US20170298033A1 - Bisphenol derivatives and their use as androgen receptor activity modulators - Google Patents

Bisphenol derivatives and their use as androgen receptor activity modulators Download PDF

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US20170298033A1
US20170298033A1 US15/489,162 US201715489162A US2017298033A1 US 20170298033 A1 US20170298033 A1 US 20170298033A1 US 201715489162 A US201715489162 A US 201715489162A US 2017298033 A1 US2017298033 A1 US 2017298033A1
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United States
Prior art keywords
propan
compound
chloro
phenoxy
alkyl
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Raymond Andersen
Marianne Dorothy Sadar
Kunzhong JIAN
Nasrin R. Mawji
Jun Wang
Carmen Adriana Banuelos
Yu-Chi Yang
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University of British Columbia
British Columbia Cancer Agency BCCA
Provincial Health Services Authority
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University of British Columbia
British Columbia Cancer Agency BCCA
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Priority to US15/489,162 priority Critical patent/US20170298033A1/en
Publication of US20170298033A1 publication Critical patent/US20170298033A1/en
Assigned to THE UNIVERSITY OF BRITISH COLUMBIA reassignment THE UNIVERSITY OF BRITISH COLUMBIA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ANDERSEN, RAYMOND JOHN, JIAN, Kunzhong
Assigned to PROVINCIAL HEALTH SERVICES AUTHORITY reassignment PROVINCIAL HEALTH SERVICES AUTHORITY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: YANG, YU-CHI, BANUELOS, CARMEN ADRIANA, MAWJI, NASRIN R., SADAR, MARIANNE DOROTHY, WANG, JUN
Priority to US16/848,061 priority patent/US11142508B2/en
Priority to US17/404,589 priority patent/US11919874B2/en
Assigned to NATIONAL INSTITUTES OF HEALTH - DIRECTOR DEITR reassignment NATIONAL INSTITUTES OF HEALTH - DIRECTOR DEITR CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: BRITISH COLUMBIA CANCER AGENCY
Priority to US18/918,840 priority patent/US20250100986A1/en
Assigned to NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT reassignment NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: BRITISH COLUMBIA CANCER AGENCY
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    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Definitions

  • This invention generally relates to bisphenol-related compounds and their use for treatment of various indications.
  • the invention relates to bisphenol ether compounds having halogenated phenyl groups and/or sulfone linking groups and their use for treatment of various cancers, for example prostate cancer, including but not limited to, primary/localized prostate cancer (newly diagnosed), locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer (CRPC), and hormone-sensitive prostate cancer.
  • This invention also relates to bisphenol-related compounds and their use for modulating androgen receptor (AR) activity including truncated AR.
  • AR androgen receptor
  • 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 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 diseases such as polycystic ovary syndrome as well as 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.
  • 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 that is still driven by AR 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 two transcriptional activation units (tau1 and tau5) within activation function-1 (AF-1). 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 androgen regulated genes, such as PSA, to initiate transcription.
  • LBD carboxy-terminal ligand-binding domain
  • DBD DNA-binding domain
  • NTD N-terminus domain
  • AF-1 activation function-1
  • 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
  • Clinically available inhibitors of the AR include nonsteroidal antiandrogens such as bicalutamide (CasodexTM), nilutamide, flutamide, and enzalutamide.
  • nonsteroidal antiandrogens such as bicalutamide (CasodexTM), nilutamide, flutamide, and enzalutamide.
  • steroidal antiandrogens such as cyproterone acetate and spironolactone. Both steroidal and non-steroidal antiandrogens target the LBD of the AR and predominantly fail presumably due to poor affinity, 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.
  • AR antagonists other than the bisphenol ether derivatives previously reported see, WO 2010/000066, WO 2011/082487; WO 2011/082488; WO 2012/145330; WO 2015/031984; WO 2016/058080; WO 2016/058082, WO 2016/112455, and WO 2016/141458 which are hereby incorporated by reference in their entireties, to the British Columbia Cancer Agency Branch and The University of British Columbia
  • AR degraders such as niclosamide (Liu C et al 2014), galeterone (Njar et al 2015; Yu Z at al 2014), and ARV-330 Androgen receptor PROTAC (Neklesa et al 2016 J Clin Oncol 34 suppl 2S; abstr 267); AR DBD inhibitor VPC-14449 (Dalal K et al 2014 J Biol Chem.
  • the AR-NTD is also a target for drug development (e.g. WO 2000/001813), since the NTD contains Activation-Function-1 (AF-1) which is the essential region required for AR transcriptional activity (Jenster et al 1991. Mol Endocrinol. 5, 1396-404).
  • AF-1 Activation-Function-1
  • the AR-NTD importantly plays a role in activation of the AR in the absence of androgens (Sadar, M. D. 1999 J. Biol. Chem. 274, 7777-7783; Sadar M D et al 1999 Endocr Relat Cancer. 6, 487-502; Ueda et al 2002 J. Biol. Chem. 277, 7076-7085; Ueda 2002 J. Biol. Chem.
  • 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 present disclosure is based in part on the surprising discovery that the compounds described herein, can be used to modulate AR activity either in vivo or in vitro for both research and therapeutic uses.
  • certain compounds disclosed herein are useful for imaging the prostate.
  • the imaging can be for any number of diagnostic purposes.
  • the compounds are useful for imaging benign prostate cancer diseases.
  • the compounds find utility for imaging of certain cancers, including prostate cancer since certain embodiments of the compounds localize in prostate tumor sites.
  • Other imaging agents are androgen mimics; however, in one embodiment, the compounds are useful for imaging AR splice variants or any AR species (i.e., those mutated in other domains or regions).
  • the AR can be mammalian.
  • the AR can be human.
  • the prostate cancer can be castration-resistant prostate cancer.
  • the prostate cancer can be androgen-dependent prostate cancer.
  • the present disclosure relates to compounds of Formula (I):
  • X is —S(O) n — or —C(R 8 R 9 )—;
  • R 1 is H, hydroxyl or OC( ⁇ O)R 13 ;
  • R 2 is hydroxyl or OC( ⁇ O)R 13 ;
  • R 3 is halo, —OH, —OR 4 ; OC( ⁇ O)R 13 , —NH 2 , —NHS(O) n R 5 , —N(C 1 -C 6 alkyl)S(O) n R 5 , —S(O) n R 5 , —N 3 , aryl, carbocyclyl, heteroaryl or heterocyclyl which are optionally substituted with one or more R 6 ;
  • R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, carbocyclyl, heteroaryl or heterocyclyl which are optionally substituted with one or more R 6 ;
  • R 5 is each independently C 1 -C 6 alkyl or aryl which are optionally substituted with one or more R 6 ;
  • R 6 is each independently selected from the group consisting of H, F, Cl, Br, I, 123 I, hydroxyl, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 6 -C 12 aryl, wherein each R 6 is optionally substituted with one or more of halogen, 123 I, 18 F, hydroxyl, —OS(O) 2 -aryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
  • R 8 and R 9 are each independently H or C 1 -C 6 alkyl
  • R 11a , R 11b , R 11c and R 11d are each independently H, methyl, F, Cl, Br, I, or 123 I;
  • R 13 is C 1 -C 6 alkyl
  • n 0, 1, or 2;
  • R 11a , R 11b , R 11c and R 11d is methyl F, Cl, Br, I, or 123 I.
  • R 11a , R 11b , R 11c and R 11d in Formula I are independently methyl, F, Cl, Br, I, or 123 I.
  • any two of R 11a , R 11b , R 11c and R 11d are independently methyl, F, Cl, Br, I, or 123 I and the remaining two of R 11a , R 11b , R 11c and R 11d are each H.
  • R 11a and R 11b are each H, and R 11c and R 11d are each independently methyl, F, Cl, Br, I, or 123 I.
  • R 11a and R 11b are each H, and R 11c and R 11d are each independently methyl, Cl, or Br.
  • R 11a and R 11b are each H, and R 11c and R 11d are each Cl.
  • R 11a and R 11c in Formula I are each H, and R 11b and R 11d in Formula I are each independently methyl, F, Cl, Br, I, or 123 I. In some embodiments, R 11a and R 11c are each H, and R 11b and R 11d are each independently methyl, Cl, or Br. In another embodiment, R 11a and R 11c are each H, and R 11b and R 11d are each Cl.
  • X in Formula I is —S(O) 2 —. In another embodiment, X in Formula I is —C(R 8 R 9 )— and R 8 and R 9 are each independently C 1 -C 3 alkyl. In one embodiment, X is —C(R 8 R 9 )— and R 8 and R 9 are each methyl.
  • R 1 in Formula I is hydroxyl or OC( ⁇ O)R 13 . In another embodiment R 1 is H.
  • R 3 in Formula I is —OH. In another embodiment, R 3 is —OC( ⁇ O)R 13 , wherein R 13 is methyl. In one embodiment, R 3 is —OR 4 and R 4 is C 1 -C 6 alkyl. In other embodiments, R 3 is —OR 4 and R 4 is methyl.
  • R 3 in Formula I is an optionally substituted 5 or 6 membered heteroaryl or an optionally substituted 3 to 7 membered heterocylyl, wherein said heteroaryl or said heterocyclyl respectively comprise at least one N atom.
  • R 3 is selected from a group consisting of pyrrole, furan, thiophene, pyrazole, pyridine, pyridazine, pyrimidine, imidazole, thiazole, isoxazole, oxadiazole, thiadiazole, oxazole, triazole, isothiazole, oxazine, triazine, azepine, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazine, and tetrazine.
  • each R 13 in Formula I when present is C 1 -C 3 alkyl. In a further embodiment, each R 13 when present is methyl.
  • R 1 and R 2 in Formula I are each independently —OH or —OC( ⁇ O)R 13 , wherein R 13 is methyl. In some embodiments, at least one of R 1 , R 2 and R 3 is —OC( ⁇ O)R 13 , wherein R 13 is methyl. In another embodiment, any two of R 1 , R 2 and R 3 are each —OC( ⁇ O)R 13 , wherein R 13 is methyl. In one embodiment, R 1 , R 2 and R 3 are each —OC( ⁇ O)R 13 , wherein R 13 is methyl.
  • the present disclosure relates to compounds of Formula (I):
  • R 1 is H, hydroxyl or —OC( ⁇ O)R 13 ;
  • R 2 is hydroxyl or —OC( ⁇ O)R 13 ;
  • R 3 is halo, —OH, —OR 4 , —OC( ⁇ O)R 13 , —NH 2 , —NHS(O) n R 5 , —N(C 1 -C 6 alkyl)S(O) n R 5 , —S(O) n R 5′ —N 3 , aryl, carbocyclyl, heteroaryl or heterocyclyl which are optionally substituted with one or more R 6 ;
  • R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, carbocyclyl, heteroaryl or heterocyclyl which are optionally substituted with one or more R 6 ;
  • R 5 is each independently C 1 -C 6 alkyl or aryl which are optionally substituted with one or more R 6 ;
  • R 6 is each independently selected from the group consisting of H, F, Cl, Br, I, 123 I, hydroxyl, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 6 -C 12 aryl, wherein each R 6 is optionally substituted with one or more of halogen, 123 I, 18 F, hydroxyl, —OS(O) 2 -aryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
  • R 8 and R 9 are each independently H or C 1 -C 6 alkyl
  • n 0, 1, or 2;
  • R 11a , R 11b , R 11c and R 11d are each independently H, methyl, F, Cl, Br, I, or 123 I.
  • R 3 in Formula II is —OH.
  • R 3 is —OC( ⁇ O)R 13 , wherein R 13 is methyl.
  • R 3 is —OR 4 , wherein R 4 is C 1 -C 6 alkyl.
  • R 3 is —OR 4 , wherein R 4 is methyl.
  • R 1 in Formula II is hydroxyl or OC( ⁇ O)R 13 . In another embodiment R 1 in Formula II is H.
  • R 3 in Formula II is an optionally substituted 5 or 6 membered heteroaryl or an optionally substituted 3 to 7 membered heterocylyl, wherein said heteroaryl or said heterocyclyl respectively comprise at least one N atom.
  • R 3 is selected from a group consisting of pyrrole, furan, thiophene, pyrazole, pyridine, pyridazine, pyrimidine, imidazole, thiazole, isoxazole, oxadiazole, thiadiazole, oxazole, triazole, isothiazole, oxazine, triazine, azepine, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazine, and tetrazine.
  • R 11a , R 11b , R 11c and R 11d in Formula II are each H.
  • each R 13 in Formula II when present is C 1 -C 3 alkyl. In a further embodiment, each R 13 when present is methyl.
  • R 1 and R 2 in Formula II are each independently —OH or —OC( ⁇ O)R 13 , wherein R 13 is methyl. In some embodiments, at least one of R 1 , R 2 and R 3 is —OC( ⁇ O)R 13 , wherein R 13 is methyl. In another embodiment, any two of R 1 , R 2 and R 3 are each —OC( ⁇ O)R 13 , wherein R 13 is methyl. In one embodiment, R 1 , R 2 and R 3 are each —OC( ⁇ O)R 13 , wherein R 13 is methyl.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I or Formula II or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and an additional therapeutic agent.
  • a pharmaceutical composition comprising a compound of Formula I or Formula II or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and an additional therapeutic agent.
  • the additional therapeutic agent is for treating prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular 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 enzalutamide, galeterone, abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, bevacizumab (Avastin), OSU-HDAC42, VITAXIN, sunitumib, ZD-4054, cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX 011, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,111, ODM-201, radium 233, ODM-204, niclosamide, apalutamide, ARV-33Q, VPC-14449, TAS3681, 3E10-AR441bsAb, sintokamide, or related compounds thereof.
  • the present disclosure provides a method for modulating androgen receptor activity, comprising administering a compound of Formula I or Formula II or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or a pharmaceutical composition comprising a compound of Formula I or Formula II or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, to a patient in need thereof.
  • the method of modulating androgen receptor activity is inhibiting androgen receptor.
  • the present disclosure provides a method for treating a condition or disease that is responsive to modulation of androgen receptor activity, comprising: administering a compound of Formula I or Formula II or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or a pharmaceutical composition comprising a compound of Formula I or Formula II or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, to a patient in need thereof.
  • the condition or disease is selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular 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 condition is prostate cancer.
  • the condition or disease is castration-resistant prostate cancer.
  • the condition or disease is androgen-dependent prostate cancer.
  • the compounds described herein can be used for diagnostic purposes to investigate diseases of the prostate, including cancer.
  • the compounds are useful for imaging diagnostics in cancer.
  • imaging allows for the detection and/or location of cancer sites (e.g., tumor sites).
  • cancer sites e.g., tumor sites.
  • these compounds can be used individually or as part of a kit for such purposes.
  • FIG. 1 shows a 13 C NMR spectrum of Compound 3a.
  • FIG. 2 shows a dose-response for selected compounds of the present disclosure in LNCaP cells transfected with the PSA (6.1 kb)-luciferase reporter and treated with androgen.
  • FIG. 3 shows tumor volume of LNCaP xenografts in SCID-NOD mice treated with Compound 1a or CMC-treated mice (control) in the course of 26 day treatment.
  • FIG. 4 shows tumor volume of LNCaP xenografts at the start and the finish (day 26) for Compound 1a treated mice and CMC-treated mice.
  • FIG. 5 shows body weight at the start and the finish (day 26) for Compound 1a treated mice and CMC-treated mice.
  • FIG. 6 shows tissues levels of PSA mRNA in five representative xenografts from each treatment group measured by QPCR.
  • Amino refers to the —NH 2 radical.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo radical.
  • Niro refers to the —NO 2 radical.
  • Oxo refers to the ⁇ O substituent.
  • Thioxo refers to the ⁇ S substituent.
  • Alkyl or “alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C 1 -C 12 alkyl, an alkyl comprising up to 10 carbon atoms is a C 1 -C 10 alkyl, an alkyl comprising up to 6 carbon atoms is a C 1 -C 6 alkyl and an alkyl comprising up to 5 carbon atoms is a C 1 -C 5 alkyl.
  • a C 1 -C 5 alkyl includes C 5 alkyls, C 4 alkyls, C 3 alkyls, C 2 alkyls and C 1 alkyl (i.e., methyl).
  • a C 1 -C 6 alkyl includes all moieties described above for C 1 -C 5 alkyls but also includes C 6 alkyls.
  • a C 1 -C 10 alkyl includes all moieties described above for C 1 -C 5 alkyls and C 1 -C 6 alkyls, but also includes C 7 , C 8 , C 9 and C 10 alkyls.
  • a C 1 -C 12 alkyl includes all the foregoing moieties, but also includes C 11 and C 12 alkyls.
  • Non-limiting examples of C 1 -C 12 alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl.
  • an alkyl group can be optionally substituted.
  • Alkylene or “alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms.
  • C 1 -C 12 alkylene include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.
  • Alkenyl or “alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included.
  • An alkenyl group comprising up to 12 carbon atoms is a C 2 -C 12 alkenyl
  • an alkenyl comprising up to 10 carbon atoms is a C 2 -C 10 alkenyl
  • an alkenyl group comprising up to 6 carbon atoms is a C 2 -C 6 alkenyl
  • an alkenyl comprising up to 5 carbon atoms is a C 2 -C 5 alkenyl.
  • a C 2 -C 5 alkenyl includes C 5 alkenyls, C 4 alkenyls, C 3 alkenyls, and C 2 alkenyls.
  • a C 2 -C 6 alkenyl includes all moieties described above for C 2 -C 5 alkenyls but also includes C 6 alkenyls.
  • a C 2 -C 10 alkenyl includes all moieties described above for C 2 -C 5 alkenyls and C 2 -C 6 alkenyls, but also includes C 7 , C 8 , C 9 and C 10 alkenyls.
  • a C 2 -C 12 alkenyl includes all the foregoing moieties, but also includes C 11 and C 12 alkenyls.
  • Non-limiting examples of C 2 -C 12 alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-noneny
  • Examples of C 1 -C 3 alkyl includes methyl, ethyl, n-propyl, and i-propyl.
  • Examples of C 1 -C 4 alkyl includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and sec-butyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.
  • alkenylene or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds.
  • C 2 -C 12 alkenylene include ethene, propene, butene, and the like.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted.
  • Alkynyl or “alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included.
  • An alkynyl group comprising up to 12 carbon atoms is a C 2 -C 12 alkynyl
  • an alkynyl comprising up to 10 carbon atoms is a C 2 -C 10 alkynyl
  • an alkynyl group comprising up to 6 carbon atoms is a C 2 -C 6 alkynyl
  • an alkynyl comprising up to 5 carbon atoms is a C 2 -C 5 alkynyl.
  • a C 2 -C 5 alkynyl includes C 5 alkynyls, C 4 alkynyls, C 3 alkynyls, and C 2 alkynyls.
  • a C 2 -C 6 alkynyl includes all moieties described above for C 2 -C 5 alkynyls but also includes C 6 alkynyls.
  • a C 2 -C 10 alkynyl includes all moieties described above for C 2 -C 5 alkynyls and C 2 -C 6 alkynyls, but also includes C 7 , C 8 , C 9 and C 10 alkynyls.
  • a C 2 -C 12 alkynyl includes all the foregoing moieties, but also includes C 11 and C 12 alkynyls.
  • Non-limiting examples of C 2 -C 12 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.
  • Alkynylene or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds.
  • C 2 -C 12 alkynylene include ethynylene, propargylene and the like.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted.
  • Alkoxy refers to a radical of the formula —OR a where R a is an alkyl, alkenyl or alknyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.
  • Alkylamino refers to a radical of the formula —NHR a or —NR a R a where each R a is, independently, an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted.
  • Alkylcarbonyl refers to the —C( ⁇ O)R a moiety, wherein R a is an alkyl, alkenyl or alkynyl radical as defined above.
  • R a is an alkyl, alkenyl or alkynyl radical as defined above.
  • a non-limiting example of an alkyl carbonyl is the methyl carbonyl (“acetal”) moiety.
  • Alkylcarbonyl groups can also be referred to as “Cw-Cz acyl” where w and z depicts the range of the number of carbon in R a , as defined above.
  • C 1 -C 10 acyl refers to alkylcarbonyl group as defined above, where R a is C 1 -C 10 alkyl, C 1 -C 10 alkenyl, or C 1 -C 10 alkynyl radical as defined above. Unless stated otherwise specifically in the specification, an alkyl carbonyl group can be optionally substituted.
  • Aryl refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring.
  • the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems.
  • Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • aryl is meant to include aryl radicals that are optionally substituted.
  • Alkyl refers to a radical of the formula —R b —R c where R b is an alkylene, alkenylene or alkynylene group as defined above and R c is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.
  • Carbocyclyl “carbocyclic ring” or “carbocycle” refers to a rings structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyl. cycloalkenyl and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.
  • Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyl radicals include, for example, adamantyl, norbomyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.
  • “Cycloalkenyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like.
  • Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted.
  • Cycloalkynyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.
  • Cycloalkylalkyl refers to a radical of the formula —R b -Rd where R b is an alkylene, alkenylene, or alkynylene group as defined above and Rd is a cycloalkyl, cycloalkenyl, cycloalkynyl radical as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group can be optionally substituted.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.
  • Haloalkenyl refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.
  • Haloalkynyl refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropynyl, 1-fluorobutynyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.
  • Heterocyclyl refers to a stable 3- to 20-membered non-aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclycl or heterocyclic rings include heteroaryls as defined below.
  • the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated.
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thio
  • N-heterocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, aN-heterocyclyl group can be optionally substituted.
  • Heterocyclylalkyl refers to a radical of the formula —R b —Re where R b is an alkylene, alkenylene, or alkynylene chain as defined above and Re is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl can be attached to the alkyl, alkenyl, alkynyl radical at the nitrogen atom. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group can be optionally substituted.
  • Heteroaryl refers to a 5- to 20-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
  • the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furany
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group can be optionally substituted.
  • Heteroarylalkyl refers to a radical of the formula —R b —R f where R b is an alkylene, alkenylene, or alkynylene chain as defined above and R f is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group can be optionally substituted.
  • 123 I refers to the radioactive isotope of iodine having atomic mass 123.
  • the compounds of Formula I can comprise at least one 123 I moiety. Throughout the present application, where structures depict a 123 I moiety at a certain position it is meant that the I moiety at this position is enriched for 123 I. In other words, the compounds contain more than the natural abundance of 123 I at the indicated position(s). It is not required that the compounds comprise 100% 123 I at the indicated positions, provided 123 I is present in more than the natural abundance.
  • the 123 I isotope is enriched to greater than 50%, greater than 60%, greater than 70%, greater than, 80% or greater than 90%, relative to 127 I.
  • 18 F refers to the radioactive isotope of fluorine having atomic mass 18.
  • F or “ 19 F” refers to the abundant, non-radioactive fluorine isotope having atomic mass 19.
  • the compounds of Formula I can comprise at least one 18 F moiety. Throughout the present application, where structures depict a 18 F moiety at a certain position it is meant that the F moiety at this position is enriched for 18 F. In other words, the compounds contain more than the natural abundance of 18 F at the indicated position(s). It is not required that the compounds comprise 100% 18 F at the indicated positions, provided 18 F is present in more than the natural abundance.
  • the 18 F isotope is enriched to greater than 50%, greater than 60%, greater than 70%, greater than 80% or greater than 90%, relative to 19 F.
  • Thioalkyl refers to a radical of the formula —SR a where R a is an alkyl, alkenyl, or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group can be optionally substituted.
  • substituted means any of the above groups (i.e., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as hydroxyl groups
  • “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced
  • “Substituted also means any of the above groups in which one or more hydrogen atoms are replaced with —C( ⁇ O)R g , —C( ⁇ O)OR g , —C( ⁇ O)NR g R h , —CH 2 SO 2 R g , —CH 2 SO 2 NR g R h .
  • R g and R h are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.
  • “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl group.
  • each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.
  • 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 bond.
  • fused refers to any ring structure described herein which is fused to an existing ring structure in the compounds of the invention.
  • the fused ring is a heterocyclyl ring or a heteroaryl ring
  • any carbon atom on the existing ring structure which becomes part of the fused heterocyclyl ring or the fused heteroaryl ring can be replaced with a nitrogen atom.
  • the invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds.
  • Such products can result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes.
  • the invention includes compounds produced by a process comprising administering a compound of this invention to a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Such products are typically identified by administering a radiolabelled compound of the invention in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • a “subject” can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat and the like.
  • the subject can be suspected of having or at risk for having a cancer, such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, or endometrial cancer, or suspected of having or at risk for having acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration.
  • a cancer such as prostate cancer, breast cancer, ovarian cancer, salivary gland carcinoma, or endometrial cancer, or suspected of having or at risk for having acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy
  • Diagnostic methods for various cancers such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, salivary gland carcinoma, or endometrial cancer, and diagnostic methods for acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration and the clinical delineation of cancer, such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, salivary gland carcinoma, or endometrial cancer, diagnoses and the clinical delineation of acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration are known to those of ordinary skill in the art.
  • “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
  • Optional or “optionally” means that the subsequently described event of circumstances can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted aryl means that the aryl radical can or cannot be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic bases are isoprop
  • solvate refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent.
  • the solvent can be water, in which case the solvate can be a hydrate.
  • the solvent can be an organic solvent.
  • the compounds of the present invention can exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
  • the compound of the invention can be true solvates, while in other cases, the compound of the invention can merely retain adventitious water or be a mixture of water plus some adventitious solvent.
  • a “pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans.
  • a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
  • an “effective amount” refers to 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 can 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 can 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 a castration-resistant form.
  • a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount can be less than a therapeutically effective amount.
  • Treating” or “treatment” as used herein covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes:
  • the compounds of the invention, or their pharmaceutically acceptable salts can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms whether or not they are specifically depicted herein.
  • Optically active (+) and ( ⁇ ), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • a “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule.
  • the present invention includes tautomers of any said compounds.
  • the terms “about” and/or “approximately” can be used in conjunction with numerical values and/or ranges.
  • the term “about” is understood to mean those values near to a recited value.
  • “about 40 [units]” can mean within +25% of 40 (e.g., from 30 to 50), within ⁇ 20%, ⁇ 15%, ⁇ 10%, ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, ⁇ 1%, less than ⁇ 1%, or any other value or range of values therein or therebelow.
  • the phrases “less than about [a value]” or “greater than about [a value]” should be understood in view of the definition of the term “about” provided herein.
  • the terms “about” and “approximately” can be used interchangeably.
  • ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range “from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range can be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).
  • certain embodiments of the present invention are directed to compounds useful for treatment of various cancers, including various types of prostate cancers. While not wishing to be bound by theory, it is believed that binding of the compounds to the androgen receptor (for example at the N-terminal domain) can contribute to the activity of the disclosed compounds.
  • the compounds of the present invention include halogenated phenyl groups (i.e., R 11a -R 11d in Formula I) and/or sulfone bridging groups (i.e., X in Formula I is —S(O) 2 — or compounds of Formula II) which impart improved properties to the compounds compared to compounds lacking the described R 3 moiety.
  • the improved properties include improved drug-like properties such as improved activity (e.g., androgen receptor (AR) modulation), longer half-life (e.g., in vivo); decreased toxicity; better solubility, improved formulation, better bioavailability, better pharmacokinetic profile; reduction in unwanted metabolites and the like.
  • improved activity e.g., androgen receptor (AR) modulation
  • longer half-life e.g., in vivo
  • decreased toxicity better solubility, improved formulation, better bioavailability, better pharmacokinetic profile
  • reduction in unwanted metabolites and the like are examples of drugs-like properties such as improved activity (e.g., androgen receptor (AR) modulation), longer half-life (e.g., in vivo); decreased toxicity; better solubility, improved formulation, better bioavailability, better pharmacokinetic profile; reduction in unwanted metabolites and the like.
  • improved drug-like properties such as improved activity (e.g., androgen receptor (AR) modulation),
  • the invention includes compounds which form covalent bonds with the androgen receptor (AR) (e.g., at the N-terminal domain), thus resulting in irreversible (or substantially irreversible) inhibition of the same.
  • AR androgen receptor
  • the certain compounds of the present invention are designed to include functional groups capable of forming covalent bonds with a nucleophile under certain in vivo conditions.
  • the reactivity of compounds of the present invention is such that they will not substantially react with various nucleophiles (e.g., glutathione) when the compounds are free in solution.
  • the compounds when the free mobility of the compounds is restricted, and an appropriate nucleophile is brought into close proximity to the compound, for example when the compounds associate with, or bind to, the androgen receptor, the compounds are capable of forming covalent bonds with certain nucleophiles (e.g., thiols).
  • nucleophiles e.g., thiols
  • the present invention includes all compounds which have the above described properties (i.e., binding and/or inhibiting to androgen receptor (AR)).
  • the present invention is directed to a compound having a structure of Formula I:
  • X is —S(O) n — or —C(R 8 R 9 )—;
  • R 1 is H, —OH, or —OC( ⁇ O)R 13 ;
  • R 2 is —OH, or —OC( ⁇ O)R 13 ;
  • R 3 is halo, —OH, —OR 4 , —OC( ⁇ O)R 13 , —NH 2 , —NHC( ⁇ O)R 13 , —N(C( ⁇ O)R 13 ) 2 , —NHS(O) n R 5 , —N(C( ⁇ O)R 13 )(S(O) n R 5 ), —N(C 1 -C 6 alkyl)(S(O) n R 5 ), —S(O) n R 5 , —N 3 , aryl, carbocyclyl, heteroaryl or heterocyclyl which are optionally substituted with one or more R 6 :
  • R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, carbocyclyl, heteroaryl or heterocyclyl which are optionally substituted with one or more R 6 ;
  • R 5 is each independently C 1 -C 6 alkyl or aryl which are optionally substituted with one or more R 6 ;
  • R 6 is each independently selected from the group consisting of H, F, Cl, Br, I, 123 I, —OH, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 6 -C 12 aryl, wherein each R 6 is optionally substituted with one or more of halogen, 123 I, 18 F, —OH, —OS(O) 2 -aryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
  • R 8 and R 9 are each independently H or C 1 -C 6 alkyl
  • R 11a , R 11b , R 11c and R 11d are each independently H, methyl, F, Cl, Br, I, or 123 I;
  • R 13 is C 1 -C 6 alkyl
  • n 0, 1, or 2;
  • R 11a , R 11b , R 11c and R 11d is methyl, F, Cl, Br, I, or 123 I.
  • stereoisomers of the compound of structure (I) are provided, for example in some embodiments the compound has one of the following structures (Ia), (Ib), (Ic) or (Id):
  • the compound has one of the following structures (le), (If), (Ig) or (Ih):
  • X is —S(O) n —. In some embodiments, X is —S(O) 2 —. In another embodiment, X is —C(R 8 R 9 )—. In one embodiment X is —C(R 8 R 9 )—, wherein R 8 and R 9 are each independently H or C 1 -C 3 alkyl. In another embodiment, X is —C(R 8 R 9 )—, wherein R 8 and R 9 are each C 1 alkyl. In some embodiments, X is —S(O) 2 — or —C(CH 3 ) 2 —.
  • R 1 is —OH. In another embodiment, R 1 is —OC( ⁇ O)R 13 . In some embodiments, R 1 is —OC( ⁇ O)R 13 , wherein R 13 is C 1 -C 4 alkyl. In other embodiments, R 1 is —OC( ⁇ O)R 13 , wherein R 13 is methyl. In one embodiment, R 1 is H.
  • R 2 is —OH. In another embodiment, R 2 is —OC( ⁇ O)R 13 . In some embodiments, R 2 is —OC( ⁇ O)R 13 , wherein R 13 is C 1 -C 4 alkyl. In other embodiments, R 2 is —OC( ⁇ O)R 13 , wherein R 13 is methyl.
  • R 3 is —OH. In another embodiment, R 3 is —OC( ⁇ O)R 13 . In some embodiments, R 3 is —OC( ⁇ O)R 13 , wherein R 13 is C 1 -C 4 alkyl. In other embodiments, R 3 is —OC( ⁇ O)R 13 , wherein R 13 is methyl.
  • At least one of R 1 , R 2 , or R 3 is —OH. In some embodiments, at least two of R 1 , R 2 , or R 3 are each —OH. In other embodiments, R 1 and R 2 are each —OH. In another embodiment, R 1 , R 2 , and R 3 are each —OH.
  • At least one of R 1 , R 2 , or R 3 is —OC( ⁇ O)R 13 , wherein R 13 is C 1 -C 4 alkyl. In another embodiment, at least one of R 1 , R 2 , or R 3 is —OC( ⁇ O)R 13 , wherein R 13 is methyl. In some embodiments, at least two of R 1 , R 2 , or R 3 are each —OC( ⁇ O)R 13 , wherein R 13 is C 1 -C 4 alkyl. In another embodiment, at least two of R 1 , R 2 , or R 3 are each —OC( ⁇ O)R 13 , wherein R 13 is methyl. In other embodiments, R 1 and R 2 are each —OC( ⁇ O)R 13 , wherein R 13 is methyl.
  • one of R 1 , R 2 , or R 3 is —OC( ⁇ O)R 13 , wherein R 13 is C 1 -C 4 alkyl. In another embodiment, one of R 1 , R 2 , or R 3 is —OC( ⁇ O)R 13 , wherein R 13 is methyl. In some embodiments, two of R 1 , R 2 , or R 3 are each —OC( ⁇ O)R 13 , wherein R 13 is C 1 -C 4 alkyl. In another embodiment, two of R 1 , R 2 , or R 3 are each —OC( ⁇ O)R 13 , wherein R 13 is methyl.
  • R 1 and R 2 are each —OC( ⁇ O)R 13 , wherein R 13 is C 1 -C 4 alkyl. In another embodiment, R 1 and R 2 are each —OC( ⁇ O)R 13 , wherein R 13 is methyl. In some embodiments, R 1 , R 2 , or R 3 are each —OC( ⁇ O)R 13 , wherein R 13 is C 1 -C 4 alkyl. In another embodiment, R 1 , R 2 , or R 3 are each —OC( ⁇ O)R 13 , wherein R 13 is methyl.
  • R 3 is —OR 4 .
  • R 3 is —OR 4 , wherein R 4 is C 1 -C 6 alkyl.
  • R 3 is —OR 4 , wherein R 4 is C 1 -C 3 alkyl.
  • R 3 is —OR 4 , wherein R 4 is methyl, ethyl, n-propyl, or i-propyl.
  • R 3 is —OR 4 , wherein R 4 is methyl.
  • R 3 is —OR 4 , wherein R 4 is i-propyl.
  • R 3 is a halogen. In other embodiments, R 3 is F, Cl, Br, or I. In one embodiment, R 3 is F.
  • R 3 is —NH 2 , —NHC( ⁇ O)R 13 , —N(C( ⁇ O)R 13 ) 2 , —NHS(O) n R 5 , —N(C( ⁇ O)R 13 )(S(O) n R 5 ), or —N(C 1 -C 6 alkyl)(S(O) n R 5 ).
  • R 3 is a —NH 2 .
  • R 3 is a —NHC( ⁇ O)R 13 .
  • R 3 is a —N(C( ⁇ O)R 13 ) 2 .
  • R 3 is a —NHS(O) n R 5 .
  • R 3 is a —NHS(O) 2 R 5 . In other embodiments, R 3 is a —NHS(O) 2 R 5 , wherein R 5 is C 1 -C 3 alkyl. In one embodiment, R 3 is a —NHS(O) 2 R 5 , wherein R 5 is C 1 alkyl. In one embodiment, R 3 is a —N(C( ⁇ O)R 13 )(S(O) n R 5 ). In one embodiment, R 3 is a —N(C 1 -C 6 alkyl)(S(O) n R 5 ).
  • R 3 is —NH 2 , —NHC( ⁇ O)(C 1 -C 4 alkyl), —N[(C( ⁇ O)(C 1 -C 4 alkyl)] 2 , —NHS(O) n (C 1 -C 3 alkyl), —N[C( ⁇ O)(C 1 -C 4 alkyl)][(S(O) n (C 1 -C 3 alkyl)], or —N[C 1 -C 6 alkyl][S(O) n (C 1 -C 3 alkyl)].
  • R 3 is —NH(C( ⁇ O)CH 3 ) or —N(C( ⁇ O)CH 3 ) 2 .
  • R 3 is —NHS(O) 2 CH 3 .
  • R 3 is —N(C( ⁇ O)CH 3 ) (S(O) 2 CH 3 ).
  • R 3 is a —S(O) 1 R 5 . In one embodiment, R 3 is a —S(O) 2 R 5 . In another embodiment, R 3 is a —S(O) 2 (C 1 -C 3 alkyl). In other embodiments, R 3 is a —S(O) 2 CH 3 . In other embodiments, R 3 is a —S(O) 2 CH 2 CH 3 .
  • R 3 is an optionally substituted 5 or 6 membered heteroaryl or an optionally substituted 3 to 7 membered heterocylyl, wherein said heteroaryl or said heterocyclyl respectively comprise at least one N atom in the ring.
  • R 3 is selected from a group consisting of pyrrole, furan, thiophene, pyrazole, pyridine, pyridazine, pyrimidine, imidazole, thiazole, isoxazole, oxadiazole, thiadiazole, oxazole, triazole, isothiazole, oxazine, triazine, azepine, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazine, and tetrazine.
  • R 3 is selected from a group consisting of pyrrole, furan, thiophene, pyrazole, pyridine, pyridazine, pyrimidine, imidazole, thiazole, isoxazole, oxadiazole,
  • At least one of R 11a , R 11b , R 11c and R 11d is Cl. In another embodiment, at least one of R 11a , R 11b , R 11c and R 11d is Br. In some embodiments, at least one of R 11a , R 11b , R 11c and R 11d is methyl.
  • R 11a , R 11b , R 11c and R 11d are methyl, F, Cl, Br, I, or 123 I. In another embodiment, exactly two of R 11a , R 11b , R 11c and R 11d are methyl, F, Cl, Br, I, or 123 I.
  • R 11a and R 11b are each H and R 11c and R 11d are each independently methyl, F, Cl, Br, I, or 123 I. In one embodiment, R 11a and R 11b are each H, and R 11c and R 11d are each Cl. In one embodiment, R 11a and R 11b are each H, and R 11c and R 11d are each Br. In one embodiment, R 11a and R 11b are each H, and R 11c and R 11d are each methyl.
  • R 11a and R 11c are each H, and R 11b and R 11d are each independently methyl, F, Cl, Br, I, or 123 I. In one embodiment, R 11a and R 11c are each H, and R 11b and R 11d are each Cl. In one embodiment, R 11a and R 11c are each H, and R 11b and R 11d are each Br. In one embodiment, R 11a and R 11c are each H, and R 11b and R 11d are each methyl.
  • R 13 is C 1 -C 3 alkyl. In other embodiments, R 13 is methyl, ethyl, or propyl. In one embodiment, R 13 is a methyl.
  • n is 0. In another embodiment n is 1. In some embodiments, n is 2.
  • the compounds comprise one F, Cl, Br, I, or 123 I substitution.
  • any three of R 11a , R 11b , R 11c and R 11d are each H, and the remaining one of R 11a , R 11b , R 11c or R 11d is F, Cl, Br, I or 123 I.
  • the compounds comprise two F, Cl, Br, I or 123 I substitutions on the phenyl rings (i.e., two of R 11a , R 11b , R 11c and R 11d are H, and the other two of R 11a , R 11b , R 11c or R 11d are F, Cl, Br, I or 123 I).
  • the compounds comprise three F, Cl, Br, I or 123 I substitutions (i.e., any one of R 11a , R 11b , R 11c and R 11d is H, and the remaining R 11a , R 11b , R 11c or R 11d is F, Cl, Br, I or 123 I) and in other embodiments the compounds comprise four F, Cl, Br, I or 123 I substitutions (i.e., each of R 11a , R 11b , R 11c and R 11d are F, Cl, Br, I or 123 I).
  • the compound comprises one or more of F, Cl, Br, I or 123 I substitutions for R 3 . In one embodiment, the compound comprises one or more of I or 123 I substitutions for R 3 .
  • the compound comprises at least one R 6 substituent on R 3 , wherein at least one R 6 is further substituted with at least one of F, Cl, Br, I or 123 I. In another embodiment, R 6 substituent on R 3 is further substituted with at least one of I or 123 I.
  • R 11a is 123 I.
  • R 11c is 123 I.
  • the compound of Formula I has one of the following structures from Table 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:
  • the compound of Formula I has one of the following structures from Table 2, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.
  • the compound of Formula I has one of the following structures from Table 3, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:
  • the compound of Formula I has one of the following structures from Table 4, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:
  • the compound of Formula I has one of the following structures from Tables 1, 2, 3, or 4, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.
  • the present invention includes all compounds which have the above described properties (i.e., binding to androgen receptor (AR)).
  • the present invention is directed to a compound having a structure of Formula II:
  • R 1 is H, hydroxyl or —OC( ⁇ O)R 13 ;
  • R 2 is hydroxyl or —OC( ⁇ O)R 13 ;
  • R 3 is halo, —OH, —OR 4 , —OC( ⁇ O)R 13 , —NH 2 , —NHC( ⁇ O)R 13 , —N(C( ⁇ O)R 13 ) 2 , —NHS(O) n R 5 , —N(C( ⁇ O)R 13 )(S(O) n R 5 ), —N(C 1 -C 6 alkyl)(S(O) n R 5 ), —S(O) n R 5 , —N 3 , aryl, carbocyclyl, heteroaryl or heterocyclyl which are optionally substituted with one or more R 6 ;
  • R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, carbocyclyl, heteroaryl or heterocyclyl which are optionally substituted with one or more R 6 ;
  • R 5 is each independently C 1 -C 6 alkyl or aryl which are optionally substituted with one or more R 6 ;
  • R 6 is each independently selected from the group consisting of H, F, Cl, Br, I, 123 I, hydroxyl, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 6 -C 12 aryl, wherein each R 6 is optionally substituted with one or more of halogen, 123 I, 18 F, hydroxyl, —OS(O) 2 -aryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
  • R 13 is C 1 -C 6 alkyl
  • n 0, 1, or 2.
  • stereoisomers of the compound of structure (II) are provided, for example in some embodiments the compound has one of the following structures (IIa), (IIb), (IIc) or (IId):
  • the compound has one of the following structures (IIe), (IIf), (IIg) or (IIh):
  • R 1 is hydroxyl. In another embodiment, R 1 is —OC( ⁇ O)R 13 . In some embodiments, R 1 is —OC( ⁇ O)R 13 , wherein R 13 is C 1 -C 4 alkyl. In other embodiments, R 1 is —OC( ⁇ O)R 13 , wherein R 13 is methyl. In one embodiment, R 1 is H.
  • R 2 is hydroxyl. In another embodiment, R 2 is —OC( ⁇ O)R 13 . In some embodiments, R 2 is —OC( ⁇ O)R 13 , wherein R 13 is C 1 -C 4 alkyl. In other embodiments, R 2 is —OC( ⁇ O)R 13 , wherein R 13 is methyl.
  • R 3 is —OH. In another embodiment, R 3 is —OC( ⁇ O)R 13 . In some embodiments, R 3 is —OC( ⁇ O)R 13 , wherein R 13 is C 1 -C 4 alkyl. In other embodiments, R 3 is —OC( ⁇ O)R 13 , wherein R 13 is methyl.
  • At least one of R 1 , R 2 , or R 3 is —OH. In another embodiment, at least one of R 1 , R 2 , or R 3 is —OH. In some embodiments, at least two of R 1 , R 2 , or R 3 are each —OH. In another embodiment, R 1 and R 2 are each —OH. In one embodiment, R 1 , R 2 , or R 3 are each —OH.
  • At least one of R 1 , R 2 , or R 3 is —OC( ⁇ O)R 13 , wherein R 13 is C 1 -C 4 alkyl. In another embodiment, at least one of R 1 , R 2 , or R 3 is —OC( ⁇ O)R 13 , wherein R 13 is methyl. In some embodiments, at least two of R 1 , R 2 , or R 3 are each —OC( ⁇ O)R 13 , wherein R 13 is C 1 -C 4 alkyl. In another embodiment, at least two of R 1 , R 2 , or R 3 are each —OC( ⁇ O)R 13 , wherein R 13 is methyl.
  • one of R 1 , R 2 , or R 3 is —OC( ⁇ O)R 13 , wherein R 13 is C 1 -C 4 alkyl.
  • one of R 1 , R 2 , or R 3 is —OC( ⁇ O)R 13 , wherein R 13 is methyl.
  • two of R 1 , R 2 , or R 3 are each —OC( ⁇ O)R 13 , wherein R 13 is C 1 -C 4 alkyl.
  • two of R 1 , R 2 , or R 3 are each —OC( ⁇ O)R 13 , wherein R 13 is methyl.
  • R 1 , R 2 , or R 3 are each —OC( ⁇ O)R 13 , wherein R 13 is C 1 -C 4 alkyl.
  • R 1 , R 2 , or R 3 are each —OC( ⁇ O)R 13 , wherein R 13 is methyl.
  • R 3 is —OR 4 . In one embodiment, R 3 is —OR 4 , wherein R 4 is C 1 -C 6 alkyl. In another embodiment, R 3 is —OR 4 , wherein R 4 is C 1 -C 3 alkyl. In one embodiment, R 3 is —OR 4 , wherein R 4 is C 1 alkyl. In another embodiment, R 3 is —OR 4 , wherein R 4 is isopropyl.
  • R 3 is a halogen. In one embodiment, R 3 is F.
  • R 3 is —NH 2 , —NHC( ⁇ O)R 13 , —N(C( ⁇ O)R 13 ) 2 , —NHS(O) n R 5 , —N(C( ⁇ O)R 13 )(S(O) n R 5 ), or —N(C 1 -C 6 alkyl)(S(O) n R 5 ).
  • R 3 is a —NH 2 .
  • R 3 is a —NHC( ⁇ O)R 13 .
  • R 3 is a —N(C( ⁇ O)R 13 ) 2 .
  • R 3 is a —NHS(O) n R 5 .
  • R 3 is a —NHS(O) 2 R 5 . In other embodiments, R 3 is a —NHS(O) 2 R 5 , wherein R 5 is C 1 -C 3 alkyl. In one embodiment, R 3 is a —NHS(O) 2 R 5 , wherein R 5 is methyl. In one embodiment, R 3 is a —N(C( ⁇ O)R 13 )(S(O) n R 5 ). In one embodiment, R 3 is a —N(C 1 -C 6 alkyl)S(O) n R 5 .
  • R 3 is —NH 2 , —NHC( ⁇ O)(C 1 -C 4 alkyl), —N[(C( ⁇ O)(C 1 -C 4 alkyl)] 2 , —NHS(O) n (C 1 -C 3 alkyl), —N[C( ⁇ O)(C 1 -C 4 alkyl)][(S(O) n (C 1 -C 3 alkyl)], or —N[C 1 -C 6 alkyl][S(O) n (C 1 -C 3 alkyl)].
  • R 3 is —NH(C( ⁇ O)CH 3 ) or —N(C( ⁇ O)CH 3 ) 2 .
  • R 3 is —NHS(O) 2 CH 3 . In other embodiments, R 3 is —N(C( ⁇ O)CH 3 ) (S(O) 2 CH 3 ).
  • R 3 is a —S(O) n R 5 . In one embodiment, R 3 is a —S(O) 2 R 5 . In another embodiment, R 3 is a —S(O) 2 (C 1 -C 3 alkyl). In other embodiments, R 3 is a —S(O) 2 CH 3 . In other embodiments, R 3 is a —S(O) 2 CH 2 CH 3 .
  • R 3 is a —S(O) n R 5 . In one embodiment, R 3 is a —S(O) 2 R 5 . In some embodiments, R 3 is a —S(O) 2 R 5 , wherein R 5 is C 1 -C 3 alkyl. In other embodiments, R 3 is a —S(O) 2 R 5 , wherein R 5 is C 1 alkyl.
  • R 3 is an optionally substituted 5 or 6 membered heteroaryl or an optionally substituted 3 to 7 membered heterocylyl, wherein said heteroaryl or said heterocyclyl respectively comprises at least one N atom in the ring.
  • R 3 is selected from a group consisting of pyrrole, furan, thiophene, pyrazole, pyridine, pyridazine, pyrimidine, imidazole, thiazole, isoxazole, oxadiazole, thiadiazole, oxazole, triazole, isothiazole, oxazine, triazine, azepine, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazine, and tetrazine.
  • R 3 is selected from a group consisting of pyrrole, furan, thiophene, pyrazole, pyridine, pyridazine, pyrimidine, imidazole, thiazole, isoxazole, oxadiazole,
  • R 13 is C 1 -C 4 alkyl. In other embodiments, R 13 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, or sec-butyl. In one embodiment, R 13 is a methyl.
  • n is 0. In another embodiment n is 1. In some embodiments, n is 2.
  • the compounds for use in the imaging and treatment methods described herein.
  • the compounds comprise one F, Cl, Br, I, or 123 I substitution.
  • the compound comprise one or more of F, Cl, Br, I or 123 I substitutions for R 3 . In one embodiment, the compound comprise one or more of I or 123 I substitutions for R 3 .
  • the compound comprises at least one R 6 substituent on R 3 , wherein at least one R 6 is further substituted with at least one of F, Cl, Br, I or 123 I. In another embodiment, R 6 substituent on R 3 is further substituted with at least one of I or 123 I.
  • the compound of Formula II has one of the following structures from Table 5, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:
  • the present invention is directed to a pharmaceutical composition, comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, as described herein. In one embodiment, the present invention is directed to a pharmaceutical composition, comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof, as described herein.
  • the pharmaceutical composition comprising a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof further comprises a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprising a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof further comprises an additional therapeutic agent.
  • the pharmaceutical composition comprising a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof further comprises a pharmaceutically acceptable carrier and an additional therapeutic agent.
  • the pharmaceutical composition comprising a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, further comprises an additional therapeutic agent which is for treating prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular 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.
  • an additional therapeutic agent which is for treating prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular 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.
  • 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 cytotoxic in nature, and pharmacological therapies which interfere with the biological production or function of androgen (hereinafter, an “additional therapeutic agent”).
  • combination therapy is meant the administration of any one or more of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, with one or more of another therapeutic 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 or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and one or more of the additional 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 or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, as a pre-mixed formulation.
  • Administration of the compound(s) of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, in combination with the additional therapeutic agents for treatment of the above disease states also includes dosing by any dosing method including without limitation, intravenous delivery (IV), oral delivery, intra-peritoneal delivery, intra-muscular delivery, or intra-tumoral delivery.
  • IV intravenous delivery
  • oral delivery intra-peritoneal delivery
  • intra-muscular delivery intra-tumoral delivery.
  • the one or more of the additional therapeutic agents can be administered to the patient before administration of the compound(s) of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
  • the compound(s) of Formula I can be co-administered with one or more of the additional therapeutic agents.
  • the one or more additional therapeutic agents can be administered to the patient after administration of the compound(s) of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
  • the ratio of the doses of compound(s) of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, to that of the one or more additional therapeutic agents can be about 1:1 or can vary, e.g., about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, and can be varied accordingly to achieve the optimal therapeutic benefit.
  • the compound(s) of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, that are combined with the one or more additional therapeutic agents for improved treatment of the above disease states can comprise, but are not limited to any compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, including those compounds shown in Tables 1, 2, 3, 4, or 5.
  • the additional 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 ODM-201 (also known as BAY1841788) and related compounds, which appears to bind to the AR and blocks its cellular function, and is currently in clinical development as a treatment for prostate cancer); the chemical entity known as ODM-204 and related compounds, which appears to be a dual inhibitor of AR and CYP17A1 and can be useful for treatment of prostate cancer; the chemical entity known as enzalutamide (4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide) and related compounds, which appears to be a blocker of the androgen receptor (AR) LBD and a FDA-approved treatment for prostate cancer; the chemical entity known as Galeterone and related compounds which appears to be a blocker of the androgen receptor (AR) LBD, and a CYP
  • Galeterone is currently in development as a treatment for prostate cancer; the chemical entity known as ARN-509 or apalutamide (4-[7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide) and related compounds which appears to be a blocker of the androgen receptor (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-1H-cyclopenta[a]phenanthren-3-ol), and related molecules, which appears to block the production of androgen and FDA
  • VPC-14449 (4-(4-(4,5-bromo-1H-imidazol-1-yl)thiazol-2-yl)morpholine) and related compounds, which appears to target the DNA-binding domain of full-length AR and can be useful for treatment of prostate cancer.
  • TAS3681 appears to be an AR antagonist with AR downregulating activity and can be useful for treatment of prostate cancer.
  • sintokamides e.g., sintokamide A also known as N-[(2R,4S)-5,5,5-trichloro-1-[(2S)-2-[(2S)-3,3-dichlororopyl]-3-methoxy-5-oxo-2H-pyrrol-1-yl]-4-methyl-1-oxopentan-2-yl]propanamide
  • sintokamide A also known as N-[(2R,4S)-5,5,5-trichloro-1-[(2S)-2-[(2S)-3,3-dichlororopyl]-3-methoxy-5-oxo-2H-pyrrol-1-yl]-4-methyl-1-oxopentan-2-yl]propanamide
  • the pharmaceutical composition comprising a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, further comprises an additional therapeutic agent selected form the group consisting of enzalutamide, galeterone, abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, bevacizumab (Avastin), OSU-HDAC42, VITAXIN, sunitumib, ZD-4054, Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX 011, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,111, ODM-201, ODM-204, radium 233, niclosamide, apalutamide, ARV-330,
  • an additional therapeutic agent selected
  • compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, which result in unstable structures and/or unsatisfied valences are not included within the scope of the invention.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising any of the foregoing compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • Compounds as described herein can be in the free form or in the form of a salt thereof.
  • compounds as described herein can 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 can be, for example, formed as a pharmaceutically acceptable salt.
  • Compounds containing one or more basic functional groups can be capable of forming a pharmaceutically acceptable salt with, for example, a pharmaceutically acceptable organic or inorganic acid.
  • Pharmaceutically acceptable salts can 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
  • Compounds containing one or more acidic functional groups can 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.
  • Pharmaceutically acceptable salts can 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, theo
  • compounds as described herein can contain both acidic and basic groups and can be in the form of inner salts or zwitterions, for example, and without limitation, betaines.
  • Salts as described herein can 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 can occur in situ during isolation and purification of the compounds or preparation of salts can occur by separately reacting an isolated and purified compound.
  • compounds and all different forms thereof can 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 can 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 can 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 can cause a single crystal form to dominate.
  • 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.
  • the present compounds find use in any number of methods.
  • the compounds are useful in methods for modulating androgen receptor (AR).
  • the present disclosure provides the use of any one of the foregoing compounds of Formula I for modulating androgen receptor (AR) activity.
  • modulating androgen receptor (AR) activity is in a mammalian cell.
  • Modulating androgen receptor (AR) can be in a subject in need thereof (e.g., a mammalian subject) and for treatment of any of the described conditions or diseases.
  • 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, bladder cancer, pancreatic cancer, hepatocellular cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, age related macular degeneration, and combinations thereof.
  • the indication is prostate cancer.
  • the prostate cancer is primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, or metastatic castration-resistant prostate cancer (CRPC), or hormone-sensitive 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.
  • compounds as described herein can be administered to a subject.
  • the present invention is directed to a method of treating primary/localized prostate cancer comprising administering a pharmaceutical composition comprising a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
  • the present invention is directed to a method of treating locally advanced prostate cancer comprising administering a pharmaceutical composition comprising a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
  • the present invention is directed to a method of treating recurrent prostate cancer comprising administering a pharmaceutical composition comprising a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
  • the present invention is directed to a method of treating metastatic prostate cancer comprising administering a pharmaceutical composition comprising a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
  • the present invention is directed to a method of treating advanced prostate cancer comprising administering a pharmaceutical composition comprising a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
  • the present invention is directed to a method of treating metastatic castration-resistant prostate cancer (CRPC) comprising administering a pharmaceutical composition comprising a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
  • CRPC metastatic castration-resistant prostate cancer
  • the present invention is directed to a method of treating hormone-sensitive prostate cancer comprising administering a pharmaceutical composition comprising a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
  • the present disclosure provides a method of modulating androgen receptor (AR) activity, the method comprising administering any one of the foregoing compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or pharmaceutical composition of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, as described herein (including compositions comprising a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, and an additional therapeutic agent), to a subject (e.g., mammal) in need thereof.
  • modulating androgen receptor (AR) activity is in a mammalian cell.
  • modulating androgen receptor (AR) activity is in a mammal.
  • modulating androgen receptor (AR) activity is in a human.
  • the modulating androgen receptor (AR) activity can be for inhibiting AR N-terminal domain activity.
  • the modulating androgen receptor (AR) activity can be for inhibiting androgen receptor (AR) activity.
  • the modulating can be in vivo.
  • the modulating androgen receptor (AR) activity can be for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular 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.
  • prostate cancer breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycys
  • the indication can be prostate cancer.
  • the prostate cancer can be castration-resistant prostate cancer.
  • the prostate cancer is primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, or metastatic castration-resistant prostate cancer (CRPC), or hormone-sensitive prostate cancer.
  • the prostate cancer can be CRPC.
  • a method of modulating androgen receptor activity comprising administering Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or pharmaceutical composition of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, as described herein, is provided.
  • the administration can be to a mammal.
  • the administering can 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, bladder cancer, pancreatic cancer, hepatocellular 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), age related macular degeneration, and combinations thereof.
  • at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular 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), age related macular degeneration, and combinations thereof
  • the presently disclosed compounds can find utility in a number of medical imaging applications, including imaging of the prostate.
  • Many currently available imaging agents tend to accumulate in the bladder, which decreases their effectiveness as imaging tools specifically for the prostate.
  • the present applicants believe the disclosed compounds are unexpectedly effective for imaging of the prostate due to their ability to accumulate in the prostate, rather than the bladder, allowing the prostate gland to be seen.
  • the compounds can be used in methods for imaging the prostate, for example to image benign prostate diseases.
  • the compounds can be used in methods to image cancerous prostate diseases, such as tumors of the prostate.
  • Androgen ablation therapy causes a temporary reduction in prostate cancer tumor burden, but the malignancy will begin to grow again in the absence of testicular androgens to form castrate resistant prostate cancer (CRPC).
  • CRPC castrate resistant prostate cancer
  • PSA serum prostate-specific antigen
  • AR androgen receptor
  • the method identifies the presence of a tumor that expresses AR (both full-length and truncated AR lacking LBD) and then treats the tumor by radiotherapy.
  • the imaging methods provide information to determine if a tumor expresses AR species.
  • AR is a transcription factor and a validated target for prostate cancer therapy.
  • Current therapies include androgen ablation and administration of antiandrogens.
  • Most CRPC is suspected to be AR-dependent.
  • AR has distinct functional domains that include the C-terminus ligand-binding domain (LBD), a DNA-binding domain (DBD), and an amino-terminal domain (NTD).
  • LBD C-terminus ligand-binding domain
  • DBD DNA-binding domain
  • NTD amino-terminal domain
  • AR NTD contains activation function-1 (AF-1) that contributes most of the transcriptional activity to the AR.
  • AF-1 activation function-1
  • Recently, splice variants of the AR that lack the LBD have been reported in prostate cancer cell lines (VCaP, LNCaP95 and 22Rv1), and in CRPC tissues. To date more than 20 splice variants of AR have been detected.
  • Splice variants V7 and V567es are clinically relevant with levels of expression correlated to poor survival and CRPC.
  • AR V567es is solely expressed in 20% of metastases. Abiraterone resistance is associated with expression of AR splice variants.
  • Enzalutamide also increases levels of expression of these constitutively active AR splice variants.
  • These splice variants lack LBD and thereby would not be inhibited by current therapies that target the AR LBD such as antiandrogens or androgen ablation therapy.
  • a single patient with advanced prostate cancer can have many lesions throughout the body and skeleton and each tumor can have differing levels of expression of AR.
  • Biopsy of metastatic tumors in a patient to determine AR species is neither widely accessible nor feasible to sample tumors in a patient that can have multiple metastases.
  • certain embodiments of the present invention provide an AR NTD-targeted molecular imaging probe (e.g., compound of formula I) which can be used to monitor response to therapy and provide insight into the role of AR in resistance mechanisms.
  • the invention employs sequential imaging with 18 F-FDHT to detect full-length AR and gamma radiation emitting probes to specifically detect the AR NTD which would be the sum of both full-length AR and variant AR.
  • the invention employs sequential imaging with two different PET imaging agents to detects only full-length AR and another to specifically detect the AR NTD which would be the sum of both full-length AR and variant AR.
  • NTD variant plus full-length AR detected with NTD isotope minus full-length AR detected with 18 F-FDHT.
  • a discordant distribution or discordant level of uptake between 18 F-FDHT and a radiolabeled compound of this invention indicates the presence of overexpression of splice variants lacking the LBD.
  • radioactive 18 F labeled compounds have found use as imaging agents not only to image AR in prostate cancer but for imaging various organs and various tumors.
  • radioactive 123 I labeled compounds have been known for the use as imaging agents.
  • the compounds of the present disclosure comprise at least one 123 I.
  • the present invention is directed to a method of imaging cancer by administering a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, to a subject.
  • the present invention is directed to a method of imaging cancer by administering a pharmaceutical composition comprising a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, to a subject.
  • the method of imaging cancer by administering a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or a pharmaceutical composition comprising Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, to a subject and detecting the presence or absence of cancer by use of SPECT or PET.
  • the method of imaging cancer by administering a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, to a subject and the method identifies the presence or absence of a tumor.
  • the method of imaging cancer by administering a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, to a subject and the method identifies the location of a tumor.
  • the method of imaging cancer by administering a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, to a subject and the method identifies a presence of a prostate cancer.
  • the prostate cancer is androgen-dependent prostate cancer.
  • the subject is a mammal such as a human.
  • the method is useful for detecting the presence of AR splice variants or other AR species that cannot be detected by imaging agents that interact with the AR LBD (i.e., mutations, truncations).
  • the present compounds bind to the AR N-terminal domain (NTD)
  • the present methods can be useful for detecting AR species, including mutants and variants, which lack the LBD or have LBD mutations, but do comprise the AR NTD.
  • the method detects the presence or overexpression of AR splice variants lacking the ligand-binding domain.
  • the method can include sequential imaging with 18 F-FDHT and a compound of the invention and a discordant distribution or discordant level of uptake between 18 F-FDHT and the compound of the invention indicates the presence or overexpression of splice variants lacking the ligand-binding domain.
  • the compounds of the invention are used in single photon emission computed tomography methods to monitor a patient's response to therapy.
  • the methods comprise use of a compound of the invention to detect the AR NTD.
  • the method of imaging a cancer is by administering a compound as described anywhere herein.
  • the method of imaging a cancer is by administering a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein said compound comprises at least one 123 I.
  • the administering and imaging can be to a mammal in need of diagnosis of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, endometrial cancer, salivary gland carcinoma, benign prostatic hyperplasia, 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 imaging can be for imaging AR splice variants, mutants or other AR species which contain AR NTD.
  • the compounds as described herein or pharmaceutically acceptable salts thereof can be used for imaging and diagnosis of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular cancer, endometrial cancer, salivary gland carcinoma, benign prostatic hyperplasia, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration.
  • the compounds as described herein or acceptable salts thereof above can be used in the preparation of a medicament or a composition for imaging the prostate, for example for imaging benign prostate conditions or for imaging prostate cancer in a subject in need of such imaging (for example for diagnosis and/or location of prostate tumors).
  • compositions useful in modulating androgen receptor (AR) activity or useful for imaging can comprise a salt of such a compound, preferably a pharmaceutically or physiologically acceptable salt.
  • compositions 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.
  • the imaging method disclosed herein is directed to imaging prostate cancer.
  • the prostate cancer is primary/localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, metastatic prostate cancer, advanced prostate cancer, or metastatic castration-resistant prostate cancer (CRPC), and hormone-sensitive prostate cancer.
  • the prostate cancer is CRPC.
  • the imaging is for imaging benign prostate conditions such as benign prostatic hyperplasia. Methods of imaging and/or 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.
  • a pharmaceutical composition suitable for imaging is administered intravenously.
  • Suitable pharmaceutical compositions can be formulated by means known in the art and their mode of administration and dose determined by the skilled practitioner.
  • a compound can 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 can be administered in a tablet, capsule or dissolved in liquid form.
  • the tablet or capsule can 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 can be employed to provide release over a prolonged period of time.
  • Many techniques known to one of skill in the art are described in Remington: the Science & Practice of Pharmacy by Alfonso Gennaro, 20 th ed., Lippencott Williams & Wilkins, (2000).
  • Formulations for parenteral administration can, 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 polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compounds.
  • Formulations for inhalation can contain excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or can be oily solutions for administration in the form of nasal drops, or as a gel.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described herein, and an additional therapeutic agent and/or a pharmaceutically acceptable carrier.
  • the additional therapeutic agent is for treating prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular 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 enzalutamide, galeterone, ODN-201 abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VITAXIN, sunitumib, ZD-4054, Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX 011, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,111, ODM-201 ODM-204, niclosamide, apalutamide, ARV-330, VPC-14449, TAS3681, 3E10-AR441bsAb, sintokamide, or related compounds thereof.
  • Ligand-independent activation of the androgen receptor (AR) refers to transactivation of the full-length androgen receptor (AR) in the absence of androgen (ligand) by, for examples, stimulation of the cAMP dependent protein kinase (PKA) pathway or the interleukin-6 (IL6)/STAT3 pathway.
  • PKA cAMP dependent protein kinase
  • IL6 interleukin-6
  • Such compounds should block a mechanism that is common to both ligand-dependent and ligand-independent activation of the androgen receptor (AR), as well as constitutively active splice variants of the androgen receptor (AR) that lack ligand-binding domain.
  • This could involve any step in activation of the androgen receptor (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.
  • 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 can be used to treat such conditions.
  • Compounds or pharmaceutical compositions in accordance with this invention or for use in this invention can be administered by means of a medical device or appliance such as an implant, graft, prosthesis, stent, etc.
  • a medical device or appliance such as an implant, graft, prosthesis, stent, etc.
  • implants can 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.
  • dosage values can vary with the exact imaging protocol.
  • specific dosage regimens can be adjusted over time according to the individual need and the professional judgment 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 can be selected by medical practitioners.
  • the amount of active compound(s) in the composition can vary according to factors such as the disease state, age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum imaging result. For example, a single bolus can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the imaging results. It can be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • 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, such as in severe disease conditions, substantial excesses of the compositions can be administered for therapeutic effects. Some compounds of this invention can be toxic at some concentrations. Titration studies can be used to determine toxic and non-toxic concentrations. Toxicity can be evaluated by examining a particular compound's or composition's specificity across cell lines using PC3 or DU145 cells as possible negative controls since these cells do not express functional AR. Animal studies can 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 castration, antiandrogens and androgen insensitivity syndrome are not fatal.
  • compounds and all different forms thereof as described herein can 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, bladder cancer, pancreatic cancer, hepatocellular 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 can 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.
  • a dose of the disclosed compounds in solution (typically 5 to 10 millicuries or 200 to 400 MBq) is typically injected rapidly into a saline drip running into a vein, in a patient. Then, the patient is placed in the SPECT for a series of one or more scans which can take from 20 minutes to as long as an hour (often, only about one quarter of the body length can be imaged at a time). Methods for SPECT scanning are well known in the art.
  • the compounds described herein can 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 androgen receptor (AR)). Furthermore, these compounds can 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.
  • orphan and nuclear receptors including steroid receptors such as androgen receptor (AR)
  • AR steroid receptor
  • these compounds can 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.
  • exemplary compounds of the present invention can be prepared with reference to the following General Reaction Scheme I:
  • step a (2,2-dimethyl-1,3-dioxolan-4-yl)methanol is toslyated under basic conditions as shown in step a.
  • step c the bisphenol derivative is halogenated on the phenyl ring (e.g., Y and Z can be Cl or Br).
  • step d the unreacted phenol portion undergoes another elimination reaction to afford a bisphenol derivative with an epoxide on one side and a protected diol on the other.
  • step e epoxide is opened using CeCl 3 .7H 2 O and the diol is deprotected in situ.
  • protecting group strategies can be employed for preparation of the compounds disclosed herein. Such strategies are well known to those of skill in the art. Exemplary protecting groups and related strategies are disclosed in Greene's Protective Groups in Organic Synthesis, Wiley-InterScience; 4 edition (Oct. 30, 2006), which is hereby incorporated by reference in its entirety. In certain embodiments, a protecting group is used to mask an alcohol moiety while performing other chemical transformations. After removal of the protecting group, the free hydroxyl is obtained. Such protecting groups and strategies are well known in the art.
  • 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.
  • Steps a and b Synthesis of (S)-4-(2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenol
  • Step c (S)-2,6-dichloro-4-(2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenol
  • Step d (S)-4-((4-(2-(3,5-dichloro-4-(((R)-oxiran-2-yl)methoxy)phenyl)propan-2-yl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxolane
  • Step e Synthesis of (R)-3-(4-(2-(3,5-dichloro-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol (Compound 1a)
  • Step a Synthesis of (S)-3-(4-(2-(3,5-dichloro-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-2-hydroxypropyl 4-methylbenzenesulfonate
  • the titled compound was synthesized by tosylation of Compound 1a under basic conditions according to commonly known protocol, such as the protocol referenced for step a in Example 1.
  • Step b Synthesis of (S)-1-chloro-3-(2,6-dichloro-4-(2-(4-(((R)-oxiran-2-yl)methoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol
  • Step c Synthesis of (S)-1-chloro-3-(2,6-dichloro-4-(2-(4-((R)-2-hydroxy-3-methoxypropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (Compound 5a)
  • Example 8 Synthesis of (R)-1-amino-3-(4-(2-(3,5-dichloro-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (Compound 12a) and N—((R)-3-(4-(2-(3,5-dichloro-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-2-hydroxypropyl)methanesulfonamide (Compound 13a)
  • Step a Synthesis of (R)-1-azido-3-(4-(2-(3,5-dichloro-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol
  • Step b Synthesis of (R)-1-amino-3-(4-(2-(3,5-dichloro-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (Compound 12a)
  • Step c Synthesis of N—((R)-3-(4-(2-(3,5-dichloro-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-2-hydroxypropyl)methanesulfonamide (Compound 13a)
  • Step a Synthesis of (S)-1-chloro-3-(2,6-dichloro-4-(2-(4-(((R)-3-(ethylthio)-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol
  • Step b Synthesis of (S)-1-chloro-3-(2,6-dichloro-4-(2-(4-((S)-3-(ethylsulfonyl)-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (Compound 14a)
  • Compound 22a was synthesized according to Example 1 by using 4,4′-(Propane-2,2-diyl)bis(2-methylphenol) (commercially available) instead of 4,4′-(propane-2,2-diyl)diphenol and omitting step c.
  • Compound 40a was synthesized according to Example 1 by using 4,4′-sulfonyldiphenol instead of 4,4′-(propane-2,2-diyl)diphenol and with only 1 equiv of NaCl in step c.
  • Compound 41a was synthesized according to Example 1 by using 4,4′-sulfonyldiphenol instead of 4,4′-(propane-2,2-diyl)diphenol.
  • Compound 48a was synthesized according to Examples 3 and 6 by starting with Compound 41a.
  • Acetic Anhydride (4.1 mg, 0.04 mmol, 4.0 equiv) was added to a solution of Compound 5a (5.0 mg, 0.01 mmol, 1.0 equiv, see Example 3), DMAP (0.1 mg, 0.001 mmol, 0.1 equiv) and Et3N (4.1 mg, 0.04 mmol, 4.0 equiv) in anhydrous dichloromethane (1 mL). The resulting solution was stirred overnight at room temperature. Dichloromethane was removed under reduced pressure and the residue was purified by column chromatography to afford the title compound as a colorless oil (5.8 mg, 98.6%).
  • Compound A1a was synthesized according to Examples 21 by using Compound 1a prepared according to Example 1.
  • Compound A1a was obtained as a colorless oil (63.0 mg, 97.1%).
  • LNCaP cells (3 ⁇ 10 4 ) were seeded into 24-well plates overnight. Next day, LNCaP cells were transiently transfected with 0.25 ⁇ g/well of PSA (6.1 kb)-luciferase reporter plasmid prior to pre-treatment with compounds of the invention or reference compounds (e.g., compounds A, B, C, 1a, 5a, 9a, 11a, 12a, 13a, and 14a) ranging in concentration from 0 ⁇ M to 35 ⁇ M for 1 hour before the addition of vehicle, or synthetic androgen, R1881 (1 nM) to induce luciferase production. After 48 h of exposure, cells were harvested in Passive lysis buffer (Promega).
  • PSA 6.1 kb
  • Luciferase activities were measured and normalized to protein concentration determined by the Bradford assay. IC 50 calculations were done using OriginPro 8.1 Software (Northampton, Mass., USA). Transfection experiments to determine IC 50 values were performed in at least 4 independent experiments (“trials”) using triplicate wells. Dose responses of representative compounds are shown in FIG. 2 . Luciferase activity is presented as the mean ⁇ standard deviation of the technical replicates.
  • Example 30 Compound 1a Treatment in LNCaP Xenograft Model
  • LNCaP cells were passaged prior to seeding in T175flasks at a concentration of ⁇ 2-3 ⁇ 10 7 /mL. The cells were grown for 7 days until 90% confluent. Cell preparations were then prepared in RPMI with 5% FBS/Matrigel (50/50, v/v) yielding a final concentration of 1 ⁇ 10 8 /mL.
  • NOD-SCID mice Six to eight week old NOD-SCID mice were received from BC Cancer Research Centre's Animal Resource Centre and acclimated for 28 days. Tumors were initiated with sub-cutaneous back of each animal. Tumors were allowed to grow to an average size of approximately 100 mm 3 . Mice were then castrated and the tumors allowed to adapt for a period of one week before first dose was administered. Tumor volume was measured as length ⁇ width ⁇ height in mm multiplied by 0.5236.
  • Compound 1a was dissolved in 100% DMSO (ATCC Lot 61908420) to yield a stock solution of 157 mg/mL.
  • Compound 1a was administered as an oral gavage once per day at dose levels of 10 and 30 mg/kg.
  • Vehicle control animals were administered 1% CMC formulation as an oral gavage once daily.
  • Oral treatment was initiated one week after castration. The start of treatment was designated “Day 1” and animals were treated once daily for a total of 24 doses. Two days after the last dose, the tumours were measured and harvested. Body weight was assessed daily throughout the treatment period. Tumor volume was measured on day ⁇ 7 (castration day), and again on days 1, 4, 8, 12, 16, 20, 24 and 26.
  • LNCaP xenografts were homogenized using TRIzol® reagent (InvitrogenTM), and total RNA was extracted using PureLink RNA Mini Kit (Life Technologies). Amplification Grade DNase I treatment (Sigma-Aldrich) was applied to the RNA before RT-PCR using High Capacity RNA-to-DNA kit (Life Technologies) to generate cDNA. cDNA and gene-specific primers were combined with Platinum® SYBR® Green qPCRSuperMix-UDG with ROX (InvitrogenTM). Transcripts were measured by quantitative real-time PCR (QPCR) using ABI PRISM 7900 Sequence Detection System (ABI PRISM®, Applied Biosystems by Life Technologies) in triplicates for each biological sample.
  • QPCR quantitative real-time PCR
  • Compound 1a demonstrated a dose-dependent inhibition of the mRNA expression of PSA, as 30 mg/kg treatment of Compound 1a caused a significant reduction of PSA expression when compared to the 10 mg/kg dose and control treatment. Together, these data indicated that Compound 1a significantly reduced the castration-resistant growth of LNCaP tumors, while demonstrating on-target activity to block androgen receptor transcriptional activity.
  • One-way ANOVA post-hoc Tukey's multiple comparisons test was performed for statistical analysis. *p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001.

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