WO2012145330A1 - Fluorene-9-bisphenol compounds and methods for their use - Google Patents

Fluorene-9-bisphenol compounds and methods for their use Download PDF

Info

Publication number
WO2012145330A1
WO2012145330A1 PCT/US2012/033959 US2012033959W WO2012145330A1 WO 2012145330 A1 WO2012145330 A1 WO 2012145330A1 US 2012033959 W US2012033959 W US 2012033959W WO 2012145330 A1 WO2012145330 A1 WO 2012145330A1
Authority
WO
WIPO (PCT)
Prior art keywords
independently
compound
prostate cancer
cancer
unsubstituted
Prior art date
Application number
PCT/US2012/033959
Other languages
French (fr)
Inventor
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 (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The University Of British Columbia, British Columbia Cancer Agency Branch filed Critical The University Of British Columbia
Publication of WO2012145330A1 publication Critical patent/WO2012145330A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • This invention relates to therapeutics, their uses and methods for the treatment of various indications, including various cancers.
  • 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) .
  • 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)).
  • 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.
  • 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.
  • 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.
  • LBD carboxy-terminal ligand-binding domain
  • DBD DNA-binding domain
  • NTD N-terminus domain
  • 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. 277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277, 38087-38094).
  • PKA cAMP-dependent protein kinase pathway
  • IL-6 interleukin-6
  • Nonsteroidal antiandrogens such as bicalutamide (CasodexTM), 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)).
  • 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.
  • 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).
  • 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.
  • the androgen receptor may be human.
  • 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.
  • 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.
  • the indication is Kennedy's disease.
  • the present disclosure provides the use of a compound of Formula I, for modulating androgen receptor (AR) activity.
  • AR androgen receptor
  • Methods for modulating AR, as well as pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable excipient are also provided.
  • 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.
  • 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.
  • 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-Ci 0 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 C 2 -Cio 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 C 2 -Cio alkynyl include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • an alkyl group may be optionally substituted (i.e., a hydrogen atom in the alkyl group may be replaced with an optional substituent).
  • 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.
  • 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.
  • 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.
  • unbranched alkyls are methyl, ethyl, n-propyl, and n-butyl.
  • 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.
  • 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).
  • 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.
  • 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.
  • unsubstituted alkyls include methyl, ethyl, tert-butyl, and pentyl.
  • 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.
  • saturated chemical entities include ethane, tert-butyl, and N + H 3 .
  • Ci-Cio alkyl may include, for example, and without limitation, saturated Ci-Cio alkyl, C 2 -C 10 alkenyl and C 2 -C 10 alkynyl.
  • saturated C 1 -C 10 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-d
  • Non-limiting examples of the saturated C3- C10 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 C 6 -Cio aryl group may include phenyl (Ph), pentalenyl, indenyl, naphthyl, and azulenyl.
  • the C 6 -9 aryl-Ci_ 4 alkyl group may be, for example, and without limitation, a Ci_ 4 alkyl group as defined anywhere above having a C 6 _ aryl group as defined anywhere above as a substituent.
  • the C 6 _8 aryl-C 2 _ 4 alkenyl group may be, for example, and without limitation, a C 2 _ 4 alkenyl as defined anywhere above having a C 6 -8 aryl group as defined anywhere above as a substituent.
  • the C 6 -8 aryl-C 2 _ 4 alkynyl group may be, for example, and without limitation, a C 2 _ 4 alkynyl group as defined anywhere above having a C 6 -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- Cio alkoxy include methoxy, ethoxy, propoxy and butoxy.
  • 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.
  • At least one Z 1 is independently C-Q
  • At least one Z 2 is independently C-T, CCH 3 , CF, CC1, CBr, CI, COH, CG 1 , COG 1 , CNH 2 , CNHG 1 , CN(G 1 ) 2 , COS0 3 H, COP0 3 H 2 , CSG 1 , CSOG 1 , or CSOzG 1 ;
  • Z 3 , Z 4 and each remaining Z 1 and Z 2 are, at each occurrence, independently C-T, N, CH, CCH 3 , CF, CC1, CBr, CI, COH, CG 1 , COG 1 , CNH 2 , CNHG 1 , CNG 2 , CSG 1 , CSOG 1 , or CSOzG 1 ;
  • J is G 1 , O, CH 2 , CHG 1 , C(G l ) 2 , S, NH, NG 1 , SO, S0 2 , or NR;
  • M is H, F, CI, Br, CH 2 OH, CH 2 OD, CH 2 F, CH 2 C1, CHC1 2 , CC1 3 , CH 2 Br, CHBr 2 , CBr 3 or C ⁇ CH;
  • L is H or A-D
  • A is O, S, NH, NG 1 , N + H 2 or N + HG 1 ;
  • each of q, r and t may independently be 0, 1 , 2, 3, 4, 5, 6 or 7;
  • n 0, 1 , 2, 3, 4, 5, 6, 7 or 8;
  • T is, at each occurrence, independently J is, at each occurrence, independently G 1 , O, CH 2 , CHG 1 , C(G 1 ) 2 , S, NH, NG 1 , SO, S0 2 , or NR;
  • M 2 is, at each occurrence, independently H, CH 3 , F, CI, Br, CH 2 F , CH 2 C1, CHCI 2 , CCI 3 , CH 2 Br, CHBr 2 , CBr 3 , CH 2 OH, CH 2 OD 2 , CH 2 OJ", G 1 , CH 2 OG 1 , CH 2 OR, CH 2 OG 1 OG 1 ', G ⁇ G 1 ', G ⁇ G ⁇ OG 1 ", CH 2 SG 1 , CH 2 NH 2 , CH 2 NHG 1 ,
  • L 2 is, at each occurrence, independently H or A 2 -D 2 ;
  • a 2 is, at each occurrence, independently O, S, SO, S02, NH, NG 1 , N + H 2 , or N + HG 1 ;
  • D 2 is, at each occurrence, independently H, G 1 , R,
  • each of u, y and j are, at each occurrence, independently 0, 1, 2, 3, 4, 5, 6 or 7;
  • n 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
  • G 1 , G 1 ' and G 1 " are, at each occurrence, independently a linear or branched, aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated C 1 -C 10 alkyl, wherein the optional substituents for the C 1 -C 10 alkyl are oxo, CH 2 CO 2 R', OJ'", COOH, R 1 , OH, OR 1 , F, CI, Br, I, NH 2 , NHR 1 , N(R 1 ) 2 , CN, SH, SR 1 , S0 3 H, SO 3 R 1 , SO 2 R 1 , OSO 3 R 1 , OR 2 , CO 2 R 1 , CONH 2 , CONHR 1 , CONHR 2 , CON(R 1 ) 2 , NHR 2 , OP0 3 H 3 , CON ⁇ R 2 , NR R 2 or N0 2 ;
  • each R' is independently H, linear or branched, aromatic cyclic or non- aromatic cyclic, substituted or unsubstituted, saturated or unsaturated C 1 -C 10 alkyl or a metal counter ion, wherien the metal counter ion is Li, Na, K, Mg or Ca;
  • each R 1 is independently unsubstituted C 1 -C 10 alkyl; and each R and R 2 are independently C 1 -C 10 acyl.
  • at least one Z 2 is C-T.
  • the compound has a structure of Formula II:
  • the compound has a structure of Formula III
  • R 7 , R 8 , R 9 and R 10 are each independently hydrogen, halo, or linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl.
  • the compound has a structure of
  • the compound has a structure of Formula V:
  • the compound has a structure of Formula Va, Vb, Vc or Vd:
  • the compound has one of the following structures:
  • R 11 is hydrogen or linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl
  • Y is CI or OH
  • J is G 1 , O, CH 2 , CHG 1 , CG ⁇ , NH, SO, or NR.
  • J is O.
  • M is CI, Br, CH 2 OH, CH 2 OD, CH 2 OG 1 , CH 2 F, CH 2 C1, CHC1 2 , CC1 3 , CH 2 Br, CHBr 2 , CBr 3 , or C ⁇ CH.
  • M is CH 2 OH, CH 2 F, C ⁇ CH, CH 2 OCH 2 C ⁇ CH, CH 2 OCH 3 , CH 2 0- -propyl, CH 2 0-n-butyl, or CH 2 OD, wherein D is or .
  • M is CH 2 OH, and in other embodiments, M is H.
  • L is H, and in other embodiments, L is A-D.
  • each of q, r and t is independently 0, 1, 2, 3, 4, 5, 6 or 7.
  • D is H, and in other embodiments D is R.
  • D is a moiety selected from TABLE 1.
  • n is 0, and in some other embodiments n is 1, 2, 3, 4, or 5. For example in some embodiments, n is 1.
  • J 2 is G 1 , O, CH 2 , CHG 1 , CG ⁇ , NH, SO, or NR.
  • J 2 is O.
  • M 2 is H, CH 2 F, CH 2 C1, CH 2 Br, CH 2 OH, CH 2 OJ", CH 2 OG 1 , or C ⁇ CH.
  • M 2 is CH 2 F.
  • M 2 is CH 2 C1.
  • M 2 is CH 2 Br.
  • M 2 is CH 2 OH, and in some embodiments M 2 is H.
  • M 2 is C ⁇ CH.
  • L 2 is H, and in other examples L 2 is A 2 -D 2 .
  • a 2 is O, and in other certain embodiments D 2 is
  • D 2 is H, and in other embodiments D 2 is R. In still other embodiments, D 2 is a moiety from TABLE 1.
  • n is 0. In still other embodiments, m is 1, 2, 3, 4, or 5. For example in some embodiments, m is 1.
  • M is CH 2 OH and L is OH.
  • M 2 is CH 2 C1 and L is OH.
  • M is CH 2 OH, M 2 is CH 2 C1, L is OH and L 2 is OH.
  • M is CH 2 F, M 2 is CH 2 C1, L is OH and L 2 is OH.
  • n and m are each 1.
  • At least one of R 1 , R 2 , R 3 or R 4 is hydrogen.
  • each of R 1 , R 2 , R 3 and R 4 is hydrogen.
  • R 1 and R 2 or R 3 and R 4 join to form substituted or unsubstituted cyclohexyl.
  • each of R 1 and R 2 and R 3 and R 4 join to form substituted or unsubstituted cyclohexyl.
  • At least one of R 7 , R 8 , R 9 , R 10 , R 11 or R 12 is
  • each of R , R , R , R and R are hydrogen.
  • At least one of R 7 , R 8 , R 9 , R 10 , R 11 or R 12 is
  • At least one of R 7 , R 8 , R 9 , R 10 , R 11 or R 12 is
  • At least one of R , R , R , R or R is chloro.
  • each of R', R°, R", R , R and R are chloro, while in other examples each of R 7 , R 8 , R 9 , and R 12 are chloro.
  • each G 1 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, NH 2 , CN, SH, S0 H, CONH 2 , OPO 3 H 3 and N0 2 .
  • T is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethy
  • n, m and q are each independently 0, 1, 2, 3, 4, 5, , 7 or 8.
  • T is N
  • 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.
  • the moiety from TABLE 1 is
  • the present disclosure provides a compound having one of the following structures:
  • one or more of the OH groups of the foregoing compounds is substituted to replace the H with a moiet from TABLE 1.
  • the present disclosure provides the use of any one of the foregoing compounds for modulating androgen receptor (AR) activity.
  • modulating androgen receptor (AR) activity is in a mammalian cell.
  • 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.
  • the indication is prostate cancer.
  • the prostate cancer is castration resistant prostate cancer.
  • the prostate cancer is androgen-dependent prostate cancer.
  • the spinal and bulbar muscular atrophy is Kennedy's disease.
  • 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.
  • AR androgen receptor
  • 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.
  • the prostate cancer is castration resistant prostate cancer.
  • the prostate cancer is androgen-dependent prostate cancer, and in other embodiments, the spinal and bulbar muscular atrophy is Kennedy's disease.
  • the present disclosure provides a pharmaceutical composition comprising any one of the foregoing compounds and a pharmaceutically acceptable carrier.
  • the present disclosure provides a pharmaceutical composition comprising any one of the foregoing compounds, an additional therapeutic agent and a pharmaceutically acceptable carrier.
  • 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.
  • the additional therapeutic agent is MDV3100 , TOK 001, TOK 001; ARN-509; abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VTTAXIN, sunitumib, ZD-4054, V / 124-1, Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX 427, OCX 01 1 , finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF 105,111 or a related compound thereof.
  • the present disclosure provides the use of any one of the foregoing pharmaceutical compositions for modulating androgen receptor (AR) activity.
  • modulating androgen receptor (AR) activity is in a
  • 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.
  • the indication is prostate cancer.
  • the prostate cancer is castration resistant prostate cancer, and in other embodiments the prostate cancer is androgen-dependent prostate cancer.
  • the spinal and bulbar muscular atrophy is Kennedy's disease.
  • 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.
  • 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.
  • the spinal and bulbar muscular atrophy is Kennedy's disease.
  • the indication is prostate cancer.
  • 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 G 1 , O, CH 2 , CHG 1 , CG ⁇ , S, NH, NG 1 , SO, S0 2 , or NR. Each J may independently be G 1 , O, CH 2 , CHG 1 , CG ⁇ , S, NH, or NG 1 . Each J may independently be O, S, NH, NG 1 , SO, S0 2 , or NR. Each J may independently be O, S, SO, or S0 2 . Each J may independently be O, NH, NG 1 , or NR. Each J may independently be S, NH, NG 1 , SO, S0 2 , or NR. Each J may independently be S, SO, or S0 2 .
  • Each J may independently be NH, NG 1 , or NR. Each J may independently be G 1 , CH 2 , CHG 1 , or CG ⁇ . Each J may independently be O, CH 2 , S, or NH. Each J may independently be O, CH 2 , or NH. Each J may independently be O, or CH 2 . Each J may independently be G 1 , O, CHG 1 , or NH. Each J may independently be G 1 , O, or CHG 1 . Each J may independently be G 1 , or O. Each J may independently be O, or S. Each J may independently be G 1 . Each J may independently be CH 2 . Each J may be CHG 1 . Each J may be CG ⁇ . Each J may be NR. Each J may be SO. Each J may be NG 1 . Each J may be NH. Each J may be S. Each J may be O.
  • Each M may independently be H, CI, Br, CH 2 OH, CH 2 OD, CH 2 F, CH 2 C1, CHC1 2 , CC1 3 , CH 2 Br, CHBr 2 , CBr 3 , or C ⁇ CH.
  • Each M may independently be CI, Br, CH 2 OH, CH 2 OD, CH 2 OG 1 , CH 2 F, CH 2 C1, CHC1 2 , CC1 3 , CH 2 Br, CHBr 2 , or CBr 3 .
  • Each M may independently be CI, CH 2 C1, CHC1 2 , or CC1 3 .
  • Each M may independently be Br, CH 2 Br, CHBr 2 , or CBr 3 .
  • Each M may independently be CI, or Br.
  • Each M may independently be CH 2 C1, or CH 2 Br. Each M may independently be CHC1 2 , or CHBr 2 . Each M may independently be CC1 3 , or CBr 3 . Each M may independently be CH 2 C1, CHC1 2 , or CC1 3 . Each M may independently be CH 2 Br, CHBr 2 , or CBr 3 . Each M may independently be CI, CH 2 C1, or CHC1 2 . Each M may independently be Br, CH 2 Br, or CHBr 2 . Each M may independently be CH 2 C1, or CHC1 2 . Each M may independently be CH 2 Br, or CHBr 2 . Each M may independently be CI, or CC1 3 . Each M may independently be Br, or CBr 3 .
  • Each M may be H. Each M may be CI. Each M may be Br. Each M may be CHC1 2 . Each M may be CC1 3 . Each M may be CH 2 Br. Each M may be CHBr 2 . Each M may be CBr 3 . Each M may be C ⁇ CH. Each M may be CH 2 C1. Each M may be CH 2 F. Each M may be CH 2 OH. Each M may be CH 2 OD. Each M may be CT ⁇ OG 1 .
  • 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+H 2 , or N+HG1.
  • Each A may independently be O, NH, or N + H 2 .
  • Each A may independently be O, S, NH, or N H 2 .
  • 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 NG 1 .
  • Each A may be N + H 2 .
  • Each A may be N HG 1 .
  • Each A may be O.
  • Each D may independently be H, G 1 , R, ⁇ , or a moiety selected from TABLE 1.
  • Each D may independently be H, G 1 , or R.
  • Each D may independently be H, or R.
  • Each D may independently be G 1 or R.
  • Each D may inde endently be H, or G 1 .
  • Ea h D may independently be , , , or a moiet selected from TABLE 1.
  • Each D may independently be ? , , ' " ; i , , “ :l or ⁇ > l .
  • Each D may independently be ⁇ '3 ⁇ 4 , or r r .
  • Each D may independently be , or a moiety selected from TABLE 1.
  • Each D may independently be , or a moiety selected from TABLE 1.
  • Each D may be H. Each D may be G 1 . Each D ma be R. Each D may be . Each D may be . Each D may be . Each D may be . Each D may be a moiety selected from TABLE 1.
  • Each J 2 may independently be G 1 , O, CH 2 , CHG 1 , CG ⁇ , S, NH, NG 1 , SO, S0 2 , or NR. Each J 2 may independently be G 1 , O, CH 2 , CHG 1 , CG ⁇ , S, NH, or NG 1 . Each J 2 may independently be O, S, NH, NG 1 , SO, S0 2 , or NR. Each J 2 may independently be O, S, SO, or S0 2 . Each J 2 may independently be O, NH, NG 1 , or NR.
  • Each J may independently be S, NH, NG , SO, S0 2 , or NR. Each J may independently be S, SO, or S0 2 . Each J 2 may independently be NH, NG 1 , or NR. Each J 2 may independently be G 1 , CH 2 , CHG 1 , or CG ⁇ . Each J 2 may independently be O, CH 2 , S, or NH. Each J may independently be O, CH 2 , or NH. Each J may independently be O, or CH 2 . Each J 2 may independently be G 1 , O, CHG 1 , or NH. Each J 2 may independently be G 1 , O, or CHG 1 . Each J 2 may independently be G 1 , or O. Each
  • Each J may independently be O, or S. Each J may independently be G . Each J may independently be CH 2 . Each J 2 may be CHG 1 . Each J 2 may be CG ⁇ . Each J 2 may be
  • Each J may be S0 2 .
  • Each J may be SO.
  • Each J may be NG .
  • Each J may be
  • Each J may be S.
  • Each J may be O.
  • Each M 2 may independently be H, CH 3 , CI, Br, CH 2 F, CH 2 C1, CHC1 2 , CC1 3 , CH 2 Br, CHBr 2 , CBr 3 , CH 2 OH, CH 2 OJ", G 1 , CH 2 OR, CH 2 OG 1 OG 1 ',
  • Each M 2 may independently be H, CH 3 , CH 2 C1, CH 2 Br, CH 2 OJ"', CH 2 OG, CH 2 OGOG', GOG', GOG'OG", CH 2 SG, CH 2 NH 2 , CH 2 NHG, or CH 2 NG 2 .
  • Each M 2 may independently be H, CH 3 , CH 2 C1, CH 2 Br, CH 2 OJ"', CH 2 OG, or CH 2 OGOG'.
  • Each M 2 may independently be CH 2 C1, CH 2 Br, CH 2 OH, CH 2 OCH 3 , CH 2 0(isopropyl), or CH 2 OC 2 H 4 OC 4 H9.
  • Each M 2 may independently be H, CH 3 , CH 3 OCH 3 , CH 3 OCH 2 CH 3 , CH 2 C1, or CH 2 Br. Each M 2 may independently be CH 3 , CH 3 OCH 2 CH 3 , CH 2 C1, CH 2 Br, CH 2 OH, CH 2 OCH 3 , or CH 2 0(isopropyl). Each M 2 may independently be CH 3 , CH 2 C1, CH 2 Br, CH 2 OH, CH 3 OCH 2 CH 3 , or CH 2 OCH 3 . Each M 2 may independently be CH 3 , CH 2 C1, CH 2 Br, CH 2 OH, or CH 2 OCH 3 . Each M 2 may independently be CH 3 , CH 2 OH, CH 2 OCH 3 , or CH 2 OCH 2 CH 3 . Each M 2 may independently be CH 3 , CH 2 OH, CH 2 OCH 3 , or CH 2 OCH 2 CH 3 .
  • Each M 2 may independently be CH 2 C1, or CH 2 Br. Each M 2 may independently be H, CI, Br, CH 2 C1, CHC1 2 , CC1 3 , CH 2 Br, CHBr 2 , CBr 3 , or C ⁇ CH. Each M 2 may independently be CI, Br, CH 2 C1, CHC1 2 , CC1 3 , CH 2 Br, CHBr 2 , or CBr 3 . Each
  • Each M may independently be CI, or Br.
  • Each M may
  • Each M may independently be CC1 3 , or CBr 3 .
  • Each M may independently be CH 2 C1, CHC1 2 , or CC1 3 .
  • Each M 2 may independently be CH 2 Br, CHBr 2 , or CBr 3 .
  • Each M 2 may
  • Each M may independently be Br, CH 2 Br, or
  • Each M may independently be CH 2 C1, or CHC1 2 .
  • Each M may independently be CH 2 C1, or CHC1 2 .
  • Each M may independently be CH 2 C1, or CHC1 2 .
  • each M 2 2 be CH 2 Br, or CHBr 2 .
  • Each M may independently be CI, or CC1 3 .
  • Each M may independently be Br, or CBr 3 .
  • Each M 2 may be H.
  • Each M 2 may be CH 3 .
  • Each M 2 may be CI.
  • Each M 2 may be Br.
  • Each M 2 may be CH 2 C1.
  • Each M 2 may be CHC1 2 .
  • Each M 2 may be CC1 3 .
  • Each M 2 may be CH 2 Br.
  • Each M 2 may be CHBr 2 .
  • Each M 2 may be CBr 3 .
  • Each M 2 may be CH 2 OH.
  • Each M 2 may be CH 2 OJ".
  • Each M 2 may be G 1 .
  • Each M 2 may be CH 2 OG 1 .
  • Each M 2 may be CH 2 OR.
  • Each M 2 may be CH 2 OG 1 OG 1 '. Each M 2 may be G ⁇ G 1 '. Each M 2 may be G ⁇ G ⁇ OG 1 ". Each M 2 may be CH 2 SG 1 . Each M 2 may be CH 2 NH 2 . Each M 2 may be CH 2 HG 1 . Each M 2 may be CH 2 NG 1 2 . Each M 2 may be C ⁇ CH. Each M 2 may be CH 2 F.
  • Each A 2 may independently be O, S, SO, S0 2 , NH, NG 1 , N + H 2 , or N + HG ⁇ Each A 2 may independently be O, S, SO, or S0 2 . Each A 2 may independently be O, NH, NG 1 , N + H 2 , or N + HG ⁇ Each A 2 may independently be S, SO, S0 2 , NH, NG 1 , N + H 2 , or N + HG ⁇ Each A 2 may independently be O, S, SO, S0 2 , NH, or N + H 2 . Each A 2 may independently be S, SO, or S0 2 .
  • Each A 2 may independently be NH, NG 1 , N + H 2 , or N + HG ⁇ Each A 2 may independently be NH, or N H 2 . Each A may independently be O, S, NH, NG 1 , N + H 2 , or N + HG ⁇ Each A 2 may independently be O,
  • Each A may independently be O, S, NH, or N H 2 .
  • Each A may independently be O, S, NH, or N H 2 .
  • Each A may independently be O, S, NH, or N H 2 .
  • Each A 2 may be NH. Each A 2 may be NG 1 . Each A 2 may be N + H 2 . Each A 2 may be N + HG ⁇ Each A 2 may be O.
  • Each D 2 may independently be H, G 1 , R,
  • Each D may
  • Each D 2 may be H. Each D 2 may be G 1 . Each D 2 may be R. Each D 2 may be
  • Each D may be .
  • Each D may be
  • Each D 2 may be a moiety selected from TABLE 1 ,
  • Each Q may independently be or
  • Each Q may be any Q.
  • Each Q m a independently be Each may independently be
  • Each Q may
  • Each Q may independently be
  • Each Q may independently be .
  • Each Q may independently be
  • Each Q may independentl .
  • Each Q may independently be Each Q
  • Each Q may independently be Each Q may independently be
  • Each Q may
  • Each Q may independently be .
  • Each Q may inde endently be Each may independently be
  • Each Q may
  • Each may independently be Each Q
  • Each Q may independently be Each Q may independently be
  • Each Q may independently be any Q.
  • Each Q may independently be 0 ⁇ cl .Br
  • Each Q may independently be
  • Each Q may independently be X .
  • Each Q may be X
  • Each Q may independently be O n Br g ac j 1 Q ma y ⁇ g O CI g ac
  • Each Q may independently be breadth. , , , , .
  • Each Q may independently be breadth. .
  • Each Q may be
  • Each may independently be OH
  • Each Q may independently
  • Each T may independently
  • Each T may independently
  • Each T may independently be
  • Each T may independently be , or
  • Each T may independently be inde endently be
  • G i Ea h T may independently be r
  • Each T may independently be r
  • T may independently be or ach T may independently be
  • Each T ma n epen enty e .
  • Each T may independently be ndependently be or
  • Each T may independently or 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 may independently be
  • Each T may independently be
  • Each T may inde endently be
  • Each T may independently be
  • Each T may endently be
  • Each T may endently be
  • Each T may be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be configured to be any T.
  • 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
  • T may independently be ⁇ " V " Br ⁇ " y " Br
  • Each T may independently be
  • Each T ma independently be .
  • Each T ma independently be Each T may
  • T ma 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 may independently be .
  • Each T may be .
  • T may independently be Each T ently
  • Each T ma independently be Each T ma independently be Each T ma independently .
  • Eac T may independently be .
  • Each T ay independently be .
  • Each T may independently be Each T
  • 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 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 may independently be
  • Each T may independently be X Each T may independently .
  • Each T may independently be X Each T may independently be X Each T may independently .
  • Each T may independently be X Each T may independently .
  • Each T may independently be X
  • Each T may independently be
  • Each T may independently be
  • Each T may independently be X .OG 1
  • Each T may independently be X .OR
  • Each T may .
  • Each T may independently
  • 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 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 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 Z 1 may independently be C-Q, at least one Z 2 may independently be COH, and each Z 3 , Z 4 and each remaining Z 1 and Z 2 may, at each occurrence, independently be N, CH, CF, CC1, CBr, CI, CG 1 , or COH. At least one Z 1 may independently be C-Q, at least one Z 2 may independently be C-T, and each Z 3 , Z 4 and each remaining Z 1 and Z 2 may, at each occurrence, independently be N, CH, CF, CC1, CBr, CI, or COH.
  • 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.
  • each of J", and V" may independently an amino acid based moiety selected from TABLE 1.
  • Each J", and J'" may be
  • Each G , G ' and G " may independently be a branched, unbranched, or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated C 1 -C3 alkyl.
  • Each G 1 , G 1 ' and G 1 " may independently be a branched, unbranched, substituted or unsubstituted, saturated or unsaturated C 1 -C 2 alkyl.
  • Each G 1 may independently be an aromatic cyclic or non- aromatic cyclic, substituted or unsubstituted, saturated or unsaturated cyclohexyl.
  • Each G 1 may independently be an aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated cycloheptyl.
  • Each G 1 may independently be an aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated cyclooctyl.
  • Each G 1 may independently be cyclohexyl.
  • Each G 1 may independently be substituted or unsubstituted methyl. Each G 1 may independently be substituted or unsubstituted, saturated or unsaturated ethyl. Each G 1 may independently be a branched, unbranched, substituted or unsubstituted, saturated or unsaturated propyl. Each G 1 may be isopropyl. Each G 1 may independently be a branched, unbranched, substituted or unsubstituted, saturated or unsaturated butyl. Each G 1 may be n-butyl. Each G 1 may independently be a branched, unbranched, substituted or unsubstituted, saturated or unsaturated pentyl.
  • 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 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 Ci-Cio acyl. Each R may independently be C 1 -C 9 acyl. Each R may independently be Ci-Cg acyl. Each R may independently be Ci- C 7 acyl. Each R may independently be Ci-C 6 acyl. Each R may independently be C 1 -C 5 acyl. Each R may independently be C 1 -C4 acyl. Each R may independently be C 1 -C 3 acyl. Each R may independently be C 1 -C 2 acyl. Each R may independently be Ci acyl. Each R may independently be C 2 acyl. Each R may independently be C 3 acyl. Each R may independently be C 4 acyl. Each R may independently be C 5 acyl. Each R may independently be C 6 acyl. Each R may independently be C 7 acyl. Each R may independently be Cg acyl. Each R may independently be C 9 acyl. Each R may independently be Ci 0 acyl.
  • Each R 1 may independently be unsubstituted Ci alkyl. Each R 1 may independently be unsubstituted C 2 alkyl. Each R 1 may independently be unsubstituted C 3 alkyl. Each R 1 may independently be unsubstituted C 4 alkyl. Each R 1 may independently be unsubstituted C 5 alkyl. Each R 1 may independently be unsubstituted C 6 alkyl. Each R 1 may independently be unsubstituted C 7 alkyl. Each R 1 may independently be unsubstituted C 8 alkyl. Each R 1 may independently be unsubstituted Cg alkyl. Each R 1 may independently be unsubstituted C 10 alkyl.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, halo, or linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C10 alkyl.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen.
  • At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10 is independently hydrogen.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently fluoro.
  • At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10 is independently fluoro.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently chloro.
  • At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10 is independently chloro.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently bromo.
  • At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10 is independently bromo.
  • At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10 is independently C 3 alkyl.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently C 4 alkyl.
  • At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently C 6 alkyl.
  • At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10 is independently C 6 alkyl.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently C 7 alkyl. At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10 is independently C 7 alkyl. R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently C 8 alkyl. At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10 is independently C 8 alkyl.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently C 9 alkyl. At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10 is independently C 9 alkyl. R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently C 10 alkyl. At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10 is independently Cio alkyl.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and at least one of R 3 , R 4 , R 5 or R 6 is independently hydrogen.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and R 3 , R 4 , R 5 and R 6 are each independently fluoro.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and at least one of R 3 , R 4 , R 5 or R 6 is independently fluoro.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and R 3 , R 4 , R 5 and R 6 are each independently chloro.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and at least one of R 3 , R 4 , R 5 or R 6 is independently chloro.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and R 3 , R 4 , R 5 and R 6 are each independently bromo.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and at least one of R 3 , R 4 , R 5 or R 6 is independently bromo.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and R 3 , R 4 , R 5 and R 6 are each independently methyl.
  • At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10 is independently methyl.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and R 3 , R 4 , R 5 and R 6 are each independently ethyl.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and at least one of R 3 , R 4 , R 5 or R 6 is independently ethyl.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and R 3 , R 4 , R 5 and R 6 are each independently C 3 alkyl.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and at least one of R 3 , R 4 , R 5 or R 6 is independently C 3 alkyl.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and R 3 , R 4 , R 5 and R 6 are each independently C 4 alkyl.
  • Each of R 7 , R 8 , R 9 and R may be hydrogen, and at least one of R 3 , R 4 , R 5 or R 6 is independently C 4 alkyl.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and R 3 , R 4 , R 5 and R 6 are each independently C5 alkyl.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and at least one of R 3 , R 4 , R 5 or R 6 is independently C 5 alkyl.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and R 3 , R 4 , R 5 and R 6 are each independently C 6 alkyl.
  • Each of R 7 , R 8 , R 9 and R may be hydrogen, and at least one of R 3 , R 4 , R 5 or R 6 is independently C 6 alkyl.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and R 3 , R 4 , R 5 and R 6 are each independently C 7 alkyl.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and at least one of R 3 , R 4 , R 5 or R 6 is independently C 7 alkyl.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and R 3 , R 4 , R 5 and R 6 are each independently C 8 alkyl.
  • Each of R 7 , R 8 , R 9 and R may be hydrogen, and at least one of R 3 , R 4 , R 5 or R 6 is independently C 8 alkyl.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and R 3 , R 4 , R 5 and R 6 are each independently C9 alkyl.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and at least one of R 3 , R 4 , R 5 or R 6 is independently C 9 alkyl.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and R 3 , R 4 , R 5 and R 6 are each independently C 10 alkyl.
  • Each of R 7 , R 8 , R 9 and R 10 may be hydrogen, and at least one of R 3 , R 4 , R 5 or R 6 is independently C 10 alkyl.
  • Each R 11 may independently be hydrogen. Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C9 alkyl. Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C10 alkyl. Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C9 alkyl. Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cs alkyl. Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C7 alkyl.
  • Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-C 6 alkyl. Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C5 alkyl. Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C4 alkyl. Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C3 alkyl. Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-C 2 alkyl.
  • Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated Ci alkyl. Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C 2 alkyl. Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C3 alkyl. Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C 4 alkyl. Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C 5 alkyl.
  • Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C 6 alkyl. Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C 7 alkyl. Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated Cs alkyl. Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C9 alkyl. Each R 11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C 10 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.
  • 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.
  • the present disclosure provide the use of any of the compounds disclosed herein for modulating androgen receptor (AR) activity.
  • modulating androgen receptor (AR) activity is in a mammalian cell.
  • 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.
  • the indication is prostate cancer, for example, castration resistant prostate cancer.
  • the prostate cancer is androgen-dependent prostate cancer.
  • the spinal and bulbar muscular atrophy is Kennedy's disease.
  • 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.
  • the spinal and bulbar muscular atrophy is Kennedy's disease.
  • 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.
  • 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.
  • 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.
  • the first four moieties are amino acid based moieties
  • the fifth and sixth are polyethylene glycol based moieties
  • the remaining moieties are phosphate based moieties.
  • amino acid side chains of naturally occurring amino acids 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.
  • naturally occurring amino acids are represented by the formula (NH 2 )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.
  • 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.
  • Prodrugs are also included within the scope of the present disclosure.
  • 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.
  • a non-limiting example of such prodrugs include glycine esters and salts thereof of compounds of Formula I as shown below.
  • 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, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty and age-related macular degeneration.
  • 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.
  • methods of systemically treating any of the indications described herein are also provided.
  • Compounds as described herein may be in the free form or in the form of a salt thereof.
  • 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 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.
  • 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.
  • compounds and all different forms thereof 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.
  • hydrates are formed when the solvent is water or alcoholates are formed when the solvent is an alcohol.
  • compounds and all different forms thereof 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.
  • Suitable pharmaceutical compositions may be formulated by means known in the art and their mode of administration and dose determined by the skilled practitioner.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • dosage values may vary with the severity of the condition to be alleviated.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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").
  • 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.
  • the one or more of the Other Therapeutic Agent may be administered to the patient before administration of the compound(s) of Formula I.
  • the compound(s) of Formula I may be co-administered with one or more of the Other Therapeutic Agents.
  • the one or more Other Therapeutic Agent may be administered to the patient after administration of the compound(s) of Formula I.
  • 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.
  • 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.
  • 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.
  • MDV3100 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide
  • TOK 001 and related
  • TOK 001 is currently in development as a treatment for prostate cancer
  • the chemical entity known as bicalutamide N-[4-cyano-3- (trifluoromethyl)phenyl] -3 - [(4-fluorophenyl)sulfonyl] -2-hydroxy-2- methylpropanamide
  • bicalutamide N-[4-cyano-3- (trifluoromethyl)phenyl] -3 - [(4
  • 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 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.
  • a "subject" may be a human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc.
  • the subject may be suspected of having or at risk for having a cancer, such as prostate cancer, breast cancer, ovarian cancer 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, or age-related macular degeneration.
  • Diagnostic methods for various cancers such as prostate cancer, breast cancer, ovarian cancer or endometrial cancer, and diagnostic methods for acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, or age-related macular degeneration and the clinical delineation of cancer, such as prostate cancer, breast cancer, ovarian cancer or endometrial cancer, diagnoses and the clinical delineation of acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, 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, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty 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 androgen-independent 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, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty 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 androgen-independent 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, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty 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 androgen-independent 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).
  • PKA cAMP-dependent protein kinase
  • FSK cAMP-dependent protein kinase
  • Some compounds and compositions of this invention may inhibit both FSK and androgen (e.g. R1881) induction of ARE-luciferase (ARE-luc).
  • Such compounds may block a mechanism that is common to both ligand-dependent and ligand-independent activation of the AR. 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 R1881 only and 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.
  • IL-6 Interleukin-6
  • IL-6 also causes ligand-independent activation of the AR in LNCaP cells and can be used in addition to FSK.
  • R -OH represents an alcohol and M, L, and n are as defined anywhere herein.
  • Bismuth triflate may be added in portions to a solution of racemic derivative A in an alcohol R 7 -OH over the course of the reaction.
  • the mixture may be stirred under suitable conditions (for example, rt for 24 h).
  • the resulting suspension may be quenched by a suitable reagent (for example, by addition of sodium bicarbonate), extracted (for example, with ethyl acetate), dried (for example, over anhydrous magnesium sulphate), and concentrated (for example, under vacuum).
  • the resulting residue may be purified by a suitable method (for example, flash column chromatography on silica gel - eluent: 90% hexane in ethyl acetate) to provide B.
  • a suitable method for example, flash column chromatography on silica gel - eluent: 90% hexane in ethyl acetate
  • the above General Scheme I may be suitably adapted to prepare compounds of the present invention which contain any ether moiety, including polyethers (or an alcohol in the case where R 7 is H), for example a propargyl ether moiety, for example, based on the following General Reaction Scheme II:
  • M, L, and n are as defined anywhere herein.
  • the General Reaction Scheme I may be suitably adapted to prepare compounds of the present invention which contain an isopropyl ether moiety, for example, based on the following General Reaction Scheme III:
  • M, L, and n are as defined anywhere herein.
  • the General Reaction Scheme I may be suitably adapted to prepare compounds of the present invention which contain an n-butyl ether moiety, for example, based on the following General Reaction Scheme IV: General Reaction Scheme IV
  • M, L, and n are as defined anywhere herein.
  • the General Reaction Scheme I may be suitably adapted to prepare compounds of the present invention which contain a cyclohexyl ether moiety, for example, based on the following General Reaction Scheme V:
  • M, L, and n are as defined anywhere herein.
  • the General Reaction Scheme I may be suitably adapted to prepare compounds of the present invention which contain an ester moiety, for example, based on the following General Reaction Scheme VII:
  • 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.
  • 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 ⁇ scale, and are referenced from the residual protium in the NMR solvent (DMSO-d 6 : ⁇ 2.50 (DMSO-d 5 ), CDC1 3 : ⁇ 7.24 (CHC1 3 )).
  • Carbon- 13 nuclear magnetic resonance ( 13 C NMR) spectra were recorded with a Bruker 400 spectrometer, are reported in parts per million on the ⁇ scale, and are referenced from the carbon resonances of the solvent (DMSO-d 6 : ⁇ 39.51, CDC1 3 : ⁇ 77.00).
  • 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).
  • PSA prostate-specific antigen
  • 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.
  • 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).
  • 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)
  • tk ARR3 -
  • racemic derivative 2 (511 mg, 1.30 mmol, 1 equiv) in a mixture of acetonitrile (4 mL) and water (2 mL) was added CeCi3-7H 2 0 (206 mg, 0.65 mmol, 1/2 equiv) and Bismuth(III) trifluoromethanesulfonate (73 mg, 0.13 mmol, 1/10 equiv) and the mixture was heated at 80-90 °C for 51 h. Then, the reaction was quenched by the addition of a saturated solution of sodium bicarbonate (2 mL), and the mixture was extracted with ethyl acetate (3 x 10 mL).
  • reaction was quenched by the addition of a saturated solution of ammonium chloride (10 mL), and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with deionized water (20 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 10% to 20% ethyl acetate in hexane) to provide 6 (1.91 g, 78%) as a white solid.
  • Boc-Gly-OH (262 mg, 1.50 mmol, 4 equiv) was disolved in anhydrous 1,4 dioxane (2 mL), and triethylamine was added (209 ⁇ , 1.50 mmol) at room temperature, and the contents were stirred under an atmosphere of argon for 10 min.
  • N- (3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (579 mg, 1.50 mmol) was added in one portion followed by the slow addition of a solution of derivative 1 (200 mg, 0.37 mmol, 1 equiv) in anhydrous 1,4 dioxane (3 mL) and catalytic 4- (Dimethylamino)pyridine ( ⁇ 2 mg), and the solution was stirred at rt for 29 h. The reaction mixture was then evaporated to dryness and extracted with dichloromethane/water (3 x 10 mL). The organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure.
  • LNCaP cells were transiently cotransfected with PSA (6.1 kb)-luciferase (0.25 ⁇ g/well) in 24-well plates for 24 h prior to pre-treatment with compounds for 1 hour before the addition of synthetic androgen, R1881 (1 nM) to induce PSA production or vehicle.
  • the total amount of plasmid DNA transfected was normalized to 0.75 ⁇ g/well 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).
  • 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.
  • mice Male athymic SCID-NOD mice, 6- to 8-weeks old, are inoculated subcutaneously with LNCaP cells (1 x 10 6 ) suspended in 75 ⁇ of RPMI 1640 (5% FBS) and 75 ⁇ 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 mm 3 .
  • mice 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 function of compound dose is plotted.

Abstract

Compounds having a structure of Formula I: or a pharmaceutically acceptable salt or tautomer thereof, wherein Z1, Z2, Z3 and Z4 are as defined herein. 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

FLUORENE-9-BISPHENOL 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. 61/476,728 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. 277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277, 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. 274, 7777-7783; Ueda et al 2002 A J. Biol. Chem. 277, 7076-7085; and Ueda et al 2002 B J. Biol. Chem. 277, 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:
Figure imgf000007_0001
I
or a pharmaceutically acceptable salt or tautomer thereof, wherein Z1, Z2 Z3 and Z4 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 "Cx-Cy 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-Ci0 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-Cio 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 Cx-Cy 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.
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+H3.
As used herein, Ci-Cio alkyl may include, for example, and without limitation, saturated Ci-Cio alkyl, C2-C10 alkenyl and C2-C10 alkynyl. Non-limiting examples of saturated C1-C10 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- C10 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_ 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- Cio 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
Figure imgf000011_0001
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.
Figure imgf000011_0002
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:
Figure imgf000012_0001
I
or a pharmaceutically acceptable salt or tautomer thereof, wherein:
at least one Z1 is independently C-Q;
at least one Z2 is independently C-T, CCH3, CF, CC1, CBr, CI, COH, CG1, COG1, CNH2, CNHG1, CN(G1)2, COS03H, COP03H2, CSG1, CSOG1, or CSOzG1;
Z3, Z4 and each remaining Z1 and Z2 are, at each occurrence, independently C-T, N, CH, CCH3, CF, CC1, CBr, CI, COH, CG1, COG1, CNH2, CNHG1, CNG 2, CSG1, CSOG1, or CSOzG1;
Figure imgf000012_0002
J is G1, O, CH2, CHG1, C(Gl)2, S, NH, NG1, SO, S02, or NR;
M is H, F, CI, Br, CH2OH, CH2OD,
Figure imgf000012_0003
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, independently H, G1, R,
Figure imgf000012_0004
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;
Figure imgf000012_0005
T is, at each occurrence, independently J is, at each occurrence, independently G1, O, CH2, CHG1, C(G1)2, S, NH, NG1, SO, S02, or NR;
M2 is, at each occurrence, independently H, CH3, F, CI, Br, CH2F , CH2C1, CHCI2, CCI3, CH2Br, CHBr2, CBr3, CH2OH, CH2OD2, CH2OJ", G1, CH2OG1, CH2OR, CH2OG1OG1', G^G1', G^G^OG1", CH2SG1, CH2NH2, CH2NHG1,
Figure imgf000013_0001
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,
Figure imgf000013_0002
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 C1-C10 alkyl, wherein the optional substituents for the C1-C10 alkyl are oxo, CH2CO2R', OJ'", COOH, R1, OH, OR1, F, CI, Br, I, NH2, NHR1, N(R1)2, CN, SH, SR1, S03H, SO3R1, SO2R1, OSO3R1, OR2, CO2R1, CONH2, CONHR1, CONHR2, CON(R1)2, NHR2, OP03H3, CON^R2, NR R2 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, wherien 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 Z2 is C-T.
In other embodiments, the compound has a structure of Formula II:
Figure imgf000014_0001
II
In yet other embodiments, the compound has a structure of Formula III
Figure imgf000014_0002
wherein:
R3, R4, R5, R6. R7, R8, R9 and R10 are each independently hydrogen, halo, or linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl.
In still other exemplary embodiments, the compound has a structure of
Formula IV:
Figure imgf000014_0003
IV
In yet other embodiments, the compound has a structure of Formula V:
Figure imgf000015_0001
V
For example, in some further embodiments, the compound has a structure of Formula Va, Vb, Vc or Vd:
Figure imgf000015_0002
Vc Vd
In other further embodiments, the compound has one of the following structures:
Figure imgf000016_0001
Figure imgf000017_0001
wherein:
R11 is hydrogen or linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl;
Y is CI or OH;
q is 0, 1 , 2, 3, 4, 5, 6 or 7; and
m is 0, 1 , 2, 3, 4, 5, 6, 7 or 8.
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, CC13, CH2Br, CHBr2, CBr3, or C≡CH. In still other embodiments, M is CH2OH, CH2F, C≡CH, CH2OCH2C≡CH, CH2OCH3, CH20- -propyl, CH20-n-butyl, or CH2OD, wherein D is
Figure imgf000018_0001
or . 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 et other embodiments A is O while in other embodiments D is H, R,
Figure imgf000018_0002
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
Figure imgf000018_0003
exam le in some embodiments, the moiety from TABLE 1 is or
Figure imgf000018_0004
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", CH2OG1, or C≡CH. For example in some embodiments, M2 is CH2F. In other embodiments, M2 is CH2C1. In still other embodiments, M2 is CH2Br. 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
Figure imgf000018_0005
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
Figure imgf000019_0001
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. other embodiments of the foregoin compound,
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000030_0002
; 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, S0 H, CONH2, OPO3H3 and N02.
In still other embodiments is
Figure imgf000030_0003
Figure imgf000030_0004
Figure imgf000031_0001
Figure imgf000032_0001
; 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 ,
Figure imgf000032_0002
Figure imgf000032_0003
Figure imgf000033_0001
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.
Figure imgf000033_0002
In still other embodiments Q is
Figure imgf000033_0003
; 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.
Figure imgf000034_0001
In other embodiments, is
Figure imgf000034_0002
Figure imgf000035_0001
n certain other embodiments of the foregoing compound, T is
Figure imgf000036_0001
Figure imgf000037_0001
; and n, m and q are each independently 0, 1, 2, 3, 4, 5, , 7 or 8.
Figure imgf000037_0002
In still other embodiments, T is
Figure imgf000037_0003
Figure imgf000038_0001
Figure imgf000039_0001
In certain further embodiments Q is
Figure imgf000039_0002
or and T is
Figure imgf000039_0003
In other embodiments, Z3, Z4 and each remaining Z1 and Z2 is, at each occurrence, independently CCH3; CH; CF, CC1 or CBr. For example in some embodiments, Z3, Z4 and each remaining Z1 and Z2 is, at each occurrence, 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
Figure imgf000039_0004
In another embodiment, the present disclosure provides a compound having one of the following structures:
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
. 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 exam le in some embodiments, the moiety from
Figure imgf000043_0002
TABLE 1 is or
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), OSU-HDAC42, VTTAXIN, sunitumib, ZD-4054, V / 124-1, Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX 427, OCX 01 1 , 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,
Figure imgf000046_0001
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 CT^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 ma independently be H, G1, R, ^
Figure imgf000046_0002
, 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 inde endently be H, or G1.
Ea h D may independently be
Figure imgf000047_0001
, ,
Figure imgf000047_0002
, or a moiet selected from TABLE 1. Each D may independently be
Figure imgf000047_0003
? , , ' "; i , , ":l or \ >l . Each D ma independently be ^ '¾ , or r r
Figure imgf000047_0004
. Each D may independently be ,
Figure imgf000047_0005
or a moiety selected from TABLE 1. Each D may independently be
Figure imgf000047_0006
, 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
Figure imgf000047_0007
. Each D may be . Each D may be
Figure imgf000047_0008
. 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, 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,
Figure imgf000048_0001
CH2OR, CH2OG1OG1',
Figure imgf000048_0002
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 CH2OG1. 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 CH2NG1 2. 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,
Figure imgf000049_0001
Figure imgf000049_0002
, 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 may independently
Figure imgf000049_0003
.OR
Ό"
, or a moiety selected from TABLE 1. Each D may
OH OGi
0' O
independently be or r
Figure imgf000050_0001
OR .OH
O 0' or Each D may independently be or
Figure imgf000050_0002
, or a moiety selected from TABLE 1. Each D may
^ ^OH
independently be ^ '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 OGi
O O
. Each D may be . Each D may be
Figure imgf000050_0003
Each D2 may be a moiety selected from TABLE 1 ,
> ma independently be
Figure imgf000050_0004
Figure imgf000050_0005
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
independently be
i
Figure imgf000057_0002
ndependently be Each Q may independently be
Figure imgf000058_0001
or
Figure imgf000058_0002
Each may independently be
Figure imgf000058_0003
or Each may n e en enty e
Figure imgf000058_0004
Figure imgf000059_0001
inde endently be
Figure imgf000059_0002
independently be
Each Q may
Figure imgf000059_0003
Each may indepen enty e
Figure imgf000059_0004
Figure imgf000060_0001
Each may independently be
Each Q m
Figure imgf000060_0002
a independently be Each may independently be
. Each Q may
Figure imgf000060_0003
independently be Each Q may independently be
Figure imgf000060_0004
. Each Q may independently be
Figure imgf000060_0005
Each Q may independently be . Each Q may
Figure imgf000061_0001
independently Q may independently
Figure imgf000061_0002
Q may independentl . Each Q
Figure imgf000061_0003
ma independently be Each may independently be
Figure imgf000061_0004
Each Q may independently be Each Q
Figure imgf000061_0005
may independently be Each Q may independently be
Figure imgf000061_0006
. Each Q endently be
. Each Q may
Figure imgf000061_0007
inde endently be Each Q may independently be
Figure imgf000061_0008
. Each Q may inde endently be
Figure imgf000062_0001
Each may independently be
. Each Q may
Figure imgf000062_0002
independently be Each may independently be
Figure imgf000062_0003
Each may independently be . Each Q
Figure imgf000062_0004
ma independently be Each may independently be
Figure imgf000062_0005
. Each may independently be Each Q
Figure imgf000062_0006
may independently be Each Q may independently be
Figure imgf000062_0007
. Each Q
Figure imgf000062_0008
ma independently be Each Q may independently be
Figure imgf000062_0009
Each Q may independently be
A .B
, -' ci A r
' ^σ O" ¾■ ^O' ^ "Br
Figure imgf000063_0001
Each Q may independently be 0^^cl .Br
■ci O^ ^ "CI ^ "Ό'
Figure imgf000063_0002
may independently be
Figure imgf000063_0003
Figure imgf000063_0004
Each Q may independently
Figure imgf000063_0005
Each Q may independently be
Figure imgf000063_0006
I
be ■or "CI . Each Q may independently be X . Each Q
Figure imgf000063_0007
may be Each Q may be X Each Q may independently be O n Br gacj1 Q may ^g O CI gac|1 Q may ^e
, , ,, . Each Q may independently be „. . Each Q may be
X, O
Each may independently be OH
o' o
Each Q may independently
Figure imgf000064_0001
independently be
Figure imgf000064_0002
Each T ma independently be
Figure imgf000064_0003
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
65
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Each T may independently
Figure imgf000073_0002
independently be
Figure imgf000073_0003
Figure imgf000074_0001
independently be
Figure imgf000074_0002
Figure imgf000075_0001
Each T ma inde endentl or
Figure imgf000075_0002
R Each T may independently
i
Figure imgf000075_0003
ndependently be ,
Each T may independently be
Figure imgf000075_0004
Figure imgf000075_0005
or i
Figure imgf000076_0001
ndependently be
Each T ma independently be
Figure imgf000076_0002
, or
Figure imgf000076_0003
. Each T ma independently e
Figure imgf000076_0004
inde endently be or
Figure imgf000076_0005
G1 Each T ma independently be
Figure imgf000076_0006
or Each T ma independently be
Figure imgf000076_0007
inde endently be
Figure imgf000077_0001
Figure imgf000077_0002
or Gi Ea h T may independently be
Figure imgf000077_0003
r Each T may independently
Figure imgf000077_0004
independently be or
Figure imgf000077_0005
ach T may independently
i
Figure imgf000077_0006
ndependently be or
Figure imgf000077_0007
Each T ma n epen enty e
Figure imgf000077_0008
. Each T may independently be
Figure imgf000078_0001
ndependently be or
Figure imgf000078_0002
OG1 Each T may independently
Figure imgf000078_0003
or Each T may independently be
i
Figure imgf000078_0004
Each T ma independently be
Figure imgf000078_0005
independently be Each T may independently be
Figure imgf000078_0006
. Each T may independently be
Figure imgf000079_0001
Each T may independently be
. Each T may
Figure imgf000079_0002
inde endently be Each T may independently be
Each T may endently be
. Each T may endently be
Each T may
Figure imgf000079_0003
independently be Each T may independently be
Figure imgf000079_0004
Figure imgf000079_0005
independently be Each T may independently be Ό" V "Br Ό" y "Br
OH 0H
. Each T ma independently be . Each T may
Figure imgf000080_0001
independently be Each T may independently be
Figure imgf000080_0002
Each T may
Figure imgf000080_0003
independently be Each T may independently be
Figure imgf000080_0004
. Each T may
Figure imgf000080_0005
inde endently be Each T may independently be
. Each T may
Figure imgf000080_0006
inde endently be Each T ma independently be
Figure imgf000080_0007
. Each T ma independently be Each T may
Figure imgf000080_0008
inde endently be Each T may independently be
Figure imgf000080_0009
. Each T may
Figure imgf000081_0001
inde endently be Each T may independently be
. Each T
Figure imgf000081_0002
ma independently be Each T ma independently be
Figure imgf000081_0003
Each T ma independently be . Each T
Figure imgf000081_0004
ma independently be Each T may independently be
Each T
Figure imgf000081_0005
ma independently be Each T ma independently be
Figure imgf000081_0006
Each T may independently be . Each T
Figure imgf000081_0007
ma independently be Each T may independently be
. Each T
Figure imgf000081_0008
may independently be Each T may independently be
Figure imgf000082_0001
. Each T ma independently be . Each T
Figure imgf000082_0002
ma independently be Each T ma independently
Figure imgf000082_0003
Each T may independently be Each T ently
. Each T
Figure imgf000082_0004
ma independently be Each T ma independently
Figure imgf000082_0005
Each T ma independently be Each T ma independently be
Figure imgf000082_0006
Each T ma independently
Figure imgf000082_0007
. Eac T may independently be . Each T ay independently be
Figure imgf000082_0008
. Each T may independently be
Figure imgf000082_0009
Each T
Figure imgf000083_0001
may independently be Each T may independently be
Figure imgf000083_0002
OR R
Each T ma independently be
. Each T m
Figure imgf000083_0003
a independently be Each T ma independently be
Figure imgf000083_0004
Each T ma independently be Each T ma independently be
Figure imgf000083_0005
Each T ma independently be
Figure imgf000083_0006
. Each T ma independently be . Each T ma independently be
Figure imgf000083_0007
Each T ma independently be
Figure imgf000083_0008
. Each T ma independently be . Each T ma independently be
Figure imgf000083_0009
Each T ma independently be
Figure imgf000083_0010
. Each T ma independently be . Each T may independently be
Figure imgf000083_0011
. Each T may independently be
Figure imgf000084_0001
. Each T ma independently be . Each T
ma independently be
Figure imgf000084_0002
Each T may independently be
Figure imgf000084_0003
. Each T ma independently be Each T may
independently be
Figure imgf000084_0004
. Each T may independently be
Figure imgf000084_0005
. Each T may independently be
Figure imgf000084_0006
Each T may independently be
Figure imgf000084_0007
.OH
O I O Br 0" X, o" .OGi
Figure imgf000084_0008
or Each T may independently be Each T may independently be
Figure imgf000085_0001
or Each T may independently be
Figure imgf000085_0002
independently be X Each T may independently
Figure imgf000085_0003
. Each T ma independently be Each T may independently be
Figure imgf000085_0004
Of "Br
Each T may independently be Each T may independently be
X, .OH
. Each T may independently be X .OG1
. Each T may independently be X .OR
o" T ma independently
. Each T may
Figure imgf000085_0005
. Each T may independently
T may independently be
Figure imgf000085_0006
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-T, CH, CCH3, CF, CC1, CBr, CI, COH, CG1, COG1, CNH2, CNHG1, CNG^, COS03H, COP03H2, CSG1, CSOG1, or and each Z3, Z4 and each remaining Z1 and Z2 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 one of Z3, Z4 or one of the remaining Z1 or Z2 may independently be C-T, and Z3, Z4 and each remaining Z1 and Z2 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 may independently be COH, and each Z3, Z4 and each remaining Z1 and Z2 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 may independently be C-T, and each Z3, Z4 and each remaining Z1 and Z2 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 may independently be COH, and each Z3, Z4 and each remaining Z1 and Z2 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 may independently be C-T, and each Z3, Z4 and each remaining Z1 and Z2 may, at each occurrence, independently be CH. At least one Z1 may independently be C-Q, at least one Z2 may independently be COH, and each Z3, Z4 and each remaining Z1 and Z2 may, at each occurrence, independently be CH. In any of the foregoing embodiments, each Z3, Z4 and each remaining Z1 and Z2 may, at each occurrence, independently be N, CH, CF, CCl, CBr, CI, COH, CCH3, CNH2, COS03H, or COPO3H2, each Z3, Z4 and each remaining Z1 and Z2 may, at each occurrence, independently be N, CH, CF, CCl, CBr, CI, COH, CNH2, COSO3H, or COP03H2, each Z3, Z4 and each remaining Z1 and Z2 may, at each occurrence, independently be N, CH, CF, CCl, CBr, CI, or COH, each Z3, Z4 and each remaining Z1 and Z2 may, at each occurrence, independently be CH, CF, CCl, CBr, or CI, each Z3, Z4 and each remaining Z1 and Z2 may, at each occurrence, independently be CH, CCl, or CBr or each Z3, Z4 and each remaining Z1 and Z2 may, at each occurrence, independently 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
Figure imgf000088_0001
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-Cg 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 G1, G1' and G1" 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 branched, unbranched, 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 R1 may independently be unsubstituted C1-C10 alkyl. Each R1 may independently be unsubstituted C1-C9 alkyl. Each R1 may independently be unsubstituted Ci-Cg alkyl. Each R1 may independently be unsubstituted Ci-C7 alkyl. Each R1 may independently be unsubstituted Ci-C6 alkyl. Each R1 may independently be unsubstituted C1-C5 alkyl. Each R1 may independently be unsubstituted C1-C4 alkyl. Each R1 may independently be unsubstituted C1-C3 alkyl. Each R1 may independently be unsubstituted C1-C2 alkyl. Each R1 may independently be unsubstituted Ci alkyl. Each R1 may independently be unsubstituted C2 alkyl. Each R1 may independently be unsubstituted C3 alkyl. Each R1 may independently be unsubstituted C4 alkyl. Each R1 may independently be unsubstituted C5 alkyl. Each R1 may independently be unsubstituted C6 alkyl. Each R1 may independently be unsubstituted C7 alkyl. Each R1 may independently be unsubstituted C8 alkyl. Each R1 may independently be unsubstituted Cg alkyl. Each R1 may independently be unsubstituted C10 alkyl.
Each R2 may independently be Ci-Cio acyl. Each R2 may independently be C1-C9 acyl. Each R2 may independently be Ci-Cs acyl. Each R2 may independently be Ci-C7 acyl. Each R2 may independently be Ci-C6 acyl. Each R2 may independently be C1-C5 acyl. Each R2 may independently be Ci-C4 acyl. Each R2 may independently be C1-C3 acyl. Each R2 may independently be C1-C2 acyl. Each R2 may independently be Ci acyl. Each R2 may independently be C2 acyl. Each R2 may independently be C3 acyl. Each R2 may independently be C4 acyl. Each R2 may independently be C5 acyl. Each R2 may independently be C6 acyl. Each R2 may independently be C7 acyl. Each R2 may independently be Cs acyl. Each R2 may independently be C9 acyl. Each R2 may independently be C10 acyl.
R3, R4, R5, R6, R7, R8, R9 and R10 are each independently hydrogen, halo, or linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C10 alkyl. R3, R4, R5, R6, R7, R8, R9 and R10 are each independently hydrogen. At least one of R3, R4, R5, R6, R7, R8, R9 or R10 is independently hydrogen. R3, R4, R5, R6, R7, R8, R9 and R10 are each independently fluoro. At least one of R3, R4, R5, R6, R7, R8, R9 or R10 is independently fluoro. R3, R4, R5, R6, R7, R8, R9 and R10 are each independently chloro. At least one of R3, R4, R5, R6, R7, R8, R9 or R10 is independently chloro. R3, R4, R5, R6, R7, R8, R9 and R10 are each independently bromo. At least one of R3, R4, R5, R6, R7, R8, R9 or R10 is independently bromo. R3, R4, R5, R6, R7, R8, R9 and R10 are each independently methyl. At least one of R3, R4, R5, R6, R7, R8, R9 or R10 is independently methyl. R3, R4, R5, R6, R7, R8, R9 and R10 are each independently ethyl. At least one of R3, R4, R5, R6, R7, R8, R9 or R10 is independently ethyl. R3, R4, R5, R6, R7, R8, R9 and R10 are each independently C3 alkyl. At least one of R3, R4, R5, R6, R7, R8, R9 or R10 is independently C3 alkyl. R3, R4, R5, R6, R7, R8, R9 and R10 are each independently C4 alkyl. At least one of R3, R4, R5, R6, R7, R8, R9 or R4, R5, R6, R7, R8, R9 and R10 are each independently C6 alkyl. At least one of R3, R4, R5, R6, R7, R8, R9 or R10 is independently C6 alkyl. R3, R4, R5, R6, R7, R8, R9 and R10 are each independently C7 alkyl. At least one of R3, R4, R5, R6, R7, R8, R9 or R10 is independently C7 alkyl. R3, R4, R5, R6, R7, R8, R9 and R10 are each independently C8 alkyl. At least one of R3, R4, R5, R6, R7, R8, R9 or R10 is independently C8 alkyl. R3, R4, R5, R6, R7, R8, R9 and R10 are each independently C9 alkyl. At least one of R3, R4, R5, R6, R7, R8, R9 or R10 is independently C9 alkyl. R3, R4, R5, R6, R7, R8, R9 and R10 are each independently C10 alkyl. At least one of R3, R4, R5, R6, R7, R8, R9 or R10 is independently Cio alkyl.
Each of R7, R8, R9 and R10 may be hydrogen, and at least one of R3, R4, R5 or R6 is independently hydrogen. Each of R7, R8, R9 and R10 may be hydrogen, and R3, R4, R5 and R6 are each independently fluoro. Each of R7, R8, R9 and R10 may be hydrogen, and at least one of R3, R4, R5 or R6 is independently fluoro. Each of R7, R8, R9 and R10 may be hydrogen, and R3, R4, R5 and R6 are each independently chloro. Each of R7, R8, R9 and R10 may be hydrogen, and at least one of R3, R4, R5 or R6 is independently chloro. Each of R7, R8, R9 and R10 may be hydrogen, and R3, R4, R5 and R6 are each independently bromo. Each of R7, R8, R9 and R10 may be hydrogen, and at least one of R3, R4, R5 or R6 is independently bromo. Each of R7, R8, R9 and R10 may be hydrogen, and R3, R4, R5 and R6 are each independently methyl. At least one of R3, R4, R5, R6, R7, R8, R9 or R10 is independently methyl. Each of R7, R8, R9 and R10 may be hydrogen, and R3, R4, R5 and R6 are each independently ethyl. Each of R7, R8, R9 and R10 may be hydrogen, and at least one of R3, R4, R5 or R6 is independently ethyl. Each of R7, R8, R9 and R10 may be hydrogen, and R3, R4, R5 and R6 are each independently C3 alkyl. Each of R7, R8, R9 and R10 may be hydrogen, and at least one of R3, R4, R5 or R6 is independently C3 alkyl. Each of R7, R8, R9 and R10 may be hydrogen, and R3, R4, R5 and R6 are each independently C4 alkyl. Each of R7, R8, R9 and R may be hydrogen, and at least one of R3, R4, R5 or R6 is independently C4 alkyl. Each of R7, R8, R9 and R10 may be hydrogen, and R3, R4, R5 and R6 are each independently C5 alkyl. Each of R7, R8, R9 and R10 may be hydrogen, and at least one of R3, R4, R5 or R6 is independently C5 alkyl. Each of R7, R8, R9 and R10 may be hydrogen, and R3, R4, R5 and R6 are each independently C6 alkyl. Each of R7, R8, R9 and R may be hydrogen, and at least one of R3, R4, R5 or R6 is independently C6 alkyl. Each of R7, R8, R9 and R10 may be hydrogen, and R3, R4, R5 and R6 are each independently C7 alkyl. Each of R7, R8, R9 and R10 may be hydrogen, and at least one of R3, R4, R5 or R6 is independently C7 alkyl. Each of R7, R8, R9 and R10 may be hydrogen, and R3, R4, R5 and R6 are each independently C8 alkyl. Each of R7, R8, R9 and R may be hydrogen, and at least one of R3, R4, R5 or R6 is independently C8 alkyl. Each of R7, R8, R9 and R10 may be hydrogen, and R3, R4, R5 and R6 are each independently C9 alkyl. Each of R7, R8, R9 and R10 may be hydrogen, and at least one of R3, R4, R5 or R6 is independently C9 alkyl. Each of R7, R8, R9 and R10 may be hydrogen, and R3, R4, R5 and R6 are each independently C10 alkyl. Each of R7, R8, R9 and R10 may be hydrogen, and at least one of R3, R4, R5 or R6 is independently C10 alkyl.
Each R11 may independently be hydrogen. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C9 alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C10 alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C9 alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cs alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C7 alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-C6 alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C5 alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C4 alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C1-C3 alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-C2 alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated Ci alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C2 alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C3 alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C4 alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C5 alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C6 alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C7 alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated Cs alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated C9 alkyl. Each R11 may independently be linear or branched, substituted or unsubstituted, saturated or unsaturated 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
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
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
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
104
Figure imgf000107_0001
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. A non-limiting example of such prodrugs include glycine esters and salts thereof of compounds of Formula I as shown below.
Figure imgf000107_0002
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, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty 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 androgen-independent prostate cancer (also referred to as hormone refractory, castration resistant, 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, 20th 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.
I l l 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^,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 OSU~HDA€42 ((S)-(H- )-N-hydroxy-4-(3-methyl-2- pheiiylbi!iyrylamino)"beiizariiide), 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 ViTAXLN 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-methyipyrazin-2-y[)- 2-[4-( l,3,4-oxadiazol"2-yl)pheiiyi]pyridiii-3-sulfonamid) 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-Hydroxy- 17-( 1 H-benzimidazol- 1 - yi)androsia-5,16-di.ene), and relaxed 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-010 (Ipilimurnab), 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 OG 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 Oil 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 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, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc. The subject may be suspected of having or at risk for having a cancer, such as prostate cancer, breast cancer, ovarian cancer 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, or age-related macular degeneration. Diagnostic methods for various cancers, such as prostate cancer, breast cancer, ovarian cancer or endometrial cancer, and diagnostic methods for acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, or age-related macular degeneration and the clinical delineation of cancer, such as prostate cancer, breast cancer, ovarian cancer or endometrial cancer, diagnoses and the clinical delineation of acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, 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, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty 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 androgen-independent 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, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty 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 androgen-independent 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, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty 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 androgen-independent 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). Such compounds may block a mechanism that is common to both ligand-dependent and ligand-independent activation of the AR. 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 R1881 only and 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 may be obtained with reference to the following General Reaction Scheme I:
General Reaction Scheme 1
Figure imgf000120_0001
wherein R -OH represents an alcohol and M, L, and n are as defined anywhere herein. Bismuth triflate may be added in portions to a solution of racemic derivative A in an alcohol R7-OH over the course of the reaction. The mixture may be stirred under suitable conditions (for example, rt for 24 h). The resulting suspension may be quenched by a suitable reagent (for example, by addition of sodium bicarbonate), extracted (for example, with ethyl acetate), dried (for example, over anhydrous magnesium sulphate), and concentrated (for example, under vacuum). The resulting residue may be purified by a suitable method (for example, flash column chromatography on silica gel - eluent: 90% hexane in ethyl acetate) to provide B. A person of skill in the art will understand that the above General Scheme I may be suitably adapted to prepare compounds of the present invention which contain any ether moiety, including polyethers (or an alcohol in the case where R7 is H), for example a propargyl ether moiety, for example, based on the following General Reaction Scheme II:
General Reaction Scheme II
Figure imgf000121_0001
wherein M, L, and n are as defined anywhere herein.
The General Reaction Scheme I may be suitably adapted to prepare compounds of the present invention which contain an isopropyl ether moiety, for example, based on the following General Reaction Scheme III:
General Reaction Scheme III
Figure imgf000121_0002
wherein M, L, and n are as defined anywhere herein.
The General Reaction Scheme I may be suitably adapted to prepare compounds of the present invention which contain an n-butyl ether moiety, for example, based on the following General Reaction Scheme IV: General Reaction Scheme IV
Figure imgf000122_0001
wherein M, L, and n are as defined anywhere herein.
The General Reaction Scheme I may be suitably adapted to prepare compounds of the present invention which contain a cyclohexyl ether moiety, for example, based on the following General Reaction Scheme V:
Reaction Scheme V
Figure imgf000122_0002
wherein M, L, and n are as defined anywhere herein.
The General Reaction Scheme I may be suitably adapted to prepare compounds of the present invention which contain a chloro moiety, for example, based on the following General Reaction Scheme VI: Reaction Scheme VI
Figure imgf000123_0001
The General Reaction Scheme I may be suitably adapted to prepare compounds of the present invention which contain an ester moiety, for example, based on the following General Reaction Scheme VII:
Reaction Scheme VII
Figure imgf000123_0002
For ease of illustration, the above General Reaction Schemes depict compounds of Formula I wherein each of Z1, Z2 Z3 and Z4 are C-H. However, one skilled in the are will recognize that varioations of the above procudures (e.g., starting with variously substituted compounds or performing any number of aromatic substitution reactions) can yield compounds of structure I wherein each of Z1, Z2 Z3 or Z4 are optionally other than C-H. General methodologies for chemical preparation of compounds of Formula I are described in the following non-limiting exemplary schemes.
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. 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 3,3'-(4,4'-(9H-FLUO ENE-9,9-DIYL)BIS(4J -PHENYLENE))BIS(OXY)BIS(1-
CHLOROPROPAN-2-OL) (1)
Figure imgf000126_0001
To a solution of racemic derivative 2 (622 mg, 1.34 mmol, 1 equiv) in acetonitrile (5 mL) was added CeCl3-7H20 (1250 mg, 3.36 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: 2% ethyl acetate in dichloromethane to 2% methanol in dichloromethane) to provide 1 (585 mg, 81%) as a white foamy solid. H NMR (400 MHz, DMSO-d6): δ 7.90 (d, J = 7.6, 2H), 7.38 (t, J = 8.0, 4H), 7.30 (t, J = 8.0, 2H), 7.01 (d, J = 8.8, 4H), 6.83 (d, J = 8.8, 4H), 5.51 (d, J = 5.2, 2H), 4.01-3.97 (m, 2H), 3.91 (d, J = 5.2, 4H), 3.73-3.69 (dd, J = 11.2, 4.8, 2H), 3.65-3.61 (dd, J = 11.2, 5.6, 2H); 13C NMR (100 MHz, DMSO-d6): δ 157.1, 151.2, 139.3, 137.8, 128.7, 127.8, 127.5, 125.9, 120.5, 114.2, 68.8, 68.5, 63.6, 46.7; HRMS (ESI) (m/z): calc'd for C^sC^NaC [M+Na]+: 557.1262, found: 557.1254.
EXAMPLE 2
SYNTHESIS OF 2,2'-(4,4,-(9H-FLUORENE-9,9-DIYL)BIS(4,1-
PHENYLENE))BIS(OXY)BIS(METHYLENE)DIOXIRANE (2)
Figure imgf000127_0001
Sodium hydride (60% dispersion in mineral oil, 502 mg, 12.5 mmol, 2.2 equiv) was added slowly to a stirred solution of 4,4'-(9-Fluorenylidene)diphenol (2000 mg, 5.70 mmol, 1 equiv, available from Aldrich Chemicals, catalog # 3236-71-3) in anhydrous dimethyl formamide (20 mL), at room temperature, and the contents were stirred under an atmosphere of argon for 20 min. Racemic epichlorohydrin (1340 ί, 17.1 mmol, 3.0 equiv) was added via syringe and the mixture was allowed to react at room temperature for 162 h. Then, the reaction was quenched by the addition of a saturated solution of ammonium chloride (10 mL), and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with deionized water (20 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 10% ethyl acetate in hexane to 20% ethyl acetate to 100% dichloromethane) to provide 2 (2.53 g, 96%) as a white solid. H NMR (400 MHz,
DMSO-de): δ 7.90 (d, J= 7.6, 2H), 7.38 (t, J= 8.4, 4H), 7.30 (t, J= 7.2, 2H), 7.02 (d, J = 9.2, 4H), 6.84 (d, J = 8.8, 4H), 4.26-4.22 (dd, J = 11.6, 2.4, 2H), 3.79-3.75 (dd, J = 11.6, 6.4, 2H), 3.29-3.25 (m, 2H), 2.81 (t, J = 4.4, 2H), 2.67-2.65 (dd, J= 5.2, 2.8, 2H); 13C NMR (100 MHz, DMSO-d6): δ 156.9, 151.1, 139.3, 137.9, 128.7, 127.8, 127.5, 125.9, 120.5, 114.3, 68.9, 63.6, 49.6, 43.7; HRMS (ESI) (m/z): calc'd for Cs^eC^Na [M+Na]+: 485.1729, found: 485.1741. EXAMPLE 3
SYNTHESIS OF 3-(4-(9-(4-(3-CHLO O-2-HYD OXYP OPOXY)PHENYL)-9H-FLUOREN-9-
YL)PHENOXY)PROPANE-1,2-DIOL (3)
Figure imgf000128_0001
To a solution of racemic derivative 2 (511 mg, 1.30 mmol, 1 equiv) in a mixture of acetonitrile (4 mL) and water (2 mL) was added CeCi3-7H20 (206 mg, 0.65 mmol, 1/2 equiv) and Bismuth(III) trifluoromethanesulfonate (73 mg, 0.13 mmol, 1/10 equiv) and the mixture was heated at 80-90 °C for 51 h. Then, the reaction was quenched by the addition of a saturated solution of sodium bicarbonate (2 mL), and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic layer was washed with deionized water (15 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 60% ethyl acetate in hexane to 80% ethyl acetate) to provide 3 (64 mg, 11%) as a white solid. Note: The same reaction yielded 231 mg (39%) of 1 as a white foam. H NMR (400 MHz, DMSO-de): δ 7.90 (d, J = 7.6, 2H), 7.38 (t, J = 7.6, 4H), 7.30 (t, J = 7.6, 2H), 7.02-6.99 (dd, J = 8.8, 3.6, 4H), 6.82 (d, J = 8.8, 4H), 5.51 (d, J = 5.2, 1H), 4.89 (d, J = 4.0, 1H), 4.62 (m, 1H), 4.01-3.97 (m, 1H), 3.93-3.90 (m, 3H), 3.80-3.69 (m, 3H), 3.65-3.61 (dd, J = 11.2, 5.2, 1H), 3.40 (m, 2H); 13C NMR (100 MHz, DMSO-d6): δ 157.5, 157.0, 151.2, 139.3, 137.9, 137.4, 128.7, 128.7, 127.8, 127.5, 125.9, 120.5, 114.2, 114.2, 69.9, 69.5, 68.8, 68.5, 63.6, 62.7, 46.7; HRMS (ESI) (m/z): calc'd for C3iH2905NaCl [M+Na]+: 539.1601, found: 539.1600. EXAMPLE 4
SYNTHESIS OF 3-(4-(9-(4-(2-HTDROXY-3-(PROP-2-YNYLOXY)PROPOXY)PHENYL)-9H- FLUOREN-9-YL)PHENOXY)PROPANE- 1 ,2-DIOL (4)
Figure imgf000129_0001
To a solution of racemic derivative 2 (200 mg, 0.43 mmol, 1 equiv) in a mixture of acetonitrile (1 mL), water (1 mL), and propargyl alcohol (1 mL) was added Bismuth(III) trifluoromethanesulfonate (28 mg, 0.043 mmol, 1/10 equiv) and the mixture was stirred at room temperature for 44 h. Then, the reaction was quenched by the addition of a saturated solution of sodium bicarbonate (1 mL), and the mixture was extracted with ethyl acetate (3 x 5 mL). The organic layer was washed with deionized water (5 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: dichloromethane to 5% methanol in dichloromethane) to provide 4 (40 mg, 17%) as a white solid. Note: The same reaction yielded 128 mg (59%) of 5 as white solid (Example 5). H NMR (400 MHz, DMSO- d6): δ 7.90 (d, J = 7.6, 2H), 7.40-7.36 (dd, J = 9.6, 7.6, 4H), 7.30 (t, J = 7.6, 2H), 7.01 (d, J = 8.8, 4H), 6.81 (d, J = 8.8, 4H), 5.14 (d, J = 4.8, 1H), 4.90 (d, J = 4.8, 1H), 4.62 (t, J = 5.6, 1H), 4.15 (d, J = 2.4, 2H), 3.94-3.87 (m, 3H), 3.84-3.73 (m, 3H), 3.53-3.46 (m, 2H), 3.43-3.40 (m, 3H); 13C NMR (100 MHz, DMSO-d6): δ 157.5, 157.3, 151.2, 139.3, 137.7, 137.5, 128.7, 127.8, 127.5, 125.9, 120.4, 114.2, 114.2, 80.3, 77.2, 70.9, 69.9, 69.5, 67.8, 63.6, 62.7, 57.9; HRMS (ESI) (m/z): calc'd for C34H3206Na [M+Na]+: 559.2097, found: 559.2086. EXAMPLE 5
SYNTHESIS OF 3,3'-(4,4,-(9H-FLUORENE-9,9-DIYL)BIS(4, 1- PHENYLENE))BIS(OXY)DIP OPANE-1 ,2-DIOL (5)
Figure imgf000130_0001
To a solution of racemic derivative 2 (200 mg, 0.43 mmol, 1 equiv) in a mixture of acetonitrile (1 mL), water (1 mL), and propargyl alcohol (1 mL) was added Bismuth(III) trifluoromethanesulfonate (28 mg, 0.043 mmol, 1/10 equiv) and the mixture was stirred at room temperature for 44 h. Then, the reaction was quenched by the addition of a saturated solution of sodium bicarbonate (1 mL), and the mixture was extracted with ethyl acetate (3 x 5 mL). The organic layer was washed with deionized water (5 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 5% methanol in dichloromethane to 30% methanol in dichloromethane) to provide 5 (128 mg, 59%) as a white solid. H NMR (400 MHz, DMSO-d6): δ 7.90 (d, J = 7.6, 2H), 7.40-7.36 (m, 4H), 7.32-7.28 (m, 2H), 7.01-6.98 (m, 4H), 6.83-6.80 (m, 4H), 4.89 (d, J = 4.8, 2H), 4.62 (t, J = 5.6, 2H), 3.94- 3.90 (dd, J = 9.6, 4.0, 2H), 3.81-3.72 (m, 4H), 3.40 (t, J = 5.6, 4H); 13C NMR (100 MHz, DMSO-de): δ 157.4, 151.3, 139.3, 137.5, 128.7, 127.8, 127.4, 125.9, 120.4, 1 14.2, 69.9, 69.5, 63.6, 62.7; HRMS (ESI) (m/z): calc'd for CsiHsoOeNa [M+Na]+: 521.1940, found: 521.1949. EXAMPLE 6
SYNTHESIS OF (2R,2,R -2,2,-(4,4,-(9H-FLUORENE-9.9-DIYL BIS(4, 1- PHENYLENE))BIS(OXY)BIS(METHYLENE)DIOXIRANE (6)
Figure imgf000131_0001
Sodium hydride (60% dispersion in mineral oil, 528 mg, 13.19 mmol, 2.5 equiv) was added slowly to a stirred solution of 4,4'-(9-Fluorenylidene)diphenol (1850 mg, 5.27 mmol, 1 equiv) in anhydrous dimethyl formamide (20 mL), at room temperature, and the contents were stirred under an atmosphere of argon for 20 min. A solution of (2i?)-(-)-glycidyl tosylate 98% (3010 mg, 13.19 mmol, 2.5 equiv) in anhydrous dimethyl formamide (5 mL) was added via syringe and the mixture was allowed to react at room temperature for 94 h. Then, the reaction was quenched by the addition of a saturated solution of ammonium chloride (10 mL), and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with deionized water (20 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 10% to 20% ethyl acetate in hexane) to provide 6 (1.91 g, 78%) as a white solid. H NMR (400 MHz, DMSO-d6): δ 7.90 (d, J = 7.6, 2H), 7.38 (t, J = 8.0, 4H), 7.30 (t, J = 7.2, 2H), 7.02 (d, J = 8.8, 4H), 6.84 (d, J = 8.8, 4H), 4.26-4.22 (dd, J = 1 1.6, 2.8, 2H), 3.79-3.74 (dd, J = 1 1.2, 6.4, 2H), 3.29-3.26 (m, 2H), 2.81 (t, J = 4.8, 2H), 2.67-2.65 (dd, J = 5.2, 2.8, 2H); 13C NMR (100 MHz, DMSO- ): δ 156.9, 151.1 , 139.3, 137.9, 128.7, 127.8, 127.5, 125.9, 120.5, 1 14.3, 68.9, 63.6, 49.6, 43.7; HRMS (ESI) (m/z): calc'd for Cs^eC^Na [M+Na]+: 485.1729, found: 485.1734. EXAMPLE 7
SYNTHESIS OF (S)- 1 -CHLORO-3-(4-(9-(4-((R)-OXIRAN-2-YLMETHOXY)PHENYL)-9H- FLUOREN-9-YL)PHENOXY)PROPAN-2-OL (7)
Figure imgf000132_0001
To a solution of derivative 6 (1910 mg, 4.14 mmol, 1 equiv) in acetonitrile (10 mL) was added CeCi3'7 H20 (770 mg, 2.06 mmol, 1/2 equiv) and the mixture was refluxed for 3.5 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: dichloromethane to 2% ethyl acetate in dichloromethane to 20% ethyl acetate in dichloromethane) to provide 7 (382 mg, 19%) as a transparent foam. Note: The same reaction yielded 77 mg of 8 as a white solid together with unreacted starting material. H NMR (400 MHz, DMSO-d6): δ 7.91 (d, J = 7.2, 2H), 7.38 (t, J = 7.6, 4H), 7.30 (t, J = 7.6, 2H), 7.03-7.00 (dd, J= 8.8, 2.0, 4H), 6.85-6.82 (dd, J= 8.8, 2.8, 4H), 5.51 (d, J = 5.2, 1H), 4.26-4.22 (dd, J = 11.2, 2.8, 1H), 4.00-3.97 (m, 1H), 3.90 (d, J = 5.6, 2H), 3.79-3.69 (m, 2H), 3.65-3.61 (dd, J= 10.8, 5.2, 1H), 3.30-3.26 (m, 1H), 2.81 (t, J = 4.8, 1H), 2.68-2.66 (dd, J = 5.2, 2.8, 1H); 13C NMR (100 MHz, DMSO-d6): δ 157.0, 156.9, 151.1, 139.3, 137.9, 137.8, 128.7, 127.8, 127.5, 125.9, 120.5, 114.3, 68.9, 68.8, 68.5, 63.6, 49.6, 46.7, 43.7; HRMS (ESI) (m/z): calc'd for C3iH2704NaCl [M+Na]+: 521.1496, found: 521.1508.
EXAMPLE 8
SYNTHESIS OF (2S,2,S -3,3,-(4,4,-(9H-FLUORENE-9,9-DIYL BIS(4,1- PHENYLENE))BIS(OXY)BIS(1-CHLOROPROPAN-2-OL) (8)
Figure imgf000133_0001
To a solution of derivative 6 (1910 mg, 4.14 mmol, 1 equiv) in acetonitrile (10 mL) was added CeCl3'7H20 (770 mg, 2.06 mmol, 1/2 equiv) and the mixture was refluxed for 3.5 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: dichloromethane to 2% ethyl acetate in dichloromethane to 20% ethyl acetate in dichloromethane) to provide 8 (77 mg, 4%) as a white solid. Note: The same method applied to obtain analogue 1 can be applied for the synthesis of derivative 8 by using 6 as starting material. H NMR (400 MHz, DMSO-d6): δ 7.90 (d, J = 7.6, 2H), 7.38 (t, J = 7.6, 4H), 7.30 (t, J= 8.0, 2H), 7.01 (d, J = 8.8, 4H), 6.83 (d, J= 8.8, 4H), 5.51 (d, J = 5.6, 2H), 4.01-3.97 (m, 2H), 3.91 (d, J = 5.2, 4H), 3.73-3.69 (dd, J = 10.8, 4.4, 2H), 3.65-3.61 (dd, J = 11.2, 5.2, 2H); 13C NMR (100 MHz, DMSO-d6): δ 157.1, 151.2, 139.3, 137.8, 128.7, 127.8, 127.5, 125.9, 120.5, 114.2, 68.8, 68.5, 63.6, 46.7; HRMS (ESI) (m/z): calc'd for Cs^sC^NaC [M+Na]+: 557.1262, found: 557.1258.
EXAMPLE 9
SYNTHESIS OF (S)-1-CHLORO-3-(4-(9-(4-((R)-2-HYDROXY-3-(PROP-2- YNYLOXY)PROPOXY)PHENYL)-9H-FLUOREN-9-YL)PHENOXY)PROPAN-2-OL (9)
Figure imgf000133_0002
To a mixture of derivative 7 (38 mg, 0.076 mmol, 1 equiv) and propargyl alcohol (1 mL) was added Erbium(III) trifluoromethanesulfonate (10 mg, 0.015 mmol, 1/5 equiv) and the brown solution was stirred at room temperature for 16 h. Water was added (1 mL) and the reaction was extracted with ethyl acetate (3 x 5 mL). The organic layer was washed with deionized water (5 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel Sep pak (5g) (eluent: dichloromethane to 5% ethyl acetate in dichloromethane) to provide 9 (33 mg, 79%) as a white solid. H NMR (400 MHz, DMSO-d6): δ 7.90 (d, J = 7.6, 2H), 7.40- 7.36 (m, 4H), 7.32-7.28 (m, 2H), 7.03-7.00 (m, 4H), 6.84-6.80 (m, 4H), 5.52 (d, J = 5.2, 1H), 5.13 (d, J = 5.2, 1H), 4.15 (d, J = 2.4, 2H), 4.01-3.98 ( m, 1H), 3.92-3.86 (m, 4H), 3.84-3.81 (m, 1H), 3.74-3.70 (dd, J = 11.2, 4.8, 1H), 3.66-3.61 (dd, J = 11.2, 5.2, 1H), 3.52-3.45 (m, 2H), 3.42 (t, J = 2.4, 1H); 13C NMR (100 MHz, DMSO-d6): δ 157.3, 157.0, 151.2, 139.3, 137.9, 137.6, 128.7, 128.7, 127.8, 127.5, 125.9, 120.5, 114.2, 80.3, 77.2, 70.9, 69.4, 68.8, 68.5, 67.8, 63.6, 57.9, 46.7; HRMS (ESI) (m/z): calc'd for C34H3i05NaCl [M+Na]+: 577.1758, found: 577.1747.
EXAMPLE 10
SYNTHESIS OF (S)-1-CHLORO-3-(4-(9-(4-((R)-2-HYDROXY-3- ISOPROPOXYPROPOXY)PHENYL)-9H-FLUOREN-9-YL)PHENOXY)PROPAN-2-OL (10)
Figure imgf000134_0001
To a solution of derivative 7 (21 mg, 0.042 mmol, 1 equiv) in isopropyl alcohol (1 mL) was added erbium(III) trifluoromethanesulfonate (6 mg, 0.008 mmol, 1/5 equiv) and the mixture was stirred at room temperature for 16 h. After the crude was concentrated under reduced pressure, the resulting residue was purified by flash column chromatography on silica gel Sep pak (5g) (eluent: dichloromethane to 5% ethyl acetate in dichloromethane) to provide 10 (23 mg, 97%) as a white foam. H NMR (400 MHz, DMSO-d6): δ 7.90 (d, J = 7.6, 2H), 7.38 (t, J = 7.6, 4H), 7.30 (t, J = 7.6, 2H), 7.02-6.99 (dd, J = 8.8, 2.4, 4H), 6.84-6.80 (dd, J = 8.4, 7.2, 4H), 5.50 (d, J = 5.2, 1H), 4.97 (d, J = 4.8, 1H), 4.01-3.97 ( m, 1H), 3.92-3.87 (m, 3H), 3.84-3.79 (m, 2H), 3.73-3.70 (dd, J = 11.2, 4.4, 1H), 3.65-3.61 (dd, J = 10.8, 5.2, 1H), 3.55-3.49 (m, 1H), 3.40-3.36 (m, 2H), 1.05 (d, J = 6.0, 6H); "c NMR (100 MHz, DMSO-d6): δ 157.4, 157.0, 151.2, 139.3, 137.9, 137.5, 128.7, 128.7, 127.7, 127.5, 125.9, 120.4, 114.2, 71.1, 69.6, 69.0, 68.8, 68.5, 68.2, 63.6, 46.7, 22.0; HRMS (ESI) (m/z): calc'd for C34H3505NaCl [M+Na]+: 581.2071, found: 581.2081
EXAMPLE 11
SYNTHESIS OF 3,3'-(4,4'-(9H-FLUO ENE-9,9-DIYL)BIS(4J -PHENYLENE))BIS(OXY)BIS(1-
CHLOROPROPANE-3,2-DIYL) BIS(2-(TERT-BUTOXYCARBONYLAMINO)ACETATE) (11)
Figure imgf000135_0001
Boc-Gly-OH (262 mg, 1.50 mmol, 4 equiv) was disolved in anhydrous 1,4 dioxane (2 mL), and triethylamine was added (209 ί, 1.50 mmol) at room temperature, and the contents were stirred under an atmosphere of argon for 10 min. N- (3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (579 mg, 1.50 mmol) was added in one portion followed by the slow addition of a solution of derivative 1 (200 mg, 0.37 mmol, 1 equiv) in anhydrous 1,4 dioxane (3 mL) and catalytic 4- (Dimethylamino)pyridine (~2 mg), and the solution was stirred at rt for 29 h. The reaction mixture was then evaporated to dryness and extracted with dichloromethane/water (3 x 10 mL). The organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 100% dichloromethane to 5% methanol in hexane) to provide 11 (57 mg) as a white solid. H NMR (400 MHz, CDC13): δ 7.79 (d, J = 7.2, 2H), 7.39 (t, J = 7.6, 4H), 7.30 (t, J = 7.2, 2H), 7.15 (d, J = 8.4, 4H), 6.79 (d, J = 8.4, 4H), 5.39-5.36 (m, 2H), 5.05-5.09 (m, 2H), 4.19-4.12 (m, 4H), 3.97 (s, 4H), 3.88-3.83 (dd, J = 11.6, 4.8, 2H), 3.81-3.77 (dd, J = 11.6, 5.2, 2H), 1.48 (s, 18H); C NMR (100 MHz, CDC13): δ 157.0, 155.8, 151.7, 140.1, 139.2, 129.4, 127.9, 127.6, 126.1, 120.4, 114.4, 80.3, 72.2, 65.9, 64.3, 42.5, 42.3, 28.5; HRMS (ESI) (m/z): calc'd for C45H5oN20ioNaCl2 [M+Na]+: 871.2740, found: 871.2729.
EXAMPLE 12
SYNTHESIS OF 2.2,-(3.3'-(4.4,-(9H-FLUORENE-9.9-DIYL BIS(4.1-
PHENYLENE))BIS(0XY)BIS( 1 -CHLO OP OPANE-3 ,2-DIYL))BIS(0XY)BIS(2-
OXOETHANAMINIUM) CHLORIDE (12)
Figure imgf000136_0001
11 (14 mg) was dissolved in 3 mL CH2C12 and Trifluoroacetic acid (0.4 mL) was added. The solution was stirred at rt for 6 h, then concentrated to dryness. Toluene (3 mL) was added, and the solution was concentrated to dryness again. The resulting residue was dissolved in 10 mL 0.2 M HCI, freeze and lyophilized to yield 12 as the bis-HCl salt (13 mg), as a white powder. EXAMPLE 13
SYNTHESIS OF (S)-1 -CHLORO-3-(4-(9-(4-(( )-2-HYDROXY-3-(2-(2-(2-
HYDROXYETHOXY)ETHOXY)ETHOXY)PROPOXY)PHENYL)-9H-FLUOREN-9- YL)PHENOXY)PROPAN-2-OL (13)
Figure imgf000137_0001
To a solution of derivative 7 (21 mg, 0.042 mmol, 1 equiv) in acetonitrile (1 mL) was added Triethylene glycol (1 mL) and bismuth(III) trifluoromethanesulfonate (~6 mg, 0.008 mmol, 1/5 equiv) and the mixture was stirred at room temperature for 4 h. After the crude was concentrated under reduced pressure, the resulting residue was extracted with ethyl acetate/water (3 x 5 mL). The organic layer was washed with deionized water (5 mL), was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: dichloromethane to 5% methanol in dichloromethane) to provide 13 (26 mg, 96%) as a white foam. H NMR (400 MHz, DMSO-d6): δ 7.90 (d, J = 7.2, 2H), 7.38 (t, J = 7.6, 4H), 7.30 (t, J = 7.6, 2H), 7.02-6.99 (dd, J = 8.8, 3.2, 4H), 6.84-6.80 (dd, J = 8.8, 6.8, 4H), 5.51 (br, 1H), 5.02 (br, 1H), 4.57 (br, 1H), 4.04-3.97 (m, 1H), 3.91-3.85 (m, 4H), 3.83-3.79 (m, 1H), 3.74-3.69 (dd, J = 11.2, 4.4, 1H), 3.65-3.61 (dd, J = 11.2, 5.6, 1H), 3.55-3.42 (m, 12H), 3.40-3.37 (m, 2H); "c NMR (100 MHz, DMSO-d6): δ 157.4, 157.0, 151.2, 139.3, 137.9, 137.5, 128.7, 128.7, 127.8, 127.5, 125.9, 120.5, 114.2, 72.3, 72.1, 70.2, 69.8, 69.7, 69.7, 69.5, 68.8, 68.5, 67.9, 63.6, 60.2, 46.7; HRMS (ESI) (m/z): calc'd for C37H4i08NaCl [M+Na]+: 671.2388, found: 671.2380. EXAMPLE 14
SYNTHESIS OF (R)-3-(4-(9-(4-((S)-3-CHLO O-2-HYD OXYP OPOXY)PHENYL)-9H- FLUOREN-9-YL)PHENOXY)PROPANE-1 ,2-DIOL (14)
Figure imgf000138_0001
To a solution of derivative 7 (17 mg, 0.034 mmol, 1 equiv) in a mixture of acetonitrile (2 mL) and water (1 mL) was added Bismuth(III) trifluoromethanesulfonate (2 mg, 0.0034 mmol, 1/10 equiv) and the mixture was stirred at room temperature for 77 h. Then, the reaction mixture was evaporated to dryness and extracted with ethyl acetate/water (3 x 5 mL). The organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 20% ethyl acetate in hexane to 70% ethyl acetate) to provide 14 (16 mg, 93%) as a white solid. H NMR (400 MHz, DMSO-d6): δ 7.90 (d, J = 7.2, 2H), 7.38 (t, J = 7.6, 4H), 7.30 (t, J = 7.6, 2H), 7.02-6.99 (dd, J = 8.8, 3.6, 4H), 6.82 (d, J = 8.4, 4H), 5.51 (d, J = 4.4, 1H), 4.88 (s, 1H), 4.60 (s, 1H), 4.01-3.97 (m, 1H), 3.94-3.90 (m, 3H), 3.81-3.69 (m, 3H), 3.65-3.61 (dd, J = 11.2, 5.6, 1H), 3.40 (d, J = 5.2, 2H); 13C NMR (100 MHz, DMSO-de): δ 157.5, 157.0, 151.2, 139.3, 137.9, 137.4, 128.7, 128.7, 127.8, 127.5, 125.9, 120.4, 114.2, 114.2, 69.9, 69.5, 68.8, 68.5, 63.6, 62.7, 46.7.
EXAMPLE 15
IN VITRO ACTIVITY OF SELECT COMPOUNDS
LNCaP cells were transiently cotransfected with PSA (6.1 kb)-luciferase (0.25 μg/well) in 24-well plates for 24 h prior to pre-treatment with compounds for 1 hour before the addition of synthetic androgen, R1881 (1 nM) to induce PSA production or vehicle. The total amount of plasmid DNA transfected was normalized to 0.75 μg/well 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.
TABLE 3
Figure imgf000139_0001
Figure imgf000140_0001
EXAMPLE 16
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 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:
Figure imgf000142_0001
I
or a pharmaceutically acceptable salt or tautomer thereof, wherein:
at least one Z1 is independently C-Q;
at least one Z2 is independently C-T, CCH3, CF, CC1, CBr, CI, COH, CG1, COG1, CNH2, CNHG1, CN(G1)2, COS03H, COP03H2, CSG1, CSOG1, or CSOzG1;
Z3, Z4 and each remaining Z1 and Z2 are, at each occurrence, independently C-T, N, CH, CCH3, CF, CC1, CBr, CI, COH, CG1, COG1, CNH2, CNHG1, CNG * C , CSG1, CSOG1, or CSO2G1;
Figure imgf000142_0002
Q is ;
J is G1, O, CH2, CHG1, C(Gl)2, S, NH, NG1, SO, S02, or NR;
M is H, F, CI, Br, CH2OH, CH2OD,
Figure imgf000142_0003
CH2F, CH2C1, CHC12, CCI3, 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, independently H, G1, R,
Figure imgf000142_0004
.OR
^ '* 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;
Figure imgf000143_0001
T is, at each occurrence, independently ;
J is, at each occurrence, independently G1, O, CH2, CHG1, C(G1)2, S, NH, NG1, SO, S02, or NR;
M2 is, at each occurrence, independently H, CH3, F, CI, Br, CH2F , CH2C1, CHC12, CCI3, CH2Br, CHBr2, CBr3, CH2OH, CH2OD2, CH2OJ", G1, CH2OG1, CH2OR, CH2OG1OG1', G^G1', G^G^OG1", CH2SG1, CH2NH2, CH2 HG1, CHz 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,
Figure imgf000143_0002
OR
01. v
'} 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;
is, at each occurrence, independently 0, 1, 2, 3, 4, 5, 6, 7 or 8;
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 C1-C10 alkyl, wherein the optional substituents for the C1-C10 alkyl are oxo, CH2C02R', OJ'", COOH, R1, OH, OR1, F, CI, Br, I, NH2, NHR1, N(R1)2, CN, SH, SR1, S03H, SO3R1,
Figure imgf000143_0003
OSO3R1, OR2, CONH2, CONHR1, CONHR2, CON(R1)2, NHR2, OP03H3, CON^R2, NR R2 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, wherien 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 Ci-Cio acyl.
2. The compound of claim 1 , wherein at least one Z2 is C-T.
3. The compound of claim 1 , wherein the compound has a structure of Formula II:
Figure imgf000144_0001
4. The compound of claim 1 , wherein the compound has a structure of Formula III:
Figure imgf000144_0002
wherein:
R3, R4, R5, R6. R7, R8, R9 and R10 are each independently hydrogen, halo, or linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl.
5. The compound of claim 1 , wherein the compound has a structure of Formula IV:
Figure imgf000144_0003
IV
6. The compound of claim 1, wherein the compound has a structure of Formula V:
Figure imgf000145_0001
V
7. The compound of claim 1, wherein the compound has a structure of Formula Va, Vb, Vc or Vd:
Figure imgf000145_0002
Vc Vd
8. The compound of any one of claims 1 to 7, wherein the compound has one of the following structures:
Figure imgf000146_0001
Figure imgf000147_0001
wherein:
11 is hydrogen or linear or branched, substituted or unsubstituted, saturated or unsaturated Ci-Cio alkyl;
Y is CI or OH;
q is 0, 1, 2, 3, 4, 5, 6 or 7; and
m is 0, 1, 2, 3, 4, 5, 6, 7 or 8.
9. The compound of any one of claims 1 to 5, wherein J is G1, O, CH2, CHG1, CG^, NH, SO, or NR.
10. The compound of any one of claims 1 to 5, wherein J is O.
11. The compound of any one of claims 1 to 7, 9 or 10, 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 7, 9 or 10, wherein M is CH2OH, CH2F, C≡CH, CH2OCH2C≡CH CH2OCH3, CH20-z-propyl, CH20- i-butyl, or
CH2OD, wherein D is
Figure imgf000148_0001
13. The compound of any one of claims 1 to 7, 9 or 10, wherein M is
CH2OH.
The compound of any one of claims 1 to 7, 9 or 10, wherein M
H.
The compound of any one of claims 1 to 7 or 9-14, wherein L
H.
16. The compound of any one of claims 1 to 7 or 9-14, wherein L is
A-D.
17. The compound of any one of claims 1 to 7 or 9-14, wherein A is
O.
18. The com ound of any one of claims 16 or 17, wherein D is H, R,
Figure imgf000148_0002
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
Figure imgf000148_0003
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 5, wherein J2 is G1, O, CH2, CHG1, CG^, NH, SO, or NR.
27. The compound of any one of claims 1 to 5, wherein J2 is O.
28. The compound of any one of claims 1 to 7 or 9-27, wherein M2 is H, CH2F, CH2C1, CH2Br, CH2OH, CH2OJ", CFLOG1, or C≡CH.
29. The compound of any one of claims 1 to 7 or 9-27, wherein M2 is
CH2F.
30. The compound of any one of claims 1 to 7 or 9-27, wherein M2 is
CH2C1.
31. The compound of any one of claims 1 to 7 or 9-27, wherein M2 is
CH2Br.
32. The compound of any one of claims 1 to 7 or 9-27, wherein M2 is
CH2OH.
33. The compound of any one of claims 1 to 7 or 9-27, wherein M2 is
H.
34. The compound of any one of claims 1 to 7 or 9-27, wherein M2 is
C≡CH.
35. The compound of any one of claims 1 to 7 or 9-34, wherein L2 is
H.
36. The compound of any one of claims 1 to 7 or 9-34, 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,
Figure imgf000149_0001
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
Figure imgf000150_0001
The compound of any one of claims 1 to 42, wherein m is 0. The compound of any one of claims 1 to 42, wherein m is 1, 2, 3,
The compound of any one of claims 1 to 42, wherein m is 1. The compound of any one of claims 1 to 7, wherein M is C¾OH
The compound of any one of claims 1 to 7, wherein M2 is CH2C1
48. The compound of any one of claims 1 to 7, 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.
50. The compound of any one of claims 4 to 49, wherein at least one of R3, R4, R5, R6, R7, R8, R9 or R10 is hydrogen.
51. The compound of any one of claims 4 to 49, wherein each of R3, R4, R5, R6, R7, R8, R9 and R10 are hydrogen.
52. The compound of any one of claims 4 to 49, wherein each of R3, R4, R5 and R6 are hydrogen.
53. The compound of any one of claims 4 to 49, wherein at least one of R3, R4, R5, R6, R7, R8, R9 or R10 is methyl.
54. The compound of any one of claims 4 to 49, wherein each of R3, R4, R5, R6, R7, R8, R9 and R10 are methyl. The compound of any one of claims 4 to 49, wherein each of R3 and R6 are methyl.
56. The compound of any one of claims 4 to 49, wherein at least one of R3, R4, R5, R6, R7, R8, R9 or R10 is fluoro.
57. The compound of any one of claims 4 to 49, wherein each R3, R4, R5, R6, R7, R8, R9 and R10 are fluoro.
The compound of any one of claims 4 to 49, wherein each of R3
R4, R5, and R° are fluoro.
The compound of any one of claims 4 to 49, wherein at least one of R3, R4, R5, R6, R7, R8, R9 or R10 is chloro.
The compound of any one of claims 4 to 49, wherein each of R3
R4, R5, R6, R7, R8, R9 and R10 are chloro.
61. The compound of any one of claims 4 to 49, wherein each of R3, R4, R5 and R6 are chloro.
62. The compound of any one of claims 4 to 49, wherein at least one of R3, R4, R5, R6, R7, R8, R9 or R10 is bromo.
63. The compound of any one of claims 4 to 49, wherein each of R3, R4, R5, R6, R7, R8, R9 and R10 are bromo.
64. The compound of any one of claims 4 to 49, wherein each of R3, R4, R5 and R6 are bromo.
The compound of an one of claims 1 to 5, wherein Q
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001

Figure imgf000160_0001
Figure imgf000161_0001
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.
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
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.
67. The com ound of any one of claims 1 to 5, wherein Q is
Figure imgf000164_0002
Figure imgf000165_0001
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-Ci0 alkyl, wherein the optional substituents are selected from oxo, OJ'", COOH, OH, F, CI, Br, I, NH2, CN, SH, S03H, CONH2, OP03H3, and N02.
68. The com ound of any one of claims 1 to 5, wherein Q is
Figure imgf000165_0002
Figure imgf000166_0001
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.
The compound of any one of claims 1 to 5, wherein q
Figure imgf000166_0002
The com ound of any one of claims 1 to 5, wherein Q
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000169_0002
167
Figure imgf000170_0001
Figure imgf000171_0001
and T is OH
Figure imgf000171_0002
74. The com ound of any one of claims 1 to 5, wherein Q is
Figure imgf000171_0003
75. The compound of any one of claims 1 to 3, wherein Z3, Z4 and each remaining Z1 and Z2 is independently CCH3; CH; CF, CCl or CBr.
76. The compound of any one of claims 1 to 3, wherein Z3, Z4 and each remaining Z1 and Z2 is CH.
77. 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.
78. The com ound of claim 77, wherein the moiety from TABLE 1
Figure imgf000172_0001
Figure imgf000173_0001
171
Figure imgf000174_0001
Figure imgf000175_0001
80. Use of the compound of any one of claims 1 to 79, for modulating androgen receptor (AR) activity.
81. The use of claim 80, wherein modulating androgen receptor (AR) activity is in a mammalian cell.
82. The use of any one of claims 80 or 81, 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.
83. The use of claim 82, wherein the indication is prostate cancer.
84. The use of claim 83, wherein the prostate cancer is castration resistant prostate cancer.
85. The use of claim 83, wherein the prostate cancer is androgen-dependent prostate cancer.
86. The use of claim 82, wherien the spinal and bulbar muscular atrophy is Kennedy's disease.
87. 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 79 to a subject in need thereof.
88. The method of claim 87, 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.
89. The method of claim 88, wherein the prostate cancer is castration resistant prostate cancer.
90. The method of claim 88, wherein the prostate cancer is androgen-dependent prostate cancer.
91. The method of claim 88, wherein the spinal and bulbar muscular atrophy is Kennedy's disease.
92. A pharmaceutical composition comprising a compound of any one of claims 1 to 79 and a pharmaceutically acceptable carrier.
93. A pharmaceutical composition comprising a compound of any one of claims 1 to 79, an additional therapeutic agent and a pharmaceutically acceptable carrier.
94. The pharmaceutical composition of claim 93, 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.
95. The pharmaceutical composition of claim 93, wherien the additional therapeutic agent is MDV3100 , TOK 001 , TOK 001 ; ARN-509; abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VITAXIN, sunitumib, ZD-4054, VN/124-1 , Cabazitaxel (XRP-6258), \1 f) ··() ! () flpiiimumab), OGX 427, OGX O I L finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105, 1 1 1 or a related compound thereof.
96. Use of the pharmaceutical composition of any one of claims 92 to 95 for modulating androgen receptor (AR) activity.
97. The use of claim 96, wherein modulating androgen receptor (AR) activity is in a mammalian cell.
98. The use of any one of claims 96 or 97, 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.
99. The use of claim 98, wherein the indication is prostate cancer.
100. The use of claim 99, wherein the prostate cancer is castration resistant prostate cancer.
101. The use of claim 99, wherein the prostate cancer is androgen-dependent prostate cancer.
102. The use of claim 98, wherien the spinal and bulbar muscular atrophy is Kennedy's disease.
103. A method of modulating androgen receptor (AR) activity, the method comprising administering the pharmaceutical composition of any one of claims 92 to 95 to a subject in need thereof.
104. The method of claim 103 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.
105. The method of claim 104, wherien the spinal and bulbar muscular atrophy is Kennedy's disease.
106. The use of claim 104, wherein the indication is prostate cancer.
107. The use of claim 106, wherein the prostate cancer is castration resistant prostate cancer.
108. The use of claim 106, wherein the prostate cancer is androgen-dependent prostate cancer.
PCT/US2012/033959 2011-04-18 2012-04-17 Fluorene-9-bisphenol compounds and methods for their use WO2012145330A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161476728P 2011-04-18 2011-04-18
US61/476,728 2011-04-18

Publications (1)

Publication Number Publication Date
WO2012145330A1 true WO2012145330A1 (en) 2012-10-26

Family

ID=47041891

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2012/033959 WO2012145330A1 (en) 2011-04-18 2012-04-17 Fluorene-9-bisphenol compounds and methods for their use

Country Status (1)

Country Link
WO (1) WO2012145330A1 (en)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8686050B2 (en) 2008-07-02 2014-04-01 The University Of British Columbia Diglycidic ether derivative therapeutics and methods for their use
WO2014113260A1 (en) * 2013-01-15 2014-07-24 Aragon Pharmaceuticals, Inc. Androgen receptor modulator and uses thereof
WO2015031984A1 (en) * 2013-09-09 2015-03-12 British Columbia Cancer Agency Branch Halogenated compounds for cancer imaging and treatment and methods for their use
US9173939B2 (en) 2013-05-10 2015-11-03 The University Of British Columbia Ester derivatives of androgen receptor modulators and methods for their use
US9268217B2 (en) 2013-08-09 2016-02-23 Cheil Industries Inc. Photosensitive resin composition and light blocking layer using the same
US9334399B2 (en) 2012-12-12 2016-05-10 Cheil Industries Inc. Photosensitive resin composition and black spacer using the same
US9365510B2 (en) 2012-04-16 2016-06-14 British Columbia Cancer Agency Branch Aziridine bisphenol ethers and related compounds and methods for their use
US9388112B2 (en) 2010-01-06 2016-07-12 The University Of British Columbia Bisphenol derivatives and their use as androgen receptor activity modulators
WO2016112455A1 (en) 2015-01-13 2016-07-21 British Columbia Cancer Agency Branch Heterocyclic compounds for cancer imaging and treatment and methods for their use
WO2017177307A1 (en) 2016-04-15 2017-10-19 British Columbia Cancer Agency Branch Bisphenol derivatives and their use as androgen receptor activity modulators
US9884054B2 (en) 2012-09-26 2018-02-06 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer
WO2018129012A1 (en) * 2017-01-04 2018-07-12 Sabic Global Technologies B.V. Methods for synthesizing high purity epoxy compounds and products obtained therefrom
US10471023B2 (en) 2015-03-12 2019-11-12 British Columbia Cancer Agency Branch Bisphenol ether derivatives and methods for using the same
US10702508B2 (en) 2017-10-16 2020-07-07 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castration-resistant prostate cancer
US10722527B2 (en) 2015-04-10 2020-07-28 Capsugel Belgium Nv Abiraterone acetate lipid formulations
US10870724B2 (en) 2014-07-22 2020-12-22 Sabic Global Technologies B.V. High heat monomers and methods of use thereof
US11059795B2 (en) 2018-10-18 2021-07-13 Essa Pharma, Inc. Androgen receptor modulators and methods for their use
US11242324B2 (en) 2020-04-17 2022-02-08 Essa Pharma, Inc. Solid forms of an n-terminal domain androgen receptor inhibitor and uses thereof
US11485713B2 (en) 2018-05-25 2022-11-01 Essa Pharma, Inc. Androgen receptor modulators and methods for their use
WO2023046283A1 (en) 2021-09-22 2023-03-30 Fundació Institut De Recerca Biomèdica (Irb Barcelona) Compounds and their use in a method for modulating ar (androgen receptor) transcriptional activity
TWI833908B (en) 2019-02-22 2024-03-01 德商馬克專利公司 Spin-on compositions comprising an inorganic oxide component and an alkynyloxy substituted spin-on carbon component useful as hard masks and filling materials with improved shelf life

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080153837A1 (en) * 2005-05-19 2008-06-26 Aventis Pharma S.A. Novel Fluorene Derivatives, Composition Containing Said Derivatives and the Use Thereof
WO2010000066A1 (en) * 2008-07-02 2010-01-07 British Columbia Cancer Agency Branch Diglycidic ether derivative therapeutics and methods for their use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080153837A1 (en) * 2005-05-19 2008-06-26 Aventis Pharma S.A. Novel Fluorene Derivatives, Composition Containing Said Derivatives and the Use Thereof
WO2010000066A1 (en) * 2008-07-02 2010-01-07 British Columbia Cancer Agency Branch Diglycidic ether derivative therapeutics and methods for their use

Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8686050B2 (en) 2008-07-02 2014-04-01 The University Of British Columbia Diglycidic ether derivative therapeutics and methods for their use
US9862667B2 (en) 2008-07-02 2018-01-09 The University Of British Columbia Diglycidic ether derivative therapeutics and methods for their use
US9388112B2 (en) 2010-01-06 2016-07-12 The University Of British Columbia Bisphenol derivatives and their use as androgen receptor activity modulators
US9365510B2 (en) 2012-04-16 2016-06-14 British Columbia Cancer Agency Branch Aziridine bisphenol ethers and related compounds and methods for their use
US10799488B2 (en) 2012-09-26 2020-10-13 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer
US10849888B2 (en) 2012-09-26 2020-12-01 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer
US10052314B2 (en) 2012-09-26 2018-08-21 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer
US9884054B2 (en) 2012-09-26 2018-02-06 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer
US10799489B2 (en) 2012-09-26 2020-10-13 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer
USRE49353E1 (en) 2012-09-26 2023-01-03 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castrate-resistant prostate cancer
US9334399B2 (en) 2012-12-12 2016-05-10 Cheil Industries Inc. Photosensitive resin composition and black spacer using the same
JP2016508991A (en) * 2013-01-15 2016-03-24 アラゴン ファーマシューティカルズ，インコーポレイテッド Androgen receptor modulator and use thereof
WO2014113260A1 (en) * 2013-01-15 2014-07-24 Aragon Pharmaceuticals, Inc. Androgen receptor modulator and uses thereof
EP2945628B1 (en) 2013-01-15 2020-04-15 Aragon Pharmaceuticals, Inc. Androgen receptor modulator in combination with abiraterone acetate and prednisone for treating prostate cancer
EA035125B1 (en) * 2013-01-15 2020-04-29 Арагон Фармасьютикалз, Инк. Method of treating prostate cancer using a combination based on androgen receptor modulator
US9173939B2 (en) 2013-05-10 2015-11-03 The University Of British Columbia Ester derivatives of androgen receptor modulators and methods for their use
US9268217B2 (en) 2013-08-09 2016-02-23 Cheil Industries Inc. Photosensitive resin composition and light blocking layer using the same
JP2016530285A (en) * 2013-09-09 2016-09-29 ブリティッシュ コロンビア キャンサー エージェンシー ブランチ Halogenated compounds for imaging and treatment of cancer and methods of use thereof
US9375496B2 (en) 2013-09-09 2016-06-28 British Columbia Cancer Agency Branch Halogenated compounds for cancer imaging and treatment and methods for their use
WO2015031984A1 (en) * 2013-09-09 2015-03-12 British Columbia Cancer Agency Branch Halogenated compounds for cancer imaging and treatment and methods for their use
US10870724B2 (en) 2014-07-22 2020-12-22 Sabic Global Technologies B.V. High heat monomers and methods of use thereof
US11345670B2 (en) 2015-01-13 2022-05-31 The University Of British Columbia Heterocyclic compounds for cancer imaging and treatment and methods for their use
EP3988541A1 (en) 2015-01-13 2022-04-27 British Columbia Cancer Agency Branch Heterocyclic compounds for cancer imaging and treatment and methods for their use
US10654811B2 (en) 2015-01-13 2020-05-19 The University Of British Columbia Heterocyclic compounds for cancer imaging and treatment and methods for their use
WO2016112455A1 (en) 2015-01-13 2016-07-21 British Columbia Cancer Agency Branch Heterocyclic compounds for cancer imaging and treatment and methods for their use
US10471023B2 (en) 2015-03-12 2019-11-12 British Columbia Cancer Agency Branch Bisphenol ether derivatives and methods for using the same
US11779550B2 (en) 2015-03-12 2023-10-10 The University Of British Columbia Bisphenol ether derivatives and methods for using the same
US10722527B2 (en) 2015-04-10 2020-07-28 Capsugel Belgium Nv Abiraterone acetate lipid formulations
US11919874B2 (en) 2016-04-15 2024-03-05 The University Of British Columbia Bisphenol derivatives and their use as androgen receptor activity modulators
US11142508B2 (en) 2016-04-15 2021-10-12 The University Of British Columbia Bisphenol derivatives and their use as androgen receptor activity modulators
WO2017177307A1 (en) 2016-04-15 2017-10-19 British Columbia Cancer Agency Branch Bisphenol derivatives and their use as androgen receptor activity modulators
WO2018129012A1 (en) * 2017-01-04 2018-07-12 Sabic Global Technologies B.V. Methods for synthesizing high purity epoxy compounds and products obtained therefrom
US20190322653A1 (en) * 2017-01-04 2019-10-24 Sabic Global Technologies B.V. Methods for synthesizing high purity epoxy compounds and products obtained therefrom
US11491149B2 (en) 2017-10-16 2022-11-08 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castration-resistant prostate cancer
US11160796B2 (en) 2017-10-16 2021-11-02 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castration-resistant prostate cancer
US10702508B2 (en) 2017-10-16 2020-07-07 Aragon Pharmaceuticals, Inc. Anti-androgens for the treatment of non-metastatic castration-resistant prostate cancer
US11485713B2 (en) 2018-05-25 2022-11-01 Essa Pharma, Inc. Androgen receptor modulators and methods for their use
US11059795B2 (en) 2018-10-18 2021-07-13 Essa Pharma, Inc. Androgen receptor modulators and methods for their use
TWI833908B (en) 2019-02-22 2024-03-01 德商馬克專利公司 Spin-on compositions comprising an inorganic oxide component and an alkynyloxy substituted spin-on carbon component useful as hard masks and filling materials with improved shelf life
US11518747B2 (en) 2020-04-17 2022-12-06 Essa Pharma, Inc. Solid forms of an N-terminal domain androgen receptor inhibitor and uses thereof
US11242324B2 (en) 2020-04-17 2022-02-08 Essa Pharma, Inc. Solid forms of an n-terminal domain androgen receptor inhibitor and uses thereof
US11814357B2 (en) 2020-04-17 2023-11-14 Essa Pharma Inc. Solid forms of an N-terminal domain androgen receptor inhibitor and uses thereof
US11358938B2 (en) 2020-04-17 2022-06-14 Essa Pharma, Inc. Solid forms of an N-terminal domain androgen receptor inhibitor and uses thereof
WO2023046283A1 (en) 2021-09-22 2023-03-30 Fundació Institut De Recerca Biomèdica (Irb Barcelona) Compounds and their use in a method for modulating ar (androgen receptor) transcriptional activity
WO2023061723A1 (en) 2021-09-22 2023-04-20 Fundació Institut De Recerca Biomèdica (Irb Barcelona) Hydroxyphenyl-ethynyl-phenol derivatives as ar (androgen receptor) transcriptional activity modulators for use in the treatment of i.a. prostate cancer

Similar Documents

Publication Publication Date Title
WO2012145330A1 (en) Fluorene-9-bisphenol compounds and methods for their use
US20180235925A1 (en) Bisphenol compounds and methods for their use
EP2744773B1 (en) Fluorinated bisphenol ether compounds and methods for their use
WO2012145328A1 (en) Dibenzylphenyl compounds and methods for their use
AU2009266379C1 (en) Diglycidic ether derivative therapeutics and methods for their use
EP2521707B1 (en) Bisphenol derivatives and their use as androgen receptor activity modulators
WO2011082488A1 (en) Bisphenol derivative therapeutics and methods for their use
AU2014262333B2 (en) Ester derivatives of androgen receptor modulators and methods for their use
US9365510B2 (en) Aziridine bisphenol ethers and related compounds and methods for their use
WO2016058080A1 (en) Fluoro-chloro bisphenol ether compounds and methods for their use
WO2016141458A1 (en) Bisphenol ether derivatives and methods for using the same
OA18988A (en) Ester derivatives of androgen receptor modulators and methods for their use.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12774840

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12774840

Country of ref document: EP

Kind code of ref document: A1