton, MA, USA).

Furthermore, toxicity was assessed by both microscopic examination and reduction of protein levels. Solubility was assessed both macroscopically (cloudy media) and microscopically (formation of granules or crystals).

TABLE 3 shows the compounds tested using the above-described assays and their respective activities.

EXAMPLE 8

IN VIVO DOSE RESPONSE OF COMPOUNDS

In vivo dose response of compounds of the invention is determined according to the following procedure: Male athymic SCID-NOD mice, 6- to 8-weeks old, are inoculated subcutaneously with LNCaP cells (1 x 10⁶) suspended in 75 μΐ of RPMI 1640 (5% FBS) and 75 μΐ of Matrigel (Becton Dickinson Labware) in the flank region via a 27-gauge needle under isofluorane anesthesia. Mice bearing LNCaP subcutaneous tumors are castrated when tumor volumes are approximately 100 mm³. Seven days after castration, mice are injected intravenously by tail vein every other day for a total of 7 doses with compounds of the invention in 15% DMSO and 25.5% PEG. The experiment is complete 2 days after the last injection. Tumours are measured with calipers and their volumes calculated by the formula L x W x H x 0.5236. Tumor volume as a a function of compound dose is plotted.

Dose reponse of comparative compounds are also determined according to the above procedure.

Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. The word "comprising" is used herein as an open-ended term, substantially equivalent to the phrase "including, but not limited to", and the word "comprises" has a corresponding meaning. As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a thing" includes more than one such thing. Citation of references herein is not an admission that such references are prior art to the present invention. Any priority document(s) and all publications, including but not limited to patents and patent applications, cited in this specification are incorporated herein by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein and as though fully set forth herein. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings.

Claims

1. A compound having a structure of Formula I:

armaceutically acceptable salt or tautomer thereof, wherein:

at least one Z¹ is independently C-Q;

at least one Z² is independently C-W, wherein W is

at least one Z³ is independently C-T, CH, CCH₃, CF, CCl, CBr, CI, COH, CG¹, COG¹, CNH₂, CNHG¹, CNG^, COS0₃H, COP0₃H₂, CSG¹, CSOG¹, or each remaining Z¹, Z² and Z³ is, at each occurrence, independently C-T, N, CH, CCH₃, CF, CCl, CBr, CI, COH, CG¹, COG¹, CNH₂, CNHG¹, CNG^, COS0₃H, COP0₃H₂, CSG¹, CSOG¹, or CSO^¹;

R¹, R², R³ and R⁴ are each independently H or a linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl, or R¹ and R², or R³ and R⁴ may independently together form a substituted or unsubstituted, saturated or unsaturated cyclic C₃-Cio alkyl or R¹ and R², or R³ and R⁴ may independently together form =CR"R"', wherein R" and R'" are each independently a linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl, aryl or aralkyl;

Q is ;

J is G¹, O, CH₂, CHG¹, CG^, S, NH, NG¹, SO, S0₂, or NR; M is H, F, CI, Br, CH₂OH, CH₂OD,

CH₂F, CH₂C1, CHC1₂, CC1₃, CH₂Br, CHBr₂, CBr₃ or C≡CH;

L is H or A-D; A is O, S, NH, NG¹, N⁺H₂ or N⁺HG¹;

.OR

O"

or a moiety from TABLE 1 ;

each of q, r and t may independently be 0, 1 , 2, 3, 4, 5, 6 or 7;

n is 0, 1 , 2, 3, 4, 5, 6, 7 or 8;

T is, at each occurrence, independently

J is, at each occurrence, independently G¹, O, CH₂, CHG¹, C(G , S, NH, NG¹, SO, S0₂, or NR;

M² is, at each occurrence, independently H, CH₃, F, CI, Br, CH₂F , CH₂C1, CHC1₂, CC1₃, CH₂

CH₂OR, CH₂OG¹OG¹',

CH^G^, or C≡CH;

L² is, at each occurrence, independently H or A²-D²;

A² is, at each occurrence, independently O, S, SO, S02, NH, NG¹, N⁺H₂, or N⁺HG¹;

D² is, at each occurrence, independently H, G¹, R,

^ °R

J or a moiety selected from TABLE 1 ;

each of u, y and j are, at each occurrence, independently 0, 1 , 2, 3, 4, 5, 6 or 7;

m is, at each occurrence, independently 0, 1 , 2, 3, 4, 5, 6, 7 or 8;

J" and V" are, at each occurrence, independently a moiety selected from

TABLE 1 ;

G¹, G¹' and G¹" are, at each occurrence, independently a linear or branched, aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl, wherein the optional substituents for the Ci-Cio alkyl are oxo, CH₂CO₂R', OJ'", COOH, R¹, OH, OR¹, F, CI, Br, I, NH₂, NHR¹, N(R¹)₂, CN, SH, SR¹, SO3H, SO3R¹, SO2R¹, OSO3R¹, OR², CO2R¹, CONH2, CONHR¹, CONHR², CON(R¹)₂, NHR², OPO₃H₃, CON^R², NR^JR² or N0₂;

each R¹ is independently unsubstituted C₁-C₁₀ alkyl; and each R and R² are independently C₁-C₁₀ acyl.

2. The compound of claim 1 , wherein in at least one Z³ is independently C-T.

3. The compound of any of claims 1 or 2, wherein the compound has a structure of Formula II or III:

II

4. The compound of claim 1 , wherein the compound has a structure of Formula IV or V:

V

5. The compound of claim 1 , wherein the compound has a structure of Formula VI or VII:

VI

VII

wherein:

R 1 , R 8 , R 9 , R 10. R 11 and R 12 are each independently hydrogen, halo, or linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Ci₀ alkyl.

6. The compound of claim 1, wherein the compound has a structure of Formula VIII or IX:

IX

7. The compound of claim 1, wherein the compound has a structure of Formula X or XI:

126

Xld

9. The compound of any one of claims 1 to 6, wherein J is G¹, O, CH₂, CHG¹, CG^, NH, SO, or NR.

10. The compound of any one of claims 1 to 6, wherein J is O.

11. The compound of any one of claims 1 to 8, wherein M is CI, Br, CH₂OH, CH₂OD, CH₂OG¹, CH₂F, CH₂C1, CHC1₂, CC1₃, CH₂Br, CHBr₂, CBr₃, or C≡CH.

12. The compound of any one of claims 1 to 8, wherein M is CH OH, CH₂F, C≡CH, CH₂OCH₂C≡CH, CH₂0- i-butyl, or CH₂OD, wherein D is

13. The compound of any one of claims 1 to 8, wherein M is

CH₂OH.

14. The compound of any one of claims 1 to 8, wherein M is H.

15. The compound of any one of claims 1 to 14, wherein L is H.

16. The compound of any one of claims 1 to 14, wherein L is A-D.

17. The compound of any one of claims 1 to 14, wherein A is O.

18. The com ound of any one of claims 16 or 17, wherein D is H, R,

moiety from TABLE 1; and each of q, r and t is independently 0, 1, 2, 3, 4, 5, 6 or 7.

19. The compound of any one of claims 16 or 17, wherein D is H.

20. The compound of any one of claims 16 or 17, wherein D is R.

21. The compound of any one of claims 16 or 17, wherein D is a moiety selected from TABLE 1.

22. The com ound of claim 21, wherein the moiety from TABLE 1

23. The compound of any one of claims 1 to 22, wherein n is 0.

24. The compound of any one of claims 1 to 22, wherein n is 1, 2, 3,

4, or 5.

25. The compound of any one of claims 1 to 22, wherein n is 1.

26. The compound of any one of claims 1 to 6, wherein J² is G¹, O, CH₂, CHG¹, CG^, NH, SO, or NR.

27. The compound of any one of claims 1 to 6, wherein J² is O.

28. The compound of any one of claims 1 to 27, wherein M² is H, CH₂F, CH₂C1, CH₂Br, CH₂OH, CH₂OJ",

or C≡CH.

29. The compound of any one of claims 1 to 27, wherein M² is

CH₂F.

30. The compound of any one of claims 1 to 27, wherein M² is

CH₂C1.

31. The compound of any one of claims 1 to 27, wherein M² is

CH₂Br. The compound of any one of claims 1 to 27, wherein M²

CH₂OH.

33. The compound of any one of claims 1 to 27, wherein M² is H.

34. The compound of any one of claims 1 to 27, wherein M² is

C≡CH.

35. The compound of any one of claims 1 to 34, wherein L² is H.

36. The compound of any one of claims 1 to 34, wherein L² is A²-D².

37. The compound of claim 36, wherein A² is O .

38. The com ound of any one of claims 36 or 37, wherein D² is H,

moiety from TABLE 1 ; and each of u, y andj is independently 0, 1 , 2, 3, 4, 5, 6 or 7.

39. The compound of any one of claims 36 or 37, wherein D² is H.

40. The compound of any one of claims 36 or 37, wherein D² is R.

41. The compound of any one of claims 36 or 37, wherein D² is a moiety from TABLE 1.

42. The com ound of claim 41 , wherein the moiety from TABLE 1

43. The compound of any one of claims 1 to 42, wherein m is 0.

44. The compound of any one of claims 1 to 42, wherein m is 1 , 2, 3,

4, or 5.

45. The compound of any one of claims 1 to 42, wherein m is 1.

46. The compound of any one of claims 1 to 8, wherein M is CH₂OH and L is OH.

47. The compound of any one of claims 1 to 8, wherein M² is CH₂C1 and L is OH.

48. The compound of any one of claims 1 to 8, wherein M is CH₂OH, M² is CH₂C1, L is OH and L² is OH.

49. The compound of claim 48, wherein n and m are each 1.

The compound of any one of claims 1 to 49, wherein at least one of R¹, R², R³ or R⁴ is mmeetthhyyll..

The compound of any one of claims 1 to 49, wherein each of R¹,

R², R³ and R⁴ is methyl.

The compound of any one of claims 1 to 49, wherein at least one of R¹, R², R³ or R⁴ is hydrogen.

53. The compound of any one of claims 1 to 49, wherein each of R¹, R², R³ and R⁴ is hydrogen.

54. The compound of any one of claims 1 to 49, wherein R¹ and R² or R³ and R⁴ join to form substituted or unsubstituted cyclohexyl.

55. The compound of any one of claims 1 to 49, wherein each of R¹ and R² and R³ and R⁴ join to form substituted or unsubstituted cyclohexyl.

56. The compound of any one of claims 5 to 55, wherein at least one of R⁷, R⁸, R⁹, R¹⁰, R¹¹ or R¹² is hydrogen.

57. The compound of any one of claims 5 to 55, wherein each of R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are hydrogen.

58. The compound of any one of claims 5 to 55, wherein at least one of R⁷, R⁸, R⁹, R¹⁰, R¹¹ or R¹² is methyl.

59. The compound of any one of claims 5 to 55, wherein each of R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are methyl.

60. The compound of any one of claims 5 to 55, wherein each of R⁷, R⁸, R⁹, and R¹² are methyl.

61. The compound of any one of claims 5 to 55, wherein at least one of R⁷, R⁸, R⁹, R¹⁰, R¹¹ or R¹² is fluoro.

62. The compound of any one of claims 5 to 55, wherein each of R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are fluoro.

63. The compound of any one of claims 5 to 55, wherein each of R , R⁸, R⁹, and R¹² are fluoro.

64. The compound of any one of claims 5 to 55, wherein at least one of R⁷, R⁸, R⁹, R¹⁰, R¹¹ or R¹² is chloro.

65. The compound of any one of claims 5 to 55, wherein each of R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are chloro.

The compound of any one of claims 5 to 55, wherein each of R ,

R⁸, R⁹, and R¹² are chloro.

The compound of any one of claims 5 to 55, wherein at least one of R⁷, R⁸, R⁹, R¹⁰, R¹¹ or R¹² is bromo.

68. The compound of any one of claims 5 to 55, wherein each of R⁷,

R⁸, R⁹, R¹⁰, R¹¹ and R¹² are bromo.

69. The compound of any one of claims 5 to 55, wherein each of R ,

R⁸, R⁹, and R¹² are bromo.

The com ound of any one of claims 1 to 6, wherein Q





n is 0, 1,2, 3, 4, 5, 6, 7 or 8;

each of q, r, and t is independently 0, 1,2, 3, 4, 5, 6 or 7; m is 0, 1,2, 3, 4, 5, 6, 7 or 8;

each of u, j and y is independently 0, 1,2, 3, 4, 5, 6 or 7; each G¹ is independently linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl, wherein the optional substituents are selected from oxo, OJ'", COOH, OH, F, CI, Br, I, NH₂, CN, SH, S0₃H, CONH₂, OP0₃H₃ and N0₂.

n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

each of q, r, and t is independently 0, 1, 2, 3, 4, 5, 6 or 7; m is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

each of u, j and y is independently 0, 1, 2, 3, 4, 5, 6 or 7; each G¹ is independently linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl, wherein the optional substituents are selected from oxo, OJ'", COOH, OH, F, CI, Br, I, NH₂, CN, SH, S0₃H, CONH₂, OP0₃H₃, and N0₂.

72. The com ound of any one of claims 1 to 6, wherein Q is

"OG¹

OH n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and each G¹ is independently linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl, wherein the optional substituents are selected from oxo, OJ'", COOH, OH, F, CI, Br, I, NH₂, CN, SH, S0₃H, CONH₂, OP0₃H₃, and N0₂.

73. The compound of an one of claims 1 to 6, wherein Q is

I

n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

q is 0, 1, 2, 3, 4, 5, 6 or 7;

m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; u is 0, 1, 2, 3, 4, 5, 6 or 7; and

each G¹ is independently linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl, wherein the optional substituents are selected from oxo, OJ"\ COOH, OH, F, CI, Br, I, NH₂, CN, SH, S0₃H, CONH₂, OP0₃H₃, and N0₂.

75. The com ound of any one of claims 1 to 6, wherein Q

The compound of any one of claims 1 to 6, wherein T

150

79. The com ound of any one of claims 1 to 6, wherein Q is

80. The compound of any one of claims 1 to 4, wherein each remaining Z¹, Z² and Z³ is independently selected from: CCH₃; CH; CF, CCl, and CBr.

81. The compound of any one of claims 1 to 4, wherein each remaining Z¹, Z² and Z³ is CH.

82. The compound of any one of claims 1 to 76, wherein one or more of the OH groups of the compound is substituted to replace the H with a moiety from TABLE 1.

85. Use of the compound of any one of claims 1 to 84, for modulating androgen receptor (AR) activity.

86. The use of claim 85, wherein modulating androgen receptor (AR) activity is in a mammalian cell.

87. The use of any one of claims 85 or 86, wherein modulating androgen receptor (AR) activity is for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration.

88. The use of claim 87, wherein the indication is prostate cancer.

89. The use of claim 88, wherein the prostate cancer is castration resistant prostate cancer.

90. The use of claim 89, wherein the prostate cancer is androgen-dependent prostate cancer.

91. The use of claim 87, wherein the spinal and bulbar muscular atrophy is Kennedy's disease.

92. A method of modulating androgen receptor (AR) activity, the method comprising administering a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1 to 84 to a subject in need thereof.

93. The method of claim 92, wherein modulating androgen receptor (AR) activity is for the treatment of one or more of the following: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration.

94. The method of claim 93, wherein the prostate cancer is castration resistant prostate cancer.

95. The method of claim 93, wherein the prostate cancer is androgen-dependent prostate cancer.

96. The method of claim 93, wherein the spinal and bulbar muscular atrophy is Kennedy's disease.

97. A pharmaceutical composition comprising a compound of any one of claims 1 to 84 and a pharmaceutically acceptable carrier.

98. A pharmaceutical composition comprising a compound of any one of claims 1 to 84, an additional therapeutic agent and a pharmaceutically acceptable carrier.

99. The pharmaceutical composition of claim 98, wherein the additional therapeutic agent is for treating prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy or age-related macular degeneration.

100. The pharmaceutical composition of claim 98, wherein the additional therapeutic agent is MDV3100 , TOK 001, TOK 001; ARN-509; abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab (Avastin), OSU-HDAC 2, VITAXIN, sunitumib, ZD-4054, VN/I24-1, Cabazitaxel (XRP-6258), MDX-010 (Jpi limumab), OGX 427, OGX OI L finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,111 or a related compound thereof.

101. Use of the pharmaceutical composition of any one of claims 97 to 100 for modulating androgen receptor (AR) activity.

102. The use of claim 101, wherein modulating androgen receptor (AR) activity is in a mammalian cell.

103. The use of any one of claims 101 or 102, wherein modulating androgen receptor (AR) activity is for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration.

104. The use of claim 103, wherein the indication is prostate cancer.

105. The use of claim 104, wherein the prostate cancer is castration resistant prostate cancer.

106. The use of claim 104, wherein the prostate cancer is androgen-dependent prostate cancer.

107. The use of claim 103, wherein the spinal and bulbar muscular atrophy is Kennedy's disease.

108. A method of modulating androgen receptor (AR) activity, the method comprising administering the pharmaceutical composition of any one of claims 97 to 100 to a subject in need thereof.

109. The method of claim 108 wherein modulating androgen receptor (AR) activity is for the treatment of one or more of the following: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration.

110. The method of claim 109, wherein the spinal and bulbar muscular atrophy is Kennedy's disease.

111. The use of claim 105, wherein the indication is prostate cancer.

112. The use of claim 111, wherein the prostate cancer is castration resistant prostate cancer.

113. The use of claim 111, wherein the prostate cancer is androgen-dependent prostate cancer.