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WO 2017/165822 Al 28 September 2017 (28.09.2017) P O P C T

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WO 2017/165822 Al 28 September 2017 (28.09.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/165822 Al 28 September 2017 (28.09.2017) P O P C T (51) International Patent Classification: Keita [US/US]; Department of Chemistry, Chevron Sci C07D 295/185 (2006.01) Λ 61Κ 31/495 (2006.01) ence Center (1301 CHVRN), 219 Parkman Avenue, Pitts C07D 403/04 (2006.01) A61K 31/496 (2006.01) burgh, PA 15260 (US). MILLIGAN, John [US/US]; De C07D 413/12 (2006.01) A61K 31/42 (2006.01) partment of Chemistry, Chevron Science Center (1301 C07D 451/02 (2006.01) A61K 31/445 (2006.01) CHVRN), 2 19 Parkman Avenue, Pittsburgh, PA 15260 C07D 409/08 (2006.01) A61K 31/46 (2006.01) (US). C07D 407/04' (2006.01) A61K 31/498 (2006.01) (72) Inventors: WIPF, Peter; Department of Chemistry, Chev C07D 403/06 (2006.01) A61K 31/12 (2006.01) ron Science Center (1301 CHVRN), 219 Parkman Avenue, C07D 401/08 (2006.01) A61K 31/407 (2006.01) Pittsburgh, PA 15260 (US). JOHNSON, James, K.; De C07D 405/06 (2006.01) A61K 31/435 (2006.01) partment of Chemistry, Chevron Science Center (1301 C07D 487/04 (2006.01) A61K 31/47 (2006.01) CHVRN), 2 19 Parkman Avenue, Pittsburgh, PA 15260 C07D 217/16 (2006.01) A61P 35/00 (2006.01) (US). SKODA, Erin, M.; 8913 Early April Way Apt G, C07C 49/563 (2006.01) Columbia, MD 21046 (US). NELSON, Joel, B.; UPMC, (21) International Application Number: 200 Lothrop St., Pittsburgh, PA 15213-2582 (US). PCT/US20 17/024 105 WANG, Zhou; Shadyside Medical Center, Suite G40, 5200 Centre Ave., Pittsburgh, PA 15232 (US). (22) International Filing Date: 24 March 2017 (24.03.2017) (74) Agent: GARNER, Gillian; Klarquist Sparkman, LLP, One World Trade Center, Suite 1600, 121 SW Salmon Street, (25) Filing Language: English Portland, OR 97204 (US). English (26) Publication Language: (81) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of national protection available): AE, AG, AL, AM, 15/080,237 24 March 2016 (24.03.2016) US AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, (71) Applicant: UNIVERSITY OF PITTSBURGH - OF DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, THE COMMONWEALTH SYSTEM OF HIGHER HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, EDUCATION [US/US]; 1st Floor Gardner Steel Confer KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, ence Center, 1300 Thackeray Avenue, Pittsburgh, PA MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, 15260 (US). NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, (72) Inventors; and RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, (71) Applicants : TAI, Serene [US/US]; Department of Chem TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, istry, Chevron Science Center (1301 CHVRN), 219 Park- ZA, ZM, ZW. man Avenue, Pittsburgh, PA 15260 (US). TAKUBO, [Continued on nextpage] (54) Title: SMALL MOLECULE INHIBITOR OF THE NUCLEAR TRANSLOCATION OF ANDROGEN RECEPTOR FOR THE TREATMENT OF CASTRATION-RESISTANT PROSTATE CANCER Vehicle 10mg/kg 75mg/kg FIG. 12 Days post-castration (III) (57) Abstract: A compound, or a stereoisomer, pharmaceutically acceptable salt, or ester thereof, according to formula (ΠΙ) or ac - cording to Table A, a pharmaceutical composition comprising said compound and at least one pharmaceutically acceptable additive, and a method for treating prostate cancer in a subject, comprising administering to the subject a therapeutically effective amount of said compound. wo 2017/165822 Ai III III II II III III III II I U M I I II il II III (84) Designated States (unless otherwise indicated, for every SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, kind of regional protection available): ARIPO (BW, GH, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Published: TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, — with international search report (Art. 21(3)) DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SMALL MOLECULE INHIBITORS OF THE NUCLEAR TRANSLOCATION OF ANDROGEN RECEPTOR FOR THE TREATMENT OF CASTRATION-RESISTANT PROSTATE CANCER CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of U.S. Application No. 15/080,237, filed March 24, 2016, which is incorporated in its entirety herein by reference. ACKNOWLEDGMENT OF GOVERNMENT SUPPORT This invention was made with government support under grant #GM067082 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND Castration-resistant prostate cancer (CRPC) is currently incurable and makes prostate cancer the second most common cause of cancer death among men in the United States. The androgen receptor (AR) is activated via multiple mechanisms including AR overexpression, mutation, hypersensitization, and/or intratumoral androgen synthesis in patients relapsed after androgen deprivation therapy (ADT). The steroidal hormones testosterone and dihydrotestosterone are the major endogenous androgens that cause nuclear translocation and subsequent activation of androgen receptor (AR). Overexpression and knockdown studies have demonstrated that AR is a key molecular determinant and an excellent therapeutic target for CRPC. Clinical use of abiraterone, a potent inhibitor of testosterone synthesis, and MDV3100 (enzalutamide) and bicalutamide, AR antagonists, indicates that AR remains a viable target in a significant number of CRPC patients. Androgen receptor (AR), a member of the steroid receptor superfamily, is a ligand-dependent transcription factor that controls the expression of androgen-responsive genes. Intracellular trafficking is an important mechanism in the regulation of many transcription factors, including AR. In order to access its target genes, a transcription factor requires localization to the nucleus. Retention of a transcription factor in the cytoplasm prevents its activity. Thus, a key regulatory step in the action of AR is its nuclear translocation. In androgen-sensitive cells, AR is localized to the cytoplasm in the absence of ligand. Upon addition of androgens, AR translocates to the nucleus and transactivates target genes. However, in CRPC cells, AR remains in the nucleus even in the absence of androgen and transactivates androgen-responsive genes, leading to uncontrolled growth of prostate tumors. Therefore, novel approaches that can block the nuclear localization of AR, degrade nuclear AR, and/or suppress nuclear AR activity may provide an effective therapy against CRPC. SUMMARY Disclosed herein is a compound, or a pharmaceutically acceptable salt or ester thereof, having a formula I of: 20 1 22 23 R - (Z)b- (Y)c - ( )a- (X)d - R - R wherein R20 is an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkoxy, aryloxy, amino, a thio-containing group, or a seleno- containing group; Z is alkanediyl, substituted alkanediyl, cycloalkanediyl, or substituted cycloalkanediyl; Y is S, O, S(=0), -S(=0)(=0)-, or NR 10 , wherein R 10 is H or alkyl; R2 1 is alkanediyl, substituted alkanediyl, cycloalkanediyl, substituted cycloalkanediyl, alkadienyl, substituted alkadienyl, cycloalkenediyl, substituted cycloalkenediyl, alkatrienyl, substituted alkatrienyl; X is -C(=0)-, -S(=0)(=0)-, or-N(H)C(=0)-; R22 is a moiety that includes at least one divalent amino radical; R23 is an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkoxy, aryloxy, amino, a thio-containing group, a seleno-containing group; a is 0 or 1; b is 0 or 1; c is 0 or 1; and d is 0 or 1. In some embodiments, if X is -C(=0)- then Y is not S. In certain embodiments, R2 1 is cycloalkanediyl. When R2 1 is cycloalkanediyl, R20 may be a phenyl optionally substituted with at least one halogen and/or R23 may be a phenyl substituted with at least one halogen and/or at least one alkyl. Also disclosed herein is a method for treating prostate cancer in a subject, comprising administering a therapeutically effective amount of an agent to the subject, wherein the agent is a compound, or a pharmaceutically acceptable salt or ester thereof, of formula I or formula II. The foregoing will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures. BRIEF DESCRIPTION OF THE DRAWINGS Figs. 1A through ID are a table showing compound structures. Figs. 2A through 21 show additional compound structures. Figs. 3A through 3E show assay results for several of the compounds. C4-2 cells were transfected with PSA6. 1-Luc, GFP-AR, and pRL-CMV and then treated with indicated doses for 24 hours. For luciferase assays, cells were lysed with passive lysis buffer (Promega) and both Firefly and Renilla luciferase activities were read using a Dual-Luciferase Reporter Assay kit (Promega) on a LmaxII384 luminometer (Molecular Devices). Firefly luciferase values were normalized to Renilla (pRL-CMV). Plotted values represent averaged normalized Firefly luciferase activities, each performed in triplicate, relative to DMSO control. This assay is described in more detail in PCT Patent Application Publication WO 2013055793, which is incorporated herein by reference. Fig. 4 is a reaction scheme showing the synthesis of 2-((isoxazol-4-ylmethyl)thio)-l-(4- phenylpiperazin-l-yl)ethanone 1. Fig. 5 is a chemical structure of 2-((isoxazol-4-ylmethyl)thio)-l-(4-phenylpiperazin-l-yl)ethanone showing zones of modification. Fig. 6 is a reaction scheme showing synthesis of certain embodiments of the disclosed compounds.
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