Bisphenol derivatives and their use as modulators of androgen receptor activity

Abstract

# imgabs0 # provides a compound having the structure of Formula I or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1, R2, R3, R11a, R11b, R11c, R11d and X are as defined herein. The use of such compounds for modulating androgen receptor activity, imaging diagnosis and treatment of cancer, and methods for treating subjects in need thereof, including prostate cancer, are also provided.

Description

[0001] This application is a divisional application of the Chinese patent application No. 201780034942.3 (Application date: April 18, 2017, Invention name: Bisphenol derivatives and their use as androgen receptor activity modulators) Government interest statement

[0002] This invention was made in part with government support under Grant No. 2R01 CA105304 awarded by the National Cancer Institute. The U.S. Government has certain rights in this invention.

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 323,196, filed on April 15, 2016, and entitled “BISPHENOL DERIVATIVES AND THEIRUSE AS ANDROGEN RECEPTOR ACTIVITY MODULATORS,” the disclosure of which is hereby incorporated by reference in its entirety for all purposes. Technical Field

[0005] The present invention generally relates to bisphenol-related compounds and their use for treating a variety of indications. In particular, the present invention relates to bisphenol ether compounds having halogenated phenyl and / or sulfone linking groups and their use for treating a variety of cancers, such as 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. The present invention also relates to bisphenol-related compounds and their use for modulating androgen receptor (AR) activity, including truncated AR. Background Art

[0006] Androgens mediate their effects through androgen receptors (AR). Androgens play a role in a variety of developmental and physiological responses and participate in male sex differentiation, the maintenance of spermatogenesis and male gonadotropin regulation (RKRoss, GACoetzee, CL Pearce, JKReichardt, P.Bretsky, LNKolonel, BEHenderson, E.Lander, D.Altshuler and G.Daley, Eur Urol 35, 355 361 (1999); AA Tomson, Reproduction 121, 187 195 (2001); N.Tanji, K.Aoki and M.Yokoyama, Arch Androl 47, 1 7 (2001)). Several pieces of evidence show that androgens are related to the development of prostate cancer. First, androgens induce prostate carcinogenesis in rodent models (RL Noble, Cancer Res 37, 1929 1933 (1977); RL Noble, Oncology 34, 138 141 (1977)), and men receiving androgens in the form of anabolic steroids have a higher incidence of prostate cancer (JT Roberts and DM Essenhigh, Lancet 2, 742 (1986); JA Jackson, J. Waxman and AM Spiekerman, Arch Intern Med 149, 2365 2366 (1989); PD Guinan, W. Sadoughi, H. Alsheik, RJ Ablin, D. Alrenga and IMBush, Am J Surg 131, 599 600 (1976)). Secondly, if humans or dogs are castrated before puberty, prostate cancer will not develop (J Clin Endocrinol Metab 84, 4324-4331 (1999); G. Wilding, Cancer Surv 14, 113-130 (1992)). Castration of adult males leads to prostate degeneration and apoptosis of prostate epithelium, while having no effect on other male external genitalia (EM Bruckheimer and N. Kyprianou, Cell Tissue Res 301, 153-162 (2000); JT Isaacs, Prostate 5, 545-557 (1984)). This dependence on androgens provides the basic principle for treating prostate cancer with chemical or surgical castration (androgen blockade).

[0007] Androgens also play a role in female diseases such as polycystic ovary syndrome and cancer. An example is ovarian cancer, where elevated androgen levels are associated with an increased risk of developing ovarian cancer (KJ Helzlsouer, AJ Alberg, GB Gordon, C. Longcope, TLBush, SCHoffman and GW Comstock, JAMA 274, 1926-1930 (1995); RJ Edmondson, JM Monaghan and BRDavies, Br J Cancer 86, 879-885 (2002)). AR has been detected in most ovarian cancers (HA Risch, J Natl Cancer Inst 90, 1774-1786 (1998); BR Rao and BJS Lotman, Endocr Rev 12, 14-26 (1991); GM Clinton and W. Hua, Crit Rev Oncol Hematol 25, 1-9 (1997)), while estrogen receptor-α (ERa) and progesterone receptor are detected in less than 50% of ovarian tumors.

[0008] The only effective treatment available for advanced prostate cancer is to remove androgens that are crucial for the survival of prostate cavity cells. Androgen deprivation therapy causes a temporary reduction in tumor load, accompanied by a reduction in serum prostate-specific antigen (PSA). Unfortunately, prostate cancer can eventually grow again in the absence of testicular androgens (castration-resistant disease) (Huber et al. 1987Scand J.Urol Nephrol.104,33-39). Castration-resistant prostate cancer still driven by AR is biochemically characterized by the rising titer of serum PSA before symptom onset (Miller et al. 1992J.Urol.147,956-961). Once the disease becomes castration-resistant, most patients will die of their disease within two years.

[0009] AR has different functional domains, including a carboxyl-terminal ligand binding domain (LBD), a DNA binding domain (DBD) containing two zinc finger motifs, and an N-terminal domain (NTD) containing two transcriptional activation units (tau1 and tau5) within activation function-1 (AF-1). The binding of androgens (ligands) to the LBD of AR leads to its activation, allowing the receptor to effectively bind to its specific DNA consensus site (called androgen response element (ARE)) on the promoter and enhancer region of androgen-regulated genes (such as PSA) to initiate transcription. AR can be activated in the absence of androgens by stimulating the cAMP-dependent protein kinase (PKA) pathway with interleukin-6 (IL-6) and by a variety of 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. 2002A J. Biol. Chem. 277, 7076-7085; and Ueda et al. 2002B J. Biol. Chem. 277, 38087-38094).

[0010] Clinically available AR inhibitors include nonsteroidal antiandrogens such as bicalutamide (Casodex TM), nilutamide, flutamide and enzalutamide. There is also a class of steroidal antiandrogens, such as cyproterone acetate and spironolactone. Both steroidal and nonsteroidal antiandrogens target the LBD of AR, and it is presumed that they fail mainly due to poor affinity, mutations that cause these same antiandrogens to activate AR (Taplin, ME, Bubley, GJ, Kom YJ, Small EJ, Uptonm M., Rajeshkumarm B., Balkm SP, Cancer Res., 59, 2511-2515 (1999)) and constitutively active AR splice variants. Antiandrogens have no effect on the constitutively active AR splice variant that lacks the ligand binding domain (LBD) and is associated with castration-recurrent prostate cancer (Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ., Cancer Res 68, 5469-77, 2008; Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J, Tepper CG, Kung HJ, Brodie AM, Edwards J, Qiu Y., Cancer Res. 69, 2305-13, 2009; Hu et al. 2009 Cancer Res. 69, 16-22; Sun et al. 2010 J Clin Invest. 2010 120, 2715-30), and is resistant to abiraterone and enzalutamide (Antonarakis et al., N Engl JMed. 2014, 371, 1028-38; Scher et al. JAMA Oncol. 2016 doi: 10.1001).

[0011] In addition to previously reported bisphenol ether derivatives (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 entirety, British Columbia Cancer Agency Branch and University of British Columbia), AR antagonists that bind to full-length AR and / or truncated AR splice variants currently under development include: AR degraders such as niclosamide (Liu C et al. 2014), galeterone (Njar et al. 2015; Yu et al. 2016). Z et 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. 289(38):26417-29; Li H et al. 2014 J Med Chem. 57(15):6458-67); anti-androgen apalutamide (Clegg NJ et al. 2012), ODM-201 (Moilanen AM et al. 2015), ODM-204 (Kallio et al. J Clin Oncol 2016 Vol. 34 No. 2_Suppl 230), TAS3681 (Minamiguchi et al. 2015 J Clin Oncol 33, Suppl 7; abstr 266); and AR NTD inhibitors 3E10-AR441 bsAb (Goicochea NL et al. 2015) and sintokamide (Sadar et al. 2008; Banuelos et al. 2016).

[0012] AR-NTD is also a target for drug development (eg WO 2000 / 001813) because the NTD contains the essential region activation function-1 (AF-1) required for AR transcriptional activity (Jenster et al. 1991. Mol Endocrinol. 5, 1396-404). AR-NTD plays an important role in the activation of AR in the absence of androgens (Sadar, MD 1999 J. Biol. Chem. 274, 7777-7783; Sadar MD et al. 1999 Endocr Relat Cancer. 6, 487-502; Ueda et al. 2002 J. Biol. Chem. 277, 7076-7085; Ueda 2002 J. Biol. Chem. 277, 38087-38094; Blaszczyk et al. 2004 Clin Cancer Res. 10, 1860-9; Dehm et al. 2006 J Biol Chem. 28, 27882-93; Gregory et al. 2004 J Biol Chem. 279, 7119-30). As shown by the use of decoy molecules, AR-NTD is important in the hormonal progression of prostate cancer (Quayle et al. 2007, Proc Natl Acad Sci US A. 104, 1331-1336).

[0013] While the crystal structure has been solved for the AR C-terminal LBD, this is not the case for the NTD due to its high flexibility and intrinsic disorder in solution (Reid et al. 2002 J. Biol. Chem. 277, 20079-20086), thereby hindering virtual docking drug discovery approaches.

[0014] Although significant advances have been made in this field, there remains a need for improved treatments for prostate cancer, particularly metastatic castration-resistant prostate cancer. Summary of the invention

[0015] The present disclosure is based in part on the following surprising discovery: the compounds described herein can be used to regulate AR activity in vivo or in vitro for research and therapeutic purposes. In some embodiments, certain compounds disclosed herein are suitable for imaging the prostate. Imaging can be used for a variety of diagnostic purposes. For example, in certain embodiments, the compound is suitable for imaging benign prostate cancer diseases. In other embodiments, the compound can be used for imaging certain cancers including prostate cancer, because certain embodiments of the compound are located in prostate tumor sites. Other imaging agents are androgen mimetics; however, in one embodiment, the compound is suitable for imaging AR splice variants or any AR species (i.e., those mutated in other domains or regions). AR can be mammalian. For example, AR can be human. Prostate cancer can be castration-resistant prostate cancer. Prostate cancer can be androgen-dependent prostate cancer.

[0016] In one embodiment, the present invention relates to compounds of formula (I):

[0017]

[0018] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:

[0019] X is -S(O) n -or-C(R 8 R 9 )-;

[0020] R 1 is H, hydroxyl or OC(=O)R 13 ;

[0021] R 2 is hydroxyl or OC(=O)R 13 ;

[0022] R 3 Halogen, -OH, -OR 4 ; OC(=O)R 13 、-NH2、-NHS(O) n R 5 、-N(C1-C6 alkane

[0023] Base)S(O) n R 5 、-S(O) n R 5 , -N3, aryl, carbocyclyl, heteroaryl or heterocyclyl, which is optionally substituted with one or more R6;

[0024] R 4is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, carbocyclyl, heteroaryl or heterocyclyl, which is optionally substituted with one or more R6;

[0025] R 5 Each is independently a C1-C6 alkyl or aryl group, which is optionally substituted by one or more R 6 replace;

[0026] R 6 Each independently selected from H, F, Cl, Br, I, 123 I, hydroxy, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 12 A group consisting of aromatic groups, wherein R 6 Each optionally halogenated, 123 I. 18 F, hydroxy, -OS(O)2-aryl, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0027] R 8 and R 9 Each independently is H or C1-C6 alkyl;

[0028] R 11a , R 11b , R 11c and R 11d Each independently is H, methyl, F, Cl, Br, I or 123 I;

[0029] R 13 is a C1-C6 alkyl group; and

[0030] n is 0, 1 or 2;

[0031] Where R 11a , R 11b , R 11c and R 11d At least one of them is methyl F, Cl, Br, I or 123 I.

[0032] In some embodiments, R in Formula I 11a , R 11b , R 11c and R 11d At least two of them are independently methyl, F, Cl, Br, I or 123 1. In other embodiments, R 11a , R 11b , R 11c and R 11dAny two of which are independently methyl, F, Cl, Br, I or 123 I, and R 11a , R 11b , R 11c and R 11d The remaining two in are each H. In one embodiment, R 11a and R 11b Each is H, and R 11c and R 11d are each independently methyl, F, Cl, Br, I or 123 I. In another embodiment, R 11a and R 11b Each is H, and R 11c and R 11d Each is independently methyl, Cl or Br. In one embodiment, R 11a and R 11b Each is H, and R 11c and R 11d Each is Cl.

[0033] In one embodiment, R in Formula I 11a and R 11c Each is H, and R in Formula I 11b and R 11d are each independently methyl, F, Cl, Br, I or 123 1. In some embodiments, R 11a and R 11c Each is H, and R 11b and R 11d Each is independently methyl, Cl or Br. In another embodiment, R 11a and R 11c Each is H, and R 11b and R 11d Each is Cl.

[0034] In some embodiments, X in Formula I is -S(O)2-. In another embodiment, X in Formula I is -C(R 8 R 9 )-and R8 and R 9 Each is independently C1-C3 alkyl. In one embodiment, X is -C(R 8 R 9 )-and R8 and R 9 Each is a methyl group.

[0035] In some embodiments, R in Formula I 1 is hydroxyl or OC(=O)R 13 In another embodiment, R 1 For H.

[0036] In some embodiments, R in Formula I 3 In another embodiment, R 3 -OC(=O)R 13 , where R 13 In one embodiment, R 3 For-OR 4 And R 4 is C1-C6 alkyl. In other embodiments, R 3 For-OR 4 And R 4 It is methyl.

[0037] In one embodiment, R in Formula I 3 is an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 3- to 7-membered heterocyclyl, wherein the heteroaryl or the heterocyclyl each comprises at least one N atom. In another embodiment, R 3 Selected from the 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.

[0038] In one embodiment, when present, each R in Formula I 13 In another embodiment, when present, each R 13 It is methyl.

[0039] In one embodiment, R in Formula I 1 and R 2 Each is independently -OH or -OC(=O)R 13 , where R 13 In some embodiments, R 1 , R 2 and R 3 At least one of them is -OC(=O)R 13 , where R 13 In another embodiment, R 1 , R 2 and R 3 Any two of which are each -OC(=O)R 13 , where R 13 In one embodiment, R 1 , R 2 and R 3 Each is -OC(=O)R 13, where R 13 It is methyl.

[0040] In one embodiment, the present disclosure relates to compounds disclosed in Tables 1, 2, 3 and 4, or pharmaceutically acceptable salts thereof.

[0041] In one embodiment, the present disclosure relates to compounds of formula (I):

[0042]

[0043] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:

[0044] R 1 is H, hydroxyl or -OC(=O)R 13 ;

[0045] R 2 is hydroxyl or -OC(=O)R 13 ;

[0046] R 3 Halogen, -OH, -OR 4 、-OC(=O)R 13 、-NH2、-NHS(O) n R 5 、-N(C1-C6 alkane

[0047] Base)S(O) n R 5 、-S(O) n R 5 , -N3, aryl, carbocyclic, heteroaryl or heterocyclic, which is optionally substituted by one or more R 6 replace;

[0048] R 4 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, carbocyclic, heteroaryl or heterocyclic group, which is optionally substituted by one or more R 6 replace;

[0049] R 5 Each is independently a C1-C6 alkyl or aryl group, which is optionally substituted by one or more R 6 replace;

[0050] R 6 Each independently selected from H, F, Cl, Br, I, 123 I, hydroxy, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 12 A group consisting of aromatic groups, wherein R 6 Each optionally halogenated, 123I. 18 F, hydroxy, -OS(O)2-aryl, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0051] R 8 and R 9 Each independently is H or C1-C6 alkyl;

[0052] n is 0, 1 or 2; and

[0053] R 11a , R 11b , R 11c and R 11d Each independently is H, methyl, F, Cl, Br, I or 123 I.

[0054] In one embodiment, R in Formula II 3 In another embodiment, R 3 -OC(=O)R 13 , where R 13 In other embodiments, R 3 For-OR 4 , where R 4 is C1-C6 alkyl. 3 For-OR 4 , where R 4 It is methyl.

[0055] In some embodiments, R in Formula II 1 is hydroxyl or OC(=O)R 13 In another embodiment, R in Formula II 1 For H.

[0056] In one embodiment, R in Formula II 3 is an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 3- to 7-membered heterocyclyl, wherein the heteroaryl or the heterocyclyl each comprises at least one N atom. 3 Selected from the 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.

[0057] In one embodiment, R in Formula II 11a , R 11b , R 11c and R 11dEach is H.

[0058] In one embodiment, when present, each R in Formula II 13 In another embodiment, when present, each R 13 It is methyl.

[0059] In one embodiment, R in Formula II 1 and R 2 Each is independently -OH or -OC(=O)R 13 , where R 13 In some embodiments, R 1 , R 2 and R 3 At least one of them is -OC(=O)R 13 , where R 13 In another embodiment, R 1 , R 2 and R 3 Any two of which are each -OC(=O)R 13 , where R 13 In one embodiment, R 1 , R 2 and R3 are each -OC(=O)R 13 , where R 13 It is methyl.

[0060] In one embodiment, the present disclosure relates to a compound disclosed in Table 5 or a pharmaceutically acceptable salt thereof.

[0061] In one embodiment, the present disclosure relates to a pharmaceutical composition comprising a compound of Formula I or Formula II or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and an additional therapeutic agent.

[0062] In some embodiments, a pharmaceutical composition is provided, comprising a compound of Formula I or Formula II or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof and an additional therapeutic agent. In one embodiment, the additional therapeutic agent is used to treat prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, alopecia, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy or age-related macular degeneration. In another embodiment, the additional therapeutic agent is enzalutamide, galactron, abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, bevacizumab (acrivastine), OSU-HDAC42, VITAXIN, sunitinib (sunitumib), ZD-4054, cabazitaxel (XRP-6258), MDX-010 (ipilimumab), OGX427, OGX 011, finasteride, dutasteride, torosterone, beclosterol, azosternol, FCE 28260, SKF105,111, ODM-201, radium 233, ODM-204, niclosamide, apalutamide, ARV-330, VPC-14449, TAS3681, 3E10-AR441bsAb, sintokamide or their related compounds.

[0063] In one embodiment, the present disclosure provides a method for regulating androgen receptor activity, the method comprising administering to a patient in need thereof 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. In some embodiments, the method for regulating androgen receptor activity is to inhibit androgen receptors.

[0064] In one embodiment, the present disclosure provides a method for treating a condition or disease that responds to the regulation of androgen receptor activity, the method 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. In one embodiment, the condition or disease is selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal cord and bulbar muscular atrophy, and age-related macular degeneration. In one embodiment, the condition is prostate cancer. In another embodiment, the condition or disease is castration-resistant prostate cancer. In some embodiments, the condition or disease is androgen-dependent prostate cancer.

[0065] Some embodiments of compounds described herein can be used for diagnostic purposes to study prostate diseases, including cancer. In specific embodiments, the compound is suitable for imaging diagnosis of cancer. In some embodiments, this imaging allows detection and / or positioning of cancer sites (e.g., tumor sites). In addition, these compounds can be used individually or as a part of a kit for this type of purpose. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] Figure 1 The compound 3a is shown 13 C NMR spectrum.

[0067] Figure 2 Shown are dose responses of selected compounds of the present disclosure in LNCaP cells transfected with a PSA (6.1 kb)-luciferase reporter gene and treated with androgen.

[0068] Figure 3 Shown are tumor volumes of LNCaP xenografts in SCID-NOD mice treated with compound 1a or CMC-treated mice (control) over a 26-day treatment course.

[0069] Figure 4 Shown are tumor volumes of LNCaP xenografts at the beginning and end (day 26) of mice treated with compound 1a and mice treated with CMC.

[0070] Figure 5 Body weights of Compound 1a-treated mice and CMC-treated mice at the start and end (day 26) are shown.

[0071] Figure 6 Shown are tissue levels of PSA mRNA measured by QPCR in five representative xenografts from each treatment group. DETAILED DESCRIPTION

[0073] definition

[0074] In the following description, certain specific details are set forth in order to provide a comprehensive understanding of multiple embodiments. However, it will be appreciated by those skilled in the art that the present invention may be implemented without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout the specification and the following claims, the wording "comprise" and its variations, such as "comprises" and "comprising" will be interpreted in an open, inclusive sense, that is, as "including but not limited to". In addition, the titles provided herein are for convenience purposes only and do not explain the scope or meaning of the claimed invention.

[0075] Reference in this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described with respect to the embodiment is included in at least one embodiment. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in multiple places in this specification do not necessarily all refer to the same embodiment. In addition, the particular features, structures or characteristics may be combined in one or more embodiments in any suitable manner. In addition, unless the context clearly dictates otherwise, as used in this specification and the appended claims, the singular forms "a", "an" and "the" include multiple references. It should also be noted that, unless the context clearly dictates otherwise, the term "or" is generally used in its meaning that includes "and / or".

[0076] Unless otherwise indicated, as used herein, the following terms have the following meanings:

[0077] "Amino" refers to the -NH2 group.

[0078] "Cyano" refers to a -CN group.

[0079] "Halo" or "halogen" refers to a bromo, chloro, fluoro or iodo group.

[0080] "Hydroxy" or "hydroxyl" refers to an -OH group.

[0081] "Imino" refers to a =NH substituent.

[0082] "Nitro" refers to a -NO2 group.

[0083] "Oxo" refers to a =0 substituent.

[0084] "Thio" refers to a =S substituent.

[0085] "Acetyl" or "Ac" refers to a -C(=O)CH3 substituent.

[0086] "Alkyl" or "alkyl group" refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms and attached to the rest of the molecule by a single bond. Alkyl groups containing any number of carbon atoms from 1 to 12 are included. Alkyl groups containing up to 12 carbon atoms are C1-C 12 Alkyl groups, containing up to 10 carbon atoms, are C1-C 10 Alkyl groups, alkyl groups containing up to 6 carbon atoms are C1-C6 alkyl groups, and alkyl groups containing up to 5 carbon atoms are C1-C5 alkyl groups. C1-C5 alkyl groups include C5 alkyl groups, C4 alkyl groups, C3 alkyl groups, C2 alkyl groups, and C1 alkyl groups (i.e., methyl groups). C1-C6 alkyl groups include all of the moieties described above for C1-C5 alkyl groups, but also include C6 alkyl groups. C1-C 10 Alkyl includes all of the moieties described above with respect to C1-C5 alkyl and C1-C6 alkyl, but also includes C7, C8, C9 and C 10 Similarly, C1-C 12 Alkyl includes all of the aforementioned moieties, but also includes C 11 and C 12 Alkyl. C1-C 12 Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl. Unless otherwise specifically specified in the specification, alkyl may be optionally substituted.

[0087] "Alkylene" or "alkylene chain" refers to a fully saturated, straight or branched divalent hydrocarbon chain radical having from one to twelve carbon atoms. 12 The non-limiting examples of alkylidene include methylene, ethylene, propylene, n-butylidene, vinylidene, propenylene, n-butenylene, propynylene, n-butynylene etc. The alkylidene chain is connected to the rest of the molecule by a single bond and is connected to the group by a single bond. The point at which the alkylidene chain is connected to the rest of the molecule and to the group can be through a carbon or any two carbons in the chain. Unless otherwise specifically specified in this specification, the alkylidene chain can be optionally substituted.

[0088] "Alkenyl" or "alkenyl group" refers to a straight or branched hydrocarbon chain radical having two to twelve carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is connected to the rest of the molecule by a single bond. Alkenyl groups containing any number of carbon atoms from 2 to 12 are included. Alkenyl groups containing up to 12 carbon atoms are C2-C 12 Alkenyl, alkenyl containing up to 10 carbon atoms is C2-C 10 Alkenyl, alkenyl containing up to 6 carbon atoms is C2-C6 alkenyl, and alkenyl containing up to 5 carbon atoms is C2-C5 alkenyl. C2-C5 alkenyl includes C5 alkenyl, C4 alkenyl, C3 alkenyl and C2 alkenyl. C2-C6 alkenyl includes all of the moieties described above for C2-C5 alkenyl, but also includes C6 alkenyl. C2-C 10 Alkenyl includes all of the moieties described above for C2-C5 alkenyl and C2-C6 alkenyl, but also includes C7, C8, C9 and C 10 Likewise, C2-C 12 Alkenyl includes all of the aforementioned moieties, but also includes C 11 and C 12 Alkenyl. C2-C 12Non-limiting examples of alkenyl groups include ethenyl / vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 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-nonenyl, 5-nonenyl, C1-C3 alkyl includes methyl, ethyl, n-propyl and isopropyl. Examples of the C1-C4 alkyl group include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group and a sec-butyl group. Unless otherwise specifically specified in the specification, the alkyl group may be optionally substituted.

[0089] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain radical having two to twelve carbon atoms and having one or more carbon-carbon double bonds. 12 Non-limiting examples of alkenylene include ethylene, propylene, butylene, etc. The alkenylene chain is connected to the rest of the molecule and to the group by a single bond. The point at which the alkenylene chain is connected to the rest of the molecule and to the group can be through one carbon or any two carbons in the chain. Unless otherwise specifically specified in this specification, the alkenylene chain may be optionally substituted.

[0090] "Alkynyl" or "alkynyl group" refers to a straight or branched hydrocarbon chain radical having two to twelve carbon atoms and having one or more carbon-carbon triple bonds. Each alkynyl group is connected to the rest of the molecule by a single bond. Alkynyl groups containing any number of carbon atoms from 2 to 12 are included. Alkynyl groups containing up to 12 carbon atoms are C2-C 12Alkynyl. Alkynyl containing up to 10 carbon atoms is C2-C 10 Alkynyl, alkynyl containing up to 6 carbon atoms is C2-C6 alkynyl, and alkynyl containing up to 5 carbon atoms is C2-C5 alkynyl. C2-C5 alkynyl includes C5 alkynyl, C4 alkynyl, C3 alkynyl and C2 alkynyl. C2-C6 alkynyl includes all of the moieties described above for C2-C5 alkynyl, but also includes C6 alkynyl. C2-C 10 Alkynyl includes all of the moieties described above for C2-C5 alkynyl and C2-C6 alkynyl, but also includes C7, C8, C9 and C 10 Likewise, C2-C 12 Alkynyl includes all of the aforementioned moieties, but also includes C 11 and C 12 Alkynyl. C2-C 12 Non-limiting examples of alkenyl include ethynyl, propynyl, butynyl, pentynyl, etc. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted.

[0091] "Alkyne" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain radical having two to twelve carbon atoms and having one or more carbon-carbon triple bonds. 12 Non-limiting examples of alkynylene include ethynylene, propargylene, etc. The alkynylene chain is connected to the rest of the molecule by a single bond and to the group by a single bond. The point at which the alkynylene chain is connected to the rest of the molecule and to the group can be through one carbon or any two carbons within the chain. Unless otherwise specifically provided in this specification, the alkynylene chain may be optionally substituted.

[0092] "Alkoxy" refers to a group of the formula -OR a A group in which R a is an alkyl, alkenyl or alkynyl group as defined above containing one to twelve carbon atoms. Unless otherwise specifically stated in the specification, an alkoxy group may be optionally substituted.

[0093] "Alkylamino" refers to a group of the formula -NHR a or -NR a R a A group in which R a Each is independently an alkyl, alkenyl or alkynyl group as defined above containing from one to twelve carbon atoms. Unless otherwise specifically stated in the specification, an alkylamino group may be optionally substituted.

[0094] "Alkylcarbonyl" refers to -C(=O)R a Part, of which R ais an alkyl, alkenyl or alkynyl group as defined above. A non-limiting example of an alkylcarbonyl group is a methylcarbonyl ("acetal") moiety. An alkylcarbonyl group may also be referred to as a "Cw-Cz acyl group," wherein w and z depict R as defined above. a For example, "C1-C 10 "Acyl" means an alkylcarbonyl group as defined above, wherein R a C1-C as defined above 10 Alkyl, C1-C 10 Alkenyl or C1-C 10 Unless stated otherwise specifically in the specification, an alkylcarbonyl group may be optionally substituted.

[0095] "Aryl" refers to a hydrocarbon ring system radical containing hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For the purposes of the present invention, an aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl groups include, but are not limited to, those derived from aceanthrene, acenaphthylene, acephenanthrene, anthracene, azulene, benzene, The term "aryl" is intended to include aryl groups which are optionally substituted, unless otherwise specifically provided in the specification.

[0096] "Arylalkyl" refers to a group of the formula -R b -R c A group in which R b is alkylene, alkenylene or alkynylene as defined above, and R c is one or more aryl groups as defined above, for example benzyl, diphenylmethyl, etc. Unless otherwise specifically stated in the specification, the aralkyl group may be optionally substituted.

[0097] "Carbocyclyl", "carbocyclic ring" or "carbocycle" refers to a ring structure in which each of the atoms forming the ring is carbon. A carbocycle may contain from 3 to 20 carbon atoms in the ring. Carbocycles include aryl and cycloalkyl, cycloalkenyl and cycloalkynyl groups as defined herein. Unless otherwise specifically provided in the specification, a carbocyclyl may be optionally substituted.

[0098] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting only of carbon and hydrogen atoms, which may include a fused ring or a bridged ring system, having three to twenty carbon atoms, preferably three to ten carbon atoms, and which is connected to the rest of the molecule by a single bond. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specifically provided in this specification, cycloalkyls may be optionally substituted.

[0099] "Cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, may include fused rings or bridged ring systems, have three to twenty carbon atoms, preferably three to ten carbon atoms, and are connected to the remainder of the molecule by a single bond. Monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc. Polycyclic cycloalkenyls include, for example, bicyclo [2.2.1] hept-2-enyl, etc. Unless otherwise specifically specified in this specification, cycloalkenyls may be optionally substituted.

[0100] "Cycloalkynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which may include fused or bridged ring systems, having three to twenty carbon atoms, preferably three to ten carbon atoms, and which is connected to the remainder of the molecule by a single bond. Monocyclic cycloalkynyls include, for example, cycloheptynyl, cyclooctynyl, etc. Unless otherwise specifically provided in this specification, cycloalkynyls may be optionally substituted.

[0101] "Cycloalkylalkyl" refers to a group of the formula -R b -R d A group in which R b is alkylene, alkenylene or alkynylene as defined above, and R d is a cycloalkyl, cycloalkenyl, cycloalkynyl group as defined above. Unless specifically stated otherwise in the specification, a cycloalkylalkyl group may be optionally substituted.

[0102] "Haloalkyl" refers to an alkyl group as defined above substituted by one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specifically stated in the specification, a haloalkyl group may be optionally substituted.

[0103] "Haloalkenyl" refers to an alkenyl group as defined above substituted by one or more halo groups as defined above, for example 1-fluoropropenyl, 1,1-difluorobutenyl, etc. Unless stated otherwise specifically in the specification, a haloalkenyl group may be optionally substituted.

[0104] "Haloalkynyl" refers to an alkynyl group as defined above substituted by one or more halo groups as defined above, for example 1-fluoropropynyl, 1-fluorobutynyl, etc. Unless stated otherwise specifically in the specification, a haloalkenyl group may be optionally substituted.

[0105] "Heterocyclyl", "heterocyclic ring" or "heterocycle" refers to a stable 3-20 membered non-aromatic ring group consisting of two to twelve carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclyl or heterocycle includes heteroaryl as defined below. Unless otherwise specifically provided in the specification, the heterocyclyl may be a monocyclic, bicyclic, tricyclic or tetracyclic system, which may include a fused or bridged ring system; and the nitrogen, carbon or sulfur atoms in the heterocyclyl may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl may be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically provided in the specification, the heterocyclic group may be optionally substituted.

[0106] "N-heterocyclyl" refers to a heterocyclyl as defined above containing at least one nitrogen, and wherein the point of attachment of the heterocyclyl to the rest of the molecule is through the nitrogen atom in the heterocyclyl. Unless otherwise specifically provided in the specification, an N-heterocyclyl may be optionally substituted.

[0107] "Heterocyclylalkyl" refers to a group of the formula -R b -R e A group in which R b is an alkylene, alkenylene or alkynylene chain as defined above, and R eis a heterocyclyl as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to an alkyl, alkenyl, alkynyl group at the nitrogen atom. Unless otherwise specifically stated in the specification, a heterocyclylalkyl group may be optionally substituted.

[0108] "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. For the purposes of the present invention, the heteroaryl may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolanyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolanyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, isothiazolyl , imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolyl, quinuclidine, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group may be optionally substituted.

[0109] "N-heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen and wherein the point of attachment of the heteroaryl group to the rest of the molecule is through the nitrogen atom in the heteroaryl group. Unless otherwise specifically stated in the specification, an N-heteroaryl group may be optionally substituted.

[0110] "Heteroarylalkyl" refers to a group of the formula -R b -R f A group in which R bis an alkylene, alkenylene or alkynylene chain as defined above, and R f is a heteroaryl group as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group may be optionally substituted.

[0111] “ 123 I" refers to a radioactive isotope of iodine with an atomic mass of 123. The compound of formula I may contain at least one 123 Part I. In which the structure depicts a position 123 In the present application of the I part, this means that the I part at this position is rich in 123 I. In other words, the compound contains more than the natural abundance at the indicated position. 123 I. The compound need not contain 100% at the indicated position 123 I, the condition is 123 I is present in excess of natural abundance. Typically, 123 I isotopes relative to 127 I is enriched to greater than 50%, greater than 60%, greater than 70%, greater than 80% or greater than 90%.

[0112] “ 18 F" refers to a radioactive isotope of fluorine with an atomic mass of 18. "F" or " 19 F" refers to an abundant, non-radioactive isotope of fluorine having an atomic mass of 19. The compound of formula I may contain at least one 18 Part F. In which the structure depicts a position 18 In the present application of the F part, this means that the F part at this position is rich in 18 F. In other words, the compound contains more than the natural abundance at the indicated position. 18 F. The compound need not contain 100% at the indicated position 18 F, the condition is 18 F is present in excess of its natural abundance. 18 F isotopes relative to 19 F is enriched to greater than 50%, greater than 60%, greater than 70%, greater than 80% or greater than 90%.

[0113] "Thioalkyl" refers to a group of the formula -SR a A group in which R a is an alkyl, alkenyl or alkynyl group as defined above containing one to twelve carbon atoms. Unless otherwise specifically stated in the specification, the thioalkyl group may be optionally substituted.

[0114] As used herein, the term "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 with a non-hydrogen atom, such as, but not limited to, a halogen atom, such as F, C l, Br and I; oxygen atoms in groups such as hydroxyl, alkoxy and ester groups; sulfur atoms in groups such as thiol, thioalkyl, sulfone, sulfonyl and sulfoxide groups; nitrogen atoms in groups such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide and enamine; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl and triarylsilyl; and other heteroatoms in various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher bond (e.g., double or triple bond) with a heteroatom, such as oxygen in oxo, carbonyl, carboxyl and ester groups; and nitrogen in groups such as imine, oxime, hydrazone and nitrile. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are replaced by -NR g R h 、-NR g C(=O)R h 、-NR g C(=O)NR g R h 、-NR g C(=O)OR h 、-NR g S02R h 、-OC(=O)NR g R h 、-OR g 、-SR g 、-SOR g 、-SO2R g 、-OSO2R g 、-SO2OR g , =NSO2R g and -SO2NR g R h "Substituted" also means any of the above groups wherein one or more hydrogen atoms are replaced by -C(=O)R g 、-C(=O)OR g 、-C(=O)NR g R h 、-CH2SO2R g 、-CH2SO2NR g R hIn the above, R g and R h is the same or different and is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, 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, wherein one or more hydrogen atoms are replaced by a bond to amino, cyano, hydroxyl, imino, nitro, oxo, thio, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. In addition, each of the aforementioned substituents may also be optionally substituted with one or more of the above substituents.

[0115] As used herein, the symbol (hereinafter may be referred to as a "connection point bond") refers to a bond that is a connection point between two chemical entities, one of which is described as being connected to the connection point bond and the other of which is not described as being connected to the connection point bond. For example, Indicates that the chemical entity "XY" is bonded to another chemical entity via the described point of attachment. In addition, specific points of attachment to chemical entities not depicted can be assigned by inference. For example, the compound CH3-R 3 (where R 3 H or ) It is inferred that when R 3 For "XY", the connection point key is the same as the one depicted in R 3 The same bond used to bond to CH3.

[0116] "Fused" refers to any ring structure described herein that is fused to an existing ring structure in a compound of the invention. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or the fused heteroaryl ring may be replaced with a nitrogen atom.

[0117] The invention disclosed herein is also intended to encompass the in vivo metabolites of the disclosed compounds. The products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, mainly due to enzyme methods. Therefore, the present invention includes compounds produced by the following method, the method comprising administering the compounds of the present invention to a mammal for a period of time sufficient to generate its metabolites. Such products are generally identified by administering a detectable dose of a radiolabeled compound of the present invention to an animal such as a rat, a mouse, a guinea pig, a monkey, or to a human, leaving enough time for metabolism to occur, and separating its conversion products from urine, blood, or other biological samples.

[0118] "Stable 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.

[0119] As used herein, a "subject" can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc. The subject can be suspected of having or at risk of having a cancer such as prostate cancer, breast cancer, ovarian cancer, salivary gland cancer, or endometrial cancer, or suspected of having or at risk of having acne, hirsutism, alopecia, benign prostatic hyperplasia, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration. Those skilled in the art know diagnostic methods for various cancers such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, salivary gland cancer or endometrial cancer, as well as 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 clinical delineation of cancers such as prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, salivary gland cancer or endometrial cancer, diagnosis and 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.

[0120] "Mammal" includes humans; and domestic animals, such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits); and non-domestic animals, such as wild animals and the like.

[0121] "Optional" or "optionally" means that the subsequently described event of a circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted aryl" means that the aryl may or may not be substituted and that the description includes substituted aryl and aryl without substitution.

[0122] "Pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the United States Food and Drug Administration for acceptable use in humans or domestic animals.

[0123] "Pharmaceutically acceptable salts" include both acid and base addition salts.

[0124] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, are biologically or otherwise desirable, and are formed from inorganic acids such as, but 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, decanoic acid, hexanoic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid Acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0125] "Pharmaceutically acceptable base addition salts" refer to those salts which retain the biological effectiveness and properties of the free acids and are biologically or otherwise desirable. These salts are prepared by the addition of inorganic or organic bases to the free acids. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are 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 (e.g., ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, halamine, choline, betaine, phenethylbenzylamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0126] Crystallization will usually produce a solvate of the compounds of the invention. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of the compounds of the invention and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as as corresponding solvated forms. The compounds of the invention may be true solvates, while in other cases, the compounds of the invention may only retain adventitious water or a mixture of water plus some adventitious solvent.

[0127] "Pharmaceutical composition" refers to a preparation of a compound of the present invention and a medium recognized in the art for delivering biologically active compounds to mammals (eg, humans). Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients thereof.

[0128] "Effective amount" refers to a therapeutically effective amount or a preventive effective amount. "Therapeutically effective amount" refers to an amount that effectively achieves the desired therapeutic outcome (such as reduced tumor size, increased life span, or increased life expectancy) at the required dose and for the required period of time. The therapeutically effective amount of a compound may vary according to factors such as the subject's disease state, age, sex, and weight, and the ability of the compound to cause the desired response in the subject. The dosing regimen may be adjusted to provide the best therapeutic response. A therapeutically effective amount is also an amount in which any toxic or deleterious effects of the compound are exceeded by the therapeutic beneficial effects. "Preventive effective amount" refers to an amount that effectively achieves the desired preventive outcome (such as smaller tumors, increased life span, increased life expectancy, or prevention of prostate cancer from progressing to a castration-resistant form) at the required dose and for the required period of time. Typically, a preventive dose is used in a subject before or in the early stages of the disease so that the preventive effective amount may be less than the therapeutically effective amount.

[0129] As used herein, "Treating" or "treatment" encompasses the treatment of a disease or condition of interest in a mammal (preferably a human) suffering from the disease or condition of interest, and includes:

[0130] (i) preventing the disease or condition from occurring in a mammal, particularly where the mammal is susceptible to the condition but has not yet been diagnosed with the condition;

[0131] (ii) inhibiting the disease or condition, i.e., arresting its development;

[0132] (iii) alleviate the disease or condition, i.e., cause regression of the disease or condition; or

[0133] (iv) Alleviate symptoms caused by the disease or condition, i.e., relieve pain without addressing the underlying disease or condition. As used herein, the terms "disease" and "condition" may be used interchangeably or may be different because a particular disease or condition may not have a known pathogen (so that a cause has not been found) and therefore it is not yet considered a disease, but only an undesirable condition or syndrome in which a specific collection of more or less symptoms has been identified by a clinician.

[0134] The compounds of the present invention, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined as (R)- or (S)- or (D)- or (L)-amino acids in terms of absolute stereochemistry. The present invention is intended to include all such possible isomers, as well as racemic and optically pure forms thereof, whether or not specifically depicted herein. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0135] "Stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds, but having different three-dimensional structures, which are not interchangeable. The present invention contemplates multiple stereoisomers and mixtures thereof and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0136] "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 of the described compounds.

[0137] The chemical naming scheme and structure diagram used herein are a modified form of the IUPAC naming system, using ACD / Name Version 9.07 software program, ChemDraw Ultra Version 11.0.1 and / or ChemDraw Ultra Version 14.0 and / or ChemDraw Professional 16.0.0.82 software naming program (CambridgeSoft), etc. For complex chemical names used herein, the substituent is named before the group to which it is attached. For example, cyclopropylethyl comprises an ethyl skeleton with a cyclopropyl substituent. Except as described below, all bonds are identified in the chemical structure diagrams herein, except for some carbon atoms, assuming that the carbon atoms are bonded to enough hydrogen atoms to complete the valence.

[0138] In this specification, the term "about" and / or "approximately" can be used in conjunction with numerical values ​​and / or ranges. The term "about" should be understood to mean those values ​​close to the value. For example, "about 40 [units]" can mean within ± 25% of 40 (e.g., 30 to 50), within ± 20%, ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, ± 1%, less than ± 1% or any other value or value therein or thereunder. In addition, the phrase "less than about [value]" or "greater than about [value]" should be understood in view of the definition of the term "about" provided herein. The terms "about" and "approximately" can be used interchangeably.

[0139] In this specification, numerical ranges are provided for certain quantities. It should be understood that these ranges include all subranges therein. Thus, the range "50 to 80" includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). In addition, all values ​​within a given range may be endpoints of the ranges thus covered (e.g., the range 50-80 includes ranges with endpoints, such as 55-80, 50-75, etc.).

[0140] II. Compounds and Pharmaceutical Compositions

[0141] As described above, certain embodiments of the present invention are directed to compounds useful for treating a variety of cancers, including various types of prostate cancer. Although not wishing to be bound by theory, it is believed that binding of the compounds to the androgen receptor (e.g., at the N-terminal domain) may contribute to the activity of the disclosed compounds. The compounds of the present invention include halophenyl (i.e., R in Formula I) 11a -R 11d ) and / or a sulfone bridging group (i.e., X in Formula I is -S(O)2- or a compound of Formula II), and lacking said R 3 The group imparts improved properties to the compound compared to a compound of the present invention. For example, the improved properties include improved drug-like properties, such as improved activity (e.g., androgen receptor (AR) regulation), longer half-life (e.g., in vivo); reduced toxicity; better solubility, improved formulation, better bioavailability, better pharmacokinetic profile; reduced unwanted metabolites, etc.

[0142] In one embodiment, the present invention includes compounds that form covalent bonds (e.g., at the N-terminal domain) with androgen receptors (ARs), resulting in irreversible (or substantially irreversible) inhibition thereof. In this regard, certain compounds of the present invention are designed to include functional groups that can form covalent bonds with nucleophiles under certain in vivo conditions. For example, in some embodiments, the reactivity of the compounds of the present invention is such that when the compound is free in solution, it will not react substantially with a variety of nucleophiles (e.g., glutathione). However, when the free mobility of the compound is restricted, and when a suitable nucleophile is brought into close proximity with the compound, for example, when the compound is associated or combined with the androgen receptor, the compound can form covalent bonds with certain nucleophiles (e.g., thiols).

[0143] The present invention includes all compounds having the above-mentioned properties (i.e., binding and / or inhibiting androgen receptor (AR)). In one embodiment, the present invention relates to a compound having a structure of Formula I:

[0144]

[0145] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:

[0146] X is -S(O) n -or-C(R 8 R 9 )-;

[0147] R 1 is H, -OH or -OC(=O)R 13 ;

[0148] R 2 -OH or -OC(=O)R 13 ;

[0149] R 3 Halogen, -OH, -OR 4 、-OC(=O)R 13 、-NH2、-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(C1-C6 alkyl)(S(O) n R 5 )、-S(O) n R 5, -N3, aryl, carbocyclic, heteroaryl or heterocyclic, which is optionally substituted by one or more R 6 replace;

[0150] R 4 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, carbocyclic, heteroaryl or heterocyclic group, which is optionally substituted by one or more R 6 replace;

[0151] R 5 Each is independently a C1-C6 alkyl or aryl group, which is optionally substituted by one or more R 6 replace;

[0152] R 6 Each independently selected from H, F, Cl, Br, I, 123 I, -OH, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 12 A group consisting of aromatic groups, wherein R 6 Each optionally halogenated, 123 I. 18 F, -OH, -OS(O)2-aryl, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0153] R 8 and R 9 Each independently is H or C1-C6 alkyl;

[0154] R 11a , R 11b , R 11c and R 11d Each independently is H, methyl, F, Cl, Br, I or 123 I;

[0155] R 13 is a C1-C6 alkyl group; and

[0156] n is 0, 1 or 2;

[0157] Where R 11a , R 11b , R 11c and R 11d At least one of is methyl, F, Cl, Br, I or 123 I.

[0158] In various embodiments, different stereoisomers of compounds of structure (I) are provided, for example, in some embodiments, the compound has one of the following structures (Ia), (Ib), (Ic), or (Id):

[0159]

[0160]

[0161] In other embodiments, the compound has one of the following structures (Ie), (If), (Ig), or (Ih):

[0162]

[0163] In one embodiment, 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 )-, where R 8 and R 9 Each is independently H or C1-C3 alkyl. In another embodiment, X is -C(R 8 R 9 )-, where R 8 and R 9 Each is a C1 alkyl group. In some embodiments, X is -S(O)2- or -C(CH3)2-.

[0164] In one embodiment, R 1 In another embodiment, R 1 -OC(=O)R 13 In some embodiments, R 1 -OC(=O)R 13 , where R 13 is C1-C4 alkyl. In other embodiments, R 1 -OC(=O)R 13 , where R 13 In one embodiment, R 1 For H.

[0165] In one embodiment, R 2 In another embodiment, R 2 -OC(=O)R 13 In some embodiments, R 2 -OC(=O)R 13 , where R 13 is C1-C4 alkyl. In other embodiments, R 2 -OC(=O)R 13 , where R 13 It is methyl.

[0166] In one embodiment, R 3 In another embodiment, R 3 -OC(=O)R 13 In some embodiments, R 3 -OC(=O)R 13 , where R 13 is C1-C4 alkyl. In other embodiments, R 3 -OC(=O)R 13 , where R 13 It is methyl.

[0167] In some embodiments, R 1 , R 2 or R 3 In some embodiments, at least one of R 1 , R 2 or R 3 In other embodiments, at least two of R are each -OH. 1 and R 2 In another embodiment, R 1 , R 2 and R 3 Each is -OH.

[0168] In some embodiments, R 1 , R 2 or R 3 At least one of them is -OC(=O)R 13 , where R 13 is C1-C4 alkyl. In another embodiment, R 1 , R 2 or R 3 At least one of them is -OC(=O)R 13 , where R 13 In some embodiments, R 1 , R 2 or R 3 At least two of them are each -OC(=O)R 13 , where R 13 is C1-C4 alkyl. In another embodiment, R 1 , R 2 or R 3 At least two of them are each -OC(=O)R 13 , where R 13 In other embodiments, R 1 and R 2 Each is -OC(=O)R13 , where R 13 It is methyl.

[0169] In some embodiments, R 1 , R 2 or R 3 One of them is -OC(=O)R 13 , where R 13 is C1-C4 alkyl. In another embodiment, R 1 , R 2 or R 3 One of them is -OC(=O)R 13 , where R 13 In some embodiments, R 1 , R 2 or R 3 The two of them are -OC(=O)R 13 , where R 13 is C1-C4 alkyl. In another embodiment, R 1 , R 2 or R 3 The two of them are -OC(=O)R 13 , where R 13 In some embodiments, R 1 and R 2 Each is -OC(=O)R 13 , where R 13 is C1-C4 alkyl. In another embodiment, R 1 and R 2 Each is -OC(=O)R 13 , where R 13 In some embodiments, R 1 , R 2 or R 3 Each is -OC(=O)R 13 , where R 13 is C1-C4 alkyl. In another embodiment, R 1 , R 2 or R 3 Each is -OC(=O)R 13 , where R 13 It is methyl.

[0170] In other embodiments, R 3 For –OR 4 In one embodiment, R 3 For –OR 4 , where R 4 is C1-C6 alkyl. In another embodiment, R 3 For –OR4 , where R 4 is C1-C3 alkyl. 3 For –OR 4 , where R 4 is methyl, ethyl, n-propyl or isopropyl. In one embodiment, R 3 For –OR 4 , where R 4 In another embodiment, R 3 For –OR 4 , where R 4 It is isopropyl.

[0171] In other embodiments, R 3 In other embodiments, R 3 is F, Cl, Br or I. In one embodiment, R 3 For F.

[0172] In other embodiments, R 3 -NH2, -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(C1-C6 alkyl)(S(O) n R 5 In one embodiment, R 3 In one embodiment, R 3 -NHC(=O)R 13 In one embodiment, R 3 -N(C(=O)R 13 )2. In another embodiment, R 3 NHS(O) n R 5 In some embodiments, R 3 -NHS(O)2R 5 In other embodiments, R 3 -NHS(O)2R 5 , where R 5 is C1-C3 alkyl. 3 -NHS(O)2R 5 , where R 5 In one embodiment, R 3 -N(C(=O)R 13)(S(O) n R 5 In one embodiment, R 3 -N(C1-C6 alkyl)(S(O) n R 5 ).

[0173] In other embodiments, R 3 -NH2, -NHC(=O)(C1-C4 alkyl), -N[(C(=O)(C1-C4 alkyl)]2, -NHS(O) n (C1-C3 alkyl), -N[C(=O)(C1-C4 alkyl)][(S(O) n (C1-C3 alkyl)] or –N[C1-C6 alkyl][S(O) n (C1-C3 alkyl)]. In some embodiments, R 3 is -NH(C(=O)CH3) or -N(C(=O)CH3)2. In other embodiments, R 3 is -NHS(O)2CH3. In other embodiments, R 3 It is -N(C(=O)CH3)(S(O)2CH3).

[0174] In another embodiment, R 3 -S(O) n R 5 In one embodiment, R 3 is -S(O)2R 5 In another embodiment, R 3 is -S(O)2(C1-C3 alkyl). In other embodiments, R 3 is -S(O)2CH3. In other embodiments, R 3 It is -S(O)2CH2CH3.

[0175] In some embodiments, R 3 is an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 3- to 7-membered heterocyclyl, wherein the heteroaryl or the heterocyclyl each comprises at least one N atom in the ring. 3 is selected from the 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. In a certain embodiment, R 3 for

[0176]

[0177] In one embodiment, R 11a , R 11b , R 11c and R 11d In another embodiment, at least one of R 11a , R 11b , R 11c and R 11d At least one of is Br. In some embodiments, R 11a , R 11b , R 11c and R 11d At least one of them is methyl.

[0178] In one embodiment, R 11a , R 11b , R 11c and R 11d At least two of them are methyl, F, Cl, Br, I or 123 I. In another embodiment, R 11a , R 11b , R 11c and R 11d Exactly two of them are methyl, F, Cl, Br, I or 123 I.

[0179] In some embodiments, R 11a and R 11b Each is 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 Each is H, and R 11c and R 11d Each is Cl. In one embodiment, R 11a and R 11b Each is H, and R 11c and R 11d Each is Br. In one embodiment, R 11a and R 11b Each is H, and R 11c and R 11d Each is a methyl group.

[0180] In some embodiments, R 11a and R 11c Each is H, and R 11b and R 11d are each independently methyl, F, Cl, Br, I or 123I. In one embodiment, R 11a and R 11c Each is H, and R 11b and R 11d Each is Cl. In one embodiment, R 11a and R 11c Each is H, and R 11b and R 11d Each is Br. In one embodiment, R 11a and R 11c Each is H, and R 11b and R 11d Each is a methyl group.

[0181] In some embodiments, R 13 is C1-C3 alkyl. In other embodiments, R 13 is methyl, ethyl or propyl. In one embodiment, R 13 It is methyl.

[0182] In one embodiment, n is 0. In another embodiment, n is 1. In some embodiments, n is 2.

[0183] Compounds for use in imaging and therapeutic methods are described herein. In some embodiments, the compound comprises one F, Cl, Br, I or 123 I is substituted. For example, in certain other embodiments, R 11a , R 11b , R 11c and R 11d Any three of them are H, and R 11a , R 11b , R 11c or R 11d The remaining one of is F, Cl, Br, I or 123 I. In some embodiments, the compound contains two F, Cl, Br, I or 123 I substitution (i.e., R 11a , R 11b , R 11c and R 11d Both of them are H, and R 11a , R 11b , R 11c or R 11d The other two are F, Cl, Br, I or 123 I). In other embodiments, the compound comprises three F, Cl, Br, I or 123 I substitution (i.e., R 11a , R 11b , R 11c and R11d Any one of them 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 compound comprises four F, Cl, Br, I or 123 I substitution (i.e., R 11a , R 11b , R 11c and R 11d Each is F, Cl, Br, I or 123 I).

[0184] In another embodiment, the compound comprises a 3 F, Cl, Br, I or 123 In one embodiment, the compound comprises one or more of 3 I or 123 I replaces one or more of.

[0185] In some embodiments, the compound comprises R 3 At least one R 6 A substituent, wherein at least one R 6 Further treated with F, Cl, Br, I or 123 In another embodiment, R 3 R 6 The substituent is further substituted by I or 123 At least one of I is replaced.

[0186] By any "R 11 " position with F, Cl, Br, I or 123 I substitution may result in favorable imaging and / or AR NTD modulation results. In some of the foregoing embodiments, R 11a for 123 1. In other embodiments, R 11c for 123 I.

[0187] In some more specific embodiments of the compound of Formula I, the compound has one of the following structures in Table 1, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof:

[0188] Table 1. Compounds

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206] In some embodiments of the compound of Formula I, the compound has one of the following structures in Table 2, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

[0207] Table 2. Compounds

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243] In some more specific embodiments of the compound of Formula I, the compound has one of the following structures in Table 3, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof:

[0244] Table 3. Compounds

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259] In some more specific embodiments of the compound of Formula I, the compound has one of the following structures in Table 4, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof:

[0260] Table 4. Compounds

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276] In some embodiments of the compound of Formula I, the compound has one of the following structures in Table 1, 2, 3, or 4, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

[0277] The present invention includes all compounds having the above-mentioned properties (ie, binding to androgen receptor (AR)). In one embodiment, the present invention relates to a compound having the structure of Formula II:

[0278]

[0279] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:

[0280] R 1 is H, hydroxyl or -OC(=O)R 13 ;

[0281] R 2 is hydroxyl or -OC(=O)R 13 ;

[0282] R 3 Halogen, -OH, -OR 4 、-OC(=O)R 13 、-NH2、-NHC(=O)R 13 、-N(C(=O)R 13 2. -NHS(O) n R 5 、-N(C(=O)R13 )(S(O) n R 5 )、-N(C1-C6 alkyl)(S(O) n R 5 )、-S(O) n R 5 , -N3, aryl, carbocyclic, heteroaryl or heterocyclic, which is optionally substituted by one or more R 6 replace;

[0283] R 4 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, carbocyclic, heteroaryl or heterocyclic group, which is optionally substituted by one or more R 6 replace;

[0284] R 5 Each is independently a C1-C6 alkyl or aryl group, which is optionally substituted by one or more R 6 replace;

[0285] R 6 Each independently selected from H, F, Cl, Br, I, 123 I, hydroxy, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 12 A group consisting of aromatic groups, wherein R 6 Each optionally halogenated, 123 I. 18 F, hydroxy, -OS(O)2-aryl, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0286] R 13 is a C1-C6 alkyl group; and

[0287] n is 0, 1 or 2.

[0288] In various embodiments, different stereoisomers of compounds of structure (II) are provided, for example, in some embodiments, the compound has one of the following structures (IIa), (IIb), (IIc), or (IId):

[0289]

[0290] In other embodiments, the compound has one of the following structures (IIe), (IIf), (IIg), or (IIh):

[0291]

[0292] In one embodiment, R 1In another embodiment, R 1 -OC(=O)R 13 In some embodiments, R 1 -OC(=O)R 13 , where R 13 is C1-C4 alkyl. In other embodiments, R 1 -OC(=O)R 13 , where R 13 In one embodiment, R 1 For H.

[0293] In one embodiment, R 2 In another embodiment, R 2 -OC(=O)R 13 In some embodiments, R 2 -OC(=O)R 13 , where R 13 is C1-C4 alkyl. In other embodiments, R 2 -OC(=O)R 13 , where R 13 It is methyl.

[0294] In one embodiment, R 3 In another embodiment, R 3 -OC(=O)R 13 In some embodiments, R 3 -OC(=O)R 13 , where R 13 is C1-C4 alkyl. In other embodiments, R 3 -OC(=O)R 13 , where R 13 It is methyl.

[0295] In some embodiments, R 1 , R 2 or R 3 In another embodiment, at least one of R 1 , R 2 or R 3 In some embodiments, at least one of R 1 , R 2 or R 3 In another embodiment, at least two of R are each -OH. 1 and R 2 In one embodiment, R 1 , R 2 or R3 Each is -OH.

[0296] In some embodiments, R 1 , R 2 or R 3 At least one of them is -OC(=O)R 13 , where R 13 is C1-C4 alkyl. In another embodiment, R 1 , R 2 or R 3 At least one of them is -OC(=O)R 13 , where R 13 In some embodiments, R 1 , R 2 or R 3 At least two of them are each -OC(=O)R 13 , where R 13 is C1-C4 alkyl. In another embodiment, R 1 , R 2 or R 3 At least two of them are each -OC(=O)R 13 , where R 13 It is methyl.

[0297] In some embodiments, R 1 , R 2 or R 3 One of them is -OC(=O)R 13 , where R 13 is C1-C4 alkyl. In another embodiment, R 1 , R 2 or R 3 One of them is -OC(=O)R 13 , where R 13 In some embodiments, R 1 , R 2 or R 3 The two of them are -OC(=O)R 13 , where R 13 is C1-C4 alkyl. In another embodiment, R 1 , R 2 or R 3 The two of them are -OC(=O)R 13 , where R 13 In some embodiments, R 1 , R 2 or R 3 Each is -OC(=O)R 13 , where R 13is C1-C4 alkyl. In another embodiment, R 1 , R 2 or R 3 Each is -OC(=O)R 13 , where R 13 It is methyl.

[0298] In other embodiments, R 3 For –OR 4 In one embodiment, R 3 For –OR 4 , where R 4 is C1-C6 alkyl. In another embodiment, R 3 For –OR 4 , where R 4 is a C1-C3 alkyl group. 3 For –OR 4 , where R 4 In another embodiment, R 3 For –OR 4 , where R 4 It is isopropyl.

[0299] In other embodiments, R 3 In one embodiment, R 3 For F.

[0300] In other embodiments, R 3 -NH2, -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(C1-C6 alkyl)(S(O) n R 5 In one embodiment, R 3 In one embodiment, R 3 -NHC(=O)R 13 In one embodiment, R 3 -N(C(=O)R 13 )2. In another embodiment, R 3 NHS(O) n R 5 In some embodiments, R 3 -NHS(O)2R 5 In other embodiments, R3 -NHS(O)2R 5 , where R 5 is a C1-C3 alkyl group. 3 -NHS(O)2R 5 , where R 5 In one embodiment, R 3 -N(C(=O)R 13 )(S(O) n R 5 In one embodiment, R 3 -N(C1-C6 alkyl)S(O) n R 5 .

[0301] In other embodiments, R 3 -NH2, -NHC(=O)(C1-C4 alkyl), -N[(C(=O)(C1-C4 alkyl)]2, -NHS(O) n (C1-C3 alkyl), -N[C(=O)(C1-C4 alkyl)][(S(O) n (C1-C3 alkyl)] or –N[C1-C6 alkyl][S(O) n (C1-C3 alkyl)]. In some embodiments, R 3 is -NH(C(=O)CH3) or -N(C(=O)CH3)2. In other embodiments, R 3 is -NHS(O)2CH3. In other embodiments, R 3 It is -N(C(=O)CH3)(S(O)2CH3).

[0302] In another embodiment, R 3 -S(O) n R 5 In one embodiment, R 3 is -S(O)2R 5 In another embodiment, R 3 is -S(O)2(C1-C3 alkyl). In other embodiments, R 3 is -S(O)2CH3. In other embodiments, R 3 It is -S(O)2CH2CH3.

[0303] In another embodiment, R 3 -S(O) n R 5 In one embodiment, R 3 is -S(O)2R 5 In some embodiments, R3 is -S(O)2R 5 , where R 5 is C1-C3 alkyl. In other embodiments, R 3 is -S(O)2R 5 , where R 5 It is a C1 alkyl group.

[0304] In some embodiments, R 3 is an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 3- to 7-membered heterocyclyl, wherein the heteroaryl or the heterocyclyl each comprises at least one N atom in the ring. 3 is selected from the 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. In a certain embodiment, R 3 for

[0305]

[0306] In some embodiments, R 13 is C1-C4 alkyl. In other embodiments, R 13 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or sec-butyl. 13 It is methyl.

[0307] In one embodiment, n is 0. In another embodiment, n is 1. In some embodiments, n is 2.

[0308] Compounds for use in imaging and therapeutic methods are described herein. In some embodiments, the compound comprises one F, Cl, Br, I or 123 I replaced.

[0309] In another embodiment, the compound comprises a 3 F, Cl, Br, I or 123 In one embodiment, the compound comprises one or more of 3 I or 123 I replaces one or more of.

[0310] In some embodiments, the compound comprises R 3 At least one R 6 A substituent, wherein at least one R 6 Further treated with F, Cl, Br, I or123 In another embodiment, R 3 R 6 The substituent is further substituted by I or 123 At least one of I is replaced.

[0311] In some more specific embodiments of the compound of Formula II, the compound has one of the following structures in Table 5, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof:

[0312] Table 5. Compounds

[0313]

[0314]

[0315] In one embodiment, the invention relates to a pharmaceutical composition comprising a compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. In one embodiment, the invention relates to a pharmaceutical composition comprising a compound of Formula I or Formula II as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0316] In some embodiments, the pharmaceutical composition comprising a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, further comprises a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprising a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, further comprises an additional therapeutic agent. In one embodiment, the pharmaceutical composition comprising a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, further comprises a pharmaceutically acceptable carrier and an additional therapeutic agent.

[0317] In another embodiment, 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 for treating prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, alopecia, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration.

[0318] Thus, one embodiment includes the use of the disclosed compounds in combination therapy with one or more currently used or experimental pharmacological therapies for treating the above-mentioned disease states, regardless of the biological mechanism of action of such pharmacological therapies, including but not limited to pharmacological therapies that directly or indirectly inhibit androgen receptors, pharmacological therapies that are cytotoxic in nature, and pharmacological therapies that interfere with the biological production or function of androgens (hereinafter referred to as "additional therapeutic agents"). "Combination therapy" means that any one or more compounds of Formula I or Formula II, or pharmaceutically acceptable salts, tautomers or stereoisomers thereof, are administered to the same patient together with one or more other therapeutic agents, such that their pharmacological effects occur simultaneously with each other, or if not simultaneously, their effects are synergistic with each other even if administered sequentially rather than simultaneously.

[0319] Such administration includes, but is not limited to, one or more compounds of Formula I or Formula II or pharmaceutically acceptable salts thereof, tautomers or stereoisomers and one or more additional therapeutic agents administered as independent agents without any mixing prior to administration, and preparations including one or more other androgen blocking therapeutic agents mixed with one or more compounds of Formula I or Formula II or pharmaceutically acceptable salts thereof, tautomers or stereoisomers are administered as premixed preparations. Administration of compounds of Formula I or Formula II or pharmaceutically acceptable salts thereof, tautomers or stereoisomers in combination with additional therapeutic agents for the treatment of the above-mentioned disease states also includes administration by any administration method, including but not limited to intravenous delivery (IV), oral delivery, intraperitoneal delivery, intramuscular delivery or intratumoral delivery.

[0320] In another aspect of the present disclosure, the one or more additional therapeutic agents may be administered to the patient prior to the administration of the compound of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In another embodiment, the compound of Formula I may be co-administered with one or more additional therapeutic agents. On the other hand, the one or more additional therapeutic agents may be administered to the patient after the administration of the compound of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

[0321] The ratio of the dose of the compound of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, to the dose of one or more additional therapeutic agents may be about 1:1 or may vary, for example, 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 may be varied accordingly to achieve the optimal therapeutic benefit.

[0322] The compounds of Formula I or Formula II, or pharmaceutically acceptable salts, tautomers or stereoisomers thereof, in combination with one or more additional therapeutic agents for improved treatment of the above-mentioned disease states may include, but are not limited to, any compound having the structure of Formula I or Formula II, or pharmaceutically acceptable salts, tautomers or stereoisomers thereof, including those compounds shown in Tables 1, 2, 3, 4 or 5.

[0323] Such additional therapeutic agents include, but are not limited to, any pharmacological agent currently approved by the FDA in the United States (or by any other regulatory agency elsewhere) for use as a pharmacological treatment for any of the above-mentioned disease states, or currently being used experimentally as part of a clinical trial program involving the above-mentioned disease states. Non-limiting examples of other pharmacological agents include, but are not limited to: a chemical entity and related compounds known as ODM-201 (also known as BAY1841788), which appears to bind to the AR and block its cellular function and is currently in clinical development as a treatment for prostate cancer); a chemical entity and related compounds known as ODM-204, which appears to be a dual inhibitor of AR and CYP17A1 and can be used to treat prostate cancer; a chemical entity and related compounds known as enzalutamide (4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide), which appears to be a blocker of the androgen receptor (AR) LBD and an FDA-approved treatment for prostate cancer; a chemical entity and related compounds known as galactron, which appears to be a blocker of the androgen receptor (AR) LBD and a CYP17 lyase inhibitor, and also appears to reduce overall androgen receptor levels in prostate cancer cells. Galactron is currently in development as a treatment for prostate cancer; a chemical entity called 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 appear to be blockers of the androgen receptor (AR) LBD and are currently in development as a treatment for prostate cancer; 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, a chemical entity called nilutamide (5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidine-2,4-dione) and related compounds, which appear to block the production of androgens and are an FDA-approved treatment for prostate cancer; a chemical entity called bicalutamide (N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide) and related compounds, which appear to be blockers of the androgen receptor (AR) LBD and are currently used to treat prostate cancer; a chemical entity called nilutamide (5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidine-2,4-dione) and related compounds, which appear to be blockers of the AR LBD and are currently used to treat prostate cancer;A chemical entity called flutamide (2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propionamide) and related compounds, which appear to be blockers of the androgen receptor (AR) LBD and are currently used to treat prostate cancer; a chemical entity called cyproterone acetate (6-chloro-1β,2β-dihydro-17-hydroxy-3'H-cyclopropa[1,2]pregna-4,6-diene-3,20-dione) and related compounds, which appear to be blockers of the androgen receptor (AR) LBD and are currently used to treat prostate cancer; a chemical entity called docetaxel (Taxotere; 1,7β,10β-trihydroxy-9-oxo-5β,20-cyclohexane) and related compounds, which appear to be blockers of the androgen receptor (AR) LBD and are currently used to treat prostate cancer. a chemical entity called oxaloxaline-11-ene-2α,4,13α-triyl 4-acetate 2-benzoate 13-{(2R,3S)-3-[(tert-butyloxycarbonyl)amino]-2-hydroxy-3-phenylpropionate}) and related compounds, which appear to be cytotoxic antimicrotubule agents and are currently used in combination with prednisone to treat prostate cancer; a chemical entity called bevacizumab (acrivastine), which is a monoclonal antibody that recognizes and blocks vascular endothelial growth factor A (VEGF-A) and can be used to treat prostate cancer; a chemical entity called OSU-HDAC42 ((S)-(+)-N-hydroxy-4-(3-methyl-2-phenylbutyrylamino)-benzamide) A chemical entity called VITAXIN and related compounds that appear to act as histone deacetylase inhibitors and are currently being developed as treatments for prostate cancer; a chemical entity called SUNITINIB (N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide) and related compounds that appear to inhibit multiple receptor tyrosine kinases (RTKs) and are useful in the treatment of prostate cancer; a chemical entity called ZD-4 a chemical entity called XRP-054 (N-(3-methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide) and related compounds, which appear to block EDTA receptors and are useful in the treatment of prostate cancer; a chemical entity called cabazitaxel (XRP-6258) and related compounds, which appear to be cytotoxic microtubule inhibitors and are currently used to treat prostate cancer; a chemical entity called MDX-010 (ipilimumab), which is a fully human monoclonal antibody that binds to CTLA-4 and blocks its activity, and is currently in development as an immunotherapeutic for the treatment of prostate cancer; a chemical entity called OGX 427, which appears to target HSP27 as an antisense agent and is currently in development to treat prostate cancer; a chemical entity called OGX 011, which appears to target clusterin as an antisense agent and is currently in development to treat prostate cancer;The chemical entity known as finasteride (Proscar, Propecia; N-(1,1-dimethylethyl)-3-oxo-(5α,17β)-4-azaandrost-1-ene-17-carboxamide) and related compounds, which appear to be 5-alpha reductase inhibitors that reduce the levels of dihydrotestosterone and are useful in treating prostate cancer; the chemical entity known as dutasteride (Avodart; 5α,17β)-N-{2,5-bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-1 7-carboxamide), which appears to be a 5-alpha reductase inhibitor that reduces the levels of dihydrotestosterone and is useful in treating prostate cancer; a chemical entity called torostanolide ((4aR,4bS,6aS,7S,9aS,9bS,11aR)-1,4a,6a-trimethyl-2-oxo-N-(propan-2-yl)-N-(propan-2-ylcarbamoyl)hexahydro-1H-indeno[5,4-f]quinoline- ... A chemical entity called beclosterol (LY-191,704; (4aS,10bR)-8-chloro-4-methyl-1,2,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one) and related compounds that appear to be 5-alpha reductase inhibitors that reduce the levels of dihydrotestosterone and are useful for treating prostate cancer; a chemical entity called azosterol (LY-320,236; (4aR,10bR)-8-chloro-4-methyl-1,2,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one) and related compounds that appear to be 5-alpha reductase inhibitors that reduce the levels of dihydrotestosterone and are useful for treating prostate cancer; [(4-ethyl-1,3-benzothiazol-2-yl)sulfanyl]-4,10b-dimethyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one) and related compounds, which appear to be 5-alpha reductase inhibitors that reduce levels of dihydrotestosterone and are useful in treating prostate cancer; a chemical entity called FCE28260 and related compounds, which appear to be 5-alpha reductase inhibitors that reduce levels of dihydrotestosterone and are useful in treating prostate cancer;Chemical entities and related compounds called SKF105,111, which appear to be 5-alpha reductase inhibitors that reduce the level of dihydrotestosterone, and can be used to treat prostate cancer. Chemical entities and related compounds called niclosamide (4.5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide), which appear to be anti-helminthic drugs as AR-V7 inhibitors, and can be used to treat prostate cancer. Chemical entities and related compounds called ARV-330 (Arvinas, Inc.), which appear to degrade androgen receptors in LNCaP and VCaP cells, and can be used to treat prostate cancer. Chemical entities and related compounds called VPC-14449 (4-(4-(4,5-bromo-1H-imidazol-1-yl)thiazol-2-yl)morpholine), which appear to target the DNA binding domain of the full-length AR, and can be used to treat prostate cancer. The chemical entity called TAS3681 appears to be an AR antagonist with AR down-regulating activity and can be used to treat prostate cancer. The chemical entity called sintokamide (e.g., sintokamide A is also known as N-[(2R,4S)-5,5,5-trichloro-1-[(2S)-2-[(2S)-3,3-dichloro-2-methylpropyl]-3-methoxy-5-oxo-2H-pyrrol-1-yl]-4-methyl-1-oxopentan-2-yl]propanamide) and related compounds, which appear to be AR antagonists and can be used to treat prostate cancer. ;

[0324] Thus, in some embodiments, the pharmaceutical composition comprising a compound having the structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, further comprises an additional therapeutic agent selected from the group consisting of enzalutamide, galactron, abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, bevacizumab (acrivastine), OSU-HDAC42, VITAXIN, sunitinib, ZD-4054, cabazitaxel (XRP-6258), MDX-010 (ipilimumab), OGX 427, OGX 011, finasteride, dutasteride, torosterone, beclosterol, azosternol, FCE 28260, SKF105,111, ODM-201, ODM-204, radium-233, niclosamide, apalutamide, ARV-330, VPC-14449, TAS3681, 3E10-AR441bsAb, sintokamide or their related compounds.

[0325] In some embodiments, compounds of Formula I or Formula II, or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof, that result in structural instability and / or unsatisfied valence are not included within the scope of the present invention.

[0326] In another embodiment, the present disclosure provides a pharmaceutical composition comprising any of the aforementioned compounds of Formula I or Formula II or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof and a pharmaceutically acceptable carrier.

[0327] Compounds as described herein may be in free form or in the form of their salts. In some embodiments, compounds as described herein may be in the form of pharmaceutically acceptable salts, which are known in the art (Berge et al., J. Pharm. Sci. 1977, 66, 1). Pharmaceutically acceptable salts as used herein include, for example, salts with the desired pharmacological activity of the parent compound (salts that maintain the biological effectiveness and / or characteristics of the parent compound and are biologically and / or otherwise desirable). Compounds as described herein with one or more functional groups capable of forming salts may, for example, be formed into pharmaceutically acceptable salts. Compounds containing one or more basic functional groups can form pharmaceutically acceptable salts with, for example, pharmaceutically acceptable organic acids or inorganic acids. Pharmaceutically acceptable salts can be derived from, for example, but not limited to, 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, glucoheptonic acid, gluconic acid, glycerophosphoric acid, glycolic acid, hemisulfonic acid, heptanoic acid, hexanoic acid, hydrochloric acid, hydrogen The compounds containing one or more acidic functional groups can form pharmaceutically acceptable salts with pharmaceutically acceptable bases (for example, but not limited to, inorganic bases based on alkali 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, but not limited to, pharmaceutically acceptable metal cations (e.g., 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, hydroxylamine, choline, betaine, ethylenediamine, glucosamine (glucosamine), The invention relates to a compound of any of the foregoing inventions and to a compound of any of the foregoing inventions. The foregoing inventions include, for example, hydroxybenzoic acid ... Those skilled in the art will appreciate that the preparation of salts can occur in situ during the isolation and purification of the compounds, or the preparation of salts can be carried out by separately reacting the isolated and purified compounds.

[0328] In some embodiments, the compounds as described herein and all their different forms (e.g., free form, salts, polymorphs, isomeric forms) may be in a solvent addition form, such as a solvate. A solvate contains a stoichiometric or non-stoichiometric amount of a solvent that is physically associated with the compound or its salt. The solvent may be, for example, but not limited to, a pharmaceutically acceptable solvent. For example, when the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholate is formed.

[0329] In some embodiments, the compounds as described herein and all their different forms (e.g., free form, salt, solvate, isomeric form) may include crystalline and non-crystalline forms, such as polymorphs, pseudopolymorphs, conformational polymorphs, non-crystalline forms, or combinations thereof. Polymorphs include different crystal packing arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stability, and / or solubility. It will be appreciated by those skilled in the art that a variety of factors, including recrystallization solvents, crystallization rates, and storage temperatures, may lead to a single crystalline form being dominant.

[0330] In some embodiments, the compounds as described herein and all of their different forms (e.g., free form, salts, solvates, polymorphs) include isomers, such as geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers, individual enantiomers, individual diastereomers, racemates, diastereomeric mixtures, and combinations thereof, and are not limited by the depiction of the formula illustrated for convenience.

[0331] III. Methods

[0332] The compounds of the present invention can be used in a variety of methods. For example, in some embodiments, the compound is suitable for use in a method for regulating androgen receptor (AR). Therefore, in one embodiment, the present disclosure provides any one of the compounds of the aforementioned formula I for use in regulating androgen receptor (AR) activity. For example, in some embodiments, regulating androgen receptor (AR) activity is in mammalian cells. Regulating androgen receptor (AR) can be in a subject in need (e.g., a mammalian subject) and is used to treat any of the conditions or diseases.

[0333] In other embodiments, regulating androgen receptor (AR) activity is for treating at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinal cord and bulbar muscular atrophy, age-related macular degeneration and combinations thereof. For example, in some embodiments, the indication is prostate cancer. In other embodiments, 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. And in other embodiments, the prostate cancer is androgen-dependent prostate cancer. In other embodiments, the spinal cord and bulbar muscular atrophy are Kennedy's disease.

[0334] In some embodiments, the compounds as described herein may be administered to a subject. In one embodiment, the present invention relates to a method for treating primary / localized prostate cancer, the method 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. In some embodiments, the present invention relates to a method for treating locally advanced prostate cancer, the method 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. In other embodiments, the present invention relates to a method for treating recurrent prostate cancer, the method 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. In other embodiments, the present invention relates to a method for treating metastatic prostate cancer, the method 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. In other embodiments, the present invention relates to a method for treating advanced prostate cancer, the method 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. In other embodiments, the present invention relates to a method for treating metastatic castration-resistant prostate cancer (CRPC), the method 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. In other embodiments, the present invention relates to a method for treating hormone-sensitive prostate cancer, the method 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.

[0335] In other embodiments, the present disclosure provides a method of regulating androgen receptor (AR) activity, the method comprising administering to a subject (e.g., a mammal) in need thereof a compound of the aforementioned formula I or formula II, or any of its pharmaceutically acceptable salts, tautomers, or stereoisomers, or a pharmaceutical composition of formula I or formula II or its pharmaceutically acceptable salts, tautomers, or stereoisomers as described herein (including the following composition, which comprises a compound of formula I or formula II, or its pharmaceutically acceptable salts, tautomers, or stereoisomers and another therapeutic agent). In some embodiments, regulating androgen receptor (AR) activity is in mammalian cells. In other embodiments, regulating androgen receptor (AR) activity is in mammals. In one embodiment, regulating androgen receptor (AR) activity is in people.

[0336] Regulating androgen receptor (AR) activity can be used to inhibit AR N-terminal domain activity. Regulating androgen receptor (AR) activity can be used to inhibit androgen receptor (AR) activity. The regulation can be in vivo. Regulating androgen receptor (AR) activity can be used to treat at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal cord and bulbar muscular atrophy (e.g., Kennedy's disease) and age-related macular degeneration. The indication may be prostate cancer. The prostate cancer may be castration-resistant prostate cancer. In one embodiment, 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 may be CRPC.

[0337] According to another embodiment, there is provided a use of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or a pharmaceutical composition of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof as described herein, for the preparation of a medicament for modulating androgen receptor (AR).

[0338] Alternatively, in one embodiment, a method for regulating androgen receptor activity is provided, the method comprising administering Formula I or Formula II or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, or a pharmaceutical composition of Formula I or Formula II or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof as described herein. In some embodiments, the administration may be directed to a mammal. In other embodiments, the administration may be directed to a mammal in need and may be used in an effective amount to treat at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, alopecia, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinal cord and bulbar muscular atrophy (e.g., Kennedy's disease), age-related macular degeneration, and combinations thereof.

[0339] As mentioned above, currently disclosed compounds can be used for multiple medical imaging applications, including the imaging of prostate.A variety of currently available imaging agents tend to accumulate in the bladder, which reduces their effectiveness as imaging tools specifically for prostate.Although not wishing to be bound by theory, the applicant believes that disclosed compounds are unexpectedly effective to the imaging of prostate due to their ability to accumulate in prostate rather than bladder, thereby allowing to see prostate.Therefore, the compound can be used in the method for making prostate imaging, for example, so that benign prostate disease imaging.In other embodiments, the compound can be used in the method for making cancerous prostate disease (such as prostate tumor) imaging.

[0340] Androgen deprivation therapy causes a temporary reduction in prostate cancer tumor load, but the malignant tumor will start growing again in the absence of testicular androgen, forming castration-resistant prostate cancer (CRPC). The rising titer of serum prostate-specific antigen (PSA) after androgen deprivation therapy indicates the appearance of biochemical failure, CRPC and the restart of androgen receptor (AR) transcriptional program. Most patients died of CRPC within two years of biochemical failure.

[0341] In one embodiment, the method confirms the presence of a tumor expressing AR (full length and truncated AR lacking the LBD), and the tumor is then treated by radiation therapy. In another embodiment, the imaging method provides information to determine whether a tumor expresses an AR species.

[0342] AR is a transcription factor and a validated target for prostate cancer therapy. Current therapies include androgen blockade and the administration of anti-androgens. Most CRPCs are suspected to be AR-dependent. AR has different functional domains, including a C-terminal ligand binding domain (LBD), a DNA binding domain (DBD), and an amino-terminal domain (NTD). AR NTD contains activation function-1 (AF-1), which provides most of the transcriptional activity to AR. Recently, splice variants of AR lacking LBD have been reported in prostate cancer cell lines (VCaP, LNCaP95, and 22Rv1) and in CRPC tissues. So far, more than 20 splice variants of AR have been detected. Splice variants V7 and V567es are clinically associated with expression levels, which are associated with poor survival and CRPC. AR V567es is expressed in only 20% of metastases. Abiraterone resistance is associated with the expression of AR splice variants. Enzalutamide also increases the expression levels of these constitutively active AR splice variants. These splice variants lack the LBD and thus will not be inhibited by current therapies that target the AR LBD, such as anti-androgens or androgen deprivation therapy.A single patient with advanced prostate cancer may have many lesions throughout the body and bones, and each tumor may have a different level of AR expression.

[0343] For sample tumors in patients with multiple metastases, biopsies of metastatic tumors in patients to determine AR species are neither widely available nor feasible. Therefore, it is necessary to develop methods for detecting the expression of all AR species for molecular classification of tumors based on the expression levels and extent of AR splice variants or other AR species that cannot be detected using imaging agents that interact with LBD, to identify patients with potential invasive diseases and poor prognosis, or to identify patients who will not respond to hormone therapy targeting AR LBD. Therefore, certain embodiments of the present invention provide AR NTD targeting molecular imaging probes (e.g., compounds of Formula I), which can be used to monitor responses to therapy and provide insights into the role of AR in resistance mechanisms.

[0344] One method currently used to image AR in prostate cancer uses positron emission tomography (PET), which uses 16β-[ 18 F]-Fluoro-5α-dihydrotestosterone ( 18 F-FDHT). Unfortunately, this imaging agent cannot detect splice variants lacking LBD. In some embodiments, the present invention uses 18 F-FDHT to detect full-length AR and use a gamma radiation emitting probe to specifically detect AR NTD, which will be the sum of full-length AR and variant AR. In other embodiments, the present invention uses continuous imaging using two different PET imaging agents to detect only full-length AR and another to specifically detect AR NTD, which will be the sum of full-length AR and variant AR. Together, these data show that there is a variant AR (variant NTD plus full-length AR detected with NTD isotope minus full-length AR detected with NTD isotope) with expression. 18 By using sequential imaging, 18 Discordant distribution or inconsistent uptake levels between F-FDHT and the radiolabeled compound of the invention (ie, compound of Formula I) indicates the presence of overexpression of the splice variant lacking the LBD.

[0345] As mentioned above, radioactivity 18 F-labeled compounds have been used as imaging agents not only for imaging AR in prostate cancer, but also for imaging a variety of organs and a variety of tumors. 123 I-labeled compounds are used as imaging agents. In one embodiment, the compounds of the present disclosure comprise at least one 123 I.

[0346] In one embodiment, the present invention relates to a method of imaging cancer by administering to a subject a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In another embodiment, the present invention relates to a method of imaging cancer by administering to a subject a pharmaceutical composition comprising a compound having a structure of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

[0347] In some embodiments, the method images cancer by administering to the subject a compound having a structure of Formula I or Formula II or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, or a pharmaceutical composition comprising Formula I or Formula II or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, and by using SPECT or PET to detect the presence or absence of cancer. In other embodiments, the method images cancer by administering to the subject a compound having a structure of Formula I or Formula II or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, and the method identifies the presence or absence of a tumor. In one embodiment, the method images cancer by administering to the subject a compound having a structure of Formula I or Formula II or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, and the method identifies the location of the tumor. In one embodiment, the method images cancer by administering to the subject a compound having a structure of Formula I or Formula II or a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, and the method identifies the presence of prostate cancer. In other embodiments, the prostate cancer is androgen-dependent prostate cancer. In some embodiments, the subject is a mammal, such as a human.

[0348] In some other embodiments, the method is suitable for detecting the presence of AR splice variants or other AR species (ie, mutations, truncations) that cannot be detected by imaging agents that interact with AR LBD. Without wishing to be bound by any particular theory, since the compounds of the present invention bind to the AR N-terminal domain (NTD), even mutants or variants lacking ARLBD can be imaged using the compounds of the present invention. Therefore, the methods of the present invention can be used to detect AR species, including mutants and variants that lack LBD or have LBD mutations but do contain AR NTD. In other embodiments, the method detects the presence or overexpression of AR splice variants that lack a ligand binding domain. For example, the method may include using 18 Sequential imaging of F-FDHT and compounds of the invention, and 18 Discordant distribution or inconsistent uptake levels between F-FDHT and the compounds of the invention indicate the presence or overexpression of a splice variant lacking the ligand binding domain.

[0349] In other embodiments, the compounds of the invention are used in single photon emission computed tomography methods to monitor a patient's response to therapy. In other embodiments, the methods comprise using the compounds of the invention to detect AR NTDs.

[0350] According to another embodiment, the method of imaging cancer is by administering a compound as described anywhere herein. In one embodiment, the method of imaging cancer is by administering a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein the compound comprises at least one 123 I.

[0351] The administration and imaging can be directed 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 carcinoma, endometrial cancer, salivary gland cancer, benign prostatic hyperplasia, alopecia, 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 used to image AR splice variants, mutants, or other AR species containing AR NTDs.

[0352] In some embodiments, the compounds as described herein or their pharmaceutically acceptable salts 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 carcinoma, endometrial cancer, salivary gland cancer, benign prostatic hyperplasia, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinal and bulbar muscular atrophy and age-related macular degeneration. In some embodiments, the compounds as described herein or their acceptable salts can be used to prepare a medicament or 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 (e.g., for diagnosis and / or localization of prostate tumors).

[0353] In some embodiments, the pharmaceutical composition suitable for regulating androgen receptor (AR) activity or for imaging according to the present invention may include a salt of such a compound, preferably a pharmaceutically or physiologically acceptable salt. The pharmaceutical preparation will generally include one or more carriers, excipients or diluents that are acceptable for the mode of administration of the preparation, which acts 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 such modes of administration.

[0354] In one embodiment, the imaging method disclosed herein relates to imaging prostate cancer. In some embodiments, 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. In some embodiments, the prostate cancer is CRPC. In other embodiments, the imaging is used to image benign prostate conditions (such as benign prostatic hyperplasia). Imaging and / or treatment methods for any indication described herein are also provided. Such methods may include administering a compound as described herein or a composition of a compound as described herein to a subject in need, or an effective amount of a compound as described herein or a composition of a compound as described herein. In one embodiment, a pharmaceutical composition suitable for imaging is administered intravenously.

[0355] Suitable pharmaceutical compositions can be formulated by methods known in the art and by its mode of administration and dosage determined by a skilled practitioner. For parenteral administration, the compound can be dissolved in sterile water or saline or in a pharmaceutically acceptable vehicle (such as those for vitamin K) for the administration of non-water-soluble compounds. For enteral administration, the compound can be administered in tablets, capsules or dissolved in liquid form. Tablets or capsules can be enteric-coated, or in the form of a formulation for sustained release. A variety of suitable preparations are known, including polymers or protein microparticles, ointments, pastes, gels, hydrogels or solutions encapsulating the compound to be released, which can be used for administering the compound surface or topically. Sustained release patches or implants can be used to provide release over an extended period of time. Many techniques known to those skilled in the art are described in Alfonso Gennaro's Remington: the Science & Practice of Pharmacy, 20th edition, Lippencott Williams & Wilkins, (2000). Preparations for parenteral administration may, for example, contain excipients polyalkylene glycols (such as polyethylene glycol), oils of plant origin or hydrogenated naphthalene. Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compound. Other potentially useful parenteral delivery systems for regulating compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems and liposomes. Preparations for suction may contain excipients, such as lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for use in the form of nasal drops, or may be in the form of gels.

[0356] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound as described herein and an additional therapeutic agent and / or a pharmaceutically acceptable carrier. In some embodiments, the additional therapeutic agent is used to treat prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, alopecia, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration. In other embodiments, the additional therapeutic agent is enzalutamide, galactron, ODN-201 abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, bevacizumab (avastatin), OSU-HDAC42, VITAXIN, sunitinib, ZD-4054, cabazitaxel (XRP-6258), MDX-010 (ipilimumab), OGX 427, OGX 011, finasteride, dutasteride, torostanolamide, beclosterol, azosterol, FCE 28260, SKF105,111, ODM-201 ODM-204, niclosamide, apalutamide, ARV-330, VPC-14449, TAS3681, 3E10-AR441 bsAb, sintokamide, or a related compound thereof.

[0357] Compounds described herein can also be used for analysis and for research purposes. The definition used includes ligand-dependent activation of androgen receptors (AR) such as dihydrotestosterone (DHT) or synthetic androgens (R1881) for research purposes. The ligand-independent activation of androgen receptors (AR) refers to the trans-activation of full-length androgen receptors (AR) by, for example, stimulating cAMP-dependent protein kinase (PKA) pathways or interleukin-6 (IL6) / STAT3 pathways in the absence of androgens (ligands). Such compounds should block the ligand-dependent and ligand-independent activation mechanisms of constitutively active splice variants of androgen receptors (AR) lacking ligand binding domains. This may involve any step in the activation of androgen receptors (AR), including the dissociation of heat shock proteins, necessary post-translational modifications (e.g., acetylation, phosphorylation), nuclear translocation, protein-protein interactions, the formation of transcriptional complexes, the release of co-repressors and / or increased degradation. There are many conditions besides prostate cancer that involve the androgen axis (eg, acne, hirsutism, alopecia, benign prostatic hyperplasia), and compounds that interfere with this mechanism may be useful in treating such conditions.

[0358] The compound or pharmaceutical composition according to or for use in the present invention can be administered by means of a medical device or appliance, such as an implant, a graft, a prosthesis, a stent, etc. In addition, implants intended to contain and release such compounds or compositions can be designed. An example would be an implant made of a polymer material adapted to release the compound over a period of time.

[0359] It should be noted that dosage values ​​may vary with the exact imaging protocol. With respect to any particular subject, a specific dosage regimen may be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition. The dosage ranges described herein are exemplary only and do not limit the dosage ranges that a medical practitioner may select. The amount of active compound in the composition may vary according to factors such as the subject's disease state, age, sex, and weight. The dosage regimen may be adjusted to provide optimal imaging results. For example, a single bolus may be administered, several divided doses may be administered over time, or the dosage may be proportionally reduced or increased as indicated by the imaging results. It may be advantageous to prepare parenteral compositions in a unit dosage form that is easy to administer and achieves uniformity of dosage.

[0360] Generally, the compounds of the present invention should be used without causing substantial toxicity. The toxicity of the compounds of the present invention can be measured using standard techniques, such as by testing in cell culture or experimental animals and determining the therapeutic index, i.e., the ratio between LD50 (lethal dose to 50% of the population) and LD100 (lethal dose to 100% of the population). In some cases, such as in severe disease states, a large amount of excess of the composition can be administered for therapeutic effect. Some compounds of the present invention may be toxic at some concentrations. Titration studies can be used to determine toxicity and non-toxic concentrations. Toxicity can be assessed by using PC3 or DU145 cells as possible negative controls to check the specificity of a particular compound or composition across cell lines, because these cells do not express functional AR. Animal studies can be used to provide an indication of whether the compound has any effect on other tissues. Systemic therapy targeting AR will not likely cause major problems to other tissues, because castration, anti-androgens, and androgen insensitivity syndrome are not fatal.

[0361] The compounds used in the present invention can be obtained from medical sources or modified from naturally occurring compounds using known methods. In addition, those skilled in the art will understand methods for preparing or synthesizing the compounds of the present invention with reference to known chemical synthesis principles. For example, Auzou et al. 1974 European Journal of Medicinal Chemistry 9 (5), 548-554 describe suitable synthetic procedures that can be considered and appropriately adapted for use in preparing any of the compounds of structure (I) as described above. Other references that may be useful include: Debasish Das, Jyh-Fu Lee and Soofin Cheng "Sulfonic acid functionalized mesoporous MCM-41 silica as a convenient catalyst for Bisphenol-A synthesis" Chemical Communications, (2001) 2178-2179; U.S. Patent 2571217 Davis, Orris L.; Knight, Horace S.; Skinner, John R. (Shell Development Co.) "Halohydrin ethers of phenols." (1951); and Rokicki, G.; Pawlicki, J.; Kuran, W. "Reactions of 4-chloromethyl-1,3-dioxolan-2-one with phenols as a new route to polyols and cyclic carbonates." Journal fuer Praktische Chemie (Leipzig) (1985) 327, 718-722.

[0362] In some embodiments, the compounds as described herein and all of their different forms can be used in combination with other treatment methods for at least one indication selected from the group consisting of, for example, but not limited to, prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovarian disease, precocious puberty, spinal and bulbar muscular atrophy, and age-related macular degeneration. For example, the compounds as described herein and all of their different forms can be used as neoadjuvant (before), adjuvant (during), and / or adjuvant (after) therapy with surgery, radiation (brachytherapy or external beam), or other therapy (e.g., HIFU), and in combination with chemotherapy, androgen blockade, anti-androgens, or any other treatment method.

[0363] In an exemplary embodiment for imaging the prostate, a dose of a solution containing a disclosed compound (typically 5 to 10 millicuries or 200 to 400 MBq) is typically injected rapidly into a saline drip into a patient's vein. The patient is then placed in SPECT for a series of one or more scans, which can take from 20 minutes to as long as an hour (typically, only about a quarter of the body length can be imaged at a time). Methods for SPECT scanning are well known in the art.

[0364] The compounds described herein can be used for in vivo or in vitro research purposes (i.e., non-clinical) to study the mechanisms of orphan and nuclear receptors, including steroid receptors, such as androgen receptor (AR). In addition, these compounds can be used individually or as part of a kit for in vivo or in vitro studies to study the activation of signal transduction pathways and / or orphan and nuclear receptors using recombinant proteins, cells maintained in culture, and / or animal models.

[0365] For example, exemplary compounds of the present invention can be prepared with reference to the following general reaction scheme 1:

[0366] General Reaction Scheme I

[0367]

[0368] It should be noted that although General Reaction Scheme I describes a racemic synthesis, one skilled in the art will recognize that different stereoisomers and diastereomers can be synthesized by using starting materials of different stereochemistry, such as stereospecific (2,2-dimethyl-1,3-dioxolan-4-yl)methanol and / or stereospecific 4-methylbenzenesulfonic acid oxiran-2-ylmethyl ester.

[0369] Referring to General Reaction Scheme I, (2,2-dimethyl-1,3-dioxolan-4-yl)methanol is tosylated under alkaline conditions as shown in step a. In step b, the tosylate group (p-toluenesulfonate group) is displaced by a bisphenol derivative under alkaline conditions (X can be -S(O)n-, where n=0, 1 or 2, or a divalent linear or branched C1-C6 alkyl). Optionally, in step c, the bisphenol derivative is halogenated on the benzene ring (e.g., Y and Z can be Cl or Br). In step d, the unreacted phenol part undergoes another elimination reaction to obtain a bisphenol derivative having an epoxide on one side and a protected diol on the other side. In step e, the epoxide is opened using CeCl3.7H2O and the diol is deprotected in situ.

[0370] Those skilled in the art will recognize that variations on the order of steps and reagents discussed with reference to General Synthetic Scheme I above are possible.

[0371] In addition, protecting group strategies can be used to prepare the compounds disclosed herein. Such strategies are well known to those skilled in the art. Exemplary protecting groups and related strategies are disclosed in Greene's Protective Groups in Organic Synthesis, Wiley-InterScience; 4th edition (October 30, 2006), which is hereby incorporated by reference in its entirety. In certain embodiments, protecting groups are used to mask alcohol moieties when performing other chemical transformations. After removing the protecting groups, free hydroxyl groups are obtained. Such protecting groups and strategies are well known in the art.

[0372] A number of alternative embodiments and examples of the present invention are described herein. These embodiments and examples are illustrative and should not be construed as limiting the scope of the present invention. The following examples are provided for illustrative and non-limiting purposes. Example

[0373] All non-aqueous reactions were performed in flame-dried round-bottom flasks. Unless otherwise specified, the flasks were equipped with rubber septa and the reactions were performed under positive argon pressure. Stainless steel syringes were used to transfer air and moisture-sensitive liquids. Flash column chromatography was performed using 230-400 mesh silica gel as described by Still et al. (Still, WC; Kahn, M.; Mitra, AJ Org. Chem. 1978, 43, 2923). Thin layer chromatography was performed using aluminum plates pre-coated with 0.25 mm 230-400 mesh silica gel, which was impregnated with a fluorescent indicator (254 nm). The thin layer chromatography plate was visualized by exposure to ultraviolet light and "Seebach" staining solution (700 mL water, 10.5 g cerium (IV) sulfate tetrahydrate, 15.0 g molybdophosphoric acid, 17.5 g sulfuric acid), followed by heating (~1 min) with a heat gun (~250 ° C). The organic solution was concentrated at 25-40°C on a Büchi R-114 rotary evaporator under reduced pressure (15-30 Torr, house vacuum).

[0374] Commercial reagents and solvents were used as received. All solvents used for extraction and chromatography were HPLC grade. Normal phase Si gel Sep paks TM Purchased from Waters, Inc. The thin layer chromatography plate is Kieselgel 60F 254 All synthetic reagents were purchased from SigmaAldrich and Fisher Scientific Canada.

[0375] Example 1: 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)

[0376]

[0377] Steps a and b: Synthesis of (S)-4-(2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenol

[0378] The title compound was synthesized as previously reported. See WO 2014 / 179867.

[0379] Step c: (S)-2,6-dichloro-4-(2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenol

[0380] To a solution of (S)-4-(2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenol (500 mg, 1.46 mmol, 1.0 equiv) in MeOH (12 mL) was added NaCl (256 mg, 4.38 mmol, 3.0 equiv) and NaOH (87.6 mg, 2.19 mmol, 1.5 equiv). Then an aqueous solution of sodium hypochlorite (6035 mg, 5.4% in H2O, 4.38 mmol, 3.0 equiv) was added dropwise at 0°C over 2 min. After 2 h, the mixture was extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with deionized water (2 x 30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by gradient flash Si gel column chromatography (elution: 10% ethyl acetate / hexanes to 20% ethyl acetate / hexanes) to provide the title compound (454 mg, 75.6%) as a viscous oil. 1 H NMR (600MHz, DMSO-D6) δ (ppm) = 9.92 (s, 1H), 7.11 (d, J = 9.0Hz, 2H), 7.07 (s, 2H), 6.84 (d, J = 8.4Hz, 2H), 4.38- 4.34(m,1H),4.08-4.05(m,1H),3.97-3.91(m,2H),3.74-3.70(m,1H),1.55(s,6H),1.33(s,3H),1.28(s,3H). 13C NMR (150MHz, DMSO-D6) δ (ppm) = 156.33, 146.75, 143.77, 141.55, 127.47, 126. 58,121.78,114.03,108.79,73.69,68.60,65.78,41.36,30.23,26.59,25.37.

[0381] 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

[0382] Sodium hydride (60% dispersion in mineral oil, 63.6 mg, 1.59 mmol, 1.5 eq) was slowly added to a stirred solution of (S)-2,6-dichloro-4-(2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)propan-2-yl)phenol (434 mg, 1.06 mmol, 1.0 eq) in anhydrous DMF (8 mL) at room temperature and the contents were stirred under argon for 10 minutes. A solution of (2R)-(-)-glycidyl toluenesulfonate (363 mg, 1.59 mmol, 1.5 eq) in anhydrous DMF (4 mL) was added via syringe and the mixture was reacted at 60° C. for 16 hours. The reaction was quenched by the addition of saturated ammonium chloride solution (1 mL) and the mixture was extracted with ethyl acetate (60 mL). The organic layer was washed with deionized water (2 x 30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by gradient flash Si gel column chromatography (elution: 10% ethyl acetate / hexanes to 20% ethyl acetate / hexanes) to provide the title compound (476 mg, 96.1%) as a viscous oil. 1 H NMR (600MHz, DMSO-D6) δ (ppm) = 7.20 (s, 2H), 7.13 (d, J = 9.0Hz, 2H), 6.86 (d, J=9.0Hz,2H),4.38-4.34(m,1H),4.25-4.22(m,1H),4.07-4.05(m,1H),3.9 8-3.91(m,2H),3.82-3.80(m,1H),3.74-3.70(m,1H),3.35-3.32(m,1H),2. 79-2.77(m,1H),2.62-2.60(m,1H),1.58(s,6H),1.32(s,3H),1.28(s,3H). 13C NMR (150MHz, DMSO-D6) δ (ppm) = 156.46, 149.15, 148.21, 141.01, 127.77, 127.54, 127.24 ,114.10,108.80,75.01,73.68,68.61,65.77,49.88,43.42,41.80,30.08,26.59,25.37.

[0383] 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)

[0384] To a solution of (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 (560 mg, 1.2 mmol, 1.0 equiv) in MeCN (12 mL) was added CeCl3.7H2O (1118 mg, 3.0 mmol, 2.5 equiv) and the mixture was heated to reflux for 16 h. The resulting white paste was collected by filtration and washed with ethyl acetate, and the clear suspension was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford the title compound (512 mg, 92%) as a viscous oil. 1 H NMR (600MHz, CDCl3) δ (ppm) = 7.15-7.12 (m, 4H), 6.86 (d, J = 9.0Hz, 2H), 4.26-4.23 (m, 1H), 4.21-4.15 (m, 2H), 4.1 5-4.11(m,1H),4.08-4.03(m,2H),3.86(dd,J=4.8Hz,10.8Hz,2H),3.78(dd,J=6.6Hz,12.6Hz,2H),1.64(s,6H); 13 C NMR (150 MHz, CDCl3) δ (ppm) = 156.76, 149.30, 148.26, 141.84, 128.52, 127.87, 127.67, 114.35, 73.69, 70.48, 69.26, 63.78, 45.55, 42.34, 30.79; for [M+Na] + ESI-LRMS calculated value 485.1, found value 485.4.

[0385] Example 2: Synthesis of (R)-3-(4-(2-(3,5-dibromo-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol (Compound 3a)

[0386]

[0387] Compound 3a was synthesized according to Example 1 by using NaBr instead of NaCl in step c. 1 H NMR (400MHz, DMSO-D6) δ (ppm) = 7.39 (s, 1H), 7.30 (dd, J = 2.0Hz, 34.4Hz, 1H), 7.15 (d,J=8.8Hz,2H),6.86(d,J=8.8Hz,2H),5.57-5.54(m,1H),4.91(d,J=4.8Hz,1H), 4.64(t,J=5.6Hz,1H),4.10-4.08(m,1H),3.98-3.92(m,3H),3.86-3.81(m,2H),3 .79-3.76(m,1H),3.71(dd,J=5.6Hz,11.2Hz,1H),3.45-3.42(m,2H),1.60(s,6H). The synthesized compound 3a 13 C NMR spectrum shows Figure 1 middle.

[0388] Example 3: 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)

[0389]

[0390] Step a: Synthesis of (S)-3-(4-(2-(3,5-dichloro-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)prop-2-yl)phenoxy)-2-hydroxypropyl 4-methylbenzenesulfonate

[0391] The title compound was synthesized according to a generally known scheme, such as that of step a in Reference Example 1, by tosylation of compound 1a under basic conditions.

[0392] 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. The title compound was synthesized via an epoxidation reaction generally known in the art under basic conditions. 1H NMR (400MHz, CDCl3) δ (ppm) = 7.13-7.10 (m, 4H), 6.86 (d, J = 6.8Hz, 2H), 4.24-4.12 (m, 4H), 3.99-3.94 (m, 1H), 3.85 (dd, J = 5.2Hz, 11.2Hz, 1H), 3.77 (dd, J = 5.6Hz, 11.2Hz, 1H), 3.38-3.33 (m, 1H), 2.93-2.89 (m, 1H), 2.76 (dd, J = 2.4Hz, 4.8Hz, 1H), 1.62 (s, 6H).

[0393] 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)

[0394] To a solution of (S)-1-chloro-3-(2,6-dichloro-4-(2-(4-(((R)-oxiran-2-yl)methoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (15 mg, 0.034 mmol, 1.0 eq) in anhydrous methanol (2 mL) was added erbium(III) trifluoromethanesulfonate (2.1 mg, 0.0034 mmol, 0.1 eq) and the mixture was stirred at room temperature for 40 hours. The reaction was quenched by the addition of saturated ammonium chloride solution (0.5 ml), and the mixture was extracted with ethyl acetate (2×10 ml). The organic layer was washed with deionized water (2×10 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by gradient flash column chromatography on silica gel (elution: 30% ethyl acetate / hexanes to 50% ethyl acetate / hexanes) to provide Compound 5a (12.5 mg, 77.1%) as a colorless oil. 1 H NMR (600MHz, CDCl3) δ (ppm) = 7.14-7.10 (m, 4H), 6.87 (d, J = 6.0Hz, 2H), 4.26-4.22 (m, 1H), 4.21-4.15 (m, 3H), 4.06-4.01 (m, 2H), 3.87 (dd, J = 6.0Hz, 11.4Hz, 1H), 3.79 (dd, J = 5.4Hz, 11.4Hz, 1H), 3.61 (dd, J = 4.2Hz, 9.6Hz, 1H), 3.57 (dd, J = 6.0Hz, 9.6Hz, 1H), 3.44 (s, 3H), 1.64 (s, 6H); 13C NMR (150MHz, CDCl3) δ (ppm) = 156.37, 148.81, 147.69, 141.04, 127.95, 127.25, 1 27.05,113.81,73.13,73.00,69.93,68.58,68.44,58.88,45.00,41.78,30.25.

[0395] Example 4: Synthesis of (S)-1-chloro-3-(2,6-dichloro-4-(2-(4-((R)-2-hydroxy-3-isopropoxypropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (Compound 7a)

[0396]

[0397] Compound 7a was synthesized according to Example 2 by using isopropanol instead of methanol in step c. 1 H NMR (400MHz, CDCl3) δ (ppm) = 7.13-7.10 (m, 4H), 6.86 (d, J = 8.8Hz, 2H), 4.25-4.12 (m, 4H), 4.03-3.98 (m, 2H), 3.85 (dd, J = 5.2Hz ,10.8Hz,1H),3.77(dd,J=5.6Hz,11.2Hz,1H),3.67-3.53(m,3H),2.83(s,1H),2.57(s,1H),1.62(s,6H),1.18(d,J=6.0Hz,6H).

[0398] Example 5: Synthesis of (S)-1-chloro-3-(2,6-dichloro-4-(2-(4-((S)-3-fluoro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (Compound 8a)

[0399]

[0400] Triethylamine trihydrofluoride (2 equivalents) and XtalFluor-M (2 equivalents) were added successively to a solution of compound 1a (1 equivalent; synthesized according to Example 1) in dichloromethane. After 3 hours, the reaction mixture was quenched with 5% aqueous sodium bicarbonate and stirred for 15 minutes at room temperature, and the resulting mixture was extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated, and the resulting crude material was purified by silica gel chromatography to provide compound 8a. 1HNMR (600MHz, CDCl3) δ (ppm) = 7.16-7.14 (m, 4H), 6.87 (d, J = 8.4Hz, 2H), 4.69-4.56 (m, 2H), 4.30-4.22 (m, 2H), 4. 22-4.16(m,2H),4.10-4.09(m,2H),3.87(dd,J=6.0Hz,11.4Hz,1H),3.79(dd,J=5.4Hz,10.8Hz,1H),1.64(s,6H).

[0401] Example 6: Synthesis of (S)-1-chloro-3-(2,6-dichloro-4-(2-(4-((R)-2-hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (Compound 9a)

[0402]

[0403] To a solution of (S)-1-chloro-3-(2,6-dichloro-4-(2-(4-(((R)-oxiran-2-yl)methoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (12.6 mg, 0.028 mmol, 1.0 eq) in anhydrous MeCN (2 mL) was added bismuth(III) trifluoromethanesulfonate (1.8 mg, 0.0028 mmol, 0.1 eq) and the mixture was stirred at room temperature for 40 hours. The reaction was quenched by addition of saturated ammonium chloride solution (0.5 ml), and the mixture was extracted with ethyl acetate (2×10 ml). The organic layer was washed with deionized water (2×10 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give Compound 9a (8.7 mg, 60.4%) as a colorless oil. 1 H NMR (600MHz, CDCl3) δ (ppm) = 7.56 (s, 1H), 7.16-7.14 (m, 4H), 7.04 (s, 1H), 7.01 (s, 1H), 6.86 (d, J = 8.4Hz, 2H), 4.29-4.23 ( m,3H),4.22-4.13(m,3H),3.98-3.92(m,2H),3.87(dd,J=6.0Hz,11.4Hz,1H),3.79(dd,J=4.8Hz,10.8Hz,1H),1.65(s,6H).

[0404] Example 7: Synthesis of (S)-1-chloro-3-(2,6-dichloro-4-(2-(4-((R)-2-hydroxy-3-morpholinopropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (Compound 11a)

[0405]

[0406] Compound 11a was synthesized according to Example 6 by using morpholine instead of 1H-imidazole. 1 H NMR (400MHz, CDCl3) δ (ppm) = 7.16-7.11 (m, 4H), 6.88 (d, J = 8.8Hz, 2H), 4.27-4.13 (m, 4H), 4.07-3.98 (m ,2H),3.90-3.77(m,6H),2.84-2.80(m,2H),2.73-2.72(m,2H),2.71-2.67(m,2H),1.65(s,6H); for [M+H] + ESI-LRMS calculated value 532.1, found value 534.6.

[0407] 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)

[0408]

[0409] 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

[0410] To a solution of (S)-3-(4-(2-(3,5-dichloro-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)-2-hydroxypropyl 4-methylbenzenesulfonate (90 mg, 0.146 mmol, 1.0 equiv) in anhydrous DMF (3 mL) was added sodium azide (9.5 mg, 0.146 mmol, 1.0 equiv) and the mixture was heated to 60-70 °C for 16 hours. The reaction was quenched by the addition of saturated ammonium chloride solution (10 ml), and the mixture was extracted with ethyl acetate (2 x 30 ml). The organic layer was washed with deionized water (2 x 30 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by gradient flash column chromatography on Si gel (elution: 20% ethyl acetate / hexanes to 50% ethyl acetate / hexanes) to provide the title compound (57.4 mg, 80.1%) as a colorless oil. 1H NMR (600MHz, CDCl3) δ (ppm) = 7.15-7.13 (m, 4H), 6.86 (d, J = 9.0Hz, 2H), 4.25-4.23 (m, 1H), 4.21-4.12 (m, 3H), 4.03-4.01 (m, 2 H), 3.86 (dd, J = 5.4Hz, 10.8Hz, 1H), 3.78 (dd, J = 5.4Hz, 11.4Hz, 1H), 3.58-3.50 (m, 2H), 3.01 (s, 1H), 2.78 (s, 1H) 1.64 (s, 6H).

[0411] 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)

[0412] To a solution of (R)-1-azido-3-(4-(2-(3,5-dichloro-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (57 mg, 0.117 mmol, 1.0 equiv) in MeCN (6 mL) was added triphenylphosphine (36.7 mg, 0.14 mmol, 1.2 equiv) and the mixture was heated to reflux for 16 h. The reaction was quenched by deionized water (2 ml) and the mixture was extracted with ethyl acetate (2 x 30 ml). The organic layer was washed with deionized water (2 x 30 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by gradient flash column chromatography on Si gel (elution: 2% methanol / dichloromethane to 30% methanol / dichloromethane) to provide Compound 12a (24.3 mg, 44.9%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ (ppm) = 7.12-7.09 (m, 4H), 6.84 (d, J = 8.4Hz, 2H), 4.24-4.21 (m, 1H), 4.17-4.13 (m, 2H), 3.97(m,3H),3.84(dd,J=5.6Hz,11.2Hz,1H),3.76(dd,J=5.6Hz,11.2Hz,1H),3.00-2.85(m,2H),1.61(s,6H); 13 C NMR (100 MHz, CDCl3) δ (ppm) = 157.00, 149.35, 148.31, 141.60, 128.52, 127.81, 127.61, 114.37, 73.78, 70.47, 70.42, 70.14, 45.65, 44.11, 42.34, 30.25; for [M+H]+ ESI-LRMS calculated value 462.1, found value 463.9.

[0413] 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)

[0414] A solution of (R)-1-azido-3-(4-(2-(3,5-dichloro-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (14.3 mg, 0.031 mmol, 1.0 equiv) in anhydrous dichloromethane (3 mL) at 0°C was treated sequentially with triethylamine (12.5 mg, 0.124 mmol, 4.0 equiv) and methanesulfonyl chloride (3.6 mg, 0.031 mmol, 1.0 equiv) for 10 min. It was then allowed to warm to room temperature for 16 h. The reaction was quenched by the addition of saturated ammonium chloride solution (2 ml), and the mixture was extracted with ethyl acetate (2 x 20 ml). The organic layer was washed with deionized water (2 x 20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by gradient flash column chromatography on silica gel (elution: 50% ethyl acetate / hexanes to 75% ethyl acetate / hexanes) to provide Compound 13a (9.7 mg, 57.9%) as a colorless oil. 1 H NMR (600MHz, CDCl3) δ (ppm) = 7.15-7.13 (m, 4H), 6.87 (d, J = 5.4Hz, 2H), 4.93-4.90 (m, 1H), 4.26-4.23 (m, 1H), 4.21-4.13 (m, 3H), 4.06-4.0 1(m,2H),3.87(dd,J=5.4Hz,11.4Hz,1H),3.79(dd,J=5.4Hz,10.8Hz,1H),3.50-3.45(m,1H),3.26-3.31(m,1H),3.03(s,3H),1.64(s,6H); 13 C NMR (150MHz, CDCl3) δ (ppm) = 155.94, 148.69, 147.73, 141.57, 127.99, 127.39, 1 27.05,113.81,73.14,69.92,68.85,68.54,45.19,44.99,41.81,39.98,30.22.

[0415] Example 9: 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)

[0416]

[0417] Step a: Synthesis of (S)-1-chloro-3-(2,6-dichloro-4-(2-(4-((S)-3-(ethylthio)-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol

[0418] To a solution of (S)-1-chloro-3-(2,6-dichloro-4-(2-(4-(((R)-oxiran-2-yl)methoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (50 mg, 0.081 mmol, 1.0 equiv) in anhydrous DMF (3 mL) was added sodium ethanethiolate (6.8 mg, 0.081 mmol, 1.0 equiv) and the mixture was heated to 60-70 °C for 16 hours. The reaction was quenched by the addition of saturated ammonium chloride solution (2 ml) and the mixture was extracted with ethyl acetate (2 x 30 ml). The organic layer was washed with deionized water (2 x 30 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by gradient flash column chromatography on silica gel (elution: 20% ethyl acetate / hexanes to 50% ethyl acetate / hexanes) to provide the title compound (16.4 mg, 39.5%) as a colorless oil.

[0419] 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)

[0420] A solution of (S)-1-chloro-3-(2,6-dichloro-4-(2-(4-((S)-3-(ethylthio)-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propan-2-ol (14.6 mg, 0.029 mmol, 1.0 equiv) in anhydrous dichloromethane (3 mL) at 0°C was treated with 3-chloroperbenzoic acid (14.0 mg, 0.081 mmol, 2.8 equiv) for 10 min. It was then allowed to warm to room temperature for 3 h. The reaction was quenched by the addition of saturated ammonium chloride solution (2 ml), and the mixture was extracted with ethyl acetate (2 x 20 ml). The organic layer was washed with saturated NaHCO3 (20 ml), deionized water (2 x 20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by gradient flash column chromatography on Si gel (elution: 30% ethyl acetate / hexanes to 75% ethyl acetate / hexanes) to provide Compound 14a (4.7 mg, 31.0%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ (ppm) = 7.18-7.15 (m, 4H), 6.88 (d, J = 8.8Hz, 2H), 4.69-4.67 (m, 1H), 4.27-4.15 (m, 3H), 4.10-4.07 (m, 2H), 3. 88(dd,J=5.2Hz,J=11.2Hz,1H),3.80(dd,J=5.2Hz,J=10.8Hz,1H),3.39-3.20(m,4H),1.66(s,6H),1.48(t,J=7.2Hz,3H); for [M+Na] + ESI-LRMS calculated value 561.1, found value 561.5.

[0421] Example 10: Synthesis of (R)-3-(4-(2-(4-((S)-3-chloro-2-hydroxypropoxy)-3-methylphenyl)propan-2-yl)-2-methylphenoxy)propane-1,2-diol (Compound 22a)

[0422]

[0423] 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)biphenol and omitting step c. 1H NMR (400MHz, DMSO-D6) δ (ppm) = 6.97-6.94 (m, 4H), 6.81-6.76 (m, 2H), 5.50 (d, J = 4.8Hz, 1H), 4.86 (s, 1H), 4.61 (s, 1H), 4.06-4. 00(m,1H),3.97-3.89(m,3H),3.86-3.76(m,3H),3.69(dd,J=5.6Hz,11.2Hz,1H),3.50-3.44(m,2H),2.10(s,6H),1.55(s,6H); 13 C NMR (100MHz, DMSO-D6) δ (ppm) = 155.14, 154.74, 143.23, 142.75, 129.32, 129.23, 125.66, 125.62, 125 .22,125.16,111.28,111.16,70.67,70.02,69.48,69.32,63.43,55.50,47.53,31.42,16.86,16.79.

[0424] Example 11: Synthesis of (R)-3-(4-((3-chloro-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)sulfonyl)phenoxy)propane-1,2-diol (Compound 40a)

[0425]

[0426] Compound 40a was synthesized according to Example 1 by using 4,4'-sulfonylbiphenol instead of 4,4'-(propane-2,2-diyl)biphenol and using only 1 equivalent of NaCl in step c. 1 H NMR (400MHz, MeOD) δ (ppm) = 7.92-7.82 (m, 4H), 7.26 (d, J = 8.8Hz, 1H), 7.13 (d, J = 8.8Hz, 2H), 4.23-4.12 (m, 4H), 4.08 -4.03(m,1H),4.00-3.96(m,1H),3.81(dd,J=4.8Hz,11.6Hz,1H),3.72(dd,J=5.2Hz,11.2Hz,1H),3.68-3.61(m,2H); 13 C NMR (100 MHz, MeOD) δ (ppm) = 163.24, 157.96, 135.21, 133.24, 129.56, 128.90, 127.82, 123.46, 115.12, 113.49, 70.23, 70.16, 69.62, 69.30, 62.64, 45.28; for [M+Na]+ ESI-LRMS calculated value 473.0, found value 472.8.

[0427] Example 12: Synthesis of (R)-3-(4-((3,5-dichloro-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)sulfonyl)phenoxy)propane-1,2-diol (Compound 41a)

[0428]

[0429] Compound 41a was synthesized according to Example 1 by using 4,4'-sulfonylbiphenol instead of 4,4'-(propane-2,2-diyl)biphenol. 1 H NMR (400MHz, MeOD) δ (ppm) = 7.94-7.89 (m, 4H), 7.14 (d, J = 8.8Hz, 2H), 4.21-4.13 (m, 4H), 4.09-4.04 (m, 1 H),4.01-3.95(m,1H),3.84(dd,J=4.4Hz,11.6Hz,1H,3.72(dd,J=5.2Hz,11.2Hz,1H),3.69-3.62(m,2H); 13 C NMR (100 MHz, MeOD) δ (ppm) = 165.08, 156.38, 141.20, 133.48, 131.65, 131.46, 129.37, 116.74, 75.60, 71.62, 71.46, 71.11, 64.06, 46.76; for [M+Na] + ESI-LRMS calculated value 506.9, experimental value 506.9.

[0430] Example 13: Synthesis of (S)-1-chloro-3-(2,6-dichloro-4-((4-((R)-2-hydroxy-3-methoxypropoxy)phenyl)sulfonyl)phenoxy)propan-2-ol (Compound 43a)

[0431]

[0432] Compound 43a was synthesized according to Example 3 by starting with compound 41a. 1H NMR (600MHz, CD3Cl) δ (ppm) = 7.91-7.85 (m, 4H), 7.06 (d, J = 9.0Hz, 2H), 4.27-4.16 (m, 4H), 4.13-4.07 (m ,2H),3.85(dd,J=4.8Hz,10.8Hz,1H),3.79(dd,J=5.4Hz,11.4Hz,1H),3.62-3.54(m,2H),3.43(s,3H); 13 C NMR (150 MHz, CD3Cl) δ (ppm) = 163.22, 154.58, 139.94, 132.47, 130.56, 130.47, 128.37, 115.67, 74.18, 73.31, 70.42, 69.70, 69.01, 59.62, 45.56; for [M+Na] + ESI-LRMS calculated value 521.0, found value 520.9.

[0433] Example 14: Synthesis of (R)-1-amino-3-(4-((3,5-dichloro-4-((S)-3-chloro-2-hydroxypropoxy)phenyl)sulfonyl)phenoxy)propan-2-ol (Compound 45a)

[0434]

[0435] Compound 45a was synthesized according to Examples 3 and 8 by starting with compound 41a. 1 H NMR (400MHz, MeOD) δ (ppm) = 7.93-7.90 (m, 4H), 7.14 (d, J = 9.2Hz, 2H), 4.19-4.13 (m, 3H), 4.10-4.01 (m, 2H), 3.95-3 .91(m,1H),3.85-3.80(m,1H),3.74-3.69(m,1H),2.85(dd,J=4.4Hz,13.2Hz,1H),2.74(dd,J=5.2Hz,13.2Hz,1H); 13 C NMR (100 MHz, MeOD) δ (ppm) = 165.08, 156.51, 141.32, 133.70, 131.76, 131.57, 129.46, 116.86, 75.71, 72.15, 71.73, 71.57, 46.83, 45.26; for [M+Na] + ESI-LRMS calculated value 506.0, found value 507.9.

[0436] Example 15: Synthesis of N-((R)-3-(4-((3,5-dichloro-4-((S)-3-chloro-2-hydroxypropyloxy)phenyl)sulfonyl)phenoxy)-2-hydroxypropyl)methanesulfonamide (Compound 46a)

[0437]

[0438] Compound 46a was synthesized according to Examples 3 and 8 by starting with compound 41a. 1 H NMR (600MHz, MeOD) δ (ppm) = 7.93-7.90 (m, 4H), 7.14 (d, J = 9.0Hz, 2H), 4.18-4.10 (m, 4H), 4.07-4.01 (m, 2H), 3.82 (dd, J =4.2Hz,11.4Hz,1H),3.71(dd,J=4.8Hz,10.8Hz,1H),3.30-3.27(m,1H),3.20(dd,J=6.0Hz,13.2Hz,1H),2.95(s,3H); 13 C NMR (150 MHz, MeOD) δ (ppm) = 165.01, 156.49, 141.31, 133.74, 131.75, 131.56, 129.46, 116.86, 75.68, 71.55, 71.47, 70.27, 46.81, 46.70, 40.22; for [M+Na] + ESI-LRMS calculated value 584.0, found value 584.0.

[0439] Example 16: Synthesis of (S)-1-chloro-3-(2,6-dichloro-4-((4-((R)-2-hydroxy-3-morpholinopropoxy)phenyl)sulfonyl)phenoxy)propan-2-ol (Compound 47a)

[0440]

[0441] Compound 47a was synthesized according to Examples 3 and 7 starting from compound 41a. 1 H NMR (600MHz, CDCl3) δ (ppm) = 7.90-7.86 (m, 4H), 7.06 (d, J = 9.0Hz, 2H), 4.28-4.19 (m, 4H), 4.08-4.07 (m, 2H), 3.87-3.77 (m, 6H), 2.77-2.58 (m, 6H); 13C NMR (150 MHz, CDCl3) δ (ppm) = 162.51, 153.88, 139.21, 131.79, 129.85, 129.75, 127.66, 114.97, 73.48, 70.03, 69.71, 66.14, 64.45, 60.50, 53.26, 44.85; for [M+H] + ESI-LRMS calculated value 554.1, found value 556.0.

[0442] Example 17: Synthesis of (S)-1-chloro-3-(2,6-dichloro-4-((4-((R)-2-hydroxy-3-(1H-imidazol-1-yl)propoxy)phenyl)sulfonyl)phenoxy)propan-2-ol (Compound 48a)

[0443]

[0444] Compound 48a was synthesized according to Examples 3 and 6 by starting with compound 41a. 1 H NMR (400MHz, CDCl3) δ (ppm) = 7.88-7.83 (m, 4H), 7.65 (s, 1H), 7.03-6.97 (m, 4H), 4.27-4.10 (m, 6H), 4.02 (d d,J=4.8Hz,9.6Hz,1H),3.96-3.90(m,1H),3.82(dd,J=4.8Hz,11.2Hz,1H),3.75(dd,J=5.2Hz,11.2Hz,1H); 13 C NMR (100 MHz, CDCl3) δ (ppm) = 162.53, 154.66, 139.49, 137.72, 132.85, 130.46, 130.40, 128.24, 128.00, 120.24, 115.50, 74.12, 70.14, 69.22, 68.64, 50.29, 45.48; for [M+H] + ESI-LRMS calculated value 535.0, found value 535.0.

[0445] Example 18: Synthesis of (S)-1-chloro-3-(2,6-dichloro-4-((4-((S)-3-(ethylsulfonyl)-2-hydroxypropoxy)phenyl)sulfonyl)phenoxy)propan-2-ol (Compound 50a)

[0446]

[0447] Compound 50a was synthesized according to Examples 3 and 9 by starting with compound 41a. 1H NMR (400MHz, CDCl3) δ (ppm) = 7.89 (d, J = 9.2Hz, 2H), 7.85 (s, 2H), 7.04 (d, J = 9.2Hz, 2H), 4.72-4.66 (m, 1H), 4.26-4.19 (m, 3H), 4.14-4.09(m,2H),3.83(dd,J=5.2Hz,11.2Hz,1H),3.77(dd,J=4.8Hz,11.2Hz,1H),3.35-3.14(m,4H),1.45(t,J=7.6Hz,3H); 13 C NMR (100 MHz, CDCl3) δ (ppm) = 162.37, 154.56, 139.59, 133.08, 130.46, 130.43, 128.27, 115.56, 74.08, 70.82, 70.29, 65.20, 54.87, 49.39, 45.41, 6.70; for [M+Na] + ESI-LRMS calculated value 583.0, found value 582.9.

[0448] Example 19: Synthesis of (R)-3-(4-((4-((S)-3-chloro-2-hydroxypropoxy)phenyl)sulfonyl)phenoxy)propane-1,2-diol (Compound 80a)

[0449]

[0450] Compound 80a was synthesized according to Example 1 by using 4,4'-sulfonylbiphenol instead of 4,4'-(propane-2,2-diyl)biphenol and omitting step c. 1 H NMR (400MHz, MeOD) δ (ppm) = 7.84 (dd, J = 2.8Hz, 9.2Hz, 4H), 7.09 (dd, J = 2.0Hz, 9.2Hz, 4H), 4. 15-4.08(m,4H),4.05-4.01(m,1H),3.99-3.93(m,1H),3.76-3.71(m,1H),3.70-3.60(m,3H); 13 CNMR (100 MHz, MeOD) δ (ppm) = 164.50, 164.17, 135.74, 135.40, 130.89, 130.87, 116.52, 71.78, 71.12, 70.97, 70.87, 64.19, 46.74; for [M+Na] + ESI-LRMS calculated value 439.1, found value 438.9.

[0451] Example 20: Synthesis of (R)-1-(4-(2-(4-((R)-2-acetoxy-3-chloropropoxy)-3,5-dichlorophenyl)propan-2-yl)phenoxy)-3-methoxypropan-2-yl acetate (Compound A5d)

[0452]

[0453] Ac2O (128 mg, 1.26 mmol, 6.0 equivalents), Et3N (127 mg, 1.26 mmol, 6.0 equivalents) and DMAP (26 mg, 0.21 mmol, 1.0 equivalents) were added to a solution of compound 5a (100 mg, 0.21 mmol, 1.0 equivalents, see Example 3) in anhydrous DCM (5 mL) at room temperature, and the resulting mixture was stirred overnight at the same temperature. The mixture was diluted with EtOAc (30 mL), and the organic layer was washed with water (15 mL) and brine (15 mL). The organic layer was further dried over anhydrous MgSO4 and evaporated under reduced pressure. The crude material was loaded onto a silica gel column and eluted with hexane / EtOAc (13 / 1 to 6 / 1) to generate 111 mg of the title compound (yield: 95.0%) as a colorless oil.

[0454] 1 H NMR (600MHz, chloroform-d) δ7.11-7.12(m,2H),7.09-7.11(m,2H),6.82-6.87(m,2H) ),5.32-5.35(m,1H),5.28-5.32(m,1H),4.18-4.26(m,2H),4.09-4.16(m,2 H),3.97(dd,J=5.14,11.74Hz,1H),3.88(dd,J=5.14,11.74Hz,1H),3.66(d d,J=2.20,4.40Hz,2H),3.40(s,3H),2.14(s,3H),2.11(s,3H),1.61(s,6H).

[0455] 13 C NMR (151 MHz, chloroform-d) δ 170.8, 170.4, 156.9, 149.4, 148.4, 141.8, 128.7, 127.9, 127.7, 114.5, 71.9, 71.1, 70.9, 66.4, 59.6, 42.7, 42.4, 30.9, 21.4, 21.2.

[0456] Example 21: Synthesis of (R)-1-(4-(2-(4-((S)-2-acetoxy-3-chloropropoxy)-3,5-dichlorophenyl)propan-2-yl)phenoxy)-3-methoxypropan-2-yl acetate (Compound A5a)

[0457]

[0458] 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 at room temperature overnight. Dichloromethane was removed under reduced pressure and the residue was purified by column chromatography to give the title compound (5.8 mg, 98.6%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ (ppm) = 7.11-7.08 (m, 4H), 6.83 (d, J = 8.8, 2H), 5.35-5.26 (m, 2H), 4.26-4.17 (m, 2H), 4.16-4.07 (m, 2H), 3.96 (dd,J=5.2Hz,11.6Hz,1H),3.86(dd,J=5.6Hz,11.6Hz,1H),3.66-3.61(m,2H),3.38(s,3H),2.13(s,3H),2.10(s,3H),1.60(s,6H); 13 C NMR (150 MHz, CDCl3) δ (ppm) = 170.80, 170.45, 156.96, 149.41, 148.39, 141.80, 128.69, 127.90, 127.70, 114.54, 71.91, 71.12, 70.54, 66.44, 59.62, 42.73, 42.43, 30.90, 21.38, 21.18; for [M+H] + ESI-LRMS calculated value 561.1, found value 561.1.

[0459] Example 22: Synthesis of (R)-1-(4-(2-(4-((S)-2-acetoxy-3-chloropropoxy)-3,5-dichlorophenyl)propan-2-yl)phenoxy)-3-isopropoxypropan-2-yl acetate (Compound A7a)

[0460]

[0461] Compound A7a was synthesized according to Example 21 by using Compound 7a prepared according to Example 4. Compound A7a (6.4 mg, 96.2%) was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ (ppm) = 7.12-7.08 (m, 4H), 6.85 (d, J = 8.8, 2H), 5.36-5.30 (m, 1H), 5.28-5.22 (m, 1H), 4.27-4.09 (m, 4H), 3.97 (dd, J = 5. 2Hz,11.6Hz,1H),3.87(dd,J=5.6Hz,11.6Hz,1H),3.71-3.57(m,3H),2.14(s,3H),2.09(s,3H),1.61(s,6H),1.15(dd,J=2.0Hz,6.0Hz,6H); 13 C NMR (150 MHz, CDCl3) δ (ppm) = 170.16, 169.78, 156.42, 148.77, 147.72, 141.03, 128.02, 127.20, 127.03, 113.91, 71.97, 71.25, 70.98, 70.30, 66.01, 65.72, 42.06, 41.76, 30.24, 21.60, 21.54, 20.74, 20.52; for [M+Na] + ESI-LRMS calculated value 611.1, found value 611.1.

[0462] Example 23: Synthesis of (S)-1-(4-(2-(4-((S)-2-acetoxy-3-(ethylsulfonyl)propoxy)phenyl)propan-2-yl)-2,6-dichlorophenoxy)-3-chloropropan-2-yl acetate (Compound A14a)

[0463]

[0464] Compound A14a was synthesized according to Example 21 by using compound 14a prepared according to Example 9. Compound A14a (3.4 mg, 97.3%) was obtained as a colorless oil. 1H NMR (400MHz, CDCl3) δ (ppm) = 7.13-7.08 (m, 4H), 6.84 (d, J = 8.8, 2H), 5.63-5.57 (m, 1H), 5.36-5.30 (m, 1H), 4.29-4.18 (m, 4H), 3.97 (dd, J = 5.2Hz, 12 .0Hz,1H),3.87(dd,J=5.6Hz,11.6Hz,1H),3.54-3.40(m,2H),3.10(q,J= 7.2Hz,2H),2.14(s,3H),2.12(s,3H),1.61(s,6H),1.44(t,J=7.2Hz,3H); 13 C NMR (150 MHz, CDCl3) δ (ppm) = 170.41, 170.16, 158.50, 154.94, 142.86, 142.39, 128.70, 128.03, 127.66, 114.48, 71.87, 71.46, 67.79, 67.05, 52.48, 48.82, 42.69, 42.44, 30.86, 21.15, 20.90, 6.80; for [M+Na] + ESI-LRMS calculated value 645.1, found value 645.1.

[0465] Example 24: Synthesis of (R)-1-(4-(2-(4-((S)-2-acetoxy-3-chloropropoxy)-3,5-dichlorophenyl)propan-2-yl)phenoxy)-3-morpholinopropan-2-yl acetate (Compound A11a)

[0466]

[0467] Compound A11a was synthesized according to Example 21 by using compound 11a prepared according to Example 7. Compound A11a (6.8 mg, 97.6%) was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ (ppm) = 7.14-7.07 (m, 4H), 6.83 (d, J = 8.8, 2H), 5.72-5.70 (m, 1H), 5.36-5.30 (m, 1H), 4.47-4.40 (m, 1H), 4.39-4.32 (m, 1H) ,4.29-4.14(m,4H),3.99-3.94(m,3H),3.87(dd,J=5.6Hz,11.6Hz,1H), 3.58-3.37(m,4H),2.97(m,2H),2.23(s,3H),2.14(s,3H),1.61(s,6H); 13C NMR (150 MHz, CDCl3) δ (ppm) = 170.54, 170.37, 156.02, 149.12, 148.39, 142.61, 128.67, 128.06, 127.60, 114.34, 71.81, 70.90, 67.26, 65.89, 63.60, 58.52, 53.17, 52.58, 42.64, 42.40, 30.78, 29.87, 21.56, 21.11; for [M+H] + ESI-LRMS calculated value 616.1, found value 616.1.

[0468] Example 25: Synthesis of (S)-1-(4-(2-(4-((R)-2-acetoxy-3-(1H-imidazol-1-yl)propoxy)phenyl)propan-2-yl)-2,6-dichlorophenoxy)-3-chloropropan-2-yl acetate (Compound A9a)

[0469]

[0470] Compound A9a was synthesized according to Example 21 by using Compound 9a prepared according to Example 6. Compound A9a (5.6 mg, 93.6%) was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ (ppm) = 9.40 (s, 1H), 7.39 (s, 1H), 7.20 (s, 1H), 7.14-7.10 (m, 4H), 6.82 (d, J = 8.4, 2H), 5.50 (m, 1H), 5.35-5.31 (m, 1H), 4 .78-4.70(m,2H),4.27-4.18(m,4H),3.96(dd,J=5.6Hz,11.6Hz,1H),3.87(dd,J=5.6Hz,11.6Hz,1H),2.14(s,3H),2.11(s,3H),1.61(s,6H); 13 C NMR (150 MHz, CDCl3) δ (ppm) = 170.21, 169.67, 155.72, 148.93, 142.61, 136.02, 128.53, 127.97, 127.46, 121.62, 120.13, 114.19, 71.66, 70.76, 69.72, 65.27, 49.70, 42.49, 42.26, 30.65, 20.96, 20.91; for [M+H] + ESI-LRMS calculated value 597.1, found value 597.1.

[0471] Example 26: Synthesis of (S)-1-(4-(2-(4-((R)-2-acetoxy-3-(N-(methylsulfonyl)acetamido)propoxy)phenyl)propan-2-yl)-2,6-dichlorophenoxy)-3-chloropropan-2-yl acetate (Compound A13a)

[0472]

[0473] Compound A13a was synthesized according to Example 21 by using compound 13a prepared according to Example 8. Compound A13a (6.0 mg, 100%) was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ (ppm) = 7.13-7.08 (m, 4H), 6.82 (d, J = 8.4, 2H), 5.47-5.42 (m, 1H), 5.36-5.30 (m, 1H), 4.29-4.07 (m, 6H), 3. 97(dd,J=5.2Hz,11.6Hz,1H),3.87(dd,J=5.6Hz,11.6Hz,1H),3.33(s,3H),2.44(s,3H),2.14(s,3H),2.10(s,3H),1.61(s,6H); 13 C NMR (150 MHz, CDCl3) δ (ppm) = 171.33, 170.47, 170.29, 156.42, 149.13, 148.29, 142.17, 128.58, 127.88, 127.54, 114.33, 71.74, 70.82, 70.36, 67.19, 46.69, 42.66, 42.57, 42.31, 30.73, 24.49, 21.07, 20.03; for [M+H] + ESI-LRMS calculated value 666.1, found value 666.1.

[0474] Example 27: Synthesis of (S)-1-(4-(2-(4-((S)-2-acetoxy-3-chloropropoxy)-3,5-dichlorophenyl)propan-2-yl)phenoxy)-3-fluoropropan-2-yl acetate (Compound A8a)

[0475]

[0476] Compound A8a was synthesized according to Example 21 by using Compound 8a prepared according to Example 5. Compound A8a (5.8 mg, 95.9%) was obtained as a colorless oil. 1H NMR (400MHz, CDCl3) δ (ppm) = 7.13-7.10 (m, 4H), 6.84 (d, J = 8.8Hz, 2H), 5.39-5.29 (m, 2H), 4.79-4.71 (m, 1H), 4.67-4.59 (m, 1H), 4.27-4 .18(m,2H),4.16-4.14(m,2H),3.97(dd,J=5.2Hz,11.6Hz,1H),3.87(dd,J=5.6Hz,11.6Hz,1H),2.14(s,3H),2.13(s,3H),1.61(s,6H); 13 C NMR (150 MHz, CDCl3) δ (ppm) = 170.58, 170.46, 156.65, 149.33, 148.43, 142.14, 128.73, 127.99, 127.70, 114.48, 82.13, 80.99 (d, J = 513.0 Hz), 71.92, 70.98, 70.77, 70.64 (d, J = 19.5 Hz), 65.19, 65.15 (d, J = 6.0 Hz), 42.73, 42.46, 30.91, 21.22, 21.19; for [M+H] + ESI-LRMS calculated value 549.1, found value 549.1.

[0477] Example 28: Synthesis of (S)-3-(4-(2-(4-((S)-2-acetoxy-3-chloropropoxy)-3,5-dichlorophenyl)propan-2-yl)phenoxy)propane-1,2-diyl diacetate (Compound A1a)

[0478]

[0479] Compound A1a was synthesized according to Example 21 by using Compound 1a prepared according to Example 1. Compound A1a (63.0 mg, 97.1%) was obtained as a colorless oil. 1H NMR (600MHz, CDCl3) δ (ppm) = 7.14-7.11 (m, 4H), 6.85 (d, J = 12.0Hz, 2H), 5.39-5.33 (m, 2H) ), 4.45 (dd, J = 4.2Hz, 12.0Hz, 1H), 4.32 (dd, J = 6.0Hz, 12.0Hz, 1H), 4.26 (dd, J = 4.8Hz, 10. 2Hz,1H),4.22(dd,J=4.8Hz,10.2Hz,1H),4.13-4.12(m,2H),3.98(dd,J=5.4Hz,12.0Hz, 1H),3.89(dd,J=5.4Hz,12.0Hz,1H),2.16(s,3H),2.12(s,3H),2.10(s,3H),1.63(s,6H); 13 C NMR (150 MHz, CDCl3) δ (ppm) = 170.21, 169.90, 169.77, 156.07, 148.66, 147.76, 141.40, 128.04, 127.28, 127.02, 113.88, 71.24, 70.31, 69.30, 65.55, 62.10, 42.05, 41.77, 30.23, 20.56, 20.50, 20.35; for [M+Na] + ESI-LRMS calculated value 611.1, found value 611.0.

[0480] Example 29: Compound Activity

[0481] LNCaP cells (3×10 4 ) were inoculated into 24-well plates overnight. The next day, LNCaP cells were transiently transfected with 0.25 μg / well PSA (6.1 kb)-luciferase reporter plasmids, followed by pretreatment with compounds of the invention or reference compounds (e.g., compounds A, B, C, 1a, 5a, 9a, 11a, 12a, 13a and 14a) in a concentration range of 0 μM to 35 μM for 1 hour, followed by addition of a vehicle or synthetic androgen R1881 (1 nM) to induce luciferase production. After 48 hours of exposure, cells were harvested in Passive lysis buffer (Promega). Luciferase activity was measured and standardized for protein concentration determined by Bradford analysis. IC was performed using OriginPro 8.1 software (Northampton, MA, USA). 50 IC was determined by performing transfection experiments using triplicate wells in at least 4 independent experiments ("trials"). 50 The dose responses of representative compounds are shown in Figure 2Luciferase activity is expressed as the mean ± standard deviation of technical replicates.

[0482]

[0483] Table 6. IC values ​​of selected compounds with standard errors 50 Value (μM)

[0484]

[0485]

[0486] Example 30: Compound 1a Treatment in LNCaP Xenograft Model

[0487] LNCaP cell preparation: LNCaP cells were cultured in T175 flasks at 2-3 × 10 7 The cells were passaged at a concentration of 1×10 400 μL / mL. The cells were grown for 7 days until 90% confluence. Cell preparations were then prepared in RPMI with 5% FBS / Matrigel (50 / 50, v / v) to obtain 1×10 8 / mL final concentration.

[0488] Tumor Induction and Treatment: Six to eight week old NOD-SCID mice were received from the Animal Resource Center of the BC Cancer Research Center and acclimated for 28 days. Tumors were initiated subcutaneously on the back of each animal. Tumors were allowed to grow to approximately 100 mm 3 The average size of the mice was 4.34 × 2.5 × 1.3 × 1.6 × 1.7 ...

[0489] Compound Formulation and Treatment: Compound 1a was dissolved in 100% DMSO (ATCC Lot No. 61908420) to generate a stock solution of 157 mg / mL. Compound 1a was administered once daily by oral gavage at dose levels of 10 and 30 mg / kg. Vehicle control animals were administered 1% CMC formulations by oral gavage once daily. CMC (n=17 tumors); 10 mg / kg (n=15 tumors); 30 mg / kg (n=14 tumors). CMC (n=9 animals); 10 mg / kg (n=9 animals); 30 mg / kg (n=9 animals).

[0490] Oral treatment was started one week after castration. Treatment was designated as "Day 1" and animals were treated once a day for a total of 24 doses. Two days after the last dose, tumors were measured and harvested. Body weight was assessed every day throughout the treatment period. Tumor volume was measured on Day -7 (castration day), and tumor volume was measured again on Days 1, 4, 8, 12, 16, 20, 24 and 26.

[0491] Quantitative real-time polymerase chain reaction (QPCR) method: Use Reagents (Invitrogen TM ) were homogenized and total RNA was extracted using the PureLink RNA Mini Kit (Life Technologies). Amplification-grade DNase I treatment (Sigma-Aldrich) was applied to the RNA, followed by RT-PCR using a high-capacity RNA-DNA kit (Life Technologies) to generate cDNA. cDNA and gene-specific primers were incubated with ROX (Invitrogen TM )of Green qPCRSuperMix-UDG combination. Transcripts were detected by quantitative real-time PCR (QPCR) using the ABI PRISM 7900 Sequence Detection System (ABI Applied Biosystems, Life Technologies), and each biological sample was measured in triplicate. Gene expression levels were normalized to the housekeeping gene RPL13A. Primers for PSA have been described previously (Andersen RJ et al. Cancer Cell. 2010; Myung JK et al. J. Clin. Invest. 2013).

[0492] Daily oral treatment with compound 1a at 10 mg / kg or 30 mg / kg resulted in inhibition of tumor growth and a significant reduction in tumor volume at the end of the treatment period ( Figure 3 and Figure 4 There was no statistical difference in tumor volume between the 10 mg / kg and 30 mg / kg doses of compound 1a. There was no significant difference in the starting and ending body weights of mice treated with compound 1a and mice treated with the control (CMC formulation) ( Figure 5 Since androgen receptor regulates PSA expression through transcription, the mRNA level of PSA in tumors was measured and examined to confirm the in vivo on-target activity of compound 1a ( Figure 6). Indeed, compound 1a demonstrated dose-dependent inhibition of mRNA expression of PSA, as 30 mg / kg of compound 1a treatment resulted in a significant decrease in PSA expression when compared to the 10 mg / kg dose and control treatment. In summary, these data indicate that compound 1a significantly reduces castration-resistant growth of LNCaP tumors, while demonstrating on-target activity in blocking androgen receptor transcriptional activity.

[0493] exist Figure 6 In the figure, bars represent mean ± SEM, with n = 5 representative tumors from each treatment group. One-way ANOVA post hoc Tukey's multiple comparison test was performed for statistical analysis. *p < 0.05; **p < 0.01; ***p < 0.001.

[0494] Although multiple embodiments of the present invention are disclosed herein, many adaptations and modifications can be made within the scope of the present invention according to the common knowledge of those skilled in the art. Such modifications include substitution with known equivalents of any aspect of the present invention so as to obtain the same results in substantially the same manner. Numerical ranges include numbers that define the range. The wording "comprising" is used as an open term in this article, which is generally equivalent to the wording "including, but not limited to", and the wording "comprises" has a corresponding meaning. Unless otherwise clearly indicated herein, as used herein, the singular forms "a", "an" and "the" include multiple references. Therefore, for example, a reference to "a thing" includes more than one of the things described. The reference to the references herein does not admit that the references are prior art of the present invention. Any priority documents and all publications (including but not limited to patents and patent applications) cited in this specification are incorporated herein by reference, just as each individual publication is specifically and individually indicated to be incorporated herein by reference and as described fully herein. The invention includes all embodiments and variations substantially as described above and with reference to the examples and drawings.

[0495] In summary, the present invention includes but is not limited to the following items:

[0496] 1. A compound having the following structure (I):

[0497]

[0498] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:

[0499] X is -S(O) n -or-C(R8 R 9 )-;

[0500] R 1 is H, hydroxyl or -OC(=O)R 13 ;

[0501] R 2 is hydroxyl or -OC(=O)R 13 ;

[0502] R 3 Halogen, -OH, -OR 4 ;-OC(=O)R 13 、-NH2、-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(C1-C6 alkyl)(S(O) n R 5 )、-S(O) n R 5 , -N3, aryl, carbocyclic, heteroaryl or heterocyclic, which is optionally substituted by one or more R 6 replace;

[0503] R 4 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, carbocyclic, heteroaryl or heterocyclic group, which is optionally substituted by one or more R 6 replace;

[0504] R 5 Each is independently a C1-C6 alkyl or aryl group, which is optionally substituted by one or more R 6 replace;

[0505] R 6 Each independently selected from H, F, Cl, Br, I, 123 I, hydroxy, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 12 A group consisting of aromatic groups, wherein R 6 Each optionally halogenated, 123 I. 18 F, hydroxy, -OS(O)2-aryl, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0506] R 8 and R9 Each independently is H or C1-C6 alkyl;

[0507] R 11a , R 11b , R 11c and R 11d Each independently is H, methyl, F, Cl, Br, I or 123 I;

[0508] R 13 is a C1-C6 alkyl group; and

[0509] n is 0, 1 or 2;

[0510] Where R 11a , R 11b , R 11c and R 11d At least one of them is methyl F, Cl, Br, I or 123 I.

[0511] 2. The compound as described in item 1, wherein R 11a , R 11b , R 11c and R 11d At least two of them are methyl, F, Cl, Br, I or 123 I.

[0512] 3. A compound as described in item 1, wherein R 11a , R 11b , R 11c and R 11d Any two of which are independently methyl, F, Cl, Br, I or 123 I, and R 11a , R 11b , R 11c and R 11d The remaining two in are each H.

[0513] 4. A compound as described in item 1, wherein R 11a and R 11b Each is H; and R 11c and R 11d are each independently methyl, F, Cl, Br, I or 123 I.

[0514] 5. A compound as described in item 4, wherein R 11c and R 11d Each is independently methyl, Cl or Br.

[0515] 6. A compound as described in item 5, wherein R 11c and R 11d Each is Cl.

[0516] 7. A compound as described in item 1, wherein R 11a and R 11c Each is H; and R 11b and R 11d are each independently methyl, F, Cl, Br, I or 123 I.

[0517] 8. A compound as described in item 7, wherein R 11b and R 11d Each is independently methyl, Cl or Br.

[0518] 9. The compound as described in item 8, wherein R 11b and R 11d Each is Cl.

[0519] 10. The compound as described in item 1, wherein X is -S(O)2-.

[0520] 11. A compound as described in item 1, wherein X is -C(R 8 R 9 )-and R 8 and R 9 Each is independently a C1-C3 alkyl group.

[0521] 12. The compound of item 11, wherein R 8 and R 9 Each is a methyl group.

[0522] 13. A compound as described in item 1, wherein R 1 and R 2 Each independently is hydroxyl or -OC(=O)R 13 .

[0523] 14. A compound as described in item 13, wherein R 1 and R 2 All are hydroxyl groups.

[0524] 15. A compound as described in item 13, wherein R 1 and R 2 All are -OC(=O)R 13 .

[0525] 16. A compound as described in item 13, wherein R 1 and R 2 All are -OC(=O)R 13 , where R 13 It is methyl.

[0526] 17. A compound as described in item 1, wherein R 1 For H.

[0527] 18. A compound as described in item 1, wherein R 3 It is -OH.

[0528] 19. A compound as described in item 1, wherein R 3 -OC(=O)R 13 .

[0529] 20. The compound of claim 1, wherein R 3 -OC(=O)R 13 , where R 13 It is methyl.

[0530] 21. A compound as described in item 1, wherein R 3 For –OR 4 And R 4 It is a C1-C6 alkyl group.

[0531] 22. A compound as described in item 21, wherein R 4 It is methyl, ethyl, n-propyl or isopropyl.

[0532] 23. A compound as described in item 1, wherein R 3 For F.

[0533] 24. A compound as described in item 1, wherein R 3 is an optionally substituted 5- or 6-membered heteroaryl group or an optionally substituted 3- to 7-membered heterocyclyl group, wherein the heteroaryl group or the heterocyclyl group respectively contains at least one N atom.

[0534] 25. A compound as described in item 1, wherein R 3 Selected from the 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.

[0535] 26. A compound as described in item 1, wherein R 3 -NH2, -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(C1-C6 alkyl)(S(O) n R 5 ) or -S(O) n R5 .

[0536] 27. A compound as described in item 26, wherein R 3 -NH2, -NHC(=O)(C1-C4 alkyl), -N[(C(=O)(C1-C4 alkyl)]2, -NHS(O) n (C1-C3 alkyl), -N[C(=O)(C1-C4 alkyl)][(S(O) n (C1-C3 alkyl)], -N[C1-C6 alkyl][S(O) n (C1-C3 alkyl)] or -S(O) n (C1-C3 alkyl).

[0537] 28. A compound as described in item 1, wherein R 13 Each is a C1-C4 alkyl group.

[0538] 29. The compound of claim 28, wherein R 13 Each is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl.

[0539] 30. A compound as described in claim 1, wherein R 1 and R 2 Each is independently -OH or -OC(=O)R 13 , where R 13 It is methyl.

[0540] 31. A compound as described in item 1, wherein R 1 , R 2 and R 3 At least one of them is -OC(=O)R 13 , where R 13 It is methyl.

[0541] 32. A compound as described in claim 1, wherein R 1 , R 2 and R 3 Any two of which are each -OC(=O)R 13 , where R 13 It is methyl.

[0542] 33. A compound as described in claim 32, wherein R 1 and R 2 Each is -OC(=O)R 13 , where R 13 It is methyl.

[0543] 34. A compound as described in item 1, wherein R 1 , R 2 and R3 Each is -OC(=O)R 13 , where R 13 It is methyl.

[0544] 35. A compound as described in item 1, wherein the compound has one of the following structures:

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573] or a pharmaceutically acceptable salt thereof.

[0574] 36. A compound as described in item 1, wherein the compound has one of the following structures:

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592] or a pharmaceutically acceptable salt thereof.

[0593] 37. A compound having the following structure (II):

[0594]

[0595] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:

[0596] R 1 is H, -OH or -OC(=O)R 13 ;

[0597] R 2 -OH or -OC(=O)R 13 ;

[0598] R 3 Halogen, -OH, -OR 4 、-OC(=O)R 13 、-NH2、NHC(=O)R 13 、-N(C(=O)R 13 2. -NHS(O) n R 5 、-N(C1-C6 alkyl)S(O) n R 5 、-N(C(=O)R 13 )(S(O) n R 5 )、-S(O) n R 5 , -N3, aryl, carbocyclic, heteroaryl or heterocyclic, which is optionally substituted by one or more R 6 replace;

[0599] R 4 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, carbocyclic, heteroaryl or heterocyclic group, which is optionally substituted by one or more R 6 replace;

[0600] R 5 Each is independently a C1-C6 alkyl or aryl group, which is optionally substituted by one or more R 6 replace;

[0601] R 6 Each independently selected from H, F, Cl, Br, I, 123 I, hydroxy, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C6-C 12 A group consisting of aromatic groups, wherein R 6 Each optionally halogenated, 123 I.18 F, hydroxy, -OS(O)2-aryl, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; and

[0602] n is 0, 1 or 2.

[0603] 38. A compound as described in item 37, wherein R 1 -OH or -OC(=O)R 13 .

[0604] 39. A compound as described in item 37, wherein R 1 For H.

[0605] 40. A compound as described in claim 37, wherein R 3 It is -OH.

[0606] 41. A compound as described in item 37, wherein R 3 -OC(=O)R 13 , where R 13 It is methyl.

[0607] 42. A compound as described in claim 37, wherein R 3 For –OR 4 , where R 4 It is a C1-C6 alkyl group.

[0608] 43. A compound as described in item 37, wherein R 4 It is methyl.

[0609] 44. A compound as described in item 37, wherein R 3 is an optionally substituted 5- or 6-membered heteroaryl group or an optionally substituted 3- to 7-membered heterocyclyl group, wherein the heteroaryl group or the heterocyclyl group respectively contains at least one N atom.

[0610] 45. A compound as described in item 37, wherein R 3 Selected from the 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.

[0611] 46. ​​A compound as described in item 1, wherein R 3 -NH2, -NHC(=O)R 13 、-N(C(=O)R 13 2. -NHS(O) n R 5 、-N(C(=O)R13 )(S(O) n R 5 )、-N(C1-C6 alkyl)(S(O) n R 5 ) or -S(O) n R 5 .

[0612] 47. A compound as described in item 46, wherein R 3 -NH2, -NHC(=O)(C1-C4 alkyl), -N[(C(=O)(C1-C4 alkyl)]2, -NH[S(O) n (C1-C3 alkyl)], -N[C(=O)(C1-C4 alkyl)][(S(O) n (C1-C3 alkyl)], -N[C1-C6 alkyl][S(O) n (C1-C3 alkyl)] or -S(O) n (C1-C3 alkyl).

[0613] 48. A compound as described in item 37, wherein R 13 Each is a C1-C4 alkyl group.

[0614] 49. A compound as described in claim 37, wherein R 1 and R 2 Each independently is OH or -OC(=O)R 13 , where R 13 It is methyl.

[0615] 50. A compound as described in claim 37, wherein R 1 , R 2 and R 3 At least one of them is -OC(=O)R 13 , where R 13 It is methyl.

[0616] 51. A compound as described in claim 37, wherein R 1 , R 2 and R 3 Any two of which are each -OC(=O)R 13 , where R 13 It is methyl.

[0617] 52. A compound as described in claim 37, wherein R 1 , R 2 and R 3 Each is -OC(=O)R 13 , where R 13 It is methyl.

[0618] 53. A compound as described in claim 37, wherein R 1 , R 2 and R 3 Each is -OH.

[0619] 54. The compound of claim 37, wherein the compound is:

[0620]

[0621] or a pharmaceutically acceptable salt thereof.

[0622] 55. A pharmaceutical composition comprising a compound as described in any one of items 1-54 and a pharmaceutically acceptable carrier.

[0623] 56. A pharmaceutical composition as described in claim 55, further comprising an additional therapeutic agent.

[0624] 57. A pharmaceutical composition as described in claim 56, wherein the additional therapeutic agent is used to treat prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy or age-related macular degeneration.

[0625] 58. A pharmaceutical composition as described in claim 56, wherein the additional therapeutic agent is enzalutamide, galactron, abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, bevacizumab (acrivastine), OSU-HDAC42, VITAXIN, sunitinib, ZD-4054, cabazitaxel (XRP-6258), MDX-010 (ipilimumab), OGX427, OGX 011, finasteride, dutasteride, torosterone, beclosterol, azosternol, FCE 28260, SKF105,111, ODM-201, ODM-204, niclosamide, apalutamide, ARV-330, VPC-14449, TAS3681, 3E10-AR441bsAb, sintokamide, radium 233 or their related compounds.

[0626] 59. A method for modulating androgen receptor activity, comprising: administering the pharmaceutical composition according to item 55 to a subject in need thereof.

[0627] 60. A method as described in claim 59, wherein the modulation of androgen receptor (AR) is inhibition of androgen receptor.

[0628] 61. A method as described in claim 60, wherein the regulation of AR is to inhibit the transactivation of the androgen receptor N-terminal domain (NTD).

[0629] 62. A method as described in claim 59, wherein the subject is human.

[0630] 63. A method as described in any of items 59-62, wherein the modulation of AR is used to treat a condition or disease selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, endometrial cancer, salivary gland cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration.

[0631] 64. A method as described in claim 63, wherein the condition or disease is prostate cancer.

[0632] 65. A method as described in claim 64, wherein the prostate cancer is primary or localized prostate cancer, locally advanced prostate cancer, recurrent prostate cancer, advanced prostate cancer, metastatic prostate cancer, metastatic castration-resistant prostate cancer (CRPC) and hormone-sensitive prostate cancer.

[0633] 66. A method as described in claim 64, wherein the prostate cancer is CRPC.

[0634] 67. A method as described in claim 64, wherein the prostate cancer expresses full-length androgen receptor (AR) or a truncated AR splice variant.

Claims

1. A compound having the following structure (I): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein ： 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 Halogen, -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 is optionally substituted by one or more R 6 replace; R 4 C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, aryl, carbocyclyl, heteroaryl or heterocyclyl, which is optionally substituted by one or more R 6 replace; R 5 Each independently is C 1 -C 6 Alkyl or aryl, which is optionally substituted by one or more R 6 replace; R 6 Each independently selected from 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 A group consisting of aromatic groups, wherein R 6 Each optionally halogenated, 123 I. 18 F, hydroxyl, -OS(O) 2 -Aryl, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or C 2 -C 6 One or more alkynyl groups are substituted; R 8 and R 9 Each independently is H or C 1 -C 6 alkyl; R 11a , R 11b , R 11c and R 11d Each independently is H, methyl, F, Cl, Br, I or 123 I; R 13 C 1 -C 6 alkyl; and n is 0, 1 or 2; Where R 11a , R 11b , R 11c and R 11d At least one of them is methyl F, Cl, Br, I or 123 I.

2. The compound of claim 1, wherein R 11a , R 11b , R 11c and R 11d At least two of them are methyl, F, Cl, Br, I or 123 I.

3. The compound as claimed in claim 1, wherein R 11a , R 11b , R 11c and R 11d Any two of which are independently methyl, F, Cl, Br, I or 123 I, and R 11a , R 11b , R 11c and R 11d The remaining two in are each H.

4. The compound as claimed in claim 1, wherein R 11a and R 11b Each is H; and R 11c and R 11d are each independently methyl, F, Cl, Br, I or 123 I.

5. The compound as claimed in claim 4, wherein R 11c and R 11d Each is independently methyl, Cl or Br.

6. The compound of claim 5, wherein R 11c and R 11d Each is Cl.

7. The compound of claim 1, wherein R 11a and R 11c Each is H; and R 11b and R 11d are each independently methyl, F, Cl, Br, I or 123 I.

8. The compound of claim 7, wherein R 11b and R 11d Each is independently methyl, Cl or Br.

9. The compound of claim 8, wherein R 11b and R 11d Each is Cl.

10. The compound of claim 1, wherein X is -S(O) 2 -.

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