USOO9623021B2

(12) United States Patent (10) Patent No.: US 9.623,021 B2 Narayanan et al. (45) Date of Patent: *Apr. 18, 2017

(54) NUCLEAR RECEPTOR BINDING AGENTS 6,756,375 B2 6/2004 Veeneman et al. 6,774,248 B2 8, 2004 Miller et al. 6,794,403 B2 9/2004 Malamas et al. (75) Inventors: Ray NAAS.R". 6,835,745 B2 12/2004 Coghlan et al. (US); Muralimohan Yepuru, Bartlett, 6,852,727 B2 2/2005 Goulet et al. TN (US); James T. Dalton, Lakeland, 6,870,055 B2 3/2005 Claremon et al. TN (US) 6,903,238 B2 6/2005 McDevitt et al. 6,914,074 B2 7/2005 Mewshaw et al. (73) Assignee: GTX, Inc., Memphis, TN (US) 6,943,162 B2 9/2005 Hale et al. 6,960,607 B2 11/2005 Malamas et al. (*) Notice: Subject to any disclaimer, the term of this 786 E: 258. Rile et al. patent is extended or adjusted under 35 7,084.276 B2 8, 2006 Vu et al. U.S.C. 154(b) by 110 days. 7,087,599 B2 8/2006 Parker et al. 7,138.426 B2 11/2006 DiNinno et al. This patent is Subject to a terminal dis- 7,151,196 B2 12/2006 Wilkening et al. claimer. 7,157.491 B2 1/2007 Mewshaw et al. 7,157,492 B2 1/2007 Mewshaw et al. 7,256.201 B2 8, 2007 Barlaam et al. (21) Appl. No.: 12/773,515 7,265,131 B2 9/2007 Johnson et al. 7,279,499 B2 10/2007 Durst et al. (22) Filed: May 4, 2010 7,294,635 B2 11/2007 Scarborough et al. 7,354,951 B2 4/2008 Norman et al. (65) Prior Publication Data 8,188,117 B2 5/2012 Plettenburg et al. 2001/0041718 A1 11/2001 Thompson et al. US 201OfO267767 A1 Oct. 21, 2010 (Continued) Related U.S. Application Data FOREIGN PATENT DOCUMENTS (63) Continuation-in-part of application No. 12/010,225, filed on Jan. 22, 2008, now Pat. No. 9,078,888. & 28: A 3. (60) Provisional application No. 60/881,476, filed on Jan. (Continued) 22, 2007, provisional application No. 60/907,754, filed on Apr. 16, 2007, provisional application No. OTHER PUBLICATIONS 61/177,214, filed on May 11, 2009. STN Search Report and Summary (Accession No. 2004:41298).* (51) Int. Cl Pinto de Souza (Indian J Chem, 29B:961-965, 1990).* we Anderson (Chem and Biol 10:787-797, 2003).* A6 IK3I/33 (2006.01) Thiel (Nature Biotechnol 2:513-519, 2004).* A 6LX 3L/24709 (2006.01) U.S. Appl. No. 09/519,079, filed Mar. 6, 2000, Roblet al. A6 IK 3/472 (2006.01) Kalin MF, et al. “Sex hormones and coronary disease: a review of C07D 21 7/22 (2006.01) the clinical studies', ; 55:330-352, 1990. C07D 21 7/24 (2006.01) Wenger NK, et al. “Cardiovascular health and disease in women', (52) U.S. Cl. N. England J. Med., 329:247-256, 1993. CPC ...... (201301), A6 IK3I/4709 cord 3,722(2013.01); (030) A61K 31/472cond getMendelsohn ME hardiovascularet al. “Mechanism ofsystem". disease: N. the England protective J. effectsMed. 21724 (2013.01) Continued (58) Field of Classification Search (Continued) None See application file for complete search history. Primary Examiner — Craig Ricci (74) Attorney, Agent, or Firm — Mark S. Cohen: Pearl (56) References Cited Cohen Zedek Latzer Baratz LLP U.S. PATENT DOCUMENTS (57) ABSTRACT 2,848,356 A 8, 1958 Pritchard et al. 4,910,208 A 3, 1990 Misra et al. The present invention relates to methods for prevention 4.942,163 A 7, 1990 Behrens et al. and/or treatment of metabolic disorders, post-menopausal 5,004,747 A 4, 1991 Ashton et al. obesity and conditions associated with high fat diet con 3:42: A 3: Saints et al. Sumption including, obesity, body weight gain, fat mass 5.416,094 A 5/1995 Laletal. formation, bone mineral content reduction, white adipose 5,612,359 A 3/1997 Murugesan et al. tissue weight gain, increased cholesterol levels, increased 5,719,144 A 2, 1998 Hartman et al. leptin levels, insulin resistance, type II diabetes, increased 39 A g28 BR et al blood glucose levels, inflammatory diseases, cardiovascular 6,043,265 A 3, 2000 WS's al diseases, fatty liver condition (accumulation of fat in the 6,486,155 B1 1/2003 Pamukcu et al. liver), decreased uncoupling protein-1 (UCP-1) levels and 6,630,508 B1 10/2003 Dodge et al. increased lipogenesis. 6,664,269 B2 12/2003 Martin et al. 6,686,351 B2 2/2004 Bhagwat et al. 6,723,747 B2 4/2004 Keith, Jr. et al. 6 Claims, 27 Drawing Sheets US 9,623,021 B2 Page 2

(56) References Cited WO WO9509842 A1 4f1995 WO WO973OO47 8, 1997 U.S. PATENT DOCUMENTS WO WO973 1940 9, 1997 WO WO9838168 A1 2/1998 2002/0077486 A1 6/2002 Scarborough et al. WO WO982.94O7 7, 1998 2003/0008896 A1 1/2003 Martin et al. WO WO9851307 A1 11, 1998 2003, OO13699 A1 1/2003 Davis et al. WO WO 98,11624 A1 3/1999 2003/0069303 A1 4/2003 Veeneman et al. WO WOOOO1389 1, 2000 2003/01 19800 A1 6/2003 Manolagas et al. WO WOOO, 19994 4/2000 2003/0220227 A1 11/2003 Gungor et al. WO WOO 109096 A2 2/2001 2003/022.0377 A1 11/2003 Chesworth et al. WO WOO 122960 A1 4, 2001 2004/0038959 A1 2/2004 Bunker et al. WO WOO168603 9, 2001 2004/004403.0 A1 3f2004 Claremon et al. WO WOO2O24655 A1 3f2002 2004/0082575 A1 4/2004 Bhagwat et al. WO WO O2,26325 4/2002 2004/0082607 A1 4, 2004 Oi et al. WO WO O2O32373 4/2002 2004/0092506 A1 5/2004 Thompson et al. WO WO O2/41835 5, 2002 2004/O138244 A1 7/2004 Dalton et al. WO WOO246.164 6, 2002 2004/0171006 A1 9, 2004 Xiao WO WOO246168 6, 2002 2004/0176361 A1 9/2004 Fujio et al. WO WOO251821 T 2002 2004/0204447 A1 10, 2004 Johnson et al. WO WO O258639 8, 2002 2004/0214790 A1 10/2004 Borgens et al. WO WOO2O62764A1 8, 2002 2005.0009784 A1 1/2005 Vu et al. WO WO O2/O91993 11 2002 2005/0059723 A1 3, 2005 Mewshaw et al. WO WOO2090334 A1 11, 2002 2005/0101584 A1 5/2005 Barlaam et al. WO WO O3O15761 2, 2003 2005/0113399 A1 5/2005 Scarborough et al. WO WOO3O37887 5, 2003 2005/0.148560 A1 7/2005 Fritzemeier et al. WO WOO3O45930 6, 2003 2005. O148624 A1 7, 2005 Itoh et al. WO WOO3053994 T 2003 2005/0182045 A1* 8/2005 Nagase et al...... 514,217.06 WO WO O3074.044 9, 2003 2005/025621.0 A1 11/2005 Olsson et al. WO WO 2004/004750 1/2004 ...... A61K 38.00 2006,0004087 A1 1/2006 Miller et al. WO WO 2004/026823 A1 1/2004 2006/0052410 A1 3, 2006 Vu WO WO 2004006906 A2 1, 2004 2006/011 1318 A1 5, 2006 Okamoto et al. WO WO2004.014378 A1 2/2004 2006/0173039 A1 8/2006 Shiga et al. WO WO 2004/OO9912 4/2004 2006/0183744 A1 8/2006 Rohrer et al. WO WO2004.048339 A1 6, 2004 2006, O1998.58 A1 9, 2006 Durst et al. WO WO2004058717 A1 T 2004 2006/0211602 A1 9/2006 Ansorge et al. WO WO 2004/073612 9, 2004 2006/0211672 Al 9, 2006 Jacobson et al. WO WO 2004O94400 11, 2004 2006/0222721 A1 10, 2006 Cohen et al. WO WO2005035520 A1 4, 2005 2006/0241094 A1 10, 2006 Chen et al. WO WO 2005/08288O 9, 2005 2006/0270591 A1 1 1/2006 Chang WO WO 2005.099700 10/2005 2006/0270704 A1 11/2006 Isaacs et al. WO WO 2005 123757 12/2005 2006/0281743 A1 12/2006 Dinsmore et al. WO WO 2006/OO7503 1, 2006 2007/0010526 A1 1/2007 Haeberlein et al. WO WO 2006009912 1, 2006 2007/0021495 A1 1/2007 Katzenellenbogen et al. WO WO 2006/0263.95 3, 2006 2007/0027177 A1 2/2007 Trotter et al. WO WO 2006O4417.6 A1 4, 2006 2007.0043077 A1 2/2007 Mewshaw et al. WO WO 2006/061437 A1 6, 2006 2007.0049605 A1 3, 2007 Mewshaw et al. WO WO 2006062876 6, 2006 2007, OO7281.0 A1 3, 2007 Asakawa WO WO 2006/08115.2 8, 2006 2007.0099880 A1 5, 2007 Blizzard et al. WO WO2006088716 8, 2006 2007.00999 12 A1 5, 2007 Zhou et al. WO WO 2006/1164O1 11 2006 2007/0105827 A1 5, 2007 Blizzard et al. WO WO2O06108.107 12/2006 2007. O197488 A1 8, 2007 Peters et al. WO WO 2007093364 A1 2/2007 2007/0203102 A1 8, 2007 Blizzard et al. WO WO 2007093366 2, 2007 2007/0225.330 A1 9, 2007 Merrill et al. WO WO2007053353 A2 5/2007 2009,003.0036 A1 1/2009 Dalton et al. WO WO2007 14903.1 6, 2007 2009/0076019 A1 3/2009 Tyers et al. WO WO O7-0892.91 8, 2007 2010, OOO9960 A1 1/2010 Rob1 et al. WO WO2007 137000 A2 11/2007 2010.0029734 A1 2/2010 White et al. WO WO 2008.016768 2, 2008 2010/0256698 A1 10, 2010 Trotter et al. WO WO 2010/0968O1 A1 8, 2010 2010/0267767 A1 10/2010 Narayanan et al. WO WO 2012/006634 1, 2012 2010/0286204 A1 11/2010 Vicker et al. 2011 0071146 A1 3f2011 Niimi et al. 2012,0009204 A1 1/2012 Reinhardt et al. OTHER PUBLICATIONS Karas RH, et al., "Human Vascular smooth muscle cells contain FOREIGN PATENT DOCUMENTS functional receptor'. Circulation, 89:1943-1950, 1994. Lindner V, et al., “Increased expression of ER b mRNA in male CN 101641013 A 2, 2010 blood vessels following vascular injury'. Circ. Res., 83:224-229, EP O0326386 A2 8, 1989 1998. EP OO482939 A1 4f1992 Wada-Hirake O, et al., “Role of beta in uterine EP 005O2575 A1 9, 1992 Stroma and epithelium: insights from -f- EP O1414443 B1 5, 2004 EP 1454898 A1 9, 2004 mice", PNAS, 103(48): 18350-5, 2006. EP O1484320 A1 12, 2004 Dubey RK, et al., “ inhibit growth and MAP kinase EP 1537880 A1 6, 2005 activity in human aortic Smooth muscle cells'. Hypertension; EP 1604983 A1 12/2005 33:177-182, 1999. JP H10-259176 9, 1998 Siow RCM, et al. Cardiovascular targets for and JP 20055.13027 5, 2005 phytoestrogens; Transcriptional regulation of nitric oxide synthase JP 2000-072675 A 3, 2010 and antioxidant defense genes. Free Radical biology and Medicine; WO WO 89.001.65 1, 1989 42:909-925, 2007. US 9,623,021 B2 Page 3

(56) References Cited emia and reperfusion by an estrogen receptor dependent mecha nism'. J. Cardiovascular Pharmacology, 49(6), 401-7. OTHER PUBLICATIONS Chadwick, C, et al (2005), “Identification of pathway-selective estrogen receptor ligands that inhibit NF-kappaB transcriptionsal Langer, “New methods of Drug Delivery”, Science 249:1627-1633, activity”. Proc. Natl. Acad. Sci. USA 102(7), 2543-8. 1990. Remmers et al. (1997) “ receptor blockade after Treat et al. “Liposomes in the Therapy of Infectious Disease and trauma-hemorrhage improves cardiac and hepatic functions in Cancer” Liss, New York pp. 353–365, 1989. males' Am. J. Physiol. Heart Circ. Physiol., 287: 2919-2925, esp Buchwald et al., “Long-term, continuous intravenous heparin administration by an implantable infusion pump in ambulatory abstract, p. H2924, col. 1. patients with recurrent venous thrombosis.”. Surgery 88:507, 1980. Mckinnon et al. (2003) "Glaucoma: ocular Alzheimer's disease? Saudek et al., “A preliminary trial of the programmable implantable Frontiers in Bioscience” 8:s 1140-1156, esp, abstract; p. 1141, col. system for insulin delivery.”, N. Engl. J. Med. 321:574. 2, para 2, p. 1150, col. 1, para 2. 1989. Chan, K. K., et al (2008), "Estrogen receptor subtypes in ovarian, Goodson, “Dental Applications'. Medical Applications of Con cancer: a clinical correlation'. Obstet. Gynecol. 111(1) 144-51. trolled Release, supra, vol. 2, pp. 116-138, 1984. Chan, Y. C. et al., “ Relaxes Rat Pulmonary Arteries and Gungor T. et al., “Synthesis and characterization of Veins: Roles of Gender, Endothelium, and Antagonism of Ca2+ 3-arylquinazolinone and 3-arylquinazolinethione derivatives as Influx.”: The Journal of Pharmacology and Experimental Therapeu selective estrogen receptor beta modulators' J. Med. Chem, 49. tics; 312(3), pp. 1266-1271, 2005. 2440-2455, 2006. Chang, E. C. etal (2006), "Impact of estrogen receptor beta on gene Crabtree JS et al., “Activity of three selective estrogen receptor networks regulated by in modulators on hormone-dependant responses in the mouse uterus cells'. Endocrinology 147(10), 4831-42. and mammary gland'. Molecular and Cellular Endocrinology, Feb. Chen, W., et al. (2007), Aza analogues of : novel ligands for 12, 2008. estrogen receptor beta, Bioorg Med Chem 15(17), 5828-36. Leventhal et al., “An estrogen receptor-3 agonist is active in models Chesworth R. et al. (2005), "Estrogen receptor beta selective of inflammatory and chemical-induced pain' European Journal of ligands: discovery and SAR of novel heterocyclic ligands'. Bioorg. Pharmacology, 553: 146-148, 2006. Med. Chem. Lett. 15(24), 5562-6. Harris HA., “The unexpected Science of estrogen receptor-3 selec Chesworth, R., et al. (2004), “Tetrahydroisoquinolines as subtype tive agonists: a new class of anti-inflammatory agents? Nuclear Receptor Signaling, 2006, pp. 1-4. Selective estrogen agonists/antagonists'. Bioorg. Med. Chem. Lett. Kajta, M. et al., “ inhibits glutamate-induced apoptosis in 14(11), 2729-33. primary neuronal cell cultures of mouse brain cortex and cerebel Christian, R. C. etal (2006). “Initial estrogen receptor (ER)beta, but lum”. Behav Pharmacol: 549 (EBPS Workshop, Abstract P27), not ERalpha expression. Is correlated with coronary calcification 2006. and atherosclerosis in pre- and postmenopausal women”. J.Clin. Katzenellenbogen J. A. et al. “Workshop 14: Nature of the ligand Endocrinol. Metab. 91(7), 2713-20. binding pocket of estrogen receptor alpha and beta: The search for Collini M.D. et al. (2004). “7-Substituted 2-phenyl-benzofurans as Subtype-selective ligands and implications for the prediction of ER beta selective ligands'. Bioorg. Med. Chem. Lett. 14(19), estrogenic activity”. Pure Appl. Chem, 75(11-12), 2397-2403, 2003. 4925-9. Krishnan, G. et al., “Pharmacological actions of a selective estrogen Compton, D. R. et al (2004). “Pyrazolo 1.5-a pyrimidines as receptor beta (ER beta} agonist in ovarlectomized rats'. J. Bone estrogen receptor ligands: defining the orientation of a novel het Miner. Res. 20(Suppl. 1): Abst SA427. 27th Annual Meeting erocyclic core”. Bioorg. Med. Chem. Lett. 14(22), 5681-4. American Society Bone Miner. Res. (ASBHR) (Sep. 23-27r Nash Compton, D. R. et al. (2004). “Pyrazolo 1.5-alpyrimidines: estro ville, United States), 2005. gen receptor ligands possessing estrogen receptor beta antagonist Sun, W. et al., “6H-Benzocchromen-6-one derivatives as selective activity”. J. Med. Chem. 47(24), 5872-93. ERbeta agonists' 230th ACS Natl Meet (Aug. 28-Sep. 1, Washing Cvoro, A., et al. (2008), "Selective estrogen receptor-beta agonists ton DC), Abst MEDI 25, 2005. repress transcription of proinflammatory genes'. J. Immunol. Ullrich, J.W. et al., “4-Hydroxy-N-phenyl substituted phthalimides 180(1), 630-6. as selective estrogen receptor beta (ER.b) ligands'. 230th ACS Nat De Angelis, et al (2005a), "Indazole estrogens: highly selective Meet (Aug. 28-Sep. 1, Washington DC), Abst MEDI 27 (), ligands for the estrogen receptor beta'. J. Med. Chem. 4S(4)s 2005. 1132-44. Akiyama, T. et al., “Genistein, a specific inhibitor of tyrosine De Angelis, et al (2005b). “Isocoumarins as estrogen receptor beta specific protein kinases”. JBiol Chem 262(12), 5592-5, 1987. Selective ligands: Isomers of Isoflavone phytoestrogens and their Arias-Loza, P. A. et al., “Both estrogen receptor Subtypes, alpha and metabolites”, Bioorg. Med. Chem. 13(23), 6529-42. beta, attenuate cardiovascular remodeling in salt-treated Dick, G. M. et al. “(Xeno)Estrogen Sensitivity of Smooth Muscle rats'. Hypertension 5(1(2), 432-8, 2007. BK Channels Conferred by the Regulatory B1 Subunit, a Study of Arias-Loza, P. A., et al., “Both estrogen receptor Subtypes, alpha and BlKnockout Mice'; The Journal of Biological Chemistry; 276(48); beta, attenuate cardiovascular remodeling in aldosterone salt-treated pp. 44835-44840; (2001). rats'. Hypertension 5(1(2), 432-8, 2007. Pinthus et al. (2007) “Androgen Induces Adaptation to Oxidative Ascenzi P. et al., “Structure-function relationship of estrogen Stress in Prostate Cancer: Implications for Treatment with Radiation receptor alpha and beta: Impact on human health'. Mol. Aspects Theraphy”. Neoplasia, vol. 9:68-80, esp. Abstract; p. 70, col. 2, para Med. 27 (4) 299-402, 2006. 6; p. 71, col. 1, para 2. Barkhem, T., et al., “Differential response of estrogen receptor alpha Edsall, R. J., et al. (2003). “ERbeta ligands. Part 1: the discovery of and estrogen receptor beta to partial estrogen agonists/antagonists'. ERbeta selective ligands which embrace the 4-hydroxy-biphenyl Mol. Pharmacol. 54(1), 10512, 1998. template”. Bioorg. Med. Chem. 11(16), 3457-74. Blizzard, T. A., et al. “Bridged analogs as ER-beta Fotsis, T. et al. (1993). “Genistein, a dietary-derived Inhibitor of in selective SERMs”, Bioorg Med Chem Lett 17(10), 2944-8, 2007a. vitro angiogenesis'. Proc. Natl. Acad. Sci. USA 90(7), 2690-4. Blizzard, T. A., “Androstene-3,5-dienes as ER-beta selective Fritzemeier, K. H., et al (2004). Biological effects of ERalpha- and SERMs”, Bioorg. Med. Chem. Lett. 17(22), 6295-8, 2007b. ERbeta-selective estrogens, Ernst Schering Res. Found Workshop Bodo, C. and Rissman, E. F. (2006), “New roles for estrogen (46), 127-50. receptor beta in behavior and neuroendocrinology'. Front Fu X. H., et al (2008). “Synthesis of genistein derivatives and Neuroendocrinology 27(2), 217-32. determination of their protective effects against vascular endothelial Booth, E. A., et al. (2007). “The pathway-selective estrogen recep cell damages caused by hydrogen peroxide'. Bioorg. Med. Chem. tor ligand WAY-169916 reduces infarct size after myocardial isch Lett. 18(2), 513-7. US 9,623,021 B2 Page 4

(56) References Cited Hoekstra, W.J., et al. (2005):Discovery of novel quinoline-based estrogen receptor ligands using peptide interaction profiling, J. Med. OTHER PUBLICATIONS Chem. 48(6), 2243-7. Imamov, O., et al. (2004). “Estrogen receptor beta in prostate Green, Kl A., and Carroll, J. S (2007). "Oestrogen-receptor-medi cancer”. N. Engl. J. Med. 351(26), 2773-4. ated transcription and the influence of co-factors and chromatin Imamov, O., et al (2005). “Estrogen receptor beta in health and state', Nat. Rev. Cancer 7(9), 713-22. disease”. Biol. Reprod. 73(5) 866-71. Greene, G. L., Shiau A. K., and Nettles, K. W. (2004). A structural Jazbutyte, V. et al. (2008). “Ligand-dependent activation of explanation for ERalpha/ERbeta SERM discrimination. Ernst Schering Res Found Workshop (46), 33-45. ER{beta} lowers blood pressure and attenuates cardiac hypertrophy Güngör, T. et al. (2006) “Synthesis and Characterization of in ovariectomized spontaneously hypertensive rats'. Cardiovasc. 3-Arylquinazolinone and 3- Arylquinazolinethione Derivatives as Res. 77(4), 774-81. Selective Estrogen Receptor Beta Modulators'. J. Med. Chem. Kai M., et al (2004). “Soybean isoflavones eliminate nifedipine 2006, 49, 2440-2455. induced flushing of tail skin in ovariectomized mice”. J. Pharmacol. Gupta, A. K., etal (2007). "QSAR analysis of indazole estrogens as Set. 95(4), 476-8. Selective beta- estrogen receptor ligands: rationalization of Kajta, M., et al. (2007). "Genistein inhibits glutamate-induced physicochemical properties'. Med Chem 3(4), 347-53. apoptotic processes in primary neuronal cell cultures: an involve Fotsis, T. et al. (1993). “Genistein, a dietary-derived Inhibitor of in ment of aryl hydrocarbon receptor and estrogen receptor/glycogen vitro angiogenesis'. Proc. Natl Acad. Sci. USA 90(7), 2690-4. Synthase kinase-3beta intracellular signaling pathway'. Neurosci Fritzemeier, K. H., et al (2004). "Biological effects of ERalpha- and ence 145(2), 592-604. ERbeta-selective estrogens”. Ernst Schering Res. Found Work Karas, R. H., et al. (1998), “Growth factor activation of the estrogen shop(46), 127-50. receptor in vascular cells occurs via a mitogen-activated protein Fu X. H., et al (2008). “Synthesis of genistein derivatives and kinase-independent pathway”. J. Clin. Invest. 101(12), 2851-61. determination of their protective effects against vascular endothelial Kim. Setal (2004), "Estrogen receptor ligands. Part 4: The SAR of cell damages caused by hydrogen peroxide’ Bioorg. Med. Chem. the syn-dihydrobenzoxathiin SERAMs'. Bioorg. Med Chem. Lett. Lett. 18(2), 513-7. 14(11), 274.1-5. Green, KL A., and Carroll, J. S (2007). "Oestrogen-receptor Koehler K., et al., (2005). “Reflections on the discovery and mediated transcription and the influence of co-factors and chromatin significance of estroger receptor beta'. Endocr: Rev. 26(3), 465-78. state”. Nat. Rev. Cancer 7(9), 713-22. Kuiper, G.G. et al. (1997). "Comparison of the ligand binding Greene, G. L., Shiau A. K., and Nettles, K.W. (2004). “A structural specificity and transcript tissue distribution of estrogen receptors explanation for ERalpha/ERbeta SERM discrimination”. Ernst alpha and beta'. Endocrinology 138(3), 863-70. Schering Res Found Workshop (46), 33-45. Lai S., et al (2004). “Metastases of prostate cancer express estrogen Güngör, T. et al. (2006) “Synthesis and Characterization of receptor-beta'. Urology 64(4), S14-20. 3-Arylquinazolinone and 3-Arylquinazolinethione Derivatives as Leung, Y.K. etal (2006). Estrogen receptor (ER)-beta isoforms: a Selective Estrogen Receptor Beta Modulators'. J. Med. Chem. key to understanding ER-Beta signaling. Proc. Natl. Acad. Sci. USA 2006, 49, 2440-2455. 103(35), 13.162-7. Gupta, A. K., etal (2007). "QSAR analysis of indazole estrogens as Luan F., et al., (2008) “Classification of estrogen receptor-beta Selective beta- estrogen receptor ligands: rationalization of ligands on the basis of their binding affinities using Support vector physicochemical properties'. Med. Chem. 3(4), 347-53. machine and linear discriminant analysis'. Eur: J. Med. Chem. Gustafsson, J. A. (2006). “ERbeta scientific visions translate to 43(1), 43-52. clinical uses”. Climacteric 9(3) 156-60. Lund, T. D., et al (2004a), “Androgen receptor expression in the rat Haas, E. et al.; “Differential Effects of 17B- on Function prostate is down-regulated by dietary phytoestrogens'. Reprod. and Expression of Estrogen Receptor O. Estrogen Receptor f3, and Biol. Endocrinol. 2, 5. GPR30 in Arteries and Veins of Patients with Atherosclerosis”; Lund, T.D et al (2004b). “Equal is a novel anti-androgen that Hypertension 49(6); pp. 1358-1363; (2007). inhibits prostate growth and hormone feedback”. Biol. Reprod. Harrington, W. et al. (2003), “Activities of estrogen receptor alpha 70(4), 1188-95. and beta-selective ligands at diverse estrogen responsive gene sites Lutty, G. et al (1999). “Changes in choriocapiliaris and retinal mediating transactivation or transrepression'. Mol. Cell Endocrinol. pigment epithelium in age-related macular degeneration'. Mol. Vis. 206(1-2), 13-22. 5, 35. Harris, H. A. (2006). “The unexpected science of estrogen receptor Malamas, M.S., et al. (2004). “Design and synthesis of aryl beta selective agonists; a new class of anti-inflammatory agents?” diphenolic azoles as potent and selective estrogen receptor-beta Nucl. Recept. Signal 4. eC)12. ligands”. J. Med. Chem. 47(21), 5021-40. Harris, H. A. (2007). “Estrogen receptor-beta: recent lessons from, Manas, E.S.,etal (2004), "Structure-based design of estrogen recep in vivo studies'. Mol. Endocrinol. 21(1), 1-13. tor-beta selective ligands”. J.Arn. Chem. Soc. 126(46), 1510649. Harris, H. A. etal (2003), “Evaluation of an estrogen receptor-beta McDevitt, R. E., et al. (2005). “Estrogen receptor ligands: design agonist in animal models of human disease’. Endocrinology and synthesis of new 2-arylindene-1-ones”. Bioorg. Med Chem. 144(10), 4241-9. Lett. 15(12), 3137-42. Hayashi, A., et al (1997). "Genistein, a protein tyrosine kinase McPherson, S.J., et al. (2006). “The role of ERalpha and ERheta in inhibitor, ameliorates retinal degeneration after ischemia-reperfu the prostate: insights from genetic models and isoform-selective sion injury in rat'. Invest. Opthalmol. Vis. Sci. 38(6), 1193-202. ligands”. Ernst Schering Found Symp. Proc. 1, 131-47. Henke, B. R. et al (2002). A new series of estrogen receptor Mewshaw, R. E. et al. (2007). “ERbeta ligands. Part 5: synthesis and modulators that display selectivity for estrogen receptor beta J. structure-activity relationships of a series of 4'-hydroxyphenyl-aryl Med. Chem. 45(25), 5492-505. carbaldehyde oxime derivatives”. Bioorg. Med. Chem. Lett. 17(4), Heynekamp, J. J., et al (2006). “Substituted trans-Stilbenes, includ 902-6. ing analogues of the natural product , inhibit the human Mewshaw, R. E., et al (2005). “ERbeta ligands. 3. Exploiting two tumor necrosis factor alpha-induced activation of transcription binding orientations of the 2-phenylnaphthalene Scaffold to achieve factor nuclear factor kappaB'. J. Med Chem. 49(24), 7182-9. ERbeta selectivity”. J. Med. Chem. 48(12), 3953-79. Hillisch, A., et al. (2004b). "Dissecting physiological roles of Miller, C. P. et al. (2003). “Constrained phytoestrogens and ana estrogen receptor alpha and beta with potent selective ligands from logues as ERbeta selective ligands'. Bioorg. Med Chem. Lett. structure-based design”, Mol. Endocrinol. 18(7), 1599-609. 13(14), 2399-403. Ho, S. M. (2004). “Estrogens and anti-estrogens: key mediators of Minutolo, F., et al. (2008). “Monoaryl-substituted prostate carcinogenesis and new therapeutic candidates'. J. Cell Salicylaldoximines as ligands for estrogen receptor Beta'. J. Med. Biochem. 91(3), 491-503. Chem. 51(5), 1344-51. US 9,623,021 B2 Page 5

(56) References Cited Setchell, K. D., et al. (2005). "S-equol, a potent ligand for estrogen receptor beta, is the exclusive enantiomeric form of the Soy OTHER PUBLICATIONS isoflavone metabolite produced by human intestinal bacterial flora', Am. J. Gin. Nutr. 81(5), 1072-9. Morani, A. etal (2006). “Lung dysfunction causes systemic hypoxia Shen, S. S. et al. (2006). “Expression of estrogen receptors-alpha in estrogen receptor beta knockout (ERbeta-i-) mice'. Proc. Natl. and -beta in bladder cancer cell lines and human bladder tumor Acad. Set. USA 103(18), 7165-9. tissue'. Cancer 106(12), 2610-6. Morissette, M et al., (2008), “Contribution of estrogen receptors Shiau, A. K. et al. (2002). "Structural characterization of a subtype alpha and beta to the effects of estradiol in the brain”. J. Selective ligand reveals a novel mode of estrogen receptor antago Biochem. Mol. Biol. 108(3-5), 327-38. nism”. Nat. Struct. Biol. 9(5), 359-64. Muthyala, R. etal (2003). “Exploration of the bicyclo[3.3.1 nonane Skliris G.P. et al., (2008) “Estrogen receptor alpha negative breast system as a template for the development of new ligands for the cancer patients: Estrogen receptor beta as a therapeutic target' J. estrogen receptor'. Bioorg. Med. Chem. Lett. 13(24). 4485-8. Steroid Biochem. Mol. Biol. 109(1-2), 140. Muthyala, R. et al. (2003), “Bridged bicyclic-cores containing a Somjen, D., et al (2002), "6-Carboxymethyl genistein: a novel 1,1-diarylethylene motif are high-affinity Subtype-selective ligands selective oestrogen receptor modulator (SERM) with unique, dif for the estrogen receptor'. J. Med. Chem. 46(9), 1589-602. ferential, effects on the vasculature, bone -and uterus'. J. Nakajima, M. et al. (2001). “Normalization of retinal, vascular Endocrinol. 173(3), 415-27. permeability in experimental diabetes with genistein'. Invest. Strom, A., et al. (2004). “Estrogen receptor beta inhibits 17beta Ophthalmol. Vis. Sci. 42(9).2U0-4. estradiol-stimulated proliferation of the breast cancer cell line Norman, B. H., et al. (2006). “Benzopyrians are selective estrogen T47D”. Proc. Natl. Acad. Sci. USA 101(6) 1566-71. receptor beta agonists with novel activity in models of benign Sun, J., etal (2003). “Molecular basis for the subtype discrimination prostatic hyperplasia”. J. Med Chem. 49(21) 6155-7. of the estrogen receptor-beta-selective ligand, '. Norman, B. H., et al. (2007). "Benzopyrians as selective estrogen Mol. Endocrinol. 17(2), 247-58. receptor beta agonists (SERBAs). Part 4: functionalization of the Sun, Wet al. (2006). “6H-Benzocchromen-6-one derivatives as benzopyran A-ring”. Bioorg. Med. Chem. Left 17(18), 5082-5. selective ERbeta agonists”. Bioorg. Med Chem. Lett. 16(6), 1468 Ohshiro, K. et al. (2006). “Biological role of estrogen receptor beta 72. in salivary gland adenocarcinoma cells”. Clin. Cancer Res. 12(20 Pt IX 5994-9. Szkudelska, K., and Nogowski, L. (2007). "Genistein-a dietary Parker, D.L., et al. (2006), “Triazoio-tetrahydrofluorenones as selec compound inducing hormonal and metabolic changes”. J. Steroid. tive estrogen receptor beta agonists'. Bioorg. Med. Chem. Lett. Biochem. Mol. Biol. 105(1-5), 37-45. 16(17), 4652-6. Takahashi. W., et al. (1997). “Effect of estrogen on nitric oxide Pike, A. et al. (1999). "Structure of the ligand-binding domain of induced relaxation of the rabbit urethra'. Eur: J. Pharmacol. 339(2- oestrogen receptor beta in, the presence of a partial agonistanda MI 3), 165-71. antagonist” Embo. J. 18(17) 4608-18. Tan, Q et al. (2004a). “Estrogen receptor ligands. Part 5: Tue SAR Pravettoni, A., et al. (2007). “Estrogen receptor beta (ERbeta) and of dihydrobenzoxathiins containing modified basic side chains”. inhibition of prostate cancer cell proliferation: Studies on the Bioorg. Med. Chem. Lett. 14(14), 3747-51. possible mechanism of action in DU145 cells”. Mol. Cell Tan, Q. et al. (2004b). “Estrogen receptor ligands. Part 6: Synthesis Endocrinol. 263(1-2), 46-54. and binding affinity of dihydrobenzodithiins”. Bioorg. Med. Chem. Prossnitz, E. R., et al. (2008). "GPR30; a novel therapeutic target in Lett. 14(14), 3753-5. estrogen-related disease'. Trends Pharmacol. Sci. 29(3%. 116-23. Tiwari-Woodruff, S., etal (2007). “Differential neuroprotective and Qin C, et al., (2008) “Understanding the Cardioprotective Effects of antiinfiammatory effects of estrogen receptor (ERalpha and ERbeta Flavonols: Discovery of Relaxant Flavonols without Antioxidant ligand treatment”. Proc. Natl. Acad. Sci. USA 104(37), 14813-8. Activity”. J. Med. Chem. 51(6) 1874-84. Traupe, T. et al. (2007). “Distinct roles of estrogen receptors alpha Rhodes, M. E. et al. (2006), “ERbeta-selective SERMs produce and beta mediating acute vasodilation of epicardial coronary arter mnemonic-enhancing effects in the inhibitory avoidance and water ies'. Hypertension 49(6) 1364–70. maze tasks”. Neurobiol. Learn Mem. 85(2), 183-91. Treeck, O., et al. (2007). “Novel estrogen receptor beta transcript Richardson. T. L., et al. (2007a), “Benzopyrians as selective estrogen variants identified in human breast cancer cells affect cell growth receptor beta agonists (SERBAs). Part 3: Synthesis of and apoptosis of COS-1 cells'. Mol. Cell Endocrinol. 264(1-2) cyclopentanone and cyclohexanone intermediates for C-ring; modi 50-60. fication”. Bioorg. Med. Chem. Lett. 17(17), 4824-8. Tremblay, A., et al. (1999). “Ligand-independent recruitment of Richardson, T.L., et al. (2007b). "Benzopyrians as selective estrogen SRC-1 to estrogen receptor beta through phosphorylation of acti receptor beta agonists (SERBAs). Part 5: Combined A- and C-ring vation function AF-1”. Mol. Cell 3(4), 513-9. structure-activity relationship studies'. Bioorg. Med Chem. Lett. Trotter, B. W., et al. (2006). “Design and synthesis of novel 17(20), 5563-6. isoquinoline-3-nitriles as orally bioavailable Kv1.5 antagonists for Richardson, TL., et al. (2007c). "Benzopyrians as selective estrogen the treatment of atrial fibrillation”. J. Med Chem. 49(24), 6954-7. receptor beta agonists (SERBAs). Part 2: structure-activity relation Ullrich, J. W. et al. (2007). “Estrogen receptor beta ligands: design ship studies on the benzopyran scaffold'. Bioorg. Med. Chem. Lett. and synthesis of new 2-phenyl-isoindole-1,3-diones'. Bioorg. Med. 17(13), 3570-4. Chem. Lett. 17(1), 118-22. Roelens, F., et al. (2006). "Subtle side-chain modifications of the Vivacqua, A. et al. (2006); "The G protein-coupled receptor GPR30 hop 8-prenylnaringenin result in distinct agonist/ mediates the proliferative effects induced by 17beta-estradiol and antagonist activity profiles for estrogen receptors alpha and beta'. J. hydroxytamoxifen in endometrial cancer cells'. Mol. Endocrinol. Med. Chem. 49(25) is 7357-65. 20(3), 631-46. Safe, S., et al. (2006). “The role of xenoestrogenic compounds in the Vu, A.T. et al. (2007). “ERbeta ligands. Part 6: 6H-Chromeno4.3- development of breast cancer'. Trends Pharmacol. Sci. 27(8), bquinolines as a new series of estrogen receptor beta-selective 447-54. ligands'. Bioorg. Med. Chem. Lett. 17(14), 4053-6. Seo J. et al. (2006). “Fluorine-substituted derivatives as Vu, A. T., et al. (2005). “ERbeta ligands. Part 4: Synthesis and estrogen receptor ligands: synthesis and structure-affinity relation structure-activity relationships of a series of 2-phenyiquinoline ship study of potential positron emission tomography agents for derivatives”. Bioorg. Med. Chem. Lett. 15(20), 4520-5. imaging estrogen receptors in breast cancer'. J. Med. Chem. 49(8)7 Walker, H. A. et al. (2001). “The phytoestrogen genistein produces 2496-511 acute nitric oxide-dependent dilation of human forearm vasculature Setchell K. D. (2006), “Assessing risks and benefits of genistein and with similar potency to 17beta-estradiol.” Circulation 103(2), 258 soy. Environ. Health Perspect. 114(6), A332-3. 62. US 9,623,021 B2 Page 6

(56) References Cited Blizzard, T. A. et al (2004). “Estrogen receptor ligands. Part 7: Dihydrobenzoxathiin SERAMs with bicyclic amine side chains”. OTHER PUBLICATIONS Bioorg. Med. Chem. Lett. 14(15), 3861-4. Diamanti-Kandarakis et al. (1998) “The Effect of a Pure Anti Wang. S. F. et al. (2005). "Genistein derivatives as selective androgen Receptor Blocker, Flutamide, on the Lipid Profile in the estrogen receptor modulators: Sonochemical synthesis and in vivo Polycystic Ovary Syndrome'. Journal of Clinical Endocrinology anti-osteoporotic action'. Bioorg. Med. Chem. 13(16) 4S80-90. and Metabolism, 1998, 83:2699-2705; esp. abstract; p. col. 1, para Wang, Y, et al. (2006), “A second binding site for 3. hydroxytamoxifen within the coactivator-binding groove of estro Price et al. (2006) “ for the Prevention of Prostate gen receptor beta”. Proc. Natl. Accid. Sci. USA 103(26), 9908-fl. Cancer in Men with High grade prostatic Intraephlthelial neoplasia; Waring, R. H., et al. (2008). “Phytoestrogens and : the Results of a Double-Blind, Placebo Controlled, Phase iB Clinical cotribution of diet and environment to endocrine disruption”. J. Trial” The Journal of Urology, 176:965-971, abstract only. Steroid. Biochem. Mol. BM 108(3-5), 213-20. Palanki M. et al. (2007) “Development of Prodrug 4-Chloro-3-(5- Weihua, Z. et al. (2002). “An endocrine pathway in the prostate, methyl-3{4-(2-pyrrolidin-1-ylethoxy) phenyl)amino-1,2,4- ERbeta, AR, 5alpha-androstane-3beta, 17beta-diol, and CYP7B1, benzotriazin-7-yl)phenyl Benzoate (TG100801): A Topically Administered Therapeutic Candidate in Clinical Trials for the regulates prostate growth'. Proc. Natl. Acad. Sci. USA 99(21), Treatment of Age-Related Macular Degeneration' J.Med...Chem. 13589-94. Meyers et al. (2001) “Estrogen Receptor BPotency-Selective Wildonger, K. L., et al (2006). “Tetrahydrofluorenones with Ligands: Structure-Activity Relationship Studies fo conformationally restricted side chains as selective estrogen recep Diarylpropionitriles and Their Acetylene and Polar Analogues' tor beta ligands'. Bioorg. Med Chem. Lett. 16(17), 4462-6. J.Med. Chem. 44, 4230-4251. Wilkening, R. R. et al. (2006a). “Estrogen receptor beta-subtype Schopfer U. etal (2002)"Toward Selective Erf Agonists for Central Selective tetrahydrofluorenones: use of a fused pyrazole as a phenol Nervous System Disorders: Synthesis and Characterization of Aryl bioisostere”, Bioorg. Med. Chem. Lett. 16(15), 3896-901. Benzthiophenes' J.Med...Chem. 45, 1399-1401. Wilkening, R. R. (2006) “The discovery of tetrahydrofluorenones as Chaum E (2002) “Retinal Neuroprotection by Growth Factors: A a new class of estrogen receptor beta-subtype selective ligands'. Mechanistic Perspecitve” JCB-02s-204. Bioorg. Med. Chem. Lett. 16(13) 3489-94. Lavie et al., “Obesity and Cardiovascular Disease: Risk Factor, Yang, C. et al. (2004a). “ERbeta ligands. Part 2: Synthesis and Paradox, and Impact of Weight Loss' 2009 J. Am. Coll. Cardiol. structure-activity relationships of a series of 4-hydroxy-biphenyl 53:1925-32. carbaldehyde oxime derivatives'. Bioorg. Med Chem. 12(10), Fabricatore et al., “Obesity', 2006 Annu Rev Clin Psychol 2:357-77. 2553-7O. Cooke et al. “The obesity pipeline: current strategies in the devel Yang, W., et al. (2004b). "Synthesis and structure-activity relation opment of anti-obesity drugs”, 2006 Nat. Rev. Drug. Discov. ship of 3-arylbenzoxazines as selective estrogen receptor beta 5:919-31 agonists'. Bioorg. Med. Chem. Lett. 14(9), 2327-30. Yu et al., “Inflamattory components of adipose tissue as target for treatment of metabolic syndrome', 2009 Forum. Nutr. 61:95-103. Yoo, J. et al. (2005). "Synthesis of an estrogen receptor beta Reisin et al., “Obesity and Hyper tension: Mechanisms, Cardio selective radioligand: 5-18Ffl-uoro-(2R.3S)-2,3-bis(4- Renal Consequences, and Therapeutic Approaches', 2009 Med. hydroxyphenyl)pentanenitrile and comparison of in vivo distribu Clin. North An. 93:733-51. tion with 16alpha-18Ffluoro-17beta-estradiol”. J. Med Chem. Allende-Vigo MZ. “Women and metabolic syndrome: an overview 48(20), 6366-78. of its peculiarities”, 2008 PR. Health Sci. J. 27:190-5. Yu, H. P. et al. (2006). "Salutary effects of estrogen receptor-beta Geer et al "Gender Differences in Insulin Resistance, Body Com agonist on lung injury after trauma-hemorrhage'. Am. J. Physiol. position, and Energy Balance” 2009 Gend. Med. 6 Suppl. 1:60-75. Lung. Cell Mol. Physiol. 290(5), L1004-9. Thomas et al., “Targeting bile-acid signaling for metabolic dis Zhou, H. B. et al. (2005). "Synthesis and evaluation of estrogen eases”, 2008 Nat. Rev. Drug Discov. 7:678-93. receptor ligands with bridged Oxabicyclic cores containing a Cariou B et al., “FXR: a promising target for the metabolic syn diarylethylene motif estrogen antagonists of unusual structure'. J. drome'? 2007 Trends Pharmacol. Sci. 28:236-43. Med. Chem. 48(23), 7261-74. Ariazi EA etal “Estrogen-Related Receptors as Emerging Targets in Munaut “Presence of Estreogen receptor type beta in human retina' Cancer and Metabolic Disorders' 2006 Curr: Top Med Chem. Br. J. Opthalmol. 2001: 85: 877-882. 6:203-15. Kaja, "Estrogen protects the inner retina from apoptosis and isch Kintscher U et al., “INT-131, a PPAR-gamma agonist for the emia-induced loss of Vsl-1L/Homer 1C immunoreactive synoptic treatment of type 2 diabetes', 2009 Curr: Opin. Investig. Drugs connections' Inv. Opthalmol and Vis. Sci., Jul. 2005, vol. 44, No. 7. 10:381-7. pp. 3155-3162. Beekum O et al., “Posttranslational Modifications of PPAR-gamma: Nakajima "Normalization of retinal vascular permeability in experi Fine-tuning the Metabolic Master Regulator” 2009 Obesity (Silver mental diabetes with genistein' Inv. Opthalmol and Vis. Sci. Aug. Spring) 17:213-9. 2001, vol. 42, No. 9, pp. 2110-2114. Billin AN, “PPAR-betagamma agonists for Type 2 diabetes and Ogueta "Estrogen receptor in the human eye: influence of gender dyslipidemia: an adopted orphan still looking for a home”, 2008 and age on gene expression' Inv. Opthalmol and Vis. Sci. Aug. Expert Opin. Investig. Drugs 17:1465-71. 1999, vol. 40, No. 9, pp. 1906-1911. Barros RP et al. “Estrogen receptors: new players in diabetes Yager, "Mitochondrial estrogen receptors—new insights into spe mellitus’ 2006 Trends Mol. Med. 12:425-31. cific functions'. Trends in Endocr. and Metabol., vol. 18, No. 3, pp. Cypess AM et al., “Identification and Importance of Brown Adipose 89-91, 2007. Tissue in Adult Humans' 2009 N. Engl. J. Med. 360:1509-17. ElloSo et al. “Suppression of experimental autoimmune encephalo Harris HA “Estrogen Receptor- : Recent Lessons from in Vivo myelitis using estrogen receptor-selective ligands' Journal of Endo Studies' 2007 Mol. Endocrino. 21:1-13. crinology, 2005, vol. 185. 243-252. Foryst-Ludwig A et al "Metabolic Actions of Estrogen Receptor Follettie et al "Organ messenger Ribonucleic Acid and plasma Beta (ER-beta) are Mediated by a Negative Cross-Talk with PPAR proteome Changes in the Adjuvant-Induced Arthritis model: gamma” 2008 PLoS Genet. 4:e 1000108. Responses to Diseas Induction and Theraphy with the Estogen Pallottini Vetal “Estrogen Regulation of Adipose Tissue Functions: Receptor-BSelective Agonist ERB-041' Endocrinology 1472):714 Involvement of Estrogen Receptor Isoforms' 2008 Infect. Disord. 723 (2006). Drug Targets 8:52-60. Harris et al "Characterization of the Biological Roles of the Estro Liang YQ etal “Estrogen receptor beta is involved in the anorectic gen Receptors, ERO-Selective Ligand” Endocrinology 143 action of estrogen', 2002 Int. J. Obes. Relat. Metab. Disord. (11):4172-4177 (2002). 26:1103-9. US 9,623,021 B2 Page 7

(56) References Cited Inoue et. al., "Acute and chronic effects of T-1032, a novel selective phosphodiesterase type 5 inhibitor, on monocrotaline-induced pull OTHER PUBLICATIONS monary hypertensition in rats'. Biol. Pharm. Bull. , 1422-1426, (2002). Lopez-Berestein, "Treatment of systemic fungal infections with Yepuru et al., “Estrogen Receptor-3-selective Ligands Alleviate liposomal-amphotericin B” Liposomes in the Therapy of Infectious High-fat Diet- and Ovariectomy-induced Obesity in Mice'. Journal Disease and Cancer, Lopez- Berestein and Fidler (eds.), pp. 317 of Biological Chemistry, vol. 285, No. 41, Jul. 23, 201, pp. 327, 1989. 31292-31303. Sefton, “Implantable pumps”. CRC Crit. Ref. Biomed. Eng. 14:201 Day et al., “Design and validation of specific Inhibotors of 17b (1987). hydroxysteriod dehydrogenases for therapeutic application in breast Abuchowski et al., “Immunosuppressive properties and circulating and prostate cancer, and in endometriosis'. Endocrine-Related life of achromobacter glutaminase-asparaginase covalently attached Cancer (2008), vol. 15, pp. 665,692. to polyethylene glycol in man'. Cancer Treat. Rep. 65: 1077-1081, Rose et al.; "The effects of a low-fat dietary intervention and 1981. adjuvant therapy on the serum estrogen and sex hor Katre et al., “Chemical modification of recombinant interleukin 2 by mone-binding globulin concentrations of postmenopausal breast polyethylene glycol increases its potency in the murine Meth A cancer patients'. Breast Cancer Research and Treatment, 1993, vol. sarcoma model” Proc. Natl. Acad. Sci., vol. 84, pp. 1487-1491, 27:253-262, p. 253. 1987. Wu et al.; "Meta-Analysis: Dietary Fat Intake, Serum Estrogen Morani A et al "Biological functions and clinical implications of Levels, and the irsk of Breast Cancer'. Journal of the National oestrogen receptors alfa and beta in epithelial tissues”, 2008 J. Cancer Institute, Mar. 17, 1999, vol. 91, No. 6. Intern. Med. 264:128-42 (From Example 22A). Byrns et al., “An Indomethacin Analogues, N-(4-Chlorobenzoyl)- Turgeon JL et al “Complex Actions of Sex Steroids in Adipose melatonin, sa Selective Inhibitor or Aldo-keto Reductase 1C3 (Type Tissue, the Cardiovascular System, and Brain: Insights from Basic 2 3Alpha-HSD, Type 5 17Beta-HSD, and Prostaglandin F Science and Clinical Studies' 2006 Endocr: Rev. 27:575-605 (From Synthase), a Potential Target for the Treatment of Hormone Depen Example 23.13). dent and Hormone Independent Malignancies'. Biochem Tontonoz Petal “Fat and Beyond: The Diverse Biology of PPAR Pharmacol. Jan. 15, 2008, vol. 75 No. 2, pp. 484-493. gamma' 2008 Annu. Rev. Biochem. 77:289-312 (From Example European Search Report for European Application No. 13174659.6 23.14). dated Aug. 2, 2013. Kersten S “Peroxisome proliferator activated receptors and lipo Supplementary European Search Report for European Application protein metabolism”, 2008 PPAR Res 2008: 132960 (From Example No. 11778.267.2 dated Oct. 7, 2013. 23.14). International Search Report for PCT Application No. PCT/US 13/ Nishigori Hetal “Mutations in the Small Heterodimer Partner Gene 58506 dated Jan. 22, 2014. are Associated with Mild Obesity in Japanese subjects' 2001 Proc. Roman et al.; “Association of Carotid Atherosclerosis and Left Natl. Acad. Sci. USA 98:575-80 (From Example 23.14). Ventricular Hypertrophy”, JACC, vol. 25 No. 1, pp. 83-90, Jan. Lai K et al “Estrogen Receptor Regulates Expression of the 1995. Orphan Receptor Small Heterodimer Partner” 2003 J. Biol. Chem. Stanbrough et al., “Increased expression of genes converting adre 278:36418-29 (From Example 23.14). nal androgens to testosterone in androgen-independent prostate Anderson, “The Process of Structure-Based Drug Design” Chem. cancer, Cancer Res, 66: 2815-2825, 2006. and Biol. 10, 787-197, 2003. Qiu et al.; “Crystal structures of the multispecific 17beta Thiel, "Structure-aided drug design's next generation” Nature hydroxysteroid dehydrogenase type 5: critical androgen regulation Biotechnol. 2, 513-519, 2004. in human peripheral tissues'. Mol Endocrinol, 18; 1798-1807, 2004. Han, “Advances in characterization of pharmaceutical hydrates'. Soderberg et al., “Direct observation of individual endogenous Trends in Bio/Pharmaceutical Industry, pp. 25-29, 2006. protein complexes in situ by proximity ligation', Nat Methods, 3: Vippagunta et al., “Crystalline solids' Adv. Drug Rev. 48: 3-26, 995-1000, 2006. 2001. Penning et al.; "Structure-function of human 3 alpha Pinto de Souza et al., “Synthesis of 3-methyl-1-(2H)-isoquinolinone hydroxysteroid dehydrogenases: genes and proteins’. Mol Cell derivates and their biological activities”, Ind. J. Chem. B. Org. Endocrinol, 215: 63-72, 2004. 29B(10): 961-965, 1990. Narayanan et al., “Cyclin-dependent kinase activity is required for Hellwinkel et al. “Synthesis of heterocycles with MF/A1203 base progesterone receptor function: novel role for cyclin A/Cdk2 as a systems: 2-arylbenzofurans and 2,3-diaryllisoquinolin-1 (2H)-ones'. progesterone receptor coactivator'. Mol Cell Biol 25(1):264-277. Synthesis 9: 1135-1141, 1995, STN Search Report Accession No. 2005. 1995:866647. Narayanan et al., “Human progesterone receptor displays cell Veeneman, “Non-steroidal subtype selective endrogens'. Current cycle-dependent changes in transcriptional activity”, Mol Cell Biol Medicinal Chemistry, vol. 12, No. 9, 2005, pp. 1077-1136. 25(8):2885-2898, 2005. CAS Registry No. 252061-78-2, 6-hydroxy-1(2H)-isoquinolinone. Office Action issued on Nov. 11, 2014 for Japanese Application No. CAS Registry No. 491-30-5; 1(2H)-Isoquinolinone. 2013-2712O2. Mahajan et. al.; “T-1032, a cyclic GMP phosphodiesterase-5 inhibi Office Action issued on Apr. 13, 2015 for Russian Patent Applica tor, acutely blocks physiologic insulin-mediated muscle tion No. 2012.151846. haemodynamic effects and glucose uptake in vivo”. British J Pharmaco, vol. 140(7), 1283-1291, (2003). * cited by examiner U.S. Patent Apr. 18, 2017 Sheet 1 of 27 US 9.623,021 B2

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-O- Wehicle 12 12 Figure 23 US 9,623,021 B2 1. 2 NUCLEAR RECEPTOR BINDING AGENTS brain, bone, immune system, gastrointestinal tract, lung, ovary, endometrium, prostate, vasculature, urogenital tract, CROSS REFERENCE TO RELATED salivary gland, etc. The role of ER-B in these tissues has APPLICATIONS been confirmed by observed phenotypes in ER-B knockout mice. Pathologies in these tissues may be treated by admin This Application is Continuation-In-Part Application of istration of ER-B selective ligands. U.S. patent application Ser. No. 12/010,225, filed Jan. 22. The prevalence of metabolic diseases, such as obesity, 2008 now U.S. Pat. No. 9,078,888 which claims the benefit insulin resistance and type II diabetes has increased dra of U.S. Provisional Patent Application Ser. No. 60/881,476, matically in the past decade. For example, it is estimated that filed Jan. 22, 2007 and U.S. Provisional Patent Application 10 400 million people were obese or overweight globally in Ser. No. 60/907,754, filed Apr. 16, 2007 and This Applica 2008, and approximately two-thirds of Americans are over tion claims the benefit of U.S. Provisional Patent Applica weight or obese, making obesity a serious health risk and tion Ser. No. 61/177,214, filed May 11, 2009, all of which economic burden to Society. Obesity is not a stand-alone are hereby incorporated by reference in their entirety. disease, as its emergence leads to various complications 15 including type-2-diabetes mellitus (T2DM), hypertension, FIELD OF THE INVENTION atherosclerosis and other cardiovascular diseases, osteopo rosis and clinical depression Lavie et al., 2009 J. Am Coll The present invention relates to methods for prevention Cardiol 53:1925-32; Fabricatore et al 2006 Annu Rev Clin and/or treatment of metabolic disorders, post-menopausal Psychol 2:357-77. Currently there are no effective pharma obesity and conditions associated with high fat diet con ceutical treatments for this pandemic problem. Although Sumption including, obesity, body weight gain, fat mass surgical procedures can reduce weight by 50-90%, it is formation, bone mineral content reduction, white adipose restricted due to the risk of Surgery and associated side tissue weight gain, increased cholesterol levels, increased effects. The best drugs currently in the market typically leptin levels, insulin resistance, type II diabetes, increased reduce weight by about 5-10% per year at most. Only two blood glucose levels, inflammatory diseases, cardiovascular 25 FDA approved drugs are available for treating over-weight diseases, fatty liver condition (accumulation of fat in the indication: 1. Amphetamines and Sibutramine that act on the liver), decreased uncoupling protein-1 (UCP-1) levels and hypothalamus to control appetite stimulation in the CNS. 2. increased lipogenesis. Orlistat that is a lipase inhibitor that blocks gastrointestinal absorption of fat and decreases energy uptake Cooke et al BACKGROUND OF THE INVENTION 30 2006 Nat Rev Drug Discov 5:919–31). Common side effects associated with these drugs including tachycardia, hyper The nuclear hormone receptor superfamily of ligand tension, fecal incontinence and/or cardiac valvopathy, mak activated transcription factors is present in various tissues, ing anti-obesity drug development of paramount impor and responsible for a multitude of effects in these tissues. tance. Therefore, there is a need in the art for more effective The nuclear receptor (NR) superfamily presently com 35 and safe drugs to treat conditions such as obesity, and other prises approximately 48 different proteins, of which 27 are related conditions and metabolic disorders. ligand regulated, most of which are believed to function as Obesity is a heterogeneous disease which occurs when ligand activated transcription factors, exerting widely dif energy uptake exceeds energy expenditure. Though the ferent biological responses by regulating gene expression. etiology of obesity remains uncertain, several mechanisms Members of this family include receptors for endogenous 40 Such as alterations in feeding behavior signals in the hypo Small, lipophilic molecules, such as Steroid hormones, ret thalamus, levels of leptin, adipokines secreted by white inoids, vitamin D and thyroid hormone. adipose tissue (WAT), neuropeptides and neurotransmitters The nuclear receptor (NR) superfamily includes the ste that control behavior, hormonal changes associated with roid nuclear receptor Subfamily, including the mineralocor age, inflammatory signals in adipose, stress and others ticoid receptor (MR) (or aldosterone receptor), the estrogen 45 trigger the onset of obesity Yu et al 2009 Forum Nutr receptors (ER), ER alpha (ER-C) and ER beta (ER-B), the 61:95-103; Rother et al 2009 Dtsch Med Wochenschr 134: androgen receptor (AR), the progesterone receptors (PR). 1057-9; Reisin et al 2009 Med Clin North Am 93:733-51. glucocorticoid receptors (GR) and others. Also closely Increase in the incidence of post-menopausal obesity, related in structure are the estrogen related receptors (ERRs) visceral obesity at andropause and gender differences in the ERR-O, ERR-B and ERR-Y. The steroid nuclear receptors 50 incidence of metabolic diseases indicate the importance of perform important functions in the body, some of which are the nuclear hormone receptor (NR) superfamily in regulat related to the transcriptional homeostasis of electrolyte and ing body weight Allende-Vigo MZ 2008 PR Health Sci J water balance, growth, development and wound healing, 27:190-5; Geer et al 2009 Gend Med 6 Suppl 1:60-75). fertility, stress responses, immunological function, and cog Many of the NRs play pivotal roles in regulating the nitive functioning. The effects may be mediated by cytoso 55 emergence of metabolic diseases. Activation of bile acid lic, mitochondrial or nuclear events. Accordingly, com NRs such as Farnesoid X Receptor (FXR), Constitutive pounds that modulate (i.e. antagonize, agonize, partially Androstane Receptor (CAR) and Pregnane X Receptor antagonize, partially agonize) the activity of steroid nuclear (PXR) promotes weight loss and also increases insulin receptors are important pharmaceutical agents that have sensitivity Thomas et al 2008 Nat Rev Drug Discov 7:678 specific utility in a number of methods, as well as for the 60 93: Cariou Bet al 2007 Trends Pharmacol Sci 28:236-43. treatment and prevention of a wide range of diseases and Similarly, Estrogen Related Receptors (ERRC., ERRB and disorders modulated by the activity of steroid nuclear recep ERRY) play significant roles in increasing energy expendi tOrS. ture, reducing adipogenesis and body weight gain Ariazi E. The biological actions of estrogens and are Aetal 2006 Curr Top Med Chem 6:203-15). Other members manifest through two distinct intracellular receptors, estro 65 of the NR belonging to the Peroxisome Proliferator Acti gen receptor alpha (ER-C) and estrogen receptor beta (ER vated Receptor (PPARs) and Estrogen Receptors (ERs) also B). For instance, ER-B is present in, among other tissues, play a role in maintenance of blood glucose and body fat, US 9,623,021 B2 3 4 making the NRs an attractive target to prevent/treat obesity increasing energy expenditure in a Subject: f) a method of and metabolic diseases Kintscher U et al 2009 Curr Opin increasinglean body mass; g) a method of treating, prevent Investig Drugs 10:381-7: Beekum O et al 2009 Obesity ing delaying the onset of reducing the incidence of, or (Silver Spring) 17:213-9: Billin A N 2008 Expert Opin reducing the severity of a metabolic disorder; h) a method of Investig Drugs 17:1465-71; Barros R P et al 2006 Trends increasing muscle weight, comprising administering to a Mol Med 12:425-31. subject in need thereof a therapeutically effective amount of ER-B in Some cases functions as an antagonist of ER-C. an estrogen receptor-beta ligand compound. through heterodimerization with ER-C. For instance, ago nists of ER-B may block the proliferative influence of ER-C. In one embodiment, this invention provides a) a method in tissues such as prostate and breast where ER-C. is known 10 of treating, delaying the onset of reducing the incidence of to promote neoplasia. In addition to its anti-ER-C. mediated or reducing the severity of a condition associated with high growth inhibition, ER-B autonomously inhibits proliferation fat diet consumption; b) a method of preventing a condition and promotes differentiation of prostate and other cancers. associated with high fat diet consumption; c) a method of ER-B is also believed to antagonize the proliferative effects treating, delaying the onset of reducing the incidence of, or AR in prostatic tissues. Prostatic hypertrophy and hyperpla 15 reducing the severity of a condition associated with post sia/dysplasia may result from a combination of androgenic menopausal obesity; d) a method of preventing a condition stimulation of proliferation and/or failed activation of ER-B associated with post-menopausal obesity; e) a method of by locally synthesized estrogens. This hypertrophy or hyper increasing energy expenditure in a Subject: f) a method of plasia/dysplasia often leads to a variety of prostatic maladies increasinglean body mass; g) a method of treating, prevent Such as BPH, prostatic inflammatory atropy (a precursor to ing delaying the onset of reducing the incidence of, or neoplasia), PIN, and CaP. Administration of exogenous reducing the severity of a metabolic disorder; h) a method of ER-B agonists can be expected to provide prostatic anti increasing muscle weight, comprising administering to a proliferation thereby being beneficial in the prevention or subject in need thereof a therapeutically effective amount of treatment of these prostatic diseases. Additionally, decreased a compound of this invention. side effects can be expected for ER-3 selective agents 25 compared to isoform nonselective ligands for treating many In one embodiment, this invention provides a method of of these diseases. treating, delaying the onset of reducing the incidence of, or Compounds that act as estrogen receptor ligands are, reducing the severity of a condition associated with high fat therefore, useful in treating a variety of conditions and diet consumption, comprising administering to a subject in disorders. Selective estrogen receptor modulators (estrogen 30 need thereof a therapeutically effective amount of an estro receptor ligands, such as ERB agonists) are disclosed, for gen receptor ligand compound represented by the structure example, in U.S. Patent Publication No. 2009/0030036. of Formula XI: Hormones are important regulators of adipose function and epidemiological Studies Suggest that estrogens regulate XI metabolism and fat distribution. The presence of ER-C. and 35 (R3) ER-B, the two receptors that mediate the actions of estradiol, O 2/ in adipose tissue implicates a direct role of the ligands in (OR), adipose function. Moreover, the observed gender and age differences in the discovery of brown adipose tissue (BAT) X N N SX in humans point towards the possibility that circulating 40 d (OR"), estradiol levels may be an important contributor toward the A. 21 ex development of BATCypess A Metal. 2009 N Engl J Med (R), (R2) 360:1509-17. Studies with individual ER Knockout (KO) mice indicated the importance of these isoforms in main wherein taining lipid and glucose homeostasis Harris H A 2007 Mol 45 Endocrinol 21:1-13. ER-OKO mice exhibit insulin resis R. R. R. are each, independently, hydrogen, aldehyde, tance, whereas, high fat diet fed ER-BKO mice demonstrate COOH, C(-NH) OH, CHNOH, CH-CHCOH, a higher magnitude of obesity than wildtype mice Foryst CH=CHCOR, —CH=CH, hydroxyalkyl, halogen, Ludwig A et al 2008 PLoS Genet 4:e1000108). Though hydroxyl, alkoxy, cyano, nitro, CFs, NH, 4-Ph-OMe, 4-Ph Some of these studies speculated that estrogenic control of 50 OH, SH, COR, COOR, OCOR, alkenyl, allyl, 2-methylallyl, body weight is mediated by ER-B, it is still not clear which alkynyl, propargyl, OSOCF, OSOCH, NHR, NHCOR, isoform mediates the beneficial effects of estradiol on body N(R), sulfonamide, SOR, alkyl, cycloalkyl, haloalkyl, fat, glucose and cholesterol Pallottini V et al 2008 Infect aryl, phenyl, benzyl, protected hydroxyl, OCHCHNRRs, Disord Drug Targets 8:52-60; Liang Y Q et al 2002 Int J Z-Alk-Q, Z-Alk-NRRs, Z-Alk-heterocycle or OCHCH Obes Relat Metab Disord 26:1103-9. 55 heterocycle in which the heterocycle is a 3-7 membered saturated or unsaturated, substituted or unsubstituted hetero SUMMARY OF THE PRESENT INVENTION cyclic ring: R is alkyl, cycloalkyl, hydrogen, haloalkyl, dihaloalkyl, In one embodiment, this invention provides a) a method trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, ben of treating, delaying the onset of reducing the incidence of 60 Zyl, -Ph-CF. -Ph-CHF. -Ph-CHF, -Ph-CFCF, halogen, or reducing the severity of a condition associated with high alkenyl, CN, NO, or OH: fat diet consumption; b) a method of preventing a condition associated with high fat diet consumption; c) a method of R" is hydrogen, Alk or COR; treating, delaying the onset of reducing the incidence of, or R" is hydrogen, Alk or COR; reducing the severity of a condition associated with post 65 Ra and Rs are independently hydrogen, phenyl, benzyl, an menopausal obesity; d) a method of preventing a condition alkyl group of 1 to 6 carbon atoms, a 3 to 7 member associated with post-menopausal obesity; e) a method of cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; US 9,623,021 B2 6 Z is O, NH, CH, or as described herein above or its isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, N-oxide, ester, hydrate or any combination thereof. In one embodiment, this invention provides a method of 1s1 5 increasing muscle weight comprising administering to a subject in need thereof a therapeutically effective amount of Q is SOH, COH, COR, NO, tetrazole, SONH or a compound of Formula XI as described herein above or its SONHR: isomer, pharmaceutically acceptable salt, pharmaceutical h is 0, 1, 2 or 3: product, polymorph, crystal, N-oxide, ester, hydrate or any i is 0, 1, 2, 3 or 4: 10 combination thereof In one embodiment this invention provides a selective n is 1, 2, 3 or 4: estrogen receptor ligand compound, wherein said compound m is 1 or 2; is 4-cyano-6,8-dihydroxy-2-(4-hydroxyphenyl)isoquinolin p is 0, 1, 2, 3, 4 or 5; and 1(2H)-one or its isomer, pharmaceutically acceptable salt, Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 15 pharmaceutical product, polymorph, crystal, N-oxide, ester, carbons, or cycloalkyl of 3-8 carbons; or its isomer, pharmaceutically acceptable salt, pharma hydrate or any combination thereof. ceutical product, polymorph, crystal, N-oxide, ester, hydrate BRIEF DESCRIPTION OF THE DRAWINGS or any combination thereof. In one embodiment this invention provides a method of FIG. 1 depicts binding constants of 12b (A), 12f (B), 12h preventing a condition associated with high fat diet con (C), 12p (D), 12s (E), 12u (F), 12y (G), 12Z (H), and Sumption, comprising administering to a subject in need estradiol (last pane) (I) to ER-O. (dashed) and ER-B (filled). thereof a therapeutically effective amount of an estrogen FIG. 2 depicts ER-C. and ER-B activation by 121, with receptor ligand compound represented by the structure of 0.1, 1, 10, 100, 1000 nM doses. Formula XI as described herein above or its isomer, phar 25 FIG. 3 depicts in vitro and in vivo characterization of maceutically acceptable salt, pharmaceutical product, poly ER-B selective SERMs. (A) Structure of 14m and 12u. (B) morph, crystal, N-oxide, ester, hydrate or any combination Binding and transactivation characteristics of ER-B SERMs. thereof. 14m and 12u: Ligand binding assay (columns 2-6) and In one embodiment this invention provides a method of transactivation assay (columns 7-8). (C) 14m and 12u treating, delaying the onset of reducing the incidence of, or 30 weakly induce Ishikawa cell proliferation. (D) 14m and 12u reducing the severity of a condition associated with post does not increase uterine weights. Data is expressed as menopausal obesity, comprising administering to a subject Mean+S.E. RBA relative binding affinity; ER-C-estro in need thereof a therapeutically effective amount of an gen receptor C.; ER-B—estrogen receptor B. s.c.—Subcuta estrogen receptor ligand compound represented by the struc neously. ture of Formula XI as described herein above or its isomer, 35 FIG. 4 depicts the effect of 14m on diet induced obesity. pharmaceutically acceptable salt, pharmaceutical product, (A) Biweekly body weight. (B) Feed consumption. Panel A polymorph, crystal, N-oxide, ester, hydrate or any combi lower graph shows the percent difference in body weight of nation thereof. high fat diet fed receiving vehicle and 14m, respectively. In one embodiment this invention provides a method of Panel A inset shows a representative mouse from H.F. and preventing a condition associated with post-menopausal 40 normal diets. Values are expressed as Mean+S.E. H.F.—high obesity, comprising administering to a Subject in need fat; N.D.—normal diet: B.Wt-body weight; *—significance thereof a therapeutically effective amount of an estrogen at p-0.05 from normal diet fed vehicle treated animals; receptor ligand compound represented by the structure of it significance at p-0.05 from high fat diet fed vehicle Formula XI as described herein above or its isomer, phar treated animals. maceutically acceptable salt, pharmaceutical product, poly- 45 FIG. 5 depicts the effects of 14m and 12u on high fat diet morph, crystal, N-oxide, ester, hydrate or any combination induced obesity. (A) Biweekly body weight represented as thereof. body weight difference from day 0. (B) 14m and 12u reduce In one embodiment this invention provides a method of fat mass (top panel) and increase muscle mass (bottom increasing energy expenditure in a Subject, comprising panel). The data are expressed as percent fat and lean mass administering to a Subject in need thereof a therapeutically 50 of body weight. N.D.—normal diet; H.F.—high fat diet; effective amount of a compound of Formula XI as described *—significance at p-0.05 from normal diet fed vehicle herein above or its isomer, pharmaceutically acceptable salt, treated animals; it significance at p-0.05 from high fat diet pharmaceutical product, polymorph, crystal, N-oxide, ester, fed vehicle treated animals. hydrate or any combination thereof. FIG. 6 depicts the effect of 14m on the reduction of fat In one embodiment this invention provides a method of 55 mass and metabolic diseases markers. (A) demonstrates the increasing lean body mass, comprising administering to a effect of 14m on body fat (left panel) and bone mineral subject in need thereof a therapeutically effective amount of content (BMC, right panel). Body fat content is expressed as a compound of Formula XI as described herein above or its percent fat of body weight. (B), (C), (E) and (F) demonstrate isomer, pharmaceutically acceptable salt, pharmaceutical the effect of 14m on metabolic diseases markers: white product, polymorph, crystal, N-oxide, ester, hydrate or any 60 adipose tissue (WAT; panel B); cholesterol (panel C); leptin combination thereof. (panel E); and the inflammatory marker MIP-1B (panel F). In one embodiment this invention provides a method of (D) demonstrates the effect of 14m on serum glucose levels treating, preventing delaying the onset of reducing the after glucose tolerance test. incidence of, or reducing the severity of a metabolic disorder FIG. 7 depicts the white adipose tissue (WAT) weight, comprising administering to a subject in need thereof a 65 brown adipose tissue (BAT) weight and gastrocnemius therapeutically effective amount of an estrogen receptor muscle (GASTROC) weight at study completion for the ligand compound represented by the structure of Formula XI mice following completion of the study. Maintenance on a US 9,623,021 B2 7 8 high fat diet significantly increased the weight of WAT and and firefly luciferase activity was measured and normalized decreased the weight of gastrocnemius muscle compared to to renilla luciferase. (E). SHP-1 is an ER-B specific target a normal diet. 14m and 12u prevented the increase in the gene. HEK-293 cells were transfected with 0.25 ug SHP WAT weight and increased gastrocnemius muscle weight in LUC, 5 ng CMV-renilla LUC and 50 ng of the indicated the high fat diet fed group compared to vehicle treated. (* receptors (FXR and ER-C. for the left panel and FXR and significant from normal diet--Vehicle, it significant from high ER-B for the right panel). The cells were treated 24 hrs after fat diet--vehicle). transfection with the indicated ligands and harvested 48 hrs FIG. 8 depicts representative liversections obtained from after transfection and firefly luciferase activity was mea normal diet fed mice, mice fed with a high fat diet and sured and normalized to renilla luciferase. PPAR peroxi vehicle treated, and mice fed with a high fat diet and treated 10 Some proliferator and activated receptor; ER-estrogen recep with 14m. The administration of 14m attenuated the accu tor; H-histidine; A–alanine; RLU relative luciferase mulation of lipid droplets in the liver. (Example 23.7). units; Tro—troglitazone; PGC-1—PPAR-Y coactivator; N.D.—normal diet; H.F.—high fat diet. SHP small heterodimer partner; FXR farsenoid X recep FIG. 9 depicts the mouse testes weight (panel A), serum tOr. testosterone (T) levels (panel B) and serum follicle stimu 15 FIG. 13 depicts the effect of 12y (FIG. 13A) and 12u lating hormone (FSH) levels (panel C) following completion (FIG. 13B) on macrophage adhesion to endothelial cells. of the study (Example 23.8). The levels were determined FIG. 14 depicts the effect of 12b on the edema volume immediately after sacrifice. 14m and 12u did not affect the which was induced by Carrageenan (i.e. Carrageenan-in serum testosterone levels. 14m did not affect serum testos duce raw paw edema as an acute inflammation model). terone and follicle stimulating hormone (FSH) levels. Serum FIG. 15 depicts treatment protocol for measuring rapid levels of total testosterone and FSH were determined imme (non-genomic) aortic ring relaxation by NRBA's of this diately prior to sacrifice after week 12 of treatment. 14m did invention. not suppress these endocrine hormones, suggesting that its FIG. 16 depicts concentration-response curves generated effects were not mediated through ERC. as in FIG. 15 for 14m, 12u and 12y. FIG. 10 depicts the effect of 12u on treating high-fat diet 25 FIG. 17 depicts response treatment protocol for measur induced obesity. (A) Biweekly body weight. (B) Fat mass. ing dose response effects attenuation of Phenylephrineaortic N.D. normal diet. (C) WAT, BAT, liver weights. H.F.— ring constriction by phenylephrine (PE). high fat diet; *—significance at p-0.05 from normal diet fed FIG. 18 depicts a concentration-response curve generated vehicle treated animals; it significance at p-0.05 from high as in FIG. 17 for 12y, 12Z, and 141. fat diet fed vehicle treated animals. 30 FIG. 19 depicts a protocol to measure the effect of FIG. 11 depicts the effect of 12u on altering body com long-term incubation of aortic rings with NRBAs of this position of ovariectomized mice. (A) Biweekly body weight invention, and an example graph for 141. (B) feed consumption (C) fat mass (left panel) and lean mass FIG. 20 depicts (A) Inhibition of RASMC proliferation by (right panel). (D) white adipose tissue (WAT) and uterus ER-B Ligand 141. Cell proliferation was estimated using the weights. OVX Ovariectomy: *—significance at p-0.05 35 WST-1 calorimetric assay. Absorbance at 450 nm was mea from normal diet fed vehicle treated animals; it signifi Sured and expressed as a percentage of the absorbance in cance at p-0.05 from high fat diet fed vehicle treated control wells containing cells only on day 0 (GO). (B) animals. Fluorescent detection of intracellular ROS. Subconfluent FIG. 12 depict the effect of ER-B ligand on PPAR-y monolayer of ARPE-19 cells were pretreated with the function through ligand binding domain (LBD). (A). HEK 40 respective drugs with or without ICI, before exposure to 293 cells were transfected with 0.25 ug PPRE-LUC, 5 ng oxidative stress with tBH. Values for cells treated with dye CMV-renilla LUC and the indicated receptors (PPAR-Y and only were subtracted from the raw fluorescence data. Fluo ER-B for the left panel and PPAR-C. and ER-B for the right rescence is reported relative to cells containing dye in the panel). The cells were treated 24 hrs after transfection with presence of oxidant alone. Each drug treatment was done in the indicated ligands and harvested 48 hrs after transfection 45 triplicate and is plotted+/-S.e.m. and firefly luciferase activity was measured and normalized FIG. 21 depicts the effect of 12b and 12u on LNCaP to renilla luciferase. (B). H475 in ER-3 LBD is important for (prostate cancer) cell proliferation. its function. H475 in ER-B LBD was mutated to alanine (A) FIG. 22 depicts the effect of 12b and 12u on C-26 (colon using a site directed mutagenesis kit. Transactivation assay cancer) cell proliferation. was performed as described in panel A in HEK-293 cells 50 FIG. 23 depicts the effect of 12b and 12u on LNCaP with a titration of ER-Bligands in wild type or ER-B H475A. stromal cell xenograft tumor growth, after 10, 14 and 21 (C). ER-B H475A does not inhibit PPAR-Y transactivation. days. HEK-293 cells were transfected with 0.25 ug PPRE-LUC, 5 ng CMV-renilla LUC and 50 ng of the indicated receptors DETAILED DESCRIPTION OF THE PRESENT (PPAR-y or PPAR-Y and wild type ER-B or PPAR-Y and 55 INVENTION ER-B H475A). The cells were treated 24 hrs after transfec tion with the indicated ligands and harvested 48 hrs after In one embodiment, a NRBA refers to a compound that transfection and firefly luciferase activity was measured and affects estrogen receptor activity. In one embodiment, a normalized to renilla luciferase. (D). ER-B ligand depend NRBA exhibits activity as an agonist, or, in another embodi ently inhibits PGC-1 coactivated PPAR-Y but not PPAR-O. 60 ment, as an antagonist, or in another embodiment, as a transactivation. HepG2 cells were transfected with 0.25 ug partial agonist, or in another embodiment, as a partial PPRE-LUC, 5 ng CMV-renilla LUC, 0.5ug PGC-1 or vector antagonist of the estrogen receptor. backbone and 100 ng of the indicated receptors (PPAR-y or In some embodiments the NRBAs are estrogen receptor PPAR-Y and wildtype ER-B or PPAR-Y and ER-B H475A for ligand compounds. In one embodiment, the estrogen recep top panels and PPAR-C. or PPAR-C. and ER-B for bottom 65 tor ligand compound is a selective estrogen receptor modu panel). The cells were treated 24 hrs after transfection with lator (SERM). In one embodiment, the estrogen receptor the indicated ligands and harvested 48 hrs after transfection ligand compound is a selective estrogen receptor B modu US 9,623,021 B2 9 10 lator (B-SERM or ER-B SERM or ER-B selective SERM). In The term “ICso refers, in some embodiments, to a one embodiment, the estrogen receptor ligand compound is concentration of the NRBA which reduces the activity of a an estrogen receptor agonist. In one embodiment, the estro target (e.g., ERC. or ERB) to half-maximal level. gen receptor ligand compound is an estrogen receptor B The term “ECso refers, in some embodiments, to a (ER-B) agonist. In one embodiment, the estrogen receptor 5 concentration of the NRBA that produces a half-maximal ligand compound is an estrogen receptor B (ER-B) antago effect. nist. In some embodiments of this invention, the compounds of In one embodiment the estrogen receptor ligand com this invention are bisphenolic agents. In some embodiments pound is selective to ER-B. In one embodiment the estrogen of this invention, the compounds of this invention are mono receptor ligand compound does not cross react with ER-C. 10 or nonphenolic agents. In some embodiments of this inven In one embodiment the estrogen receptor ligand compound tion, the compounds of this invention are Substituted iso does not cross react with ER-O. up to concentration of 10 quinolines. In some embodiments of this invention, the LM. In one embodiment the estrogen receptor ligand com compounds of this invention are substituted isoquinolinones. pound does not cross react with ER-O. up to concentration of 15 In some embodiments of this invention, the compounds of 1 LM. In one embodiment the estrogen receptor ligand this invention are Substituted dihydroisoquinolinones. In compound is bound to ER-B with at least 5 fold selectivity some embodiments of this invention, the NRBAs have compared to ER-O. In one embodiment the estrogen receptor selectivity for ER-B. In some embodiment of this invention, ligand compound is bound to ER-B with at least 10 fold the NRBAs are agonists of ER-B. In some embodiment of selectivity compared to ER-O. In one embodiment the this invention, the NRBAs are partial agonists of ER-B. In estrogen receptor ligand compound is bound to ER-B with at some embodiment of this invention, the NRBAs are antago least 50 fold selectivity compared to ER-C. In one embodi nists of ER-B. ment the estrogen receptor ligand compound is bound to In some embodiments of this invention, the NRBAs have ER-B with almost 100 fold selectivity compared to ER-O. In anti-oxidant activity. In some embodiments, the antioxidant one embodiment the estrogen receptor ligand compound is 25 activity is independent of the nuclear receptor binding B-SERM agonist. activity. In some embodiments, the NRBAs of this invention In one embodiment the estrogen receptor ligand com exhibit non-genomic signaling in cells. In some embodi pound functions as agonist to ER-B. In one embodiment the ments, the NRBAs of this invention exhibit mitochondrial estrogen receptor ligand compound functions as antagonist signaling. to ER-B. In one embodiment the estrogen receptor ligand 30 In one embodiment, the present invention provides a compound functions as agonist to ER-C. In one embodiment NRBA or its prodrug, analog, isomer, metabolite, derivative, the estrogen receptor ligand compound functions as antago pharmaceutically acceptable salt, pharmaceutical product, nist to ER-C. In one embodiment the estrogen receptor ligand compound functions as agonist to both ER-B and polymorph, crystal, impurity, N-oxide, ester, hydrate or any ER-C. In one embodiment the estrogen receptor ligand 35 combination thereof, represented by the structure of For compound functions as agonist to both ER-B and ER-O. with mula I: a selectivity of at least 5 fold towards ER-B. In one embodi ment the estrogen receptor ligand compound functions as agonist to both ER-B and ER-C. with a selectivity of at least 10 fold towards ER-3. In one embodiment the estrogen 40 receptor ligand compound functions as agonist to both ER-B and ER-C. with a selectivity of 20-30 fold towards ER-B and with ECso of less than 10 nM. In one embodiment, the NRBA exerts its effects on the estrogen receptor (e.g., ER-O, ER-B or ERRs) in a tissue 45 dependent manner. In some embodiments, the NRBA of this invention can act as estrogen receptor agonists in some wherein tissues (e.g., bone, brain, and/or heart) and as antagonists in A is a 5-14 membered saturated or unsaturated, Substi other tissue types, for example in the breast and/or uterine tuted or unsubstituted carbocyclic or heterocyclic ring which lining. 50 is optionally a fused ring system, or a combination thereof. In one embodiment, a NRBA of this invention will have wherein the saturated or unsaturated carbocyclic or hetero an ICs or ECs with respect to ERC. and/or ERB of up to cyclic rings are optionally substituted by 1 to 5 substituents about 10 uM as determined using the ERC. and/or ERB independently selected from R or OR"; and X is O or S; or transactivation assays, as known in the art, or, in other A is nothing, N forms a double bond with the cyclic embodiments, as described herein. In some embodiments, 55 the NRBA exhibit ECs or ICs values (as agonists or carbon and X is OH or OCHCH-heterocycle in which the antagonists, respectively) of about 5uM, or less than about heterocycle is a 3-7 membered saturated or unsaturated 5 uM. Representative compounds of the present invention substituted or unsubstituted heterocyclic ring: have been discovered to exhibit agonist or antagonist activ R. R. and R are independently hydrogen, aldehyde, ity with respect to the estrogen receptor. Compounds of the 60 COOH, C(-NH) OH, CHNOH, CH=CHCOH, present invention exhibit, in some embodiments, an antago CH=CHCOR, —CH=CH, hydroxyalkyl, halogen, nist or agonist ICso or ECso with respect to ERC. and/or ERB hydroxyl, alkoxy, cyano, nitro, CFs, NH, 4-Ph-OMe, 4-Ph of about 5 uM or less than about 5 uM, or in some OH SH, COR, COOR, OCOR, alkenyl, allyl, 2-methylallyl, embodiments, up to about 500 nM, or in other embodiments, alkynyl, propargyl, OSOCF, OSOCH, NHR, NHCOR, up to about 50 nM, or in other embodiments, up to about 10 65 N(R), sulfonamide, SOR, alkyl, haloalkyl, aryl, phenyl, nM, or in other embodiments, up to about 1 nM, as measured benzyl, protected hydroxyl, OCH2CHNRRs, Z-Alk-Q, in ERC. and/or ERB transactivation assays. Z-Alk-NRRs. Z-Alk-heterocycle or OCHCH-hetero US 9,623,021 B2 11 12 cycle, in which the heterocycle is a 3-7 membered saturated OH, SH, COR, COOR, OCOR, alkenyl, allyl, 2-methylallyl, or unsaturated, substituted or unsubstituted heterocyclic alkynyl, propargyl, OSOCF, OSOCH, NHR, NHCOR, ring: N(R), sulfonamide, SOR, alkyl, haloalkyl, aryl, phenyl, R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, benzyl, protected hydroxyl, OCHCHNRRs, Z-Alk-Q, Z-Alk-NRRs, Z-Alk-heterocycle or OCHCH-hetero CHF, CHF, CF, CFCF, aryl, heteroaryl, phenyl, benzyl, cycle, in which the heterocycle is a 3-7 membered saturated -Ph-CF, -Ph-CHF. -Ph-CHF, -Ph-CFCF, halogen, alk or unsaturated, substituted or unsubstituted heterocyclic enyl, CN, NO, or OH: r1ng. R" is hydrogen, Alk, or COR; In one embodiment of the compound of Formula I, A is R" is hydrogen, Alk, or COR; nothing, N forms a double bond with the cyclic carbon and Ra and Rs are independently hydrogen, phenyl, benzyl, an 10 X is OCHCH-heterocycle in which the heterocycle is a 3-7 alkyl group of 1 to 6 carbon atoms, a 3 to 7 member membered heterocycloalkyl. In one embodiment, when X is cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; OCHCH-heterocycle, the heterocycle is substituted or Z is O, NH, CH, or unsubstituted piperidine, pyrrolidine, morpholine or pipera Zine. In another embodiment, when R. R. R. are indepen 15 dently Z-Alk-heterocycle or, in another embodiment, OCHCH-heterocycle, either heterocycle may be substi 1s1 tuted or unsubstituted piperidine, pyrrolidine, morpholine or piperazine. In another embodiment, when R and Rs are independently a 3 to 7 membered heterocycloalkyl, either Q is SOH, COH, COR, NO, tetrazole, SONH or heterocycle may be substituted or unsubstituted piperidine, SONHR: pyrrolidine, morpholine or piperazine. In another embodi n is an integer of between 1-3: ment, any heterocycle is optionally substituted by one or m is an integer between 1-2; and more Substituents comprising halogen, cyano, nitro, COOH, Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, het carbons, or cyclic alkyl of 3-8 carbons. erocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alky In some embodiments the NRBA of Formula I is an 25 lamino, N.N dialkylamino, aminoalkyl, haloalkyl, aryl, het estrogen receptor ligand compound. In one embodiment, the eroaryl, alkoxy or haloalkoxy, wherein R is as defined for estrogen receptor ligand compound is a selective estrogen Formula I. receptor modulator (SERM). In one embodiment, the estro In another embodiment of the compound of Formula I, R. gen receptor ligand compound is a selective estrogen recep is a halogen. In another embodiment R is a bromide. In tor modulator (B-SERM). In one embodiment, the estrogen 30 another embodiment R is a chloride. In another embodi receptor ligand compound is an estrogen receptoragonist. In ment R is a fluoride. In another embodiment R is an iodide. one embodiment, the estrogen receptor ligand compound is In another embodiment R is hydrogen. In another embodi an estrogen receptor B (ERB) agonist. In one embodiment, ment R is a cyano. In another embodiment, R is a phenyl. the estrogen receptor ligand compound is an estrogen recep In another embodiment, R is —CH=CH. In another tor B (ERB) antagonist. 35 embodiment, R is —CH=CH-CH. In another embodi In one embodiment, the NRBA is represented by the ment, R is —CH=CH-COOEt. In another embodiment structure of Formula I: R is a hydroxyl group. In another embodiment R is O—(CO)-Ph-CF. In another embodiment R is COOH. In another embodiment R is COOMe. In another embodiment 40 R is hydrogen. In another embodiment R is a hydroxyl group and n is 1. In another embodiment R is in position 8 of the isoquinolinone group. In another embodiment R is halogen. In another embodiment R is fluoride. In another embodiment R is chloride. In another embodiment R is 45 bromide. In another embodiment R is iodide. In another embodiment R is hydrogen. In another embodiment R' is H. In another embodiment R' is a methyl group. In another embodiment R' is a COMe group. In another embodiment R" wherein A, X, R. R. R', n and mare as described above, is H. In another embodiment R" is a methyl group. In wherein if X is oxo and A is phenyl, then A is not substituted 50 another embodiment R" is a COMe group. with: In another embodiment this invention provides a NRBA NHCOR and halogen without further substitution, or or its prodrug, analog, isomer, metabolite, derivative, phar NHCOR and an alkyl without further substitution. maceutically acceptable salt, pharmaceutical product, poly In one embodiment, A is morph, crystal, impurity, N-oxide, ester, hydrate or any 55 combination thereof, represented by the structure of For mula II: (R3) NS

II exO 60 OR"; p is an integer between 1-4: R" is hydrogen, Alk, or COR; R is hydrogen, aldehyde, COOH, C(=N) OH, CHNOH, 65 CH=CHCOH, -CH=CH, hydroxyalkyl, halogen, hydroxyl, alkoxy, cyano, nitro, CF, NH, 4-Ph-OMe, 4-Ph US 9,623,021 B2 13 14 wherein

A is a 5-14 membered saturated or unsaturated, Substi II tuted or unsubstituted carbocyclic or heterocyclic ring which is optionally a fused ring system, or a combination thereof. wherein the saturated or unsaturated carbocyclic or hetero cyclic ring are optionally substituted by 1 to 5 substituents independently selected from R or OR"; and X is O or S; or A is nothing, N forms a double bond with the cyclic carbon and X is OH or OCHCH-heterocycle in which the 10 A, X, R. R. R', n and m are as described above, wherein heterocycle is a 3-7 membered saturated or unsaturated, if X is oxo and A is phenyl, then A is not substituted with: substituted or unsubstituted heterocyclic ring: NHCOR and halogen without further substitution, or R. R. R. are independently hydrogen, aldehyde, COOH, NHCOR and an alkyl without further substitution. C(-NH) OH, CHNOH, CH=CHCOH, In one embodiment, A is CH=CHCOR, —CH=CH, hydroxyalkyl, halogen, 15 hydroxyl, alkoxy, cyano, nitro, CF, NH, 4-Ph-OMe, 4-Ph OH, SH, COR, COOR, OCOR, alkenyl, allyl, 2-methylallyl, alkynyl, propargyl, OSOCF, OSOCH, NHR, NHCOR, (R3) N(R), sulfonamide, SOR, alkyl, haloalkyl, aryl, phenyl, benzyl, protected hydroxyl, OCH2CHNRRs, Z-Alk-Q, Z-Alk-NRRs, Z-Alk-heterocycle or OCHCH-heterocycle ex in which the heterocycle is a 3-7 membered saturated or OR" unsaturated, Substituted or unsubstituted heterocyclic ring; R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, 25 wherein p is an integer between 1-4; R" is hydrogen, Alk, or CHF, CHF, CF, CFCF, aryl, phenyl, benzyl, -Ph-CF, COR: R is hydrogen, aldehyde, COOH, C(=N) OH, CHNOH, CH=CHCOH, -CH=CH, hydroxyalkyl, -Ph-CHF, -Ph-CHF. -Ph-CFCF, halogen, alkenyl, CN, halogen, hydroxyl, alkoxy, cyano, nitro, CF, NH, 4-Ph NO, or OH: OMe, 4-Ph-OH, SH, COR, COOR, OCOR, alkenyl, allyl, R" is hydrogen, Alk or COR; 30 2-methylallyl, alkynyl, propargyl, OSOCF. OSOCH, R" is hydrogen, Alk or COR; NHR, NHCOR, N(R), sulfonamide, SOR, alkyl, haloalkyl, Ra and Rs are independently hydrogen, phenyl, benzyl, an aryl, phenyl, benzyl, protected hydroxyl, OCHCHNRRs, alkyl group of 1 to 6 carbon atoms, a 3 to 7 member Z-Alk-Q, Z-Alk-NRRs. Z-Alk-heterocycle or OCHCH cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; heterocycle, in which the heterocycle is a 3-7 membered 35 saturated or unsaturated, substituted or unsubstituted hetero Z is O, NH, CH, or cyclic ring: In one embodiment of the compound of Formula II, A is nothing, N forms a double bond with the cyclic carbon and 1s-1 X is OCHCH-heterocycle, in which the heterocycle is a 40 3-7 membered heterocycloalkyl. In one embodiment, when X is OCHCH-heterocycle, the heterocycle is substituted or Q is SOH, COH, COR, NO, tetrazole, SONH or unsubstituted piperidine, pyrrolidine, morpholine or pipera SONHR: Zine. In another embodiment, when R. R. R. are indepen dently Z-Alk-heterocycle or, in another embodiment, n is an integer between 1-3: 45 OCHCH-heterocycle, either heterocycle may be substi m is an integer between 1-2; tuted or unsubstituted piperidine, pyrrolidine, morpholine or p is an integer between 1-4; and piperazine. In another embodiment, when Ra and Rs are Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 independently a 3 to 7 membered heterocycloalkyl, either carbons, or cyclic alkyl of 3-8 carbons. heterocycle may be substituted or unsubstituted piperidine, 50 pyrrolidine, morpholine or piperazine. In another embodi In some embodiments the NRBA of Formula II is an ment, any heterocycle is optionally substituted by one or estrogen receptor ligand compound. In one embodiment, the more Substituents comprising halogen, cyano, nitro, COOH, estrogen receptor ligand compound is a selective estrogen COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, het receptor modulator (SERM). In one embodiment, the estro erocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alky gen receptor ligand compound is a selective estrogen recep 55 lamino, N.N dialkylamino, aminoalkyl, haloalkyl, aryl, het tor B modulator (B-SERM). In one embodiment, the estro eroaryl, alkoxy or haloalkoxy, wherein R is as defined for gen receptor ligand compound is an estrogen receptor Formula II. agonist. In one embodiment, the estrogen receptor ligand In another embodiment of the compound of Formula II, compound is an estrogen receptor B (ERB) agonist. In one R is a halogen. In another embodiment R is a bromide. In embodiment, the estrogen receptor ligand compound is an 60 another embodiment R is a chloride. In another embodi estrogen receptor B (ERB) antagonist. ment R is a fluoride. In another embodiment R is an iodide. In another embodiment this invention provides a NRBA In another embodiment R is hydrogen. In another embodi or its prodrug, analog, isomer, metabolite, derivative, phar ment R is a cyano. In another embodiment, R is a phenyl. maceutically acceptable salt, pharmaceutical product, poly In another embodiment, R is —CH=CH-CH. In another morph, crystal, impurity, N-oxide, ester, hydrate or any 65 embodiment, R is —CH=CH2. In another embodiment, R combination thereof, represented by the structure of For is —CH=CH-COOEt. In another embodiment R is mula II: O (CO)-Ph-CF. In another embodiment R is COOH. In US 9,623,021 B2 15 16 another embodiment R is COOMe. In another embodiment Q is SOH, COH, COR, NO, tetrazole, SONH, or R is a hydroxyl group. In another embodiment R is SONHR; and hydrogen. In another embodiment R is a hydroxyl group Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 and n is 1. In another embodiment R is in position 8 of the isoquinolinone group. In another embodiment R is halogen. carbons, or cyclic alkyl of 3-8 carbons; In another embodiment R is fluoride. In another embodi wherein if A is a phenyl, X is an oxo group and Rio is a ment R is chloride. In another embodiment R is bromide. benzene ring, then: In another embodiment R is iodide. In another embodiment R is not COOR, if R is a hydrogen or an ester; or R is hydrogen. In another embodiment R' is H. In another R is not CONRRs, if R and Rs are as described above. embodiment R is a methyl group. In another embodiment R' In some embodiments the NRBA of Formula III is an is a COMe group. In another embodiment R" is H. In another 10 estrogen receptor ligand compound. In one embodiment, the embodiment R" is a methyl group. In another embodiment estrogen receptor ligand compound is a selective estrogen R" is a COMe group. receptor modulator (SERM). In one embodiment, the estro In another embodiment this invention provides a NRBA gen receptor ligand compound is a selective estrogen recep or its prodrug, analog, isomer, metabolite, derivative, phar tor B modulator (B-SERM). In one embodiment, the estro maceutically acceptable salt, pharmaceutical product, poly 15 gen receptor ligand compound is an estrogen receptor morph, crystal, impurity, N-oxide, ester, hydrate or any agonist. In one embodiment, the estrogen receptor ligand combination thereof, represented by the structure of For compound is an estrogen receptor B (ERB) agonist. In one mula III: embodiment, the estrogen receptor ligand compound is an estrogen receptor B (ERB) antagonist. III In another embodiment this invention provides a NRBA or its prodrug, analog, isomer, metabolite, derivative, phar maceutically acceptable salt, pharmaceutical product, poly morph, crystal, impurity, N-oxide, ester, hydrate or any 25 combination thereof, represented by the structure of For mula III:

III

wherein 30 A is a 5-14 membered saturated or unsaturated, Substi tuted or unsubstituted carbocyclic or heterocyclic ring which is optionally a fused ring system, or a combination thereof. wherein the saturated or unsaturated carbocyclic or hetero cyclic ring are optionally substituted by 1 to 5 substituents 35 independently selected from R or OR"; and X is O or S; or A is nothing and N forms a double bond with the cyclic carbon and X is OH or OCHCH-heterocycle in which the A, X, R. R. R. R. R. and R' are as described above, heterocycle is a 3-7 membered saturated or unsaturated, wherein if X is oxo and A is phenyl, then A is not substituted substituted or unsubstituted heterocyclic ring: 40 with: R. R. R. R. Rio, R are independently selected from NHCOR and halogen without further substitution; or hydrogen, aldehyde, COOH, -C(=NH) OH, CHNOH, NHCOR and an alkyl without further substitution. CH=CHCOH, CH=CHCOR, -CH=CH, hydroxy alkyl, halogen, hydroxyl, alkoxy, cyano, nitro, CF, NH, In one embodiment, A is 4-Ph-OMe, 4-Ph-OH, SH, COR, COOR, OCOR, alkenyl, 45 allyl, 2-methylallyl, alkynyl, propargyl, OSOCF, OSOCH. NHR, NHCOR, N(R), sulfonamide, SOR, R6 alkyl, haloalkyl, aryl, phenyl, benzyl, protected hydroxyl, OR" OCHCHNRRs, Z-Alk-NRRs, Z-Alk-heterocycle or OCHCH-heterocycle in which the heterocycle is a 3-7 membered Saturated or unsaturated. Substituted or unsubsti 50 tuted heterocyclic ring; R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, Rs CHF, CHF, CF, CFCF, aryl, phenyl, benzyl, -Ph-CF, -Ph-CHF, -Ph-CHF, -Ph-CFCF, halogen, alkenyl, CN, NO, or OH: 55 R. R. R. Rs, are independently selected from hydrogen, R" is hydrogen, Alk, or COR; aldehyde, COOH, C(-NH) OH CHNOH, R" is hydrogen, Alk, or COR CH=CHCOH, CH=CHCOR CH=CH, hydroxy Ra and Rs are independently hydrogen, phenyl, benzyl, an alkyl, halogen, hydroxyl, alkoxy, cyano, nitro, CFs, NH2, alkyl group of 1 to 6 carbon atoms, a 3 to 7 member 4-Ph-OMe, 4-Ph-OH, SH, COR, COOR, OCOR, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; 60 allyl, 2-methylallyl, alkynyl, propargyl, OSOCF, OSOCH, NHR, NHCOR, N(R), sulfonamide, SOR, Z is O, NH, CH, or alkyl, haloalkyl, aryl, phenyl, benzyl, protected hydroxyl, OCHCHNRRs, Z-Alk-Q, Z-Alk-NRRs, Z-Alk-hetero cycle or OCHCH-heterocycle in which the heterocycle is 1s1 65 a 3-7 membered saturated or unsaturated, substituted or unsubstituted heterocyclic ring; R" is hydrogen, Alk, or COR; US 9,623,021 B2 17 18 In another embodiment, if A is In one embodiment, the compound of Formula I may be represented by the structure of Formula IV: R6 IV OR" (R3) O 2A RO X^n 1S-X Rs 10 d OR" A 21 ex (RI) (R2) in X is an oxo group and Rio is a benzene ring, then Ro is not COOR, if R is an ester residue or CONRRs. In one 15 wherein embodiment of the compound of Formula III, A is nothing, R. R. R. are independently hydrogen, aldehyde, COOH, N forms a double bond with the cyclic carbon and X is C(-NH) OH, CHNOH, CH=CHCOH, OCHCH-heterocycle in which the heterocycle is a 3-7 CH=CHCOR, —CH=CH, hydroxyalkyl, halogen, membered heterocycloalkyl. In one embodiment, when X is hydroxyl, alkoxy, cyano, nitro, CFs, NH, 4-Ph-OMe, 4-Ph OCHCH-heterocycle, the heterocycle is substituted or OH, SH, COR, COOR, OCOR, alkenyl, allyl, 2-methylallyl, unsubstituted piperidine, pyrrolidine, morpholine or pipera alkynyl, propargyl, OSOCF, OSOCH, NHR, NHCOR, N(R), sulfonamide, SOR, alkyl, haloalkyl, aryl, phenyl, Zine. In another embodiment, when R. R. R. are indepen benzyl, protected hydroxyl, OCHCHNRRs, Z-Alk-Q, dently Z-Alk-heterocycle or, in another embodiment, Z-Alk-NRRs, Z-Alk-heterocycle or OCHCH-heterocycle OCHCH-heterocycle, either heterocycle may be substi 25 in which the heterocycle is a 3-7 membered saturated or tuted or unsubstituted piperidine, pyrrolidine, morpholine or unsaturated, Substituted or unsubstituted heterocyclic ring; piperazine. In another embodiment, when R and Rs are R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, independently a 3 to 7 membered heterocycloalkyl, either CHF, CHF, CF, CFCF, aryl, phenyl, benzyl, -Ph-CF, heterocycle may be substituted or unsubstituted piperidine, -Ph-CHF, -Ph-CHF, -Ph-CFCF, halogen, alkenyl, CN, 30 NO, or OH: pyrrolidine, morpholine or piperazine. In another embodi R" is hydrogen, Alk or COR; ment, any heterocycle is optionally substituted by one or R" is hydrogen, Alk or COR; more Substituents comprising halogen, cyano, nitro, COOH, Ra and Rs are independently hydrogen, phenyl, benzyl, an COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, het alkyl group of 1 to 6 carbon atoms, a 3 to 7 member erocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alky 35 cycloalkyl heterocycloalkyl, aryl or heteroaryl group; lamino, N.N dialkylamino, aminoalkyl, haloalkyl, aryl, het Z is O, NH, CH, or eroaryl, alkoxy or haloalkoxy, wherein R is as defined for Formula III.

40 1s-1 In another embodiment of the compound of Formula III, Ro is a halogen. In another embodiment Ro is a bromide. Q is SOH, COH, COR, NO, tetrazole, SONH, or SONHR: In another embodiment Ro is a chloride. In another embodi n is an integer between 1-3: ment Ro is a fluoride. In another embodiment Ro is an 45 m is an integer between 1-2; iodide. In another embodiment Ro is hydrogen. In another p is an integer between 1-4; and embodiment Ro is a cyano. In another embodiment, Ro is Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons. a phenyl. In another embodiment, Ro is —CH=CH-CH. In some embodiments the NRBA of Formula IV is an In another embodiment, Ro is —CH=CH2. In another 50 estrogen receptor ligand compound. In one embodiment, the embodiment, Ro is —CH=CH-COOEt. In another estrogen receptor ligand compound is a selective estrogen receptor modulator (SERM). In one embodiment, the estro embodiment R is a hydroxyl group. In another embodiment gen receptor ligand compound is a selective estrogen recep R is hydrogen. In another embodiment R is O—(CO)-Ph tor B modulator (B-SERM). In one embodiment, the estro CF. In another embodiment R is COOH. In another 55 gen receptor ligand compound is an estrogen receptor embodiment R is COOMe. In another embodiment R, is a agonist. In one embodiment, the estrogen receptor ligand compound is an estrogen receptor B (ERB) agonist. In one halogen. In another embodiment R, is fluoride. In another embodiment, the estrogen receptor ligand compound is an embodiment R, is chloride. In another embodiment R is estrogen receptor B (ERB) antagonist. bromide. In another embodiment R, is iodide. In another 60 In another embodiment of the compound of Formula IV. embodiment R. R. R., and Rs are hydrogens. In another R is a halogen. In another embodiment R is a bromide. In embodiment R is H. In another embodiment R' is a methyl another embodiment R is a chloride. In another embodi ment R is a fluoride. In another embodiment R is an iodide. group. In another embodiment R is a COMe. In another In another embodiment R is hydrogen. In another embodi embodiment R" is H. In another embodiment R" is a methyl 65 ment R is a cyano. In another embodiment, R is a phenyl. group. In another embodiment R" is COMe. In another In another embodiment, R is —CH=CH-CH. In another embodiment R. R. R. R. Rs. Ro and R are hydrogens. embodiment, R is —CH=CH2. In another embodiment, R US 9,623,021 B2 19 20 is —CH=CH-COOEt. In another embodiment R is Q is SOH, COH, COR, NO, tetrazole, SONH or O-(CO)-Ph-CF. In another embodiment R is COOH. In SONHR: another embodiment R is COOMe. In another embodiment n is an integer between 1-3: R is a hydroxyl group. In another embodiment R is m is an integer between 1-2; hydrogen. In another embodiment R is halogen. In another p is an integer between 1-4; and embodiment R is fluoride. In another embodiment R is Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 chloride. In another embodiment R is bromide. In another carbons or cyclic alkyl of 3-8 carbons. embodiment R is iodide. In another embodiment R is In some embodiments the NRBA of Formula V is an hydrogen. In another embodiment R is H. In another estrogen receptor ligand compound. In one embodiment, the embodiment R is a methyl group. In another embodiment R' estrogen receptor ligand compound is a selective estrogen is COMe. In another embodiment R" is H. In another 10 receptor modulator (SERM). In one embodiment, the estro embodiment R" is a methyl group. In another embodiment gen receptor ligand compound is a selective estrogen recep R" is COMe. In another embodiment, when R. R. R. are tor modulator (B-SERM). In one embodiment, the estrogen independently Z-Alk-heterocycle or, in another embodi receptor ligand compound is an estrogen receptoragonist. In ment, OCHCH-heterocycle, either heterocycle may be one embodiment, the estrogen receptor ligand compound is Substituted or unsubstituted piperidine, pyrrolidine, morpho 15 an estrogen receptor B (ERB) agonist. In one embodiment, line or piperazine. In another embodiment, when R and Rs the estrogen receptor ligand compound is an estrogen recep are independently a 3 to 7 membered heterocycloalkyl, tor (ERB) antagonist. either heterocycle may be substituted or unsubstituted pip In another embodiment of the compound of Formula V. eridine, pyrrolidine, morpholine or piperazine. In another R is a halogen. In another embodiment R is a bromide. In embodiment, the heterocycles are optionally substituted by another embodiment R is a chloride. In another embodi one or more substituents comprising halogen, cyano, nitro, ment R is a fluoride. In another embodiment R is an iodide. COOH, COOR, NHCOR, hydroxyl, amine, alkyl, In another embodiment R is hydrogen. In another embodi cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, ment R is a cyano. In another embodiment, R is a phenyl. alkylthio, alkylamino, N.N dialkylamino, aminoalkyl, In another embodiment, R is —CH=CH-CH. In another 25 embodiment, R is —CH=CH. In another embodiment, R. haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy, wherein R is —CH=CH-COOEt. In another embodiment R is is as defined for Formula IV. O—(CO)-Ph-CF. In another embodiment R is COOH. In In another embodiment, the compound of formula II may another embodiment R is COOMe. In another embodiment be represented by the structure of Formula V: R is a hydroxyl group. In another embodiment R is hydrogen. In another embodiment R is halogen. In another 30 embodiment R is fluoride. In another embodiment R is OR" V chloride. In another embodiment R is bromide. In another O N embodiment R is iodide. In another embodiment R is hydrogen. In another embodiment R is H. In another (RI) embodiment R' is a methyl group. In another embodiment R' XN N 1.x 35 is a COMe group In another embodiment R" is H. In another d (R3) embodiment R" is a methyl group. In another embodiment RO 2n 2x1 R" is a COMe. In another embodiment, when R. R. Rare (R2) independently Z-Alk-heterocycle or, in another embodi ment, OCHCH-heterocycle, either heterocycle may be 40 Substituted or unsubstituted piperidine, pyrrolidine, morpho wherein line or piperazine. In another embodiment, when R and Rs R. R. Rare independently hydrogen, aldehyde, COOH, are independently a 3 to 7 membered heterocycloalkyl, C(-NH) OH, CHNOH, CH=CHCOH, either heterocycle may be substituted or unsubstituted pip CH=CHCOR, —CH=CH, hydroxyalkyl, halogen, eridine, pyrrolidine, morpholine or piperazine. In another hydroxyl, alkoxy, cyano, nitro, CF, NH, 4-Ph-OMe, 4-Ph 45 embodiment, any heterocycle is optionally substituted by OH, SH, COR, COOR, OCOR, alkenyl, allyl, 2-methylallyl, one or more substituents comprising halogen, cyano, nitro, alkynyl, propargyl, OSOCF, OSOCH, NHR, NHCOR, COOH, COOR, NHCOR, hydroxyl, amine, alkyl, N(R), sulfonamide, SOR, alkyl, haloalkyl, aryl, phenyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, benzyl, protected hydroxyl, OCH2CHNRRs, Z-Alk-Q, alkylthio, alkylamino, N.N dialkylamino, aminoalkyl, Z-Alk-NRRs, Z-Alk-heterocycle or OCHCH-heterocycle 50 haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy; and R is as in which the heterocycle is a 3-7 membered saturated or defined for Formula V. unsaturated, Substituted or unsubstituted heterocyclic ring; In another embodiment, the compound of formula III may R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, be represented by the structure of Formula VI: CHF, CHF, CF, CFCF, aryl, phenyl, benzyl, -Ph-CF, -Ph-CHF, -Ph-CHF, -Ph-CFCF, halogen, alkenyl, CN, 55 NO, or OH: VI R" is hydrogen, Alk or COR; R6 R" is hydrogen, Alk or COR; R3 OR" Ra and Rs are independently hydrogen, phenyl, benzyl, an R O alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; 60 R Z is O, NH, CH, or N R R8 RO 2 Ro 1s1 65 R11 R10 US 9,623,021 B2 21 22 wherein embodiment R. R. R. R. Rs. Ro and R are hydrogens. R. R. R. R. R-7, Rs. R. Rio, R are independently In another embodiment, when R. R. R. R. R. R. R. selected from hydrogen, aldehyde, COOH, - C(=NH)— Rio R are independently Z-Alk-heterocycle or, in another OH, CHNOH, CH=CHCOH, CH=CHCOR, embodiment, OCHCH-heterocycle, either heterocycle —CH=CH2 hydroxyalkyl, halogen, hydroxyl, alkoxy, may be substituted or unsubstituted piperidine, pyrrolidine, cyano, nitro, CFs, NH, 4-Ph-OMe, 4-Ph-OH, SH, COR, morpholine or piperazine. In another embodiment, when R. COOR, OCOR, alkenyl, allyl, 2-methylallyl, alkynyl, prop and Rs are independently a 3 to 7 membered heterocy argyl, OSOCF, OSOCH, NHR, NHCOR, N(R), sulfo cloalkyl, either heterocycle may be substituted or unsubsti namide, SOR, alkyl, haloalkyl, aryl, phenyl, benzyl, pro tuted piperidine, pyrrolidine, morpholine or piperazine. In tected hydroxyl, OCHCHNRRs, Z-Alk-Q, Z-Alk 10 another embodiment, any heterocycle is optionally Substi NRRs, Z-Alk-heterocycle or OCHCH-heterocycle in tuted by one or more Substituents comprising halogen, which the heterocycle is a 3-7 membered saturated or cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, unsaturated, Substituted or unsubstituted heterocyclic ring; alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, R" is hydrogen, Alk or COR; alkanoyl, alkylthio, alkylamino, N.N dialkylamino, amino R" is hydrogen, Alk or COR; 15 Ra and Rs are independently hydrogen, phenyl, benzyl, an alkyl, haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy, alkyl group of 1 to 6 carbon atoms, a 3 to 7 member wherein R is as defined for Formula VI. cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; In one embodiment, the compound of formula I may be Z is O, NH, CH, or represented by the structure of Formula VII:

VII 1s1 (R3)

Q is SOH, COH, COR, NO, tetrazole, SONH or 25 RO S O p SONHR: X1S 1s-X t R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, d OR CHF, CHF, CF, CFCF, aryl, phenyl, benzyl, -Ph-CF, A 21 ex -Ph-CHF, -Ph-CHF, -Ph-CFCF, halogen, alkenyl, CN, (R), (R2) in NO, or OH and; 30 and Alk is a linear alkyl of 1-7 carbons, branched alkyl of wherein 1-7 carbons or cyclic alkyl of 3-8 carbons; R. R. Rare independently hydrogen, aldehyde, COOH, wherein, if R is a benzene ring, then: C(-NH) OH, CHNOH, CH=CHCOH, R is not COOR, if R is hydrogen or an ester residue; or CH=CHCOR, —CH=CH, hydroxyalkyl, halogen, R is not CONRRs, if R and Rs are as described above. 35 hydroxyl, alkoxy, cyano, nitro, CFs, NH, 4-Ph-OMe, 4-Ph In some embodiments the NRBA of Formula VI is an OH, SH, COR, COOR, OCOR, alkenyl, allyl, 2-methylallyl, estrogen receptor ligand compound. In one embodiment, the alkynyl, propargyl, OSOCF, OSOCH, NHR, NHCOR, estrogen receptor ligand compound is a selective estrogen N(R), sulfonamide, SOR, alkyl, haloalkyl, aryl, phenyl, receptor modulator (SERM). In one embodiment, the estro benzyl, protected hydroxyl, OCH2CHNRRs, Z-Alk-Q, gen receptor ligand compound is a selective estrogen recep 40 Z-Alk-NRRs, Z-Alk-heterocycle or OCHCH-heterocycle tor B modulator (B-SERM). In one embodiment, the estro in which the heterocycle is a 3-7 membered saturated or gen receptor ligand compound is an estrogen receptor unsaturated, Substituted or unsubstituted heterocyclic ring; agonist. In one embodiment, the estrogen receptor ligand R" is hydrogen, Alk or COR; compound is an estrogen receptor B (ERB) agonist. In one R" is hydrogen, Alk or COR; embodiment, the estrogen receptor ligand compound is an 45 Ra and Rs are independently hydrogen, phenyl, benzyl, an estrogen receptor B (ERB) antagonist. alkyl group of 1 to 6 carbon atoms, a 3 to 7 member In another embodiment of the compound of Formula VI, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; Ro is a halogen. In another embodiment Ro is a bromide. Z is O, NH, CH, or In another embodiment Ro is a chloride. In another embodi ment R is a fluoride. In another embodiment Ro is an 50 iodide. In another embodiment Ro is hydrogen. In another embodiment Ro is a cyano. In another embodiment, Ro is 1s1 a phenyl. In another embodiment, Ro is —CH=CH-CH. In another embodiment, Ro is —CH=CH. In another Q is SOH, COH, COR, NO, tetrazole, SONH, or embodiment, Ro is —CH=CH-COOEt. In another 55 SONHR: embodiment R is a hydroxyl group. In another embodiment R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, R is hydrogen. In another embodiment R is O—(CO)-Ph CHF, CHF, CF, CFCF, aryl, phenyl, benzyl, -Ph-CF, CF. In another embodiment R is COOH. In another -Ph-CHF, -Ph-CHF, -Ph-CFCF, halogen, alkenyl, CN, embodiment R is COOMe. In another embodiment R, is a NO, or OH: halogen. In another embodiment R-7 is fluoride. In another 60 n is an integer between 1-3: embodiment R, is chloride. In another embodiment R is m is an integer between 1-2; bromide. In another embodiment R, is iodide. In another p is an integer between 1-4; and embodiment R. R. R., and Rs are hydrogens. In another Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 embodiment R is H. In another embodiment R' is a methyl carbons or cyclic alkyl of 3-8 carbons. group. In another embodiment R is a COMe. In another 65 In some embodiments the NRBA of Formula VII is an embodiment R" is H. In another embodiment R" is a methyl estrogen receptor ligand compound. In one embodiment, the group. In another embodiment R" is COMe. In another estrogen receptor ligand compound is a selective estrogen US 9,623,021 B2 23 24 receptor modulator (SERM). In one embodiment, the estro in which the heterocycle is a 3-7 membered saturated or gen receptor ligand compound is a selective estrogen recep unsaturated, Substituted or unsubstituted heterocyclic ring; tor B modulator (B-SERM). In one embodiment, the estro R" is hydrogen, Alk or COR; gen receptor ligand compound is an estrogen receptor R" is hydrogen, Alk or COR; agonist. In one embodiment, the estrogen receptor ligand Ra and Rs are independently hydrogen, phenyl, benzyl, an compound is an estrogen receptor B (ERB) agonist. In one alkyl group of 1 to 6 carbon atoms, a 3 to 7 member embodiment, the estrogen receptor ligand compound is an cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; estrogen receptor B (ERB) antagonist. Z is O, NH, CH, or In another embodiment of the compound of Formula VII, R is a halogen. In another embodiment R is a bromide. In 10 another embodiment R is a chloride. In another embodi 1s1 ment R is a fluoride. In another embodiment R is an iodide. In another embodiment R is hydrogen. In another embodi Q is SOH, COH, COR, NO, tetrazole, SONH, or ment R is a cyano. In another embodiment, R is a phenyl. 15 SONHR: In another embodiment, R is —CH=CH-CH. In another R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, embodiment, R is —CH=CH2. In another embodiment, R CHF, CHF, CF, CFCF, aryl, phenyl, benzyl, -Ph-CF, is —CH=CH-COOEt. In another embodiment R is -Ph-CHF, -Ph-CHF, -Ph-CFCF, halogen, alkenyl, CN, O-(CO)-Ph-CF. In another embodiment R is COOH. In NO, or OH: another embodiment R is COOMe. In another embodiment n is an integer between 1-3: R is a hydroxyl group. In another embodiment R is m is an integer between 1-2; hydrogen. In another embodiment R is halogen. In another p is an integer between 1-4; and embodiment R is fluoride. In another embodiment R is Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 chloride. In another embodiment R is bromide. In another carbons or cyclic alkyl of 3-8 carbons. embodiment R is iodide. In another embodiment R is 25 In some embodiments the NRBA of Formula VIII is an hydrogen. In another embodiment R is H. In another estrogen receptor ligand compound. In one embodiment, the embodiment R is a methyl group. In another embodiment R' estrogen receptor ligand compound is a selective estrogen is COMe. In another embodiment R" is H. In another receptor modulator (SERM). In one embodiment, the estro embodiment R" is a methyl group. In another embodiment gen receptor ligand compound is a selective estrogen recep R" is a COMe. In another embodiment, when R. R. R. are 30 tor modulator (B-SERM). In one embodiment, the estrogen independently Z-Alk-heterocycle or, in another embodi receptor ligand compound is an estrogen receptoragonist. In ment, OCHCH-heterocycle, either heterocycle may be one embodiment, the estrogen receptor ligand compound is Substituted or unsubstituted piperidine, pyrrolidine, morpho an estrogen receptor (ERB) agonist. In one embodiment, the line or piperazine. In another embodiment, when R and Rs estrogen receptor ligand compound is an estrogen receptor B are independently a 3 to 7 membered heterocycloalkyl, 35 (ERB) antagonist. either heterocycle may be substituted or unsubstituted pip In another embodiment of the compound of Formula VIII, eridine, pyrrolidine, morpholine or piperazine. In another R is a halogen. In another embodiment R is a bromide. In embodiment, any heterocycle is optionally substituted by another embodiment R is a chloride. In another embodi one or more substituents comprising halogen, cyano, nitro, ment R is a fluoride. In another embodiment R is an iodide. COOH, COOR, NHCOR, hydroxyl, amine, alkyl, 40 In another embodiment R is hydrogen. In another embodi cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, ment R is a cyano. In another embodiment, R is a phenyl. alkylthio, alkylamino, N.N dialkylamino, aminoalkyl, In another embodiment, R is —CH=CH-CH. In another haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy, and R is as embodiment, R is —CH=CH2. In another embodiment, R defined for Formula VII. is —CH=CH-COOEt. In another embodiment R is In another embodiment, the compound of formula II may 45 O (CO)-Ph-CF. In another embodiment R is COOH. In be represented by the structure of Formula VIII: another embodiment R is COOMe. In another embodiment R is a hydroxyl group. In another embodiment R is hydrogen. In another embodiment R is hydrogen. In another VIII OR" embodiment R is halogen. In another embodiment R is 50 fluoride. In another embodiment R is chloride. In another r embodiment R is bromide. In another embodiment R is ex iodide. In another embodiment R is H. In another embodi (R3) ment R is a methyl group. In another embodiment R is COMe. In another embodiment R" is H. In another embodi 55 ment R" is a methyl group. In another embodiment R" is COMe. In another embodiment, when R. R. R. are inde pendently Z-Alk-heterocycle or, in another embodiment, wherein OCHCH-heterocycle, either heterocycle may be substi R. R. Rare independently hydrogen, aldehyde, COOH, tuted or unsubstituted piperidine, pyrrolidine, morpholine or C(-NH) OH, CHNOH, CH=CHCOH, 60 piperazine. In another embodiment, when R and Rs are CH=CHCOR, —CH=CH, hydroxyalkyl, halogen, independently a 3 to 7 membered heterocycloalkyl, either hydroxyl, alkoxy, cyano, nitro, CF, NH, 4-Ph-OMe, 4-Ph heterocycle may be substituted or unsubstituted piperidine, OH, SH, COR, COOR, OCOR, alkenyl, allyl, 2-methylallyl, pyrrolidine, morpholine or piperazine. In another embodi alkynyl, propargyl, OSOCF, OSOCH, NHR, NHCOR, ment, any heterocycle is optionally substituted by one or N(R), sulfonamide, SOR, alkyl, haloalkyl, aryl, phenyl, 65 more Substituents comprising halogen, cyano, nitro, COOH, benzyl, protected hydroxyl, OCH2CHNRRs, Z-Alk-Q, COOR, NHCOR, hydroxyl, amine, alkyl, cycloalkyl, het Z-Alk-NRRs, Z-Alk-heterocycle or OCHCH-heterocycle erocycloalkyl, alkenyl, alkynyl, alkanoyl, alkylthio, alky US 9,623,021 B2 25 26 lamino, N.N dialkylamino, aminoalkyl, haloalkyl, aryl, het iodide. In another embodiment Ro is hydrogen. In another eroaryl, alkoxy or haloalkoxy, and R is as defined for embodiment Ro is a cyano. In another embodiment, Ro is Formula VIII. a phenyl. In another embodiment, Ro is —CH=CH-CH. In another embodiment, the compound of formula III may In another embodiment, Ro is —CH=CH2. In another be represented by the structure of Formula IX: embodiment, Ro is —CH=CH-COOEt. In another embodiment R is a hydroxyl group. In another embodiment R is hydrogen. In another embodiment R is O—(CO)-Ph IX CF. In another embodiment R is COOH. In another R6 embodiment R is COOMe. In another embodiment R, is a R3 OR" 10 halogen. In another embodiment R, is fluoride. In another R2 S embodiment R, is chloride. In another embodiment R is R bromide. In another embodiment R, is iodide. In another N R7 embodiment R. R. R., and Rs are hydrogens. In another embodiment R is H. In another embodiment R' is a methyl Rs 15 RO 2 R9 group. In another embodiment R is a COMe. In another embodiment R' is H. In another embodiment R" is a methyl R11 R10 group. In another embodiment R" is COMe. In another embodiment R. R. R. R. Rs. Ro and R are hydrogens. In another embodiment, when R. R. R. R. R7, Rs. Ro, wherein Rio R are independently Z-Alk-heterocycle or, in another R. R. R. R. R-7, Rs. R. Rio, R are independently embodiment, OCHCH-heterocycle, either heterocycle selected from hydrogen, aldehyde, COOH, - C(=NH)— may be substituted or unsubstituted piperidine, pyrrolidine, OH, CHNOH, CH=CHCOH, CH=CHCOR, morpholine or piperazine. In another embodiment, when R. —CH=CH2 hydroxyalkyl, halogen, hydroxyl, alkoxy, and Rs are independently a 3 to 7 membered heterocy cyano, nitro, CFs, NH, 4-Ph-OMe, 4-Ph-OH, SH, COR, 25 cloalkyl, either heterocycle may be substituted or unsubsti COOR, OCOR, alkenyl, allyl, 2-methylallyl, alkynyl, prop tuted piperidine, pyrrolidine, morpholine or piperazine. In argyl, OSOCF, OSOCH, NHR, NHCOR, N(R), sulfo another embodiment, any heterocycle is optionally Substi namide, SOR, alkyl, haloalkyl, aryl, phenyl, benzyl, pro tuted by one or more Substituents comprising halogen, tected hydroxyl, OCHCHNRRs, Z-Alk-Q, Z-Alk cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, NRRs, 30 alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, Z-Alk-heterocycle or OCHCH-heterocycle in which the alkanoyl, alkylthio, alkylamino, N.N dialkylamino, amino heterocycle is a 3-7 membered saturated or unsaturated, alkyl, haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy, and substituted or unsubstituted heterocyclic ring: R is as defined for Formula IX. R" is hydrogen, Alk or COR; In one embodiment, the present invention provides a R" is hydrogen, Alk or COR; 35 NRBA or its prodrug, analog, isomer, metabolite, derivative, Ra and Rs are independently hydrogen, phenyl, benzyl, an pharmaceutically acceptable salt, pharmaceutical product, alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; polymorph, crystal, impurity, N-oxide, ester, hydrate or any Z is O, NH, CH, or combination thereof, represented by the structure of For 40 mula X:

1s1

Q is SOH, COH, COR, NO, tetrazole, SONH or 45 SONHR: R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CHF, CHF, CF, CFCF, aryl, phenyl, benzyl, -Ph-CF, -Ph-CHF, -Ph-CHF. -Ph-CFCF, halogen, alkenyl, CN, NO, or OH; and 50 Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 wherein carbons or cyclic alkyl of 3-8 carbons. A is a 5-14 membered saturated or unsaturated, Substi In some embodiments the NRBA of Formula IX is an tuted or unsubstituted carbocyclic or heterocyclic ring which estrogen receptor ligand compound. In one embodiment, the is optionally a fused ring system, or a combination thereof. estrogen receptor ligand compound is a selective estrogen 55 wherein the saturated or unsaturated carbocyclic or hetero receptor modulator (SERM). In one embodiment, the estro cyclic ring are optionally substituted by 1 to 5 substituents gen receptor ligand compound is a selective estrogen recep independently selected from R or OR"; and X is O or S; or tor B modulator (B-SERM). In one embodiment, the estro A is nothing, N forms a double bond with the cyclic gen receptor ligand compound is an estrogen receptor carbon and X is OH or OCHCH-heterocycle in which the agonist. In one embodiment, the estrogen receptor ligand 60 heterocycle is a 3-7 membered saturated or unsaturated, compound is an estrogen receptor B (ERB) agonist. In one substituted or unsubstituted heterocyclic ring: embodiment, the estrogen receptor ligand compound is an R. R. Rare independently hydrogen, aldehyde, COOH, estrogen receptor B (ERB) antagonist. C(-NH) OH, CHNOH, CH=CHCOH, In another embodiment of the compound of Formula IX, CH=CHCOR, —CH=CH, hydroxyalkyl, halogen, Ro is a halogen. In another embodiment Ro is a bromide. 65 hydroxyl, alkoxy, cyano, nitro, CFs, NH, 4-Ph-OMe, 4-Ph In another embodiment Ro is a chloride. In another embodi OH, SH, COR, COOR, OCOR, alkenyl, allyl, 2-methylallyl, ment R is a fluoride. In another embodiment Ro is an alkynyl, propargyl, OSOCF, OSOCH, NHR, NHCOR, US 9,623,021 B2 27 28 N(R), sulfonamide, SOR, alkyl, haloalkyl, aryl, phenyl, In one embodiment, A is benzyl, protected hydroxyl, OCHCHNRRs, Z-Alk-Q, Z-Alk-NRRs, Z-Alk-heterocycle or OCHCH-heterocycle in which the heterocycle is a 3-7 membered saturated or (R3) unsaturated, Substituted or unsubstituted heterocyclic ring; sas R" is hydrogen, Alk or COR; R" is hydrogen, Alk or COR; ex Ra and Rs are independently hydrogen, phenyl, benzyl, an (OR"), alkyl group of 1 to 6 carbon atoms, a 3 to 7 member 10 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; p is an integer between 1-5; i is an integer between 0-4: R" Z is O, NH, CH, or is hydrogen, Alk or COR; and R is hydrogen, aldehyde, COOH, C(-NH) OH, CHNOH, CH=CHCOH, —CH=CH2 hydroxyalkyl, halogen, hydroxyl, alkoxy, 15 cyano, nitro, CFs, NH, 4-Ph-OMe, 4-Ph-OH, SH, COR, 1s1 COOR, OCOR, alkenyl, allyl, 2-methylallyl, alkynyl, prop argyl, OSOCF, OSOCH, NHR, NHCOR, N(R), sulfo namide, SOR, alkyl, haloalkyl, aryl, phenyl, benzyl, pro Q is SOH, COH, COR, NO, tetrazole, SONH or tected hydroxyl, OCHCHNRRs, Z-Alk-Q, Z-Alk SONHR: NRRs. Z-Alk-heterocycle or OCHCH-heterocycle in R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, which the heterocycle is a 3-7 membered saturated or CHF, CHF, CF, CFCF, aryl, phenyl, benzyl, -Ph-CF, unsaturated, Substituted or unsubstituted heterocyclic ring. -Ph-CHF, -Ph-CHF, -Ph-CFCF, halogen, alkenyl, CN, In one embodiment of the compound of Formula X, A is NO, or OH: 25 nothing, N forms a double bond with the cyclic carbon and h is an integer between 0-3: X is OCHCH-heterocycle in which the heterocycle is a 3-7 membered heterocycloalkyl. In one embodiment, when X is n is an integer between 1-4; OCHCH-heterocycle, the heterocycle is substituted or m is an integer between 1-2; and unsubstituted piperidine, pyrrolidine, morpholine or pipera Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 30 Zine. In another embodiment, when R. R. R. are indepen carbons or cyclic alkyl of 3-8 carbons. dently Z-Alk-heterocycle or, in another embodiment, In some embodiments the NRBA of Formula X is an OCHCH-heterocycle, either heterocycle may be substi estrogen receptor ligand compound. In one embodiment, the tuted or unsubstituted piperidine, pyrrolidine, morpholine or estrogen receptor ligand compound is a selective estrogen 35 piperazine. In another embodiment, when Ra and Rs are receptor modulator (SERM). In one embodiment, the estro independently a 3 to 7 membered heterocycloalkyl, either gen receptor ligand compound is a selective estrogen recep heterocycle may be substituted or unsubstituted piperidine, tor B modulator (B-SERM). In one embodiment, the estro pyrrolidine, morpholine or piperazine. In another embodi gen receptor ligand compound is an estrogen receptor ment, any heterocycle is optionally substituted by one or agonist. In one embodiment, the estrogen receptor ligand 40 more Substituents comprising halogen, cyano, nitro, COOH, compound is an estrogen receptor B (ERB) agonist. In one COOR, NHCOR, hydroxyl, amine, alkyl, haloalkyl, embodiment, the estrogen receptor ligand compound is an cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, estrogen receptor B (ERB) antagonist. alkylthio, alkylamino, N.N dialkylamino, aminoalkyl, haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy, and R is as In one embodiment, the present invention provides a 45 defined for Formula X. NRBA or its prodrug, analog, isomer, metabolite, derivative, In another embodiment of the compound of Formula X, pharmaceutically acceptable salt, pharmaceutical product, R is a halogen. In another embodiment R is a bromide. In polymorph, crystal, impurity, N-oxide, ester, hydrate or any another embodiment R is a chloride. In another embodi combination thereof, represented by the structure of For ment R is a fluoride. In another embodiment R is an iodide. mula X: 50 In another embodiment R is hydrogen. In another embodi ment R is a cyano. In another embodiment, R is a phenyl. In another embodiment, R is —CH=CH-CH. In another embodiment, R is —CH=CH. In another embodiment, R. is —CH=CH-COOEt. In another embodiment R is 55 O (CO)-Ph-CF. In another embodiment R is COOH. In another embodiment R is COOMe. In another embodiment R is a hydroxyl group. In another embodiment R is hydrogen. In another embodiment R is halogen. In another 60 embodiment R is fluoride. In another embodiment R is chloride. In another embodiment R is bromide. In another wherein A, X, R. R. R', n, m and h are as described above, embodiment R is iodide. In another embodiment R is however, hydrogen. In another embodiment R is H. In another if X is oxo and A is phenyl, then A is not substituted with: embodiment R' is a methyl group. In another embodiment R' 65 is COMe. In another embodiment R" is H. In another NHCOR and halogen without further substitution, or embodiment R" is a methyl group. In another embodiment NHCOR and an alkyl without further substitution. R" is COMe. US 9,623,021 B2 29 30 In one embodiment, the compound of Formula X may be represented by the structure of Formula XI: XIa OR" OR O 21

XI 5 i-(R), (R3) N N N (R)- it RO 2n 2 (OR)N(N O 1sxC d (OR"), 10 R2 A-4NeX (RI), (R2) wherein n is 1 or 2: wherein 15 p is 0, 1, 2, 3 or 4; and R. R. R. are independently hydrogen, aldehyde, COOH, R. R. R. R' and R" are as described above for Formula C(-NH) OH, CHNOH, CH=CHCOH, I. CH=CHCOR, —CH=CH, hydroxyalkyl, halogen, or its prodrug, analog, isomer, metabolite, derivative, hydroxyl, alkoxy, cyano, nitro, CF, NH, 4-Ph-OMe, 4-Ph pharmaceutically acceptable salt, pharmaceutical product, OH, SH, COR, COOR, OCOR, alkenyl, allyl, 2-methylallyl, polymorph, crystal, impurity, N-oxide, ester, hydrate or any alkynyl, propargyl, OSOCF, OSOCH, NHR, NHCOR, combination thereof. N(R), sulfonamide, SOR, alkyl, haloalkyl, aryl, phenyl, In some embodiments the NRBA of Formula XIa is an benzyl, protected hydroxyl, OCHCHNRRs, Z-Alk-Q, estrogen receptor ligand compound. In one embodiment, the Z-Alk-NRRs, Z-Alk-heterocycle or OCHCH-heterocycle estrogen receptor ligand compound is a selective estrogen in which the heterocycle is a 3-7 membered saturated or 25 receptor modulator (SERM). In one embodiment, the estro unsaturated, Substituted or unsubstituted heterocyclic ring; gen receptor ligand compound is a selective estrogen recep tor B modulator (B-SERM). In one embodiment, the estro R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, gen receptor ligand compound is an estrogen receptor CHF, CHF, CF, CFCF, aryl, phenyl, benzyl, -Ph-CF, agonist. In one embodiment, the estrogen receptor ligand -Ph-CHF, -Ph-CHF. -Ph-CFCF, halogen, alkenyl, CN, compound is an estrogen receptor B (ERB) agonist. In one NO, or OH: 30 embodiment, the estrogen receptor ligand compound is an R" is hydrogen, Alk or COR; estrogen receptor f3 (ERB) antagonist. R" is hydrogen, Alk or COR; In another embodiment, the compound of formula XI may Ra and Rs are independently hydrogen, phenyl, benzyl, an be represented by the structure of Formula XIb: alkyl group of 1 to 6 carbon atoms, a 3 to 7 member 35 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; XIb Z is O, NH, CH, or OR" R O

40 1s1 N R3 RO 2 Q is SOH, COH, COR, NO, tetrazole, SONH or R2 SONHR: 45 h is an integer between 0-3: i is an integer between 0-4. wherein R. R. R. R' and R" are as described above for Formula XI; n is an integer between 1-4; or its prodrug, analog, isomer, metabolite, derivative, m is an integer between 1-2; 50 pharmaceutically acceptable salt, pharmaceutical product, p is an integer between 0-5; and polymorph, crystal, impurity, N-oxide, ester, hydrate or any combination thereof. Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 In some embodiments the NRBA of Formula XIb is an carbons, or cyclic alkyl of 3-8 carbons. estrogen receptor ligand compound. In one embodiment, the In some embodiments the NRBA of Formula XI is an 55 estrogen receptor ligand compound is a selective estrogen estrogen receptor ligand compound. In one embodiment, the receptor modulator (SERM). In one embodiment, the estro estrogen receptor ligand compound is a selective estrogen gen receptor ligand compound is a selective estrogen recep receptor modulator (SERM). In one embodiment, the estro tor B modulator (B-SERM). In one embodiment, the estro gen receptor ligand compound is a selective estrogen recep gen receptor ligand compound is an estrogen receptor tor B modulator (B-SERM). In one embodiment, the estro 60 agonist. In one embodiment, the estrogen receptor ligand gen receptor ligand compound is an estrogen receptor compound is an estrogen receptor B (ERB) agonist. In one agonist. In one embodiment, the estrogen receptor ligand embodiment, the estrogen receptor ligand compound is an compound is an estrogen receptor B (ERB) agonist. In one estrogen receptor B (ERB) antagonist. embodiment, the estrogen receptor ligand compound is an In one embodiment, R of formula XI, XIa and XIb is a estrogen receptor B (ERB) antagonist. 65 halogen. In another embodiment R is a bromide. In another In one embodiment, the compound of formula XI is embodiment R is a chloride. In another embodiment R is represented by the structure of Formula XIa: a fluoride. In another embodiment R is an iodide. In another US 9,623,021 B2 31 32 embodiment R is hydrogen. In another embodiment R is a Z is O, NH, CH, or cyano. In another embodiment, R is a phenyl. In another embodiment, R is —CH=CH-CH. In another embodi ment, R is —CH=CH2. In another embodiment, R is —CH=CH-COOEt. In one embodiment R of formula 1s1 XI, XIa and XIb is O (CO)-Ph-CF. In another embodi ment R is COOH. In another embodiment R is COOMe. In Q is SOH, COH, COR, NO, tetrazole, SONH, or another embodiment R is a hydroxyl group. In another SONHR: embodiment R is a hydrogen. In one embodiment R of R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, formula XI, XIa and XIb is a hydrogen. In another embodi 10 ment R is a halogen. In another embodiment R is fluoride. CHF, CHF, CF, CFCF, aryl, phenyl, -Ph-CF, -Ph In another embodiment R is chloride. In another embodi CHF. -Ph-CHF, -Ph-CFCF, halogen, alkenyl, CN, NO. ment R is bromide. In another embodiment R is iodide. In or OH: one embodiment R of formula XI, XIa and XIb is H. In n is an integer between 1-3: another embodiment R is a methyl group. In another 15 p is an integer between 1-4; and embodiment R is a COMe. In one embodiment R" of Alk is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 formula XI, XIa and XIb is H. In another embodiment R" is carbons, or cyclic alkyl of 3-8 carbons. a methyl group. In another embodiment R" is a COMe. In In some embodiments the NRBA of Formula XII is an one embodiment h of formula XI, XIa and XIb is 1. In estrogen receptor ligand compound. In one embodiment, the another embodiment his 2. In one embodiment, when R. estrogen receptor ligand compound is a selective estrogen R. R. of formula XI, XIa and XIb are independently receptor modulator (SERM). In one embodiment, the estro Z-Alk-heterocycle or, in another embodiment, OCHCH gen receptor ligand compound is a selective estrogen recep heterocycle, either heterocycle may be substituted or unsub tor B modulator (B-SERM). In one embodiment, the estro stituted piperidine, pyrrolidine, morpholine or piperazine. In gen receptor ligand compound is an estrogen receptor one embodiment, when Ra and Rs of formula XI, XIa and 25 agonist. In one embodiment, the estrogen receptor ligand XIb are independently a 3 to 7 membered heterocycloalkyl, compound is an estrogen receptor B (ERB) agonist. In one either heterocycle may be substituted or unsubstituted pip embodiment, the estrogen receptor ligand compound is an eridine, pyrrolidine, morpholine or piperazine. In another estrogen receptor B (ERB) antagonist. embodiment, any heterocycle is optionally substituted by In another embodiment of the compound of Formula XII, one or more substituents comprising halogen, cyano, nitro, 30 R is a halogen. In another embodiment R is a bromide. In COOH, COOR, NHCOR, hydroxyl, amine, alkyl, another embodiment R is a chloride. In another embodi cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkanoyl, ment R is a fluoride. In another embodiment R is an iodide. alkylthio, alkylamino, N.N dialkylamino, aminoalkyl, In another embodiment R is hydrogen. In another embodi haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy, and R of ment R is a cyano. In another embodiment, R is a phenyl. formula XI, XIa and XIb is as defined for Formula XI. 35 In another embodiment, R is —CH=CH-CH. In another In one embodiment, the present invention provides a embodiment, R is —CH=CH2. In another embodiment, R NRBA or its prodrug, analog, isomer, metabolite, derivative, is —CH=CH-COOEt. In another embodiment R is pharmaceutically acceptable salt, pharmaceutical product, O (CO)-Ph-CF. In another embodiment R is COOH. In polymorph, crystal, impurity, N-oxide, ester, hydrate or any another embodiment R is COOMe. In another embodiment combination thereof, represented by the following structure: 40 R is an hydroxyl group. In another embodiment R is hydrogen. In another embodiment R is halogen. In another XII embodiment R is fluoride. In another embodiment R is OH chloride. In another embodiment R is bromide. In another O 4. embodiment R is iodide. In another embodiment R is 45 hydrogen. In another embodiment p is 1. In another embodi N 1s Sn(R), ment, when R. R. R. are independently Z-Alk-heterocycle or, in another embodiment, OCHCH-heterocycle, either (R)- heterocycle may be substituted or unsubstituted piperidine, HO 21N 21 pyrrolidine, morpholine or piperazine. In another embodi 50 ment, when R and Rs are independently a 3 to 7 membered R heterocycloalkyl, either heterocycle may be substituted or unsubstituted piperidine, pyrrolidine, morpholine or pipera wherein Zine. In another embodiment, any heterocycle is optionally R. R. and R are independently hydrogen, aldehyde, Substituted by one or more substituents comprising halogen, COOH, C(-NH) OH, CHNOH, CH-CHCOH, 55 cyano, nitro, COOH, COOR, NHCOR, hydroxyl, amine, —CH=CH2 hydroxyalkyl, halogen, hydroxyl, alkoxy, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, cyano, nitro, CFs, NH, 4-Ph-OMe, 4-Ph-OH, SH, COR, alkanoyl, alkylthio, alkylamino, N.N dialkylamino, amino COOR, OCOR, alkenyl, allyl, 2-methylallyl, alkynyl, prop alkyl, haloalkyl, aryl, heteroaryl, alkoxy or haloalkoxy, and argyl, OSOCF, OSOCH, NHR, NHCOR, N(R), sulfo R is as defined for Formula XII. namide, SOR, alkyl, haloalkyl, aryl, phenyl, benzyl, pro 60 In one embodiment the NRBA of this invention is tected hydroxyl, OCHCHNRRs, Z-Alk-Q, Z-Alk 4-cyano-6,8-dihydroxy-2-(4-hydroxyphenyl)isoquinolin-1 NRRs, Z-Alk-heterocycle or OCHCH-heterocycle in (2H)-one. In another embodiment the NRBA of this inven which the heterocycle is a 3-7 membered saturated or tion is 4-bromo-6,8-dihydroxy-2-(4-hydroxyphenyl)isoqui unsaturated, Substituted or unsubstituted heterocyclic ring; nolin-1 (2H)-one. In another embodiment the NRBA of this Ra and Rs are independently hydrogen, phenyl, benzyl, an 65 invention is 1-(2-(piperidin-1-yl)ethoxy)isoquinolin-6-ol. In alkyl group of 1 to 6 carbon atoms, a 3 to 7 member another embodiment the NRBA of this invention is 6-hy cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; droxy-2-(4-hydroxyphenyl)isoquinolin-1 (2H)-one. In US 9,623,021 B2 33 34 another embodiment the NRBA of this invention is the NRBA of this invention is 6-methoxy-2-(4-methoxyphe 4-bromo-6-hydroxy-2-(4-hydroxyphenyl)isoquinolin-1 nyl)-1-oxo-1,2-dihydroisoquinoline-8-carbonitrile. In (2H)-one. In another embodiment the NRBA of this inven another embodiment the NRBA of this invention is tion is 4-bromo-2-(4-hydroxyphenyl)-6-methoxyisoquino 4-bromo-6-methoxy-2-(4-methoxyphenyl)-1-oxo-1,2-dihy lin-1 (2H)-one. In another embodiment the NRBA of this droisoquinoline-8-carbonitrile. In another embodiment the invention is 4-bromo-2-(3-fluoro-4-hydroxyphenyl)-6-hy NRBA of this invention is 4-bromo-6-hydroxy-2-(4-hy droxyisoquinolin-1 (2H)-one. In another embodiment the droxyphenyl)-1-oxo-1,2-dihydroisoquinoline-8-carboni NRBA of this invention is 4-bromo-2-(4-fluorophenyl)-6- trile. In another embodiment the NRBA of this invention is hydroxyisoquinolin-1 (2H)-one. In another embodiment the 6,8-dihydroxy-2-(4-hydroxyphenyl)-4-vinylisoquinolin-1 NRBA of this invention is 4-chloro-6-hydroxy-2-(4-hy 10 (2H)-one. In another embodiment the NRBA of this inven droxyphenyl)isoquinolin-1 (2H)-one. In another embodi tion is 6,8-dihydroxy-2-(4-hydroxyphenyl)-1-oxo-1,2-dihy ment the NRBA of this invention is 4-chloro-2-(3-fluoro-4- droisoquinoline-4-carbonitrile or 4-cyano-6,8-dihydroxy-2- hydroxyphenyl)-6-hydroxyisoquinolin-1 (2H)-one. In (4-hydroxyphenyl)isoquinolin-1 (2H)-one. In another another embodiment the NRBA of this invention is 6-hy embodiment the NRBA of this invention is 6-hydroxy-2-(4- droxy-2-(4-hydroxyphenyl)-4-iodoisoquinolin-1 (2H)-one. 15 hydroxyphenyl)-1-oxo-1,2-dihydroisoquinoline-8-carboni In another embodiment the NRBA of this invention is trile. In another embodiment the NRBA of this invention is 4-bromo-6-hydroxy-2-(3-hydroxyphenyl)isoquinolin-1 6-hydroxy-2-(4-hydroxyphenyl)-1-oxo-4-vinyl-1,2-dihy (2H)-one. In another embodiment the NRBA of this inven droisoquinoline-8-carbonitrile. In another embodiment the tion is 8-hydroxy-2-(4-hydroxyphenyl)-6-methoxy-isoqui NRBA of this invention is 4-chloro-6-hydroxy-2-(4-hy nolin-1 (2H)-one. In another embodiment the NRBA of this droxyphenyl)-1-oxo-1,2-dihydroisoquinoline-8-carboni invention is 5-bromo-8-hydroxy-2-(4-hydroxyphenyl)-6- trile. In another embodiment the NRBA of this invention is methoxy-isoquinolin-1 (2H)-one. In another embodiment the 4-bromo-6-methoxy-2-(4-methoxyphenyl)isoquinolin-1 NRBA of this invention is 6,8-dihydroxy-2-(4-hydroxyphe (2H)-one. In another embodiment the NRBA of this inven nyl)-isoquinolin-1 (2H)-one. In another embodiment the tion is 8-hydroxy-6-methoxy-2-(4-methoxyphenyl)isoqui NRBA of this invention is 5-bromo-6,8-dihydroxy-2-(4- 25 nolin-1 (2H)-one. In another embodiment the NRBA of this hydroxyphenyl)isoquinolin-1 (2H)-one. In another embodi invention is 4-chloro-6-methoxy-2-(4-methoxyphenyl)-1- ment the NRBA of this invention is 2-(3-fluoro-4-hydroxy oxo-1,2-dihydroisoquinolin-8-yl trifluoromethanesulfonate. phenyl)-6-hydroxy-4-iodoisoquinolin-1 (2H)-one. In another In another embodiment the NRBA of this invention is embodiment the NRBA of this invention is 4-bromo-6- 4-chloro-6-methoxy-2-(4-methoxyphenyl)-1-oxo-1,2-dihy hydroxy-2-(4-hydroxy-3-methylphenyl)isoquinolin-1 (2H)- 30 droisoquinoline-8-carbonitrile. In another embodiment the one. In another embodiment the NRBA of this invention is NRBA of this invention is isoquinoline-1,6-diol. In another 2-(4-hydroxyphenyl)-6,8-dihydroxy-isoquinoline-1 (2H)- embodiment the NRBA of this invention is 4-bromo-6- thione. In another embodiment the NRBA of this invention hydroxy-2-(4-methoxyphenyl)isoquinolin-1 (2H)-one. In is 8-hydroxy-2-(4-hydroxyphenyl)-6-methoxy-1-oxo-1,2- another embodiment the NRBA of this invention is 4-(6- dihydroisoquinoline-5-carbonitrile. In another embodiment 35 acetoxy-4-bromo-1-oxoisoquinolin-2(1H)-yl)phenyl the NRBA of this invention is 4-bromo-6-hydroxy-2-(4- acetate. In another embodiment the NRBA of this invention hydroxyphenyl)isoquinoline-1 (2H)-thione. In another is 4-(4-bromo-6-methoxy-1-oxoisoquinolin-2(1H)-yl)phe embodiment the NRBA of this invention is 2-(3-fluoro-4- nyl acetate. In another embodiment the NRBA of this hydroxyphenyl)-6,8-dihydroxyisoquinolin-1 (2H)-one. In invention is 4-bromo-6-hydroxy-2-(4-hydroxyphenyl)-1- another embodiment the NRBA of this invention is 2-(3- 40 oXo-1,2-dihydroisoquinoline-8-carbimidic acid. In another fluoro-4-hydroxyphenyl)-8-hydroxy-6-methoxyisoquinolin embodiment the NRBA of this invention is methyl 4-bromo 1(2H)-one. In another embodiment the NRBA of this inven 6-hydroxy-2-(4-hydroxyphenyl)-1-oxo-1,2-dihydroisoqui tion is 4-bromo-8-hydroxy-2-(4-hydroxyphenyl)-6- noline-8-carboxylate. In another embodiment the NRBA of methoxyisoquinolin-1 (2H)-one. In another embodiment the this invention is 4-bromo-6-hydroxy-2-(4-hydroxyphenyl)- NRBA of this invention is 4-chloro-6,8-dihydroxy-2-(4- 45 1-oxo-1,2-dihydroisoquinoline-8-carboxylic acid. In hydroxyphenyl)isoquinolin-1 (2H)-one. In another embodi another embodiment the NRBA of this invention is 6-hy ment the NRBA of this invention is 4-bromo-6,8-dihydroxy droxy-2-(4-hydroxyphenyl)-4-phenylisoquinolin-1 (2H)- 2-(3-fluoro-4-hydroxyphenyl)isoquinolin-1 (2H)-one. In one. In another embodiment the NRBA of this invention is another embodiment the NRBA of this invention is 4,5- 6-hydroxy-2-(4-hydroxyphenyl)-4-(4-methoxyphenyl)iso dibromo-2-(3,5-dibromo-4-hydroxyphenyl)-6-hydroxyiso 50 quinolin-1 (2H)-one. In another embodiment the NRBA of quinolin-1 (2H)-one. In another embodiment the NRBA of this invention is 2-(3-fluoro-4-hydroxyphenyl)-6,8-dihy this invention is 6,8-dihydroxy-2-(4-hydroxyphenyl)-5-(tri droxy-4-vinylisoquinolin-1 (2H)-one. In another embodi fluoromethylsulfonyl)isoquinolin-1 (2H)-one. In another ment the NRBA of this invention is 2-(3-fluoro-4-hydroxy embodiment the NRBA of this invention is 4-(1,2-dibromo phenyl)-6,8-dihydroxy-1-oxo-1,2-dihydroisoquinoline-4- ethyl)-6-hydroxy-2-(4-hydroxyphenyl)isoquinolin-1 (2H)- 55 carbonitrile. In another embodiment the NRBA of this one. In another embodiment the NRBA of this invention is invention is 6-hydroxy-2-(4-hydroxyphenyl)-8-vinylisoqui 6-methoxy-2-(4-methoxyphenyl)-1-oxo-1,2-dihydroisoqui nolin-1 (2H)-one. In another embodiment the NRBA of this nolin-8-yltrifluoromethanesulfonate. In another embodi invention is 4-bromo-6-hydroxy-2-(4-hydroxyphenyl)-8-vi ment the NRBA of this invention is 4,5-dibromo-6,8-dihy nylisoquinolin-1 (2H)-one. In another embodiment the droxy-2-(4-hydroxyphenyl)isoquinolin-1 (2H)-one. In 60 NRBA of this invention is 6,8-dihydroxy-2-(4-hydroxyphe another embodiment the NRBA of this invention is 6-hy nyl)-4-(4-methoxyphenyl)isoquinolin-1 (2H)-one. In another droxy-2-(4-hydroxyphenyl)-4-vinylisoquinolin-1 (2H)-one. embodiment the NRBA of this invention is 6,8-dihydroxy In another embodiment the NRBA of this invention is 2-(4-hydroxyphenyl)-4-phenylisoquinolin-1 (2H)-one. In 6-methoxy-2-(4-methoxyphenyl)-1-oxo-1,2-dihydroisoqui another embodiment the NRBA of this invention is (E)-6, noline-4-carbonitrile. In another embodiment the NRBA of 65 8-dihydroxy-2-(4-hydroxyphenyl)-4-(prop-1-enyl)isoquino this invention is 6-hydroxy-2-(4-hydroxyphenyl)-1-oxo-1,2- lin-1 (2H)-one. In another embodiment the NRBA of this dihydroisoquinoline-4-carbonitrile. In another embodiment invention is (E)-ethyl 3-(8-hydroxy-6-methoxy-2-(4- US 9,623,021 B2 35 36 methoxyphenyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)acry lamido, dialkylamido, nitro, amino, alkylamino, dialky late. In another embodiment the NRBA of this invention is lamino, carboxyl, thio and/or thioalkyl. (E)-3-(6-hydroxy-2-(4-hydroxyphenyl)-1-oxo-1,2-dihy The term “cycloalkyl refers to a monocyclic, bicyclic or droisoquinolin-4-yl)acrylic acid. In another embodiment the tricyclic nonaromatic Saturated hydrocarbon radical having NRBA of this invention is (E)-3-(6,8-dihydroxy-2-(4-hy 3 to 10 carbon atoms, such as 3 to 8 carbon atoms, for droxyphenyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)acrylic example, 3 to 6 carbon atoms. Non limiting examples of acid. In another embodiment the NRBA of this invention is cycloalkyl groups include cyclopropyl, cyclobutyl, cyclo 4-chloro-6-methoxy-2-(4-methoxyphenyl)-1-oxo-1,2-dihy pentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, droisoquinolin-8-yl 4-(trifluoromethyl)benzoate or any 1-decalin, adamant-1-yl, and adamant-2-yl. Other Suitable combination thereof. 10 cycloalkyl groups include, but are not limited to, spiropen In one embodiment, the estrogen receptor ligand com tyl, bicyclo[2.1.0pentyl, bicyclo[3.1.0 hexyl, spiro[2.4] pound is 4-bromo-6,8-dihydroxy-2-(4-hydroxyphenyl)iso heptyl, spiro2.5octyl, bicyclo[5.1.0 octyl, spiro[2.6nonyl, quinolin-1 (2H)-one, or its prodrug, analog, isomer, metabo bicyclo[2.2.0 hexyl, spiro 3.3 heptyl, bicyclo[4.2.0loctyl, lite, derivative, pharmaceutically acceptable salt, and spiro 3.5nonyl. pharmaceutical product, polymorph, crystal, impurity, N-OX 15 A "haloalkyl group refers, in another embodiment, to an ide, ester, hydrate, or any combination thereof. alkyl group as defined above, which is substituted by one or In one embodiment, the estrogen receptor ligand com more halogen atoms, e.g. by F, Cl, Br or I. pound is 4-chloro-6,8-dihydroxy-2-(4-hydroxyphenyl)iso An “aryl group refers, in another embodiment, to an quinolin-1 (2H)-one, or its prodrug, analog, isomer, metabo aromatic group having at least one carbocyclic aromatic lite, derivative, pharmaceutically acceptable salt, group or heterocyclic aromatic group, which may be unsub pharmaceutical product, polymorph, crystal, impurity, N-OX stituted or substituted by one or more groups selected from ide, ester, hydrate, or any combination thereof. halogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alky In one embodiment, the estrogen receptor ligand com lamido, dialkylamido, nitro, amino, alkylamino, dialky pound is 4-bromo-6,8-dihydroxy-2-(3-fluoro-4-hydroxy lamino, carboxy or thio or thioalkyl. Nonlimiting examples phenyl)isoquinolin-1 (2H)-one, or its prodrug, analog, iso 25 of aryl rings are phenyl, naphthyl, pyranyl, pyrrolyl pyrazi mer, metabolite, derivative, pharmaceutically acceptable nyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl, salt, pharmaceutical product, polymorph, crystal, impurity, thiazolyl, imidazolyl, isoxazolyl, and the like. N-oxide, ester, hydrate, or any combination thereof. A “hydroxyl group refers, in another embodiment, to an In one embodiment, the estrogen receptor ligand com OH group. In some embodiments, when R, R or R of the pound is 4-cyano-6,8-dihydroxy-2-(4-hydroxyphenyl)iso 30 compounds of the present invention is OR, then R is not OH. quinolin-1 (2H)-one (or 6,8-dihydroxy-2-(4-hydroxyphe In one embodiment, the term “halo' refers to a halogen, nyl)-1-oxo-1,2-dihydroisoquinoline-4-carbonitrile), or its such as F, Cl, Br or I. prodrug, analog, isomer, metabolite, derivative, pharmaceu In another embodiment, the phrase “phenol refers to an tically acceptable salt, pharmaceutical product, polymorph, alcohol (OH) derivative of benzene. crystal, impurity, N-oxide, ester, hydrate, or any combina 35 A "heterocycle' group refers, in one embodiment, to a tion thereof. ring structure comprising in addition to carbon atoms, Sulfur, In some embodiments, the NRBA of this invention, oxygen, nitrogen or any combination thereof, as part of the compositions of this invention or uses thereof may comprise ring. In another embodiment the heterocycle is a 3-12 any combinations of such NRBA as described herein. membered ring. In another embodiment the heterocycle is a The term “alkyl refers, in one embodiment, to a saturated 40 6 membered ring. In another embodiment the heterocycle is aliphatic hydrocarbon, including straight-chain, branched a 5-7 membered ring. In another embodiment the hetero chain and cyclic alkyl groups. In one embodiment, the alkyl cycle is a 4-8 membered ring. In another embodiment, the group has 1-12 carbons. In another embodiment, the alkyl heterocycle group may be unsubstituted or Substituted by a group has 1-7 carbons. In another embodiment, the alkyl halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alky group has 1-6 carbons. In another embodiment, the alkyl 45 lamido, dialkylamido, cyano, nitro, COH, amino, alky group has 1-4 carbons. In another embodiment, the cyclic lamino, dialkylamino, carboxyl, thio and/or thioalkyl. In alkyl group has 3-8 carbons. In another embodiment, the another embodiment, the heterocycle ring may be fused to cyclic alkyl group has 3-12 carbons. In another embodiment, another saturated or unsaturated cycloalkyl or heterocyclic the branched alkyl is an alkyl substituted by alkyl side chains 3-8 membered ring. In another embodiment, the heterocyclic of 1 to 5 carbons. In another embodiment, the branched alkyl 50 ring is a saturated ring. In another embodiment, the hetero is an alkyl substituted by haloalkyl side chains of 1 to 5 cyclic ring is an unsaturated ring. Examples of a heterocycle carbons. The alkyl group may be unsubstituted or substituted group comprise pyridine, piperidine, morpholine, pipera by a halogen, haloalkyl, hydroxyl, cyano, alkoxy carbonyl, Zine, thiophene, pyrrole or indole. amido, alkylamido, dialkylamido, nitro, amino, alkylamino, In one embodiment the 5-14 member saturated or unsatu dialkylamino, carboxyl, thio and/or thioalkyl. 55 rated, substituted or unsubstituted carbocyclic or heterocy An “alkenyl group refers, in another embodiment, to an clic ring comprises a phenyl, naphthalene, anthracene, pyri unsaturated hydrocarbon, including straight chain, branched dine, piperidine, thiophene, morpholine, piperazine, chain and cyclic groups having one or more double bonds. pyrimidine, cyclohexyl, cycloheptyl, pyrrole, pyrazole, The alkenyl group may have one double bond, two double furan, oxazole, quinoline, pyrazine or indole groups. bonds, three double bonds, etc. In another embodiment, the 60 In one embodiment unsaturated cycloalkyl or heterocy alkenyl group has 2-12 carbons. In another embodiment, the cloalkyl groups refer to cycloalkyl or heterocycloalkyl com alkenyl group has 2-6 carbons. In another embodiment, the prising at list one double bond. In another embodiment alkenyl group has 2-4 carbons. In another embodiment the unsaturated cycloalkyl or heterocycloalkyl refer to an aryl or alkenyl group is vinyl ( CH=CH-). Examples of alkenyl heteroaryl group. groups are vinyl, propenyl, butenyl, cyclohexenyl, etc. The 65 In some embodiments, protected hydroxyl includes the alkenyl group may be unsubstituted or Substituted by a incorporation of a Substituent bonded to an oxygen atom halogen, hydroxy, cyano, alkoxy carbonyl, amido, alky bound to a benzene ring, wherein the Substituent may be US 9,623,021 B2 37 38 readily removed. In some embodiments, phenolic protecting provides a metabolite of an estrogen receptor ligand com groups may comprise a: methyl ether, methoxymethyl pound. In another embodiment, this invention provides a (MOM) ether, benzoyloxymethyl (BOM) ether, methoxy pharmaceutically acceptable salt of an estrogen receptor ethoxymethyl (MEM) ether, 2-(trimethylsilyl)ethoxymethyl ligand compound. In another embodiment, this invention (SEM) ether, methylthiomethyl (MTM) ether, phenylthiom- 5 provides a pharmaceutical product of the estrogen receptor ethyl (PTM) ether, azidomethyl ether, cyanomethyl ether, ligand compound. In another embodiment, this invention 2,2-dichloro-1,1-difluoroethyl ether, 2-chloroethyl ether, provides a hydrate of an estrogen receptor ligand compound. 2-bromoethyl ether, tetrahydropyranyl (THP) ether, In another embodiment, this invention provides an N-oxide 1-ethoxyethyl (EE) ether, phenacyl ether, 4-bromophenacyl of an estrogen receptor ligand compound. In another ether, cyclopropylmethyl ether, allyl ether, propargyl ether, 10 embodiment, this invention provides a prodrug of an estro isopropyl ether, cyclohexyl ether, t-butyl ether, benzyl ether, gen receptor ligand compound. In another embodiment, this 2,6-dimethylbenzyl ether, 4-methoxybenzyl ether, o-ni invention provides an ester of an estrogen receptor ligand trobenzyl ether, 2,6-dichlorobenzyl ether, 3,4-dichloroben compound. In another embodiment, this invention provides Zyl ether, 4-(dimethylamino)carbonylbenzyl ether, 4-meth a polymorph of an estrogen receptor ligand compound. In ylsulfinylbenzyl ether, 4-anthrylmethyl ether, 4-picolyl 15 another embodiment, this invention provides a crystal of an ether, heptafluoro-p-tolyl, tetrafluoro-4-pyridyl ether, trim estrogen receptor ligand compound. In another embodiment, ethylsilyl (TMS) ether, t-butyldimethylsilyl (TBDMS) ether, this invention provides an impurity of an estrogen receptor t-butyldiphenylsilyl (TBDPS) ether, triisopropylsilyl (TIPS) ligand compound. ether, aryl formate, arylacetate, aryl levulinate, arylpiv In one embodiment, the term "isomer' includes, but is not aloate, arylbenzoate, aryl 9-fluorencarboxylate, aryl methyl limited to, optical isomers and analogs, structural isomers carbonate, 1-adamantyl carbonate, t-butyl carbonate, and analogs, conformational isomers and analogs, and the 4-methylsulfinylbenzyl carbonate, 2,4-dimethylpent-3-yl like. carbonate, aryl-2.2.2-trichloroethyl carbonate, aryl benzyl In one embodiment, the term "isomer' is meant to encom carbonate, aryl carbamate, dimethylphosphinyl ester (Dmp pass stereoisomers of the compound. The compounds of this OAr), dimethylphosphinothionyl ester (Mpt-OAr), diphe 25 invention possess an amide bond which may be in its cis or nylphosphinothionyl ester (Dpt-OAr), aryl methanesul trans isomerisation. In one embodiment, the NRBAs are the fonate, aryl toluenesulfonate O aryl pure (E)-isomers. In another embodiment, the NRBAs are 2-formylbenzenesulfonate. the pure (Z)-isomers. In another embodiment, the NRBAs In one embodiment, this invention provides a NRBA are a mixture of the (E) and the (Z) isomers. In one and/or its analog, derivative, isomer, metabolite, pharma 30 embodiment, the NRBAs are the pure (R)-isomers. In ceutically acceptable salt, pharmaceutical product, hydrate, another embodiment, the NRBAs are the pure (S)-isomers. N-oxide, prodrug, ester, polymorph, impurity or crystal or In another embodiment, the NRBAs are a mixture of the (R) combinations thereof. In one embodiment, this invention and the (S) isomers. It is to be understood that the present provides an analog of the NRBA. In another embodiment, invention encompasses any optically-active, or stereroiso this invention provides a derivative of the NRBA. In another 35 meric form, or mixtures thereof, and use of these for any embodiment, this invention provides an isomer of the application is to be considered within the scope of this NRBA. In another embodiment, this invention provides a invention. metabolite of the NRBA. In another embodiment, this The invention includes “pharmaceutically acceptable invention provides a pharmaceutically acceptable salt of the salts' of the compounds of this invention, which may be NRBA. In another embodiment, this invention provides a 40 produced, by reaction of a compound of this invention with pharmaceutical product of the NRBA. In another embodi an acid or base. ment, this invention provides a hydrate of the NRBA. In Suitable pharmaceutically-acceptable salts of amines of another embodiment, this invention provides an N-oxide of Formula I-XII may be prepared from an inorganic acid or the NRBA. In another embodiment, this invention provides from an organic acid. In one embodiment, examples of a prodrug of the NRBA. In another embodiment, this 45 inorganic salts of amines are bisulfates, borates, bromides, invention provides an ester of the NRBA. In another chlorides, hemisulfates, hydrobromates, hydrochlorates, embodiment, this invention provides a polymorph of the 2-hydroxyethylsulfonates (hydroxyethanesulfonates), NRBA. In another embodiment, this invention provides a iodates, iodides, isothionates, nitrate, persulfates, , crystal of the NRBA. In another embodiment, this invention Sulfates, Sulfamates, Sulfanilates, Sulfonic acids (alkylsul provides an impurity of the NRBA. In another embodiment, 50 fonates, arylsulfonates, halogen Substituted alkylsulfonates, this invention provides composition comprising a NRBA, as halogen Substituted arylsulfonates), Sulfonates and thiocya described herein, or, in another embodiment, a combination nates. of an analog, derivative, isomer, metabolite, pharmaceuti In one embodiment, examples of organic salts of amines cally acceptable salt, pharmaceutical product, hydrate, may be selected from aliphatic, cycloaliphatic, aromatic, N-oxide, prodrug, polymorph, ester, impurity or crystal of 55 araliphatic, heterocyclic, carboxylic and Sulfonic classes of the NRBA of the present invention. organic acids, examples of which are acetates, arginines, In one embodiment, this invention provides use of an aspartates, ascorbates, adipates, anthranilate, algenates, estrogen receptor ligand compound and/or its analog, alkane carboxylates, Substituted alkane carboxylates, alg derivative, isomer, metabolite, pharmaceutically acceptable inates, benzenesulfonates, benzoates, bisulfates, butyrates, salt, pharmaceutical product, hydrate, N-oxide, prodrug, 60 bicarbonates, bitartrates, citrates, camphorates, camphorsul ester, polymorph, impurity or crystal or combinations fonates, cyclohexylsulfamates, cyclopentanepropionates, thereof. In one embodiment, this invention provides an calcium edetates, camsylates, carbonates, clavulanates, cin analog of an estrogen receptor ligand compound. In another namates, dicarboxylates, digluconates, dodecylsulfonates, embodiment, this invention provides a derivative of an dihydrochlorides, decanoates, enanthuates, ethanesul estrogen receptor ligand compound. In another embodiment, 65 fonates, edetates, edisylates, estolates, esylates, fumarates, this invention provides an isomer of an estrogen receptor formates, fluorides, galacturonates gluconates, glutamates, ligand compound. In another embodiment, this invention glycolates, glucorate, glucoheptanoates, glycerophosphates, US 9,623,021 B2 39 40 gluceptates, glycolylarsanilates, glutarates, glutamate, hep can be made with aliphatic and aromatic carboxylic acids, tanoates, hexanoates, hydroxymaleates, hydroxycarboxlic for example, acetic acid and benzoic acid esters. acids, hexylresorcinates, hydroxybenzoates, hydroxynaph This invention provides, in some embodiments, deriva thoate, hydrofluorate, lactates, lactobionates, laurates, tives of the NRBAs. In one embodiment, the term "deriva malates, maleates, methylenebis(beta-oxynaphthoate), tives’ refers to ether derivatives, acid derivatives, amide malonates, mandelates, mesylates, methane Sulfonates, derivatives, ester derivatives or others, as known in the art. methylbromides, methylnitrates, methylsulfonates, mono In another embodiment, this invention further includes potassium maleates, mucates, monocarboxylates, mitrates, hydrates of the NRBAs. In one embodiment, the term naphthalenesulfonates, 2-naphthalenesulfonates, nicoti “hydrate' refers to hemihydrate, monohydrate, dihydrate, nates, napsylates, N-methylglucamines, oxalates, octano 10 trihydrate or others, as known in the art. ates, oleates, pamoates, phenylacetates, picrates, phenylben This invention provides, in other embodiments, metabo Zoates, pivalates, propionates, , phenylacetate, lites of the NRBAs. In one embodiment, the term “metabo pectinates, phenylpropionates, palmitates, pantothenates, lite' refers to any substance produced from another sub polygalacturates, pyruvates, quinates, Salicylates, succi stance by metabolism or a metabolic process. nates, Stearates, Sulfanilate, Subacetates, tartrates, theophyl 15 In some embodiments, a NRBA this invention will com lineacetates, p-toluenesulfonates (tosylates), trifluoroac prise the compounds listed in Table 1. etates, terephthalates, tannates, teoclates, trihaloacetates, In one embodiment, this invention provides use of a triethiodide, tricarboxylates, undecanoates and Valerates. composition comprising an estrogen receptor ligand com In one embodiment, examples of inorganic salts of car pound, as described herein, or, in another embodiment, any boxylic acids or phenols may be selected from ammonium, combination of an analog, derivative, isomer, metabolite, alkali metals to include lithium, Sodium, potassium, cesium; pharmaceutically acceptable salt, pharmaceutical product, alkaline earth metals to include calcium, magnesium, alu hydrate, N-oxide, prodrug, polymorph, ester, impurity or minium; Zinc, barium, cholines, quaternary ammoniums. crystal of an estrogen receptor ligand as described herein. In another embodiment, examples of organic salts of In some embodiments, the NRBAs of this invention will carboxylic acids or phenols may be selected from arginine, 25 have a selective affinity for a particular nuclear hormone organic amines to include aliphatic organic amines, alicyclic receptor, with varying affinities at other nuclear receptors. In organic amines, aromatic organic amines, benzathines, t-bu some embodiments of this invention, NRBAs of this inven tylamines, benethamines (N-benzylphenethylamine), dicy tion will vary in terms of their activity, for example, some clohexylamines, dimethylamines, diethanolamines, ethano NRBAS possess greater activity in terms of stimulating bone lamines, ethylenediamines, hydrabamines, imidazoles, 30 growth, while Some exhibit greater antagonistic activity, etc. lysines, methylamines, meglamines, N-methyl-D-glu It is to be understood that all such NRBAs are to be camines, N,N'-dibenzylethylenediamines, , considered as part of this invention. organic amines, ornithines, pyridines, picolies, piperazines, In some embodiments, the NRBAs of this invention may procain, tris(hydroxymethyl)methylamines, triethylamines, exhibit nonselective affinity for or binding to a nuclear triethanolamines, trimethylamines, tromethamines and 35 receptor, which in Some embodiments, is an estrogen recep leaS. tor C. and/or estrogen receptor f3 molecule. In some embodi In one embodiment, the salts may be formed by conven ments, the NRBAs of this invention may exhibit selective tional means, such as by reacting the free base or free acid affinity for a nuclear receptor such as ER-3. In some form of the product with one or more equivalents of the embodiment, the NRBAs of this invention may exhibit appropriate acid or base in a solvent or medium in which the 40 selective affinity for receptors that do not translocate to the salt is insoluble or in a solvent such as water, which is cell nucleus. In some embodiments, the NRBAs of this removed in vacuo or by freeze drying or by exchanging the invention may exhibit agonist activity. In some embodi ions of a existing salt for another ion or Suitable ion ments, the NRBAs of this invention may exhibit antagonist exchange resin. activity. In some embodiments, the NRBAs of this invention In one embodiment the pharmaceutically acceptable salt 45 may exhibit agonist activity for a particular receptor, and is a hydrochloride salt. In one embodiment the pharmaceu antagonist activity for a different receptor, or vice versa, or tically acceptable salt is an acrylate salt. In one embodiment in some embodiments, the NRBAs of this invention may the pharmaceutically acceptable Salt is a benzoate salt. In exhibit agonist activity for a particular receptor under certain one embodiment the pharmaceutically acceptable salt is a experimental conditions, yet exhibit antagonist activity for trifluoromethanesulfonate salt. In one embodiment the phar 50 the same receptor under different experimental conditions, maceutically acceptable salt is an acetate salt. or vice versa, or in some embodiments, the NRBAs of this In one embodiment, the pharmaceutically acceptable salt invention may exhibit agonist activity for a particular recep of a NRBA comprising a piperidine ring is an HCl salt or an tor in a particular tissue, yet exhibit antagonist activity for amine salt as described herein. In another embodiment, the the same receptor in a different tissue, or vice versa, etc. It pharmaceutically acceptable salt of a NRBA comprising a 55 is to be understood that a single described activity for a pyrrolidine ring is an HCl salt, or an amine salt as described NRBA this invention is not to be taken as limiting the herein. In another embodiment, the pharmaceutically compound to Such activity/condition/tissue exclusively, but acceptable Salt of a NRBA comprising a morpholine ring is rather to represent an embodiment of one such activity for an HCl salt or an amine salt as described herein. In another the indicated NRBA. embodiment, the pharmaceutically acceptable salt of a 60 In some embodiments, the NRBAs of this invention may NRBA comprising a piperazine ring is an HCl salt, or an exhibit anti-proliferative activity. amine salt as described herein or others as will be appreci In some embodiments, the NRBAs of this invention may ated by one skilled in the art. exhibit anti-inflammatory activity. Pharmaceutically acceptable salts can be prepared from In some embodiments, the NRBAs of this invention may the phenolic compounds, in other embodiments, by treat 65 exhibit anti-oxidant activity. ment with inorganic bases, for example, sodium hydroxide. In some embodiments, the NRBAs of this invention may In another embodiment, esters of the phenolic compounds exhibit vasodilatory activity. US 9,623,021 B2 41 42 In some embodiments, the NRBAs of this invention may vice versa. In some embodiments, NRBA’s are dissociated exhibit pro-differentiation activity. in their ability to affect transactivation but not transrepres ER-C. and ER-B binding and agonistandantagonist activi Sion, or vice versa. ties, anti-proliferative and anti-inflammatory activities for This invention provides, in other embodiments, pharma representative NRBAs are exemplified hereinbelow, where 5 ceutical products of the NRBAs. The term “pharmaceutical such activity is described in the context of specific experi product” refers, in other embodiments, to a composition mental conditions employed, representing only certain Suitable for pharmaceutical use (pharmaceutical composi embodiments of this invention, and in no way to be taken to tion), for example, as described herein. limiting the invention. It is to be understood that while the The NRBAs useful in the compositions of the present indicated compounds may exhibit a particular activity under 10 invention may exist in prodrug form. As used herein, "pro certain experimental conditions employed, as a function, in drug is intended to include any covalently bonded carriers Some embodiments, of the particular cells utilized, etc., Such which release the active parent drug according to Formula compounds may possess alternate, varied, or partial activity (I) or other formulas or compounds of the present invention in different experimental settings. 15 in Vivo when such prodrug is administered to a Subject. Steroid nuclear hormone receptors are known to have Since prodrugs are known to enhance numerous desirable rapid, tissue-specific effects that are mediated by cell-sur qualities of pharmaceuticals (e.g., Solubility, bioavailability, face and cytosolic receptors through protein-protein inter manufacturing, etc.) the compounds useful in the composi action or phosphorylation of kinases, which are known as tions of the present invention may be delivered in prodrug non-genomic effects. For instance, NRBAs are known to form. Thus, the present invention includes compositions have distinct rapid effects in the cardiovascular and central containing prodrugs of the disclosed compounds and meth nervous systems which may be mediated by distinct recep ods of delivering the same. Prodrugs of a compound of the tors. Putative receptors for these non-genomic effects present invention may be prepared by modifying functional include a variety of G-protein coupled receptors (GPCRs) groups present in the compound in Such a way that the such as GPR130, as well as cell-membrane associated or 25 modifications are cleaved, either in routine manipulation or cytosolic nuclear receptors. NRBAs of this invention may in vivo, to the parent compound. also bind to receptors involved in these non-genomic effects Accordingly, prodrugs include, for example, compounds allowing differential pharmacological exploitation of of the present invention wherein a hydroxy, amino, or genomic, non-genomic, and tissue-selective steroid receptor carboxy group is bonded to any group that, when the 30 prodrug is administered to a mammalian Subject, cleaves to activities. As such these NRBAs may have a wide variety of form a free hydroxyl, free amino, or carboxylic acid, respec specific and targeted steroid responses broadening their tively. Examples include, but are not limited to, acetate, potential to have beneficial medical properties. formate and benzoate derivatives of alcohol and amine In some embodiments, a NRBA of this invention is a functional groups; and alkyl, carbocyclic, aryl, and alkylaryl non-genomic agonist, or in Some embodiments, a non 35 esters such as methyl, ethyl, propyl, isopropyl, butyl, isobu genomic antagonist, or in Some embodiments, a non-ge tyl, sec-butyl, tert-butyl, cyclopropyl, phenyl, benzyl, and nomic partial agonist of a nuclear receptor. In some embodi phenethyl esters, and the like. ments, the NRBAs of this invention are tissue selective, As known in the art, polymorphism is an ability of a non-genomic nuclear receptors, such as for example, estro compound to crystallize as more than one distinct crystalline gen or androgen receptor agonists, or in Some embodiments, 40 or “polymorphic' species. As used herein a “polymorph” is tissue selective, non-genomic nuclear receptor antagonists, a solid crystalline phase of a compound with at least two or in Some embodiments, tissue selective, non-genomic different arrangements or polymorphic forms of that com nuclear receptor partial agonists. In some embodiments, the pound molecule in the solid state. Polymorphic forms of any NRBAs of this invention are non-selective non-genomic given compound are defined by the same chemical formula nuclear receptor agonists, such as for example, estrogen or 45 or composition and are as distinct in structure as crystals of androgen receptor agonists, or in some embodiments, non two different chemical compounds. selective non-genomic nuclear receptor antagonists, or in The term “about' or “approximately as used herein Some embodiments, non-selective non-genomic nuclear means within an acceptable error range for the particular receptor partial agonists. In some embodiments, the NRBAs value as determined by one of ordinary skill in the art, which of this invention are non-selective genomic nuclear receptor 50 will depend in part on how the value is measured or agonists, such as for example, estrogen or androgen receptor determined, i.e., the limitations of the measurement system. agonists, or in some embodiments, antagonists, or in some For example, “about can mean within 1 or more than 1 embodiments, partial agonists. standard deviations, per the practice in the art. Alternatively, In some embodiments, the NRBAs of this invention are “about can mean a range of up to 20%, up to 10% or up to tissue selective genomic nuclear receptor modulators. Such 55 5% of a given value. as for example, estrogen or androgen receptoragonists, or in In one embodiment, this invention provides a method of Some embodiments, antagonists, or in Some embodiments, binding any NRBA of this invention to an estrogen receptor partial agonists. In some embodiments, the NRBAs of this or an estrogen related receptors, comprising the step of invention are genomic agents which selectively transactivate contacting an estrogen receptor with said NRBA. In another nuclear receptor-regulated genes. In some embodiments, 60 embodiment, this invention provides a method of binding selective transactivation is in a tissue selective manner. In any NRBA of this invention to a nuclear hormone receptor some embodiments, the NRBAs of this invention are or one related thereto. genomic agents which selectively transrepress nuclear In one embodiment, this invention provides general and receptor-regulated genes. In some embodiments, selective specific synthetic routes for embodiments of isoquinolino tranrepression is in a tissue selective manner. In some 65 nes and isoquinolin-6-ols. embodiments, the NRBAs are dissociated in their ability to Some embodiments of a synthetic procedure for some of affect non-genomic process but not genomic processes, or the NRBAs are provided below:

US 9,623,021 B2 45 46 -continued OR" OR"

RO X RO X RO O 21 RO O |C.

NN or NN 1s-X3 p a (RI) - X^^ -ny,3p

(RI) (R2) in (R) (R2) (RI) (R2) in (R2) 7 7 8 8

PS5 O Lawesson's h. reagent

OR" S 2y ROX^n-1\1\sy d (R3) A-4Nex (RI) (R2) in 9

25 Intermediate compound 4 can be prepared by three dif- -continued ferent paths starting from 2-(2-carboxy-vinyl) benzoic acid (compound 1) via step a; or starting with 3-phenyl-acrylic acid, (compound 2) together with sodium azide (step b) to 30 21 C NaNs obtain an acyl derivative of compound 3, followed by HCO Dioxane/H2O Curtius rearrangement and a cyclization step (step c) in the O presence of diphenyl ether and tributylamine at 230° C. to obtain compound 4; or starting with 2-iodo benzonitrile (compound 10) via the Sonogashira reaction (step i) fol- is Ph2O, BuN lowed by methanolysis (step) to obtain compound 4. HCO 21 N so Compound 4 is further coupled with an iodo substituted 3 formula A (step d), yielding compound 5, which may be O further brominated, chlorinated, or iodinated (using NBS, NCS, or NIS, respectively) followed by further substitutions to obtain the desired R group (step f) compound 8 or OCH2 compound 8', or obtain the Sulfone compound 9 using PSs reagent (step h). Compounds 8 or 9 can be optionally OH demethylated with BBr to yield the phenolic products, N I however if step h is executed, then the phenol must be 45 N - - protected. 2 DMSO, 120° C. Alternatively, compound 4 may be brominated, chlori nated, or iodinated (using NBS, NCS, or NIS, respectively) and further substituted (step e) to obtain the desired R2 of compound 6 or 6'. Compound 6 or 6' may be coupled 50 OCH together with an iodo Substituted formula A (step d), yielding O compound 8 or 8', or the OH group of compound 6 or 6' is NBS further substituted (step g) to obtain the desired X group of -- compound 7 or compound 7. N CHCN In some embodiments this invention provides synthetic 55 2 route for embodiments of 4-halogenated isoquinolinones. H3CO For example, one embodiment of a synthetic procedure for a compound of this invention, 4-bromo-6-hydroxy-2-(4- hydroxyphenyl)isoquinolin-1 (2H)-one, is as follows: OCH 60 O

N BBr: 21 OH - SSE - 21 CHCl22 HCO CHCl2 H2CO 65 Br US 9,623,021 B2 47 -continued -continued OH CF

5 N O

HO 2 NBS OCH3 CHCN Br O O O 10 In some embodiments this invention provides synthetic N route for embodiments of 6,8-dihydroxy-isoquinolinones. An example of these embodiments of this invention provides HCO 21 a synthetic route for 4-bromo-6, 8-dihydroxy-2-(4-hydroxy 15 phenyl) isoquinolin-1 (2H)-one (12u). CF

OCH OCH BBr: H2O SOCl O O O -e- 21 OH CHCl2 H3CO 25 N O H3CO 21 OCH Br NaN OH - is 21 C Dioxane/H2O H3CO N O OCH 35 HO 2

Br Ph2O, BuN --- OH 21 N HCO 40 O N OCH OCH O H H3CO 2 45 Br 11 CuIL-Proline DMSO, 120° C. In some embodiments this invention provides synthetic HCO C2 route for embodiments of 4-alkenyl isoquinolinones. An 50 example of these embodiments of this invention provides a synthetic route for 6-hydroxy-2-(4-hydroxyphenyl)-4-vi OCH nylisoquinolin-1 (2H)-one (14f) compound.

OMe O O LiCl HCI His H DMF 55 OH HCO C.2 O

N (4N B1 O )3 60 Pol(PPh3)4 OCH K2CO3 HO 21 DME/HO OH O O 1. NaH He 2. O Br HCO C27 65 12b C US 9,623,021 B2 49 50 -continued -continued OH FC O O

5 O -kO O OCH N Zn(CN)2 He Pd(dba)3 HO 2 N dppf DMF 2 S 10 H3CO 14f 14d OCH CN O In some embodiments this invention provides synthetic NBS route for embodiments of 4-carbonitrile derivatives of 15 N CICN 1-oxo-1,2-dihydroisoquinolines. For example, this invention provides synthetic routes for 6-hydroxy-2-(4-hydroxyphe- HCO 21 nyl)-1-oxo-1,2-dihydroisoquinoline-4-carbonitrile (14h). 3 14i. 2O CCH OCH CN O O BBr3 H2O N MeOH N Zn(CN)2 HePd(dba)3/dppf 25 2 2 DMF H3CO HCO Br Br 14 14 l 30 OH OCH CN O O

N N BBr3 -- 35 2 21 HO H3CO Br CN 14k 14g OH 40 O In some embodiments this invention provides synthetic route for 14o compound N

HO 2 45 OH

CN CN O O O 14h N (4N- ) Pol(PPh3)4 HO 2 DME/HOK2CO3 In some embodiments this invention provides synthetic route for embodiments of 8-carbonitrile derivatives of Br 1-oxo-1,2-dihydroisoquinolines. For example, this invention 14k provides synthetic routes for 4-bromo-6-hydroxy-2-(4-hy- OH droxyphenyl)-1-oxo-1,2-dihydroisoquinoline-8-carbonitrile SS CN O (14k): N

OCH OH O 3 60 HO 21

NaH N N PhN(SO3CF3) 14o HCO 2 65 14s In some embodiments this invention provides synthetic route for 14p compound US 9,623,021 B2

-continued O OCH CN O FC SleO OCH N-Cl N BBr HO2 o21 No O PhCl O 21 CHCN HCO N reflux C 10 H3CO 21 14u. OH 14d CN O FC 2O2 21 S No O OCH 15 N Z n(CN)2 2 Pd2dba HO N dppf/DMF C H3CO 2 2O 14p

C 14t In some embodiments this invention provides synthetic routes for 14xME, 14xME AC and 14XAC compounds.

OCH OH O O OCH O O n N --> N -b- N 21 HCO 2 HCO H3CO 21 3 Br 14q

C BBr c C| DCM ( 3 eq.DCM Rp.) ( 6 eq.DCM Rpt.)

OH OH OH O OCH O O O O nN N N C N N ea a HO 21 HO 21 HCO HO Br Br 14v. 14w 12c 12b / y t

OCH O CH3 O CH3

O O |ON N O O N O HO 21 HO ea to so a Br Br Br 14xME 14xME AC 14XAC

US 9,623,021 B2 55 56 In some embodiments this invention provides synthetic -continued routes for 6-hydroxy-2-(4-hydroxyphenyl)-4-phenylisoqui- OH nolin-1 (2H)-one (15a). OH O Na1\bot, 5 N Pd(PPh3)4 OCH K2CO3 O HO 2 DME/HO B(OH)2 N Her Br Pd(PPh3)4 21 K2CO3 10 H3CO DME/HO Br OCH O OH O 15

N N BBr3 H3CO 21 CHCl2 HO 21 2O

OH O 25 N

O N 15 HO 2 30

CF 3 O 35 to-su-o 15a b OCH O O O In some embodiments the following compounds are syn- Pd(dba) thesized via Suzuki coupling reactions as described for 40 N die, compound 15a. 21 DMF HCO Br OH OH O 45 HCO B(OH)2 N -e- Pol(PPh3)4 HO ea K2CO3 B DME/HO r 50 OCH OH O

OH OH O N BBr N 55 H3CO 21 -e-

HO 2

60

S

OCH 65 O OCH2CH3 US 9,623,021 B2 58 -continued prising the described compounds. As used herein, OH “pharmaceutical composition” means a “therapeuti OH O cally effective amount of the active ingredient, i.e. the compound of this invention, together with a pharma N ceutically acceptable carrier or diluent. A “therapeuti cally effective amount’ as used herein refers to that HO 2 amount which provides a therapeutic effect for a given condition and administration regimen. As used herein, the term “administering refers to bring 10 ing a subject in contact with a compound of the present invention. As used herein, administration can be accom plished in vitro, i.e. in a test tube, or in Vivo, i.e. in cells or tissues of living organisms, for example humans. In one embodiment, the present invention encompasses adminis 15 tering the compounds of the present invention to a Subject. 2 The pharmaceutical compositions containing the com O OH pounds of this invention can be administered to a subject by 151 any method known to a person skilled in the art, Such as O orally, parenterally, intravascularly, paracancerally, transmu cosally, transdermally, intramuscularly, intranasally, intrave OCH --- -0 nously, intradermally, Subcutaneously, Sublingually, intrap eritonealy, intraventricularly, intracranially, intravaginally, by inhalation, rectally, intratumorally, or by any means in N which the recombinant virus/composition can be delivered 21 Pd(dba)3 25 to tissue (e.g., needle or catheter). Alternatively, topical H3CO dppf Cs2Co3 administration may be desired for application to mucosal Br DMF cells, for skin or ocular application. Another method of OCH administration is via aspiration or aerosol formulation. O In one embodiment, the pharmaceutical compositions are 30 administered orally, and are thus formulated in a form N Suitable for oral administration, i.e. as a solid or a liquid preparation. Suitable solid oral formulations include tablets, 2 BBr3 capsules, pills, granules, pellets, powders, and the like. H3CO CHCl2 Suitable liquid oral formulations include Solutions, Suspen 35 sions, dispersions, emulsions, oils and the like. In one embodiment of the present invention, the compounds are formulated in a capsule. In accordance with this embodi ment, the compositions of the present invention comprise in addition to a compound of this invention and the inert carrier S 40 or diluent, a hard gelatin capsule. In one embodiment, the micronized capsules comprise particles containing a compound of this invention, wherein O OCH2CH3 the term “micronized' used herein refers to particles having OH a particle size is of less than 200 microns, or in another O 45 embodiment less than 100 microns, or in another embodi ment, less than 60 microns, or in another embodiment, less N than 36 microns, or in another embodiment, less than 16 microns, or in another embodiment, less than 10 microns, or HO 21 in another embodiment, less than 6 microns. 50 Further, in another embodiment, the pharmaceutical com positions are administered by intravenous, intraarterial, or intramuscular injection of a liquid preparation. Suitable liquid formulations include Solutions, Suspensions, disper sions, emulsions, oils and the like. In one embodiment, the 55 pharmaceutical compositions are administered intrave nously, and are thus formulated in a form suitable for intravenous administration. In another embodiment, the pharmaceutical compositions are administered intraarteri O OH ally, and are thus formulated in a form suitable for intraar 15k 60 terial administration. In another embodiment, the pharma ceutical compositions are administered intramuscularly, and are thus formulated in a form suitable for intramuscular administration. Pharmaceutical Compositions Further, in another embodiment, the pharmaceutical com 65 positions are administered topically to body Surfaces, and In some embodiments, this invention provides methods of are thus formulated in a form suitable for topical adminis use which comprise administering a composition com tration. Suitable topical formulations include gels, oint US 9,623,021 B2 59 60 ments, creams, lotions, drops and the like. For topical chloride Solution, Ringer's dextrose, dextrose and sodium administration, the compounds of this invention or their chloride, lactated Ringer's and fixed oils. Intravenous physiologically tolerated derivatives such as salts, esters, vehicles include fluid and nutrient replenishers, electrolyte N-oxides, and the like are prepared and applied as Solutions, replenishers such as those based on Ringer's dextrose, and Suspensions, or emulsions in a physiologically acceptable the like. Examples are sterile liquids Such as water and oils, diluent with or without a pharmaceutical carrier. with or without the addition of a surfactant and other Further, in another embodiment, the pharmaceutical com pharmaceutically acceptable adjuvants. In general, water, positions are administered as a Suppository, for example a saline, aqueous dextrose and related Sugar Solutions, and rectal Suppository or a urethral Suppository. Further, in glycols such as propylene glycols or polyethylene glycol are another embodiment, the pharmaceutical compositions are 10 administered by Subcutaneous implantation of a pellet. In a preferred liquid carriers, particularly for injectable solutions. further embodiment, the pellet provides for controlled Examples of oils are those of petroleum, animal, vegetable, release of a compound as herein described over a period of or synthetic origin, for example, peanut oil, soybean oil, time. In a further embodiment, the pharmaceutical compo mineral oil, olive oil, Sunflower oil, and fish-liver oil. sitions are administered intravaginally. 15 In addition, the compositions may further comprise bind In another embodiment, the active compound can be ers (e.g. acacia, cornstarch, gelatin, carbomer, ethyl cellu delivered in a vesicle, in particular a liposome (see Langer, lose, guar gum, hydroxypropyl cellulose, hydroxypropyl Science 249:1627-1633 (1990); Treat et al., in Liposomes in methyl cellulose, povidone), disintegrating agents (e.g. the Therapy of Infectious Disease and Cancer, Lopez-Ber cornstarch, potato starch, alginic acid, silicon dioxide, cros estein and Fidler (eds.), Liss, New York, pp. 363-366 (1989); carmelose sodium, crospovidone, guar gum, Sodium starch Lopez-Berestein, ibid., pp. 317-327; see generally ibid). glycolate), buffers (e.g., Tris-HCl, acetate, phosphate) of As used herein “pharmaceutically acceptable carriers or various pH and ionic strength, additives Such as albumin or diluents' are well known to those skilled in the art. The gelatin to prevent absorption to Surfaces, detergents (e.g., carrier or diluent may be a solid carrier or diluent for solid Tween 20, Tween 80, Pluronic F68, bile acid salts), protease formulations, a liquid carrier or diluent for liquid formula 25 inhibitors, Surfactants (e.g. sodium lauryl Sulfate), perme tions, or mixtures thereof. ation enhancers, Solubilizing agents (e.g., cremophor, glyc Solid carriers/diluents include, but are not limited to, a erol, polyethylene glycerol, benzlkonium chloride, benzyl gum, a starch (e.g. corn starch, pregeletanized starch), a benzoate, cyclodextrins, Sobitan esters, Stearic acids), anti Sugar (e.g., lactose, mannitol. Sucrose, dextrose), a cellulosic oxidants (e.g., ascorbic acid, Sodium metabisulfite, butylated material (e.g. microcrystalline cellulose), an acrylate (e.g. 30 hydroxyanisole), stabilizers (e.g. hydroxypropyl cellulose, polymethylacrylate), calcium carbonate, magnesium oxide, hyroxypropylmethyl cellulose), Viscosity increasing agents talc, or mixtures thereof. (e.g. carbomer, colloidal silicon dioxide, ethyl cellulose, In one embodiment, the compositions of this invention guar gum), Sweetners (e.g. aspartame, citric acid), preser may include, a compound of this invention or any combi Vatives (e.g., Thimerosal, benzyl alcohol, ), color nation thereof, together with one or more pharmaceutically 35 ing agents, lubricants (e.g. Stearic acid, magnesium Stearate, acceptable excipients. polyethylene glycol, Sodium lauryl Sulfate), flow-aids (e.g. It is to be understood that this invention encompasses any colloidal silicon dioxide), plasticizers (e.g. diethyl , embodiment of a compound as described herein, which in triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl some embodiments is referred to as “a compound of this cellulose, Sodium lauryl Sulfate), polymer coatings (e.g., invention'. 40 poloxamers or poloxamines), coating and film forming Suitable excipients and carriers may be, according to agents (e.g. ethyl cellulose, acrylates, polymethacrylates), embodiments of the invention, solid or liquid and the type is and/or adjuvants. generally chosen based on the type of administration being In one embodiment, the pharmaceutical compositions used. Liposomes may also be used to deliver the composi provided herein are controlled release compositions, i.e. tion. Examples of suitable solid carriers include lactose, 45 compositions in which the compound of this invention is Sucrose, gelatin and agar. Oral dosage forms may contain released over a period of time after administration. Con Suitable binders, lubricants, diluents, disintegrating agents, trolled or Sustained release compositions include formula coloring agents, flavoring agents, flow-inducing agents, and tion in lipophilic depots (e.g. fatty acids, waxes, oils). In melting agents. Liquid dosage forms may contain, for another embodiment, the composition is an immediate example, Suitable solvents, preservatives, emulsifying 50 release composition, i.e. a composition in which all of the agents, Suspending agents, diluents, Sweeteners, thickeners, compound is released immediately after administration. and melting agents. Parenteral and intravenous forms should In yet another embodiment, the pharmaceutical compo also include minerals and other materials to make them sition can be delivered in a controlled release system. For compatible with the type of injection or delivery system example, the agent may be administered using intravenous chosen. Of course, other excipients may also be used. 55 infusion, an implantable osmotic pump, a transdermal patch, For liquid formulations, pharmaceutically acceptable car liposomes, or other modes of administration. In one embodi riers may be aqueous or non-aqueous Solutions, Suspensions, ment, a pump may be used (see Langer, Supra; Sefton, CRC emulsions or oils. Examples of non-aqueous solvents are Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., propylene glycol, polyethylene glycol, and injectable Surgery 88:607 (1980); Saudek et al., N. Engl. J. Med. organic esters such as ethyl oleate. Aqueous carriers include 60 321:674 (1989). In another embodiment, polymeric materi water, alcoholic/aqueous solutions, cyclodextrins, emulsions als can be used. In yet another embodiment, a controlled or Suspensions, including saline and buffered media. release system can be placed in proximity to the therapeutic Examples of oils are those of petroleum, animal, vegetable, target, i.e., the brain, thus requiring only a fraction of the or synthetic origin, for example, peanut oil, soybean oil, systemic dose (see, e.g., Goodson, in Medical Applications mineral oil, olive oil, Sunflower oil, and fish-liver oil. 65 of Controlled Release, supra, vol. 2, pp. 116-138 (1984). Parenteral vehicles (for subcutaneous, intravenous, Other controlled release systems are discussed in the review intraarterial, or intramuscular injection) include Sodium by Langer (Science 249:1627-1633 (1990). US 9,623,021 B2 61 62 The compositions may also include incorporation of the pounds of this invention include acid addition salts which active material into or onto particulate preparations of may, for example, be formed by mixing a solution of the polymeric compounds such as polylactic acid, polglycolic compound according to the invention with a solution of a acid, hydrogels, etc, or onto liposomes, microemulsions, pharmaceutically acceptable acid Such as hydrochloric acid, micelles, unilamellar or multilamellar vesicles, erythrocyte Sulphuric acid, methaneSulphonic acid, fumaric acid, maleic ghosts, or spheroplasts.) Such compositions will influence acid, Succinic acid, acetic acid, benzoic: acid, oxalic acid, the physical state, solubility, stability, rate of in vivo release, citric acid, tartaric acid, carbonic acid or phosphoric acid. and rate of in Vivo clearance. In one embodiment, this invention provides pharmaceu Also comprehended by the invention are particulate com tical compositions comprising a compound of this invention. positions coated with polymers (e.g. poloxamers or poloX 10 In one embodiment. Such compositions are useful for oral amines) and the compound coupled to antibodies directed testosterone replacement therapy. against tissue-specific receptors, ligands or antigens or In one embodiment, this invention also provides a com coupled to ligands of tissue-specific receptors. position comprising two or more compounds of this inven Also comprehended by the invention are compounds tion, or polymorphs, isomers, hydrates, salts, N-oxides, etc., modified by the covalent attachment of water-soluble poly 15 thereof. The present invention also relates to compositions mers such as polyethylene glycol, copolymers of polyeth and pharmaceutical compositions which comprise a com ylene glycol and polypropylene glycol, carboxymethyl cel pound of this invention alone or in combination with a lulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone or progestin or estrogen, or in another embodiment, chemo polyproline. The modified compounds are known to exhibit therapeutic compound, osteogenic or myogenic compound, substantially longer half-lives in blood following intrave or other agents suitable for the applications as herein nous injection than do the corresponding unmodified com described. In one embodiment, the compositions of this pounds (Abuchowski et al., 1981; Newmarket al., 1982; and invention will comprise a suitable carrier, diluent or salt. Katre et al., 1987). Such modifications may also increase the In one embodiment, the methods of this invention may compounds solubility in aqueous solution, eliminate aggre comprise administration of a compound of this invention at gation, enhance the physical and chemical stability of the 25 various dosages. In one embodiment, the compound of this compound, and greatly reduce the immunogenicity and invention is administered at a dosage of about 0.1 to about reactivity of the compound. As a result, the desired in vivo 2000 mg per day. In one embodiment, the compound of this biological activity may be achieved by the administration of invention is administered at a dosage of about 0.1 to about Such polymer-compound abducts less frequently or in lower 10 mg, or in another embodiment, about 0.1 to about 25 mg, doses than with the unmodified compound. 30 or in another embodiment, about 0.1 to about 60 mg. or in The preparation of pharmaceutical compositions which another embodiment, about 0.1 to about 200 mg. or in contain an active component is well understood in the art, another embodiment, about 0.3 to about 15 mg. or in another for example by mixing, granulating, or tablet-forming pro embodiment, about 0.3 to about 30 mg, or in another cesses. The active therapeutic ingredient is often mixed with embodiment, about 0.5 to about 25 mg, or in another excipients which are pharmaceutically acceptable and com 35 embodiment, about 0.5 to about 60 mg, or in another patible with the active ingredient. For oral administration, embodiment, about 0.5 to about 15 mg, or in another the compounds of this invention or their physiologically embodiment, about 0.5 to about 60 mg, or in another tolerated derivatives Such as salts, esters, N-oxides, and the embodiment, about 1 to about 5 mg. or in another embodi like are mixed with additives customary for this purpose, ment, about 1 to about 20 mg. or in another embodiment, Such as vehicles, stabilizers, or inert diluents, and converted 40 about 3 to about 15 mg, or in another embodiment, 30 to 60 by customary methods into Suitable forms for administra mg, or in another embodiment, about 30 to 75 mg. or in tion, Such as tablets, coated tablets, hard or soft gelatin another embodiment, about 100 to about 2000 mg. capsules, aqueous, alcoholic or oily Solutions. For parenteral In one embodiment, the methods of this invention may administration, the compounds of this invention or their comprise administration of a compound of this invention at physiologically tolerated derivatives such as salts, esters, 45 various dosages. In one embodiment, the compound of this N-oxides, and the like are converted into a solution, Sus invention is administered at a dosage of about 0.1 to about pension, or emulsion, if desired with the Substances custom 2000 mg per day. In one embodiment, the compound of this ary and Suitable for this purpose, for example, Solubilizers or invention is administered at a dosage of about 0.1 to about other. 10 mg per day, or in another embodiment, about 0.1 to about An active component can be formulated into the compo 50 25 mg per day, or in another embodiment, about 0.1 to about sition as neutralized pharmaceutically acceptable salt forms. 60 mg per day, or in another embodiment, about 0.1 to about Pharmaceutically acceptable salts include the acid addition 200 mg per day, or in another embodiment, about 0.3 to salts (formed with the free amino groups of the polypeptide about 15 mg per day, or in another embodiment, about 0.3 or antibody molecule), which are formed with inorganic to about 30 mg per day, or in another embodiment, about 0.5 acids such as, for example, hydrochloric or phosphoric 55 to about 25 mg per day, or in another embodiment, about 0.5 acids, or Such organic acids as acetic, oxalic, tartaric, man to about 60 mg per day, or in another embodiment, about 0.5 delic, and the like. Salts formed from the free carboxyl to about 15 mg per day, or in another embodiment, about 0.5 groups can also be derived from inorganic bases such as, for to about 60 mg per day, or in another embodiment, about 1 example, sodium, potassium, ammonium, calcium, or ferric to about 5 mg per day, or in another embodiment, about 1 to hydroxides, and Such organic bases as isopropylamine, 60 about 20 mg per day, or in another embodiment, about 3 to trimethylamine, 2-ethylamino ethanol, histidine, procaine, about 15 mg per day, or in another embodiment, 30 to 60 mg and the like. per day, or in another embodiment, about 30 to 75 mg per For use in medicine, the salts of the compound will be day, or in another embodiment, about 100 to about 2000 mg pharmaceutically acceptable salts. Other salts may, however, per day, or in another embodiment, about 100 to about 500 be useful in the preparation of the compounds according to 65 mg per day. the invention or of their pharmaceutically acceptable salts. In one embodiment, the compound of this invention is Suitable pharmaceutically acceptable salts of the com administered at a dosage of about 0.01 to about 200 mg per US 9,623,021 B2 63 64 kg per day. In one embodiment, the compound of this or non-aqueous, Suspensions or emulsions. In one embodi invention is administered at a dosage of about 0.01 to about ment, the compositions may comprise propylene glycol, 10 mg per kg per day, or in another embodiment, about 0.01 polyethylene glycol, injectable organic esters, for example to about 25 mg per kg per day, or in one embodiment, the ethyl oleate, or cyclodextrins. In another embodiment, com compound of this invention is administered at a dosage of 5 positions may also comprise wetting, emulsifying and/or about 0.01 to about 50 mg per kg per day, or in another dispersing agents. In another embodiment, the compositions embodiment, about 0.01 to about 60 mg per kg per day or in may also comprise sterile water or any other sterile inject another embodiment, about 0.03 to about 15 mg per kg per able medium. day, or in another embodiment, about 0.03 to about 30 mg In one embodiment, the invention provides compounds per kg per day, or in another embodiment, about 0.05 to 10 and compositions, including any embodiment described about 25 mg per kg per day, or in another embodiment, about herein, for use in any of the methods of this invention, as 0.05 to about 60 mg per kg per day, or in another embodi described herein. In one embodiment, use of a compound of ment, about 30 mg per kg per day, or in another embodiment, this invention or a composition comprising the same, will about 20 mg per kg per day, or in another embodiment, about have utility in inhibiting, Suppressing, enhancing or stimu 15 mg per kg per day, or in another embodiment, about 10 15 lating a desired response in a Subject, as will be understood mg per kg per day, or in another embodiment, about 5 mg per by one skilled in the art. In another embodiment, the kg per day. compositions may further comprise additional active ingre In one embodiment, the compound of this invention is dients, whose activity is useful for the particular application administered at a dosage of about 1 mg. In another embodi for which the compound of this invention is being admin ment the compound of this invention is administered at a istered. dosage of about 5 mg, about 10 mg, about 15 mg, about 20 In some embodiments, the methods of this invention mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg. make use of compositions comprising compounds of this about 45 mg, about 50 mg, about 55 mg, about 60 mg, about invention, which offer the advantage that the compounds are 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 ligands for the estrogen receptor, and exhibit mg, about 90 mg, about 95 mg, about 100 mg, about 150 mg 25 estrogenic activity in vivo. According to this aspect, Such or about 200 mg. compounds are unaccompanied by serious side effects, pro In one embodiment, the present invention provides meth vide convenient modes of administration, and lower pro ods of use comprising the administration of a pharmaceuti duction costs and are orally bioavailable, lack significant cal composition comprising a) any embodiment of a com cross-reactivity with other undesired steroid receptors, and pound as described herein; and b) a pharmaceutically 30 may possess long biological half-lives. acceptable carrier or diluent; which is to be understood to For administration to mammals, and particularly humans, include an analog, isomer, metabolite, derivative, pharma it is expected that the physician will determine the actual ceutically acceptable salt, N-oxide, hydrate or any combi dosage and duration of treatment, which will be most nation thereof of a compound as herein described. Suitable for an individual and can vary with the age, weight In Some embodiments, the present invention provides 35 and response of the particular individual. methods of use of a pharmaceutical composition comprising In one embodiment, the compositions for administration a) any embodiment of the compounds as described herein, may be sterile Solutions, or in other embodiments, aqueous including an analog, isomer, metabolite, derivative, phar or non-aqueous, Suspensions or emulsions. In one embodi maceutically acceptable salt, pharmaceutical product, N-OX ment, the compositions may comprise propylene glycol, ide, hydrate thereof or any combination thereof; b) a phar 40 polyethylene glycol, injectable organic esters, for example maceutically acceptable carrier or diluent; c) a flow-aid; and ethyl oleate, or cyclodextrins. In another embodiment, com d) a lubricant. positions may also comprise wetting, emulsifying and/or In another embodiment, the present invention provides dispersing agents. In another embodiment, the compositions methods of use of a pharmaceutical composition comprising may also comprise sterile water or any other sterile inject a) any embodiment of the compounds as described herein, 45 able medium. including an analog, isomer, metabolite, derivative, phar In one embodiment, the invention provides compounds maceutically acceptable salt, pharmaceutical product, N-OX and compositions, including any embodiment described ide, hydrate thereof or any combination thereof; b) lactose herein, for use in any of the methods of this invention. In one monohydrate; c) microcrystalline cellulose; d) magnesium embodiment, use of a compound of this invention or a Stearate; and e) colloidal silicon dioxide. 50 composition comprising the same, will have utility in inhib In some embodiments, the methods of this invention iting, Suppressing, enhancing or stimulating a desired make use of compositions comprising compounds of this response in a subject, as will be understood by one skilled invention, which offer the advantage that the compounds are in the art. In another embodiment, the compositions may nonsteroidal ligands for the estrogen receptor, and exhibit further comprise additional active ingredients, whose activ estrogenic activity in vivo. According to this aspect, Such 55 ity is useful for the particular application for which the compounds are unaccompanied by serious side effects, pro compound of this invention is being administered. vide convenient modes of administration, and lower pro The invention contemplates, in some embodiments, duction costs and are orally bioavailable, lack significant administration of compositions comprising the individual cross-reactivity with other undesired steroid receptors, and agents, administered separately and by similar or alternative may possess long biological half-lives. 60 routes, formulated as appropriately for the route of admin For administration to mammals, and particularly humans, istration. The invention contemplates, in some embodi it is expected that the physician will determine the actual ments, administration of compositions comprising the indi dosage and duration of treatment, which will be most vidual agents, administered in the same formulation. The Suitable for an individual and can vary with the age, weight invention contemplates, in Some embodiments, staggered and response of the particular individual. 65 administration, concurrent administration, of administration In one embodiment, the compositions for administration of the various agents over a course of time, however, their may be sterile Solutions, or in other embodiments, aqueous effects are synergistic in the Subject. US 9,623,021 B2 65 66 It is to be understood that any of the above means, of administering to the Subject a composition comprising timings, routes, or combinations thereof, of administration toremifene, raloxifene, tamoxifen or an analogue, functional of two or more agents is to be considered as being encom derivative, metabolite or a combination thereof, or a phar passed by the phrase “administered in combination', as maceutically acceptable salt thereof. In one embodiment, described herein. Such metabolites may comprise ospennifene, fispennifene or In one embodiment, bone turnover markers have been their combination. In one embodiment, the cancer is prostate demonstrated as an effective, validated tool for the clinical CaCC. Scientist to monitor hone activity. In another embodiment, A person skilled in the art would readily recognize that urinary hydroxyproline, serum alkaline phosphatase, tar changes in the antineoplastic therapy according to the meth trate-resistant acid phosphatase, and osteocalcin levels, 10 ods provided herein, utilizing the compositions provided along with the urinary calcium-creatinine ratio are used as bone turnover markers. In another embodiment osteocalcin herein may be conducted as a function of, or adjusted or levels is used as a bone formation marker. In another varied as a function of inter-alia, the severity of the under embodiment c-telopeptide is used as a bone resorption lying disease, the source of the underlying disease, the marker. 15 extent of the patients’ pain and Source of the patients’ pain, In one embodiment, this invention provides for the treat as well as the stage of the disease. The therapeutic changes ment, prevention, Suppression or inhibition of, or the reduc may include in certain embodiments, changes in the route of tion of the risk of developing a skeletal-related event (SRE), administration (e.g. intracavitarily, intraartiarly, intratumor Such as bone fractures, Surgery of the bone, radiation of the ally etc.), forms of the compositions administered (e.g. bone, spinal cord compression, new bone metastasis, bone tablets, elixirs, Suspensions etc.), changes in dosage and the loss, or a combination thereof in a Subject with cancer, like. Each of these changes are well recognized in the art and comprising administering to the Subject a compound of this are encompassed by the embodiments provided herein. invention and/or its analog, derivative, isomer, metabolite, In one embodiment, the skeletal-related events area result pharmaceutically acceptable salt, pharmaceutical product, of cancer therapy. In one embodiment, the skeletal-related hydrate, N-oxide, or any combination thereof. The invention 25 events are a result of hormone deprivation therapy, while in relates, interalia to treatment of an SRE with the compound another embodiment; they are a product of ADT. of this invention in a Subject with prostate cancer undergoing In one embodiment, the compounds of this invention are or having undergone androgen deprivation therapy (ADT). useful in prevention or reversal of ADT induced side effects In one embodiment, the skeletal-related events treated Such as reduced muscle mass, reduced muscle strength, using the methods provided herein and/or utilizing the 30 frailty, hypogonadism, osteoporosis, osteopenia, decreased compositions provided herein, are fractures, which in one BMD and/or decreased bone mass. embodiment, are pathological fractures, non-traumatic frac In males, while the natural decline in sex-hormones at tures, vertebral fracture, non-vertebral fractures, morpho maturity (direct decline in androgens as well as lower levels metric fractures, or a combination thereof. of estrogens derived from peripheral aromatization of andro In another embodiment, the methods and/or compositions 35 gens) is associated with the frailty of bones, this effect is provided herein, are effective in treatment, prevention, Sup more pronounced in males who have undergone androgen pression, inhibition or reduction of the risk of skeletal deprivation therapy. related events such as pathologic fractures, spinal cord In one embodiment, the compound is administered in compression, hypercalcemia, bone-related pain, or their combination with an antidiabetic agent. In one embodiment, combination. 40 the antidiabetic agent is a Sulfonylurea. In one embodiment, In another embodiment, the skeletal-related events sought sulfonylureas include but are not limited to tolbutamide, to be treated using the methods provided herein and/or acetohexamide, tolaZamide, chlorpropamide, glipizide, gly utilizing the compositions provided herein, comprise the buride, glimepiride, or gliclazide. In one embodiment, the necessity for bone Surgery and/or bone radiation, which in antidiabetic agent is a meglitinide. In one embodiment, Some embodiments, is for the treatment of pain resulting in 45 meglitinides include but are not limited to prandin or nat one embodiment from bone damage, or nerve compression. eglinide. In one embodiment, the antidiabetic agent is a In another embodiment, the skeletal-related events sought to biguanide. In one embodiment, biguanides include but are be treated using the methods provided herein and/or utilizing not limited to metformin. In one embodiment, the antidi the compositions provided herein, comprise spinal cord abetic agent is a thiazolidinedione. In one embodiment, compression, or the necessity for changes in antineoplastic 50 thiazolidinediones include but are not limited to rosiglita therapy, including changes in hormonal therapy, in a subject. Zone, pioglitaZone, or troglitaZone. In one embodiment, the In some embodiments, skeletal-related events sought to be antidiabetic agent is an alpha glucosidase inhibitor. In one treated using the methods provided herein and/or utilizing embodiment, alpha glucosidase inhibitors include but are the compositions provided herein, comprise treating, Sup not limited to miglitol or acarbose. In one embodiment, the pressing, preventing, reducing the incidence of, or delaying 55 antidiabetic agent is PPARO/Y ligand, dipeptidylpeptidase 4 progression or severity of bone metastases, or bone loss. In (DPP-4) inhibitor, SGLT (sodium-dependent glucose trans one embodiment, bone loss may comprise osteoporosis, porter 1) inhibitor, or FBPase (fructose 1,6-bisphosphatase) osteopenia, or a combination thereof. In one embodiment, inhibitor. In one embodiment, the antidiabetic agent is skeletal-related events may comprise any combination of the insulin. In one embodiment, the insulin is rapid-acting embodiments listed herein. 60 insulin. In one embodiment, the insulin is short-acting In one embodiment, the methods provided herein and/or insulin. In one embodiment, the insulin is intermediate utilizing the compositions provided herein, are effective in acting insulin. In one embodiment, the insulin is interme reducing metastases to the hone, such as in terms of number diate- and short-acting insulin mixtures. In one embodiment, of foci, the size of foci, or a combination thereof. According the insulin is long-acting insulin. In one embodiment, the to this aspect of the invention and in one embodiment, 65 antidiabetic agents are inhibitors of fatty acid binding pro provided herein is a method of preventing or inhibiting tein (alP2) such as those disclosed in U.S. Ser. No. 09/519, cancer metastasis to bone in a subject, comprising the step 079 filed Mar. 6, 2000, glucagon-like peptide-1 (GLP-1), US 9,623,021 B2 67 68 and dipeptidyl peptidase IV (DPP4) inhibitors such as those In one embodiment, the compound is administered in disclosed in WO 0168603, which are incorporated by ref combination with a nicotinic acid agent. In some embodi CCC. ments, nicotinic acid agents include but are not limited to In one embodiment, the compound is administered in , niacor, or slo-niacin. combination with an agent treating the cardiovascular sys 5 In one embodiment, the compound is administered in tem. In one embodiment, the agent treating the cardiovas combination with a fibrate. In some embodiments, fibrates cular system is a hypercholesterolemic agent Such as niacin include but are not limited to gemfibrozil, or fenofibrate. lovastatin, colestipol HCl, fluvastatin Sodium, atorvastatin In one embodiment, the compound is administered in calcium, simvastatin, gemfibrozil, lovastatin, pravastatin combination with an agent treating the endocrine system. In Sodium, cholestyramine, cholestyramine light, fenofibrate, 10 one embodiment, the agent treating the endocrine system is a SARM compound. In some embodiments, SARMs include colesevelam HCl, or ezetimibe. but are not limited to RU-58642, RU-56279, WS9761A and In one embodiment, the compound of this invention is B, RU-59063, RU-58841, bexlosteride, LG-2293, administered in combination with an agent treating a meta L-245976, LG-121071, LG-121091, LG-121104, LGD bolic disease, disorder or condition, which in some embodi 15 2226, LGD-2941, LGD-3303, YM-92088, YM-175735, ments refers to metabolic syndrome. LGD-1331, BMS-357597, BMS-391197, S-40503, BMS In some embodiments, agents treating a metabolic disease 482404, EM-4283, EM-4977, BMS-564929, BMS-391197, include but are not limited to a vitamin, Coenzyme Q10. BMS-434588, BMS-487745, BMS-501949, SA-766, glucosidase alfa, Sodium bicarbonate, bisphosphonate, bio YM-92088, YM-580, LG-123303, LG-123129, PMCol, tin, allopurinol, levodopa, diazepam, phenobarbital, halo YM-175735, BMS-591305, BMS-591309, BMS-665139, peridol, folic acid, antioxidants, activators of cation chan BMS-665539, CE-590, 116BG33, 154BG31, arcarine, or nels haptoglobin, or carnitine. ACP-105. In some embodiments, such agents comprise, inter alia, In one embodiment, the agent treating the endocrine pancreatic lipase inhibitors, such as for example, orlistat, system includes but is not limited to tamoxifen, 4-hy cetilistat, serotonin and norepinephrine reuptake inhibitors, 25 droxytamoxifen, , toremifene, , drolox Such as sibutramine, insulin-sensitizers such as biguanides ifene, raloxifene, , , PPT (1,3,5-tris (metformin) or PPAR agonists, dual-acting PPAR agonists (4-hydroxyphenyl)-4-propyl-1H-pyrazole), DPN, (muraglitazar, tesaglitazar, naveglitazar). PPAR-delta ago , , EM-800, EM-652, , nists (GW-501516), DPP-IV inhibitors (vildagliptin, sita , tesmilifene, phosphate, RU 30 58,688, EM 139, ICI 164,384, ICI 182,780, clomiphene, gliptin), alpha glucosidase inhibitors (acarbose), anti-dia MER-25, diethylstibestrol, , genistein, GW5638, betic combinations (ActoPlus Met, AvandaMet, metformin/ LY353581, Zuclomiphene, enclomiphene, delmadinone pioglitaZone, metformin/rosiglitaZone, Glucovance, etc.), acetate, DPPE, (N,N-diethyl-2-4-(phenylmethyl)- glucagon-like peptide-1 analogues (exenatide, liraglutide), phenoxyethanamine), TSE-424, WAY-070, WAY-292, amylin analogues (pramlintide), statins (atorvastatin, simv 35 WAY-818, cyclocommunol, , ERB-041, WAY astatin, rosuvastatin, pravastatin, fluvastatin, lovastatin, 397, WAY-244, ERB-196, WAY-169122, MF-101, ERb-002, pitavastatin), cholesterol absorption inhibitors (ezetimibe), ERB-037, ERB-017, BE-1060, BE-380, BE-381, WAY-358, nicotinic acid derivatives (immediate release and controlled 18FFEDNP. LSN-500307, AA-102, Ban Zhilian, CT-101, release , niaslo, etc.), antidyslipidemic fixed combi CT-102, or VG-101. nations (simvastatin/ezetimibe, lovastatin/nicotinic acid, 40 In one embodiment, the agent treating the endocrine atorvastatin/amlodipine, atorvastatin/torcetrapib, simvasta system is a gonadotropin-releasing hormone agonist or tin/nicotinic acid (ER), ACE inhibitors (ramipril, captopril, antagonist. In some embodiments, gonadotropin-releasing lisinopril), AT-II receptor antagonists (valsartan, telmisar hormone agonists or antagonists include but are not limited tan), cannabinoid receptor antagonists (rimonabant), choles to leuprolide, goserelin, triptorelin, alfaprostol, histrelin, teryl ester transfer protein or CETP Inhibitors (JTT-705, 45 detirelix, ganirelix, antide iturelix, cetrorelix, ramorelix, CETi-1), beta3 adrenergic agonists, PPARC. ligands, or ganirelix, antarelix, teverelix, abarelix, Ozarelix, Sufugolix, combinations thereof. prazarelix, degarelix, NBI-56418, TAK-810, or acyline. In one embodiment, the compound is administered in In one embodiment, the agent treating the endocrine combination with an agent treating the liver. In one embodi system is a steroidal or nonsteroidal glucocorticoid receptor ment, the agent treating the liver is cortisone, cortisol or 50 ligand. In some embodiments, nonsteroidal glucocorticoid corticosterone. In some embodiments, the agent treating the receptor ligands include but are not limited to ZK-216348, liver is colchicine, methotrexate, urSodeoxycholic acid, or ZK-243149, ZK-243185, LGD-5552, mifepristone, RPR penicillamine. 106541, ORG-34517, GW-215864X, Sesquicillin, CP-472555, CP-39.4531, A-222977, AL-438, A-216054, In one embodiment, the compound is administered in 55 A-276575, CP-39.4531, CP-409069, or UGR-07. combination with a statin. In some embodiment, statins In one embodiment, the agent treating the endocrine include but are not limited to atorvastatin, fluvastatin, lov system is a steroidal or non-steroidal progesterone receptor astatin, pravastatin, simvastatin, or rosuvastatin. ligand. In one embodiment, the agent treating the endocrine In one embodiment, the compound is administered in system is a steroidal or nonsteroidal androgen receptor combination with a bile acid sequestrant. 60 antagonist. In some embodiments, steroidal or nonsteroidal In some embodiment, bile acid sequestrants include but androgen receptor antagonists include but are not limited to are not limited to cholestyramine, colestipol, or coleseve flutamide, hydroxyflutamide, bicalutamide, nilutamide, or lam. hydroxysteroid dehydrogenase inhibitor. In one embodiment, the compound is administered in In one embodiment, the agent treating the endocrine combination with a cholesterol absorption inhibitor. In some 65 system is a peroxisome proliferator-activated receptor embodiment, cholesterol absorption inhibitors include but ligand. In some embodiments, peroxisome proliferator-ac are not limited to eZetimibe. tivated receptor ligands include but are not limited to US 9,623,021 B2 69 70 beZafibrate, fenofibrate, gemfibrozil, dargilitaZone, pioglita methods of treating Such diseases, disorders and conditions Zone, rosiglitaZone, isaglitaZone, rivoglitaZone, netoglita in a Subject by administering a compound as herein Zone, naveglitazar, fargilitazar, tesaglitazar, ragaglitazar, described, or compounds 12u, 14m, 12Z, or 12y listed in oxeglitazar, or PN-2034. Table 1, alone or as part of the combined therapy or using the In some embodiments, any of the compositions of this compositions of this invention represent additional embodi invention will comprise a compound of this invention, in any ments of this invention. form or embodiment as described herein. In some embodi In one embodiment, this invention provides: a) a method ments, any of the compositions of this invention will com of treating a condition associated with high fat diet con prise a compound of formula 12u, 14m, 12Z or 12y listed in Sumption; b) a method of preventing a condition associated Table 1 of this invention, in any form or embodiment as 10 with high fat diet consumption; c) a method of treating a described herein. In some embodiments, any of the compo condition associated with post-menopausal obesity; d) a sitions of this invention will consist of a compound of this method of preventing a condition associated with post invention, in any form or embodiment as described herein. menopausal obesity; e) a method of increasing energy In some embodiments, any of the compositions of this expenditure in a subject, f) a method of increasing lean body invention will consist of a compound of formula 12u, 14m, 15 mass; g) a method of treating a metabolic disorder; h) a 12Z or 12y listed in Table 1 of this invention, in any form or method of increasing muscle weight; comprising the step of embodiment as described herein. In some embodiments, of administering to said Subject a compound of this invention the compositions of this invention will consist essentially of and/or an analog, derivative, isomer, metabolite, pharma a compound of this invention, in any form or embodiment as ceutically acceptable salt, pharmaceutical product, hydrate, described herein. In some embodiments, of the compositions N-oxide, prodrug, polymorph, impurity or crystal of said of this invention will consist essentially of a compound of compound, or any combination thereof. In another embodi formula 12u, 14m, 12Z or 12y listed in Table 1 of this ment, a compound of formula I-XII or its analog, derivative, invention, in any form or embodiment as described herein. isomer, metabolite, pharmaceutically acceptable salt, phar In some embodiments, the term “comprise' refers to the maceutical product, hydrate, N-oxide, prodrug, polymorph, inclusion of the indicated active agent, Such as the com 25 impurity or crystal of said compound, or any combination pound of this invention, as well as inclusion of other active thereof. In another embodiment a compound of formula XI agents, and pharmaceutically acceptable carriers, excipients, or its analog, derivative, isomer, metabolite, pharmaceuti emollients, stabilizers, etc., as are known in the pharmaceu cally acceptable salt, pharmaceutical product, hydrate, tical industry. N-oxide, prodrug, polymorph, impurity or crystal of said In some embodiments, the term “consisting essentially 30 compound, or any combination thereof. In another embodi of refers to a composition, whose only active ingredient is ment the compound is compound 12u, listed in Table 1. In the indicated active ingredient, however, other compounds another embodiment the compound is compound 12y, listed may be included which are for stabilizing, preserving, etc. in Table 1. In another embodiment the compound is com the formulation, but are not involved directly in the thera pound 12Z, listed in Table 1. In another embodiment the peutic effect of the indicated active ingredient. In some 35 compound is compound 14m, listed in Table 1. embodiments, the term “consisting essentially of may refer In one embodiment, “high fat diet' (HFD) refers to a diet to components which facilitate the release of the active that includes more than 10% fat. In another embodiment ingredient. In some embodiments, the term "consisting “high fat diet' (HFD) refers to a diet that includes more than refers to a composition, which contains the active ingredient 20% fat. In another embodiment “high fat diet” (HFD) refers and a pharmaceutically acceptable carrier or excipient. 40 to a diet that includes between 10-20% fat. In another In one embodiment, the present invention provides com embodiment “high fat diet' (HFD) refers to a diet that bined preparations. In one embodiment, the term "a com includes more than 30% fat. In another embodiment “high bined preparation' defines especially a “kit of parts” in the fat diet” (HFD) refers to a diet that includes between 10-30% sense that the combination partners as defined above can be fat. In another embodiment “high fat diet' (HFD) refers to dosed independently or by use of different fixed combina 45 a diet that includes between 10-15% fat. In another embodi tions with distinguished amounts of the combination part ment “high fat diet' (HFD) refers to a diet that includes ners i.e., simultaneously, concurrently, separately or sequen between 20-40% fat. In another embodiment “high fat diet tially. In some embodiments, the parts of the kit of parts can (HFD) refers to a diet that includes more than 30% fat. In then, e.g., be administered simultaneously or chronologi another embodiment “high fat diet' (HFD) refers to a diet cally staggered, that is at different time points and with equal 50 that includes between 30-60% fat. In another embodiment or different time intervals for any part of the kit of parts. The “high fat diet' (HFD) refers to a diet that includes between ratio of the total amounts of the combination partners, in 30-40% fat. In another embodiment “high fat diet” (HFD) Some embodiments, can be administered in the combined refers to a diet that includes between 40-50% fat. In another preparation. In one embodiment, the combined preparation embodiment “high fat diet' (HFD) refers to a diet that can be varied, e.g., in order to cope with the needs of a 55 includes between 50-60% fat. In another embodiment “high patient subpopulation to be treated or the needs of the single fat diet” (HFD) refers to a diet that includes between 60-70% patient which different needs can be due to a particular fat. In another embodiment “high fat diet' (HFD) refers to disease, severity of a disease, age, sex, or body weight as can a diet that includes protein (23.5%), carbohydrates (27.3%) be readily made by a person skilled in the art. and fat (34.3%), with a digestible energy of 5.1 Kcal/g. Biological Activity of NRBA Compounds 60 In one embodiment, “normal diet” (N.D) refers to a diet It is to be understood that this invention is directed to that includes less than 10% fat. In one embodiment, “normal compositions and combined therapies as described herein, diet” (N.D) refers to a diet that includes less than 30% fat. for any disease, disorder or condition, as appropriate, as will In another embodiment, “normal diet” (N.D) refers to a diet be appreciated by one skilled in the art. Certain applications that includes protein (16.7%), carbohydrates (56%) and fat of Such compositions and combined therapies have been 65 (4.2%), with a digestible energy of 3.3. Kcal/g. In another described hereinabove, for specific diseases, disorders and embodiment, “normal diet' refers to a diet that includes conditions, representing embodiments of this invention, and 10-30% fat. In another embodiment, “normal diet' refers to US 9,623,021 B2 71 72 a diet that includes 30-50% fat. In another embodiment, in Table 1. In another embodiment the compound is com “normal diet' refers to a diet that includes 40-50% fat. In pound 12y, listed in Table 1. In another embodiment the another embodiment, “normal diet' is a “high fat diet. compound is compound 12Z, listed in Table 1. In another In one embodiment, “obesity' refers to a medical condi embodiment the compound is compound 14m, listed in tion in which excess body fat has accumulated to the extent Table 1. that it may have an adverse effect on health, leading to In one embodiment the condition associated with high fat increased health problems. In another embodiment, “obe diet consumption is body weight gain. In another embodi sity” refers to a weight increase, which is at least 5% of the ment the condition associated with high fat diet consumption total body weight. is obesity. In another embodiment the condition associated “Postmenopausal obesity' refers to body weight gain of a 10 with high fat diet consumption is fat mass formation. In Subject after menopause that is not induced by a diet. another embodiment the condition associated with high fat Postmenopausal obesity emanates due to reduced circulating diet consumption is bone mineral content reduction. In estrogens and lost repression on adipose tissue proliferation another embodiment the condition associated with high fat and adipokine synthesis. diet consumption is white adipose tissue weight gain. In “Visceral obesity” refers to a form of obesity due to 15 another embodiment the condition associated with high fat excessive deposition of fat in the abdominal viscera and diet consumption is increased cholesterol levels. In another omentum, rather than Subcutaneously, associated with dys embodiment the condition associated with high fat diet lipidemia (increased plasma triglyceride, low high-density consumption is increased leptin levels. In another embodi lipoprotein cholesterol). ment the condition associated with high fat diet consumption “Visceral obesity at andropause' refers to a body weight is insulin resistance. In another embodiment the condition gain that accompanies androgen deficiency in aging men. associated with high fat diet consumption is type II diabetes. In one embodiment, the methods of this invention are In another embodiment the condition associated with high useful for a subject, which is a human. In another embodi fat diet consumption is increased blood glucose levels. In ment, the Subject is a mammal. In another embodiment the another embodiment the condition associated with high fat Subject is an animal. In another embodiment the Subject is an 25 diet consumption is inflammatory diseases. In another invertebrate. In another embodiment the subject is a verte embodiment the condition associated with high fat diet brate. consumption is cardiovascular diseases. In another embodi In one embodiment, the Subject is male. In another ment the condition associated with high fat diet consumption embodiment, the Subject is female. In some embodiments, is fatty liver condition (accumulation of fat in the liver). In while the methods as described herein may be useful for 30 another embodiment the condition associated with high fat treating either males or females, females may respond more diet consumption is decreased uncoupling protein-1 (UCP advantageously to administration of certain compounds, for 1) levels. In another embodiment the condition associated certain methods, as described and exemplified herein. with high fat diet consumption is increased lipogenesis. In some embodiments, while the methods as described In one embodiment, the present invention provides meth herein may be useful for treating either males or females, 35 ods for treating, delaying the onset of reducing the inci males may respond more advantageously to administration dence of, or reducing the severity of condition associated of certain compounds, for certain methods, as described with post-menopausal obesity. In another embodiment, the herein. present invention provides methods for preventing a condi In other embodiments, the invention provides methods tion associated with post-menopausal obesity. In another comprising administering a therapeutically effective amount 40 embodiment the methods comprise administering a com of an estrogen receptor ligand compound as described herein pound of this invention. In another embodiment, the com or its prodrug, analog, isomer, metabolite, derivative, phar pound is compound of formula I-XII or its analog, deriva maceutically acceptable salt, pharmaceutical product, poly tive, isomer, metabolite, pharmaceutically acceptable salt, morph, crystal, impurity, N-oxide, hydrate or any combina pharmaceutical product, hydrate, N-oxide, prodrug, poly tion thereof, or a composition comprising the same, to a 45 morph, impurity or crystal of said compound, or any com subject in need thereof, so as to achieve a desired effect. bination thereof. In another embodiment the compound is In one embodiment, the present invention provides meth compound of formula XI or its analog, derivative, isomer, ods of treating metabolic diseases comprising administering metabolite, pharmaceutically acceptable salt, pharmaceuti estrogen receptor ligand compounds of this invention. cal product, hydrate, N-oxide, prodrug, polymorph, impurity In one embodiment, the present invention provides meth 50 or crystal of said compound, or any combination thereof. In ods for treating, delaying the onset of reducing the inci another embodiment the compound is compound 12u, listed dence of, or reducing the severity of condition associated in Table 1. In another embodiment the compound is com with high fat diet consumption. In another embodiment, the pound 12y, listed in Table 1. In another embodiment the present invention provides methods for preventing a condi compound is compound 12Z, listed in Table 1. In another tion associated with high fat diet consumption. In another 55 embodiment the compound is compound 14m, listed in embodiment the methods comprise administering a com Table 1. pound of this invention. In another embodiment, the com In one embodiment the condition associated with post pound is a compound of formula I-XII or its analog, deriva menopausal obesity is body weight gain. In another embodi tive, isomer, metabolite, pharmaceutically acceptable salt, ment the condition associated with post-menopausal obesity pharmaceutical product, hydrate, N-oxide, prodrug, poly 60 is fat mass formation. In another embodiment the condition morph, impurity or crystal of said compound, or any com associated with post-menopausal obesity is bone mineral bination thereof. In another embodiment the compound is a content reduction. In another embodiment the condition compound of formula XI or its analog, derivative, isomer, associated with post-menopausal obesity is white adipose metabolite, pharmaceutically acceptable salt, pharmaceuti tissue weight gain. In another embodiment the condition cal product, hydrate, N-oxide, prodrug, polymorph, impurity 65 associated with post-menopausal obesity is increased cho or crystal of said compound, or any combination thereof. In lesterol levels. In another embodiment the condition asso another embodiment the compound is compound 12u, listed ciated with post-menopausal obesity is increased leptin US 9,623,021 B2 73 74 levels. In another embodiment the condition associated with In another embodiment, this invention relates to a method post-menopausal obesity is insulin resistance. In another of decreasing, Suppressing, inhibiting or reducing appetite of embodiment the condition associated with post-menopausal a Subject, comprising the step of administering to the Subject obesity is type II diabetes. In another embodiment the a compound as herein described and/or its analog, deriva condition associated with post-menopausal obesity is tive, isomer, metabolite, pharmaceutically acceptable salt, increased blood glucose levels. In another embodiment the pharmaceutical product, hydrate, N-oxide, prodrug, poly condition associated with post-menopausal obesity is morph, crystal, or any combination thereof, in an amount inflammatory diseases. In another embodiment the condition effective to decrease, Suppress, inhibit or reduce the appetite associated with post-menopausal obesity is cardiovascular of the subject. In another embodiment the compound is 10 compound of formula I-XII or its analog, derivative, isomer, diseases. In another embodiment the condition associated metabolite, pharmaceutically acceptable salt, pharmaceuti with post-menopausal obesity is fatty liver condition (accu cal product, hydrate, N-oxide, prodrug, polymorph, impurity mulation of fat in the liver). In another embodiment the or crystal of said compound, or any combination thereof. In condition associated with post-menopausal obesity is another embodiment the compound is a compound of for decreased uncoupling protein-1 (UCP-1) levels. In another 15 mula XI or its analog, derivative, isomer, metabolite, phar embodiment the condition associated with post-menopausal maceutically acceptable salt, pharmaceutical product, obesity is increased lipogenesis. hydrate, N-oxide, prodrug, polymorph, impurity or crystal of In one embodiment, the present invention provides meth said compound, or any combination thereof. In another ods for treating, delaying the onset of reducing the inci embodiment the compound is compound 12u, listed in Table dence of, or reducing the severity of obesity. In another 1. In another embodiment the compound is compound 12y, embodiment, the present invention provides methods for listed in Table 1. In another embodiment the compound is preventing obesity. In one embodiment, the obesity is post compound 12Z, listed in Table 1. In another embodiment the menopausal obesity. In another embodiment, the obesity is compound is compound 14m, listed in Table 1. visceral obesity. In another embodiment, the obesity is In another embodiment, this invention relates to methods visceral obesity at andropause. In another embodiment the 25 of reducing body weight gain in a Subject. In another obesity is diet induced obesity. In another embodiment the embodiment, this invention relates to methods of reducing obesity is induced by prolonged rest. In another embodiment body weight gain in a Subject, without affecting total caloric the methods comprise administering a compound of this intake. In another embodiment, this invention relates to invention. In another embodiment the compound is com methods of reducing body weight gain in a subject, without pound 12u, listed in Table 1. In another embodiment the 30 reducing lean mass or body water content. In another compound is compound 12y, listed in Table 1. In another embodiment, this invention relates to methods of preventing embodiment, the compound is compound of formula I-XII body weight gain in a subject. In another embodiment, this or its analog, derivative, isomer, metabolite, pharmaceuti invention relates to methods of preventing body weight gain cally acceptable salt, pharmaceutical product, hydrate, in a subject, without affecting total caloric intake. In another N-oxide, prodrug, polymorph, impurity or crystal of said 35 embodiment, this invention relates to methods of preventing compound, or any combination thereof. In another embodi body weight gain in a subject, without reducing lean mass or ment the compound is compound of formula XI or its body water content. In one embodiment the body weight analog, derivative, isomer, metabolite, pharmaceutically gain is due to high fat diet consumption. In another embodi acceptable salt, pharmaceutical product, hydrate, N-oxide, ment the body weight gain is related to post-menopausal prodrug, polymorph, impurity or crystal of said compound, 40 obesity. In another embodiment the body weight gain is or any combination thereof. In another embodiment the related to visceral obesity at andropause. In another embodi compound is compound 12Z, listed in Table 1. In another ment the body weight gain is related to visceral obesity. In embodiment the compound is compound 14m, listed in another embodiment the methods comprise administering a Table 1. compound of this invention. In another embodiment the In another embodiment, this invention relates to a method 45 compound is a compound of formula I-XII or its analog, of promoting, increasing or facilitating weight loss in a derivative, isomer, metabolite, pharmaceutically acceptable Subject, comprising the step of administering to the Subject salt, pharmaceutical product, hydrate, N-oxide, prodrug, a compound as herein described and/or its analog, deriva polymorph, impurity or crystal of said compound, or any tive, isomer, metabolite, pharmaceutically acceptable salt, combination thereof. In another embodiment the compound pharmaceutical product, hydrate, N-oxide, prodrug, poly 50 is a compound of formula XI or its analog, derivative, morph, crystal, or any combination thereof, in an amount isomer, metabolite, pharmaceutically acceptable salt, phar effective to promote, increase or facilitate weight loss in the maceutical product, hydrate, N-oxide, prodrug, polymorph, Subject. In another embodiment, the compound is compound impurity or crystal of said compound, or any combination of formula I-XII or its analog, derivative, isomer, metabolite, thereof. In another embodiment the compound is compound pharmaceutically acceptable salt, pharmaceutical product, 55 12u, listed in Table 1. In another embodiment the compound hydrate, N-oxide, prodrug, polymorph, impurity or crystal of is compound 12y, listed in Table 1. In another embodiment said compound, or any combination thereof. In another the compound is compound 12Z, listed in Table 1. In another embodiment the compound is compound of formula XI or its embodiment the compound is compound 14m, listed in analog, derivative, isomer, metabolite, pharmaceutically Table 1. acceptable salt, pharmaceutical product, hydrate, N-oxide, 60 In one embodiment this invention relates to methods of prodrug, polymorph, impurity or crystal of said compound, preventing body weight increase of between 10%400% of or any combination thereof. In another embodiment the the body weight. In another embodiment, the methods of this compound is compound 12u, listed in Table 1. In another invention prevent body weight increase of between 10-25% embodiment the compound is compound 12y, listed in Table of the body weight. In another embodiment, the methods of 1. In another embodiment the compound is compound 12Z. 65 this invention prevent body weight increase of between listed in Table 1. In another embodiment the compound is 25-50% of the body weight. In another embodiment, the compound 14m, listed in Table 1. methods of this invention prevent body weight increase of US 9,623,021 B2 75 76 between 30-70% of the body weight. In another embodi embodiment the compound is compound 12y, listed in Table ment, the methods of this invention prevent body weight 1. In another embodiment the compound is compound 12Z. increase of between 50-100% of the body weight. In another listed in Table 1. In another embodiment the compound is embodiment the methods comprise administering a com compound 14m, listed in Table 1. pound of this invention. In another embodiment the com In one embodiment this invention relates to methods of pound is a compound of formula I-XII or its analog, deriva preventing increase in body fat mass of between 10%-100% tive, isomer, metabolite, pharmaceutically acceptable salt, of the body fat mass. In another embodiment this invention pharmaceutical product, hydrate, N-oxide, prodrug, poly relates to methods of preventing increase in body fat mass of morph, impurity or crystal of said compound, or any com between 25%-35% of the body fat mass. In another embodi bination thereof. In another embodiment the compound is a 10 ment this invention relates to methods of preventing increase compound of formula XI or its analog, derivative, isomer, in body fat mass of between 35%-45% of the body fat mass. metabolite, pharmaceutically acceptable salt, pharmaceuti In another embodiment this invention relates to methods of cal product, hydrate, N-oxide, prodrug, polymorph, impurity preventing increase in body fat mass of between 45%-55% or crystal of said compound, or any combination thereof. In of the body fat mass. In another embodiment this invention another embodiment the compound is compound 12u, listed 15 relates to methods of preventing increase in body fat mass of in Table 1. In another embodiment the compound is com between 55%-65% of the body fat mass. In another embodi pound 12y, listed in Table 1. In another embodiment the ment this invention relates to methods of preventing increase compound is compound 12Z, listed in Table 1. In another in body fat mass of between 65%-7.5% of the body fat mass. embodiment the compound is compound 14m, listed in In another embodiment this invention relates to methods of Table 1. preventing increase in body fat mass of between 75%-100% In another embodiment, this invention relates to a method of the body fat mass. In another embodiment the methods of altering the body composition of a subject, comprising the comprise administering a compound of this invention. In step of administering to the Subject a compound as herein another embodiment the compound is a compound of for described and/or its analog, derivative, isomer, metabolite, mula I-XII or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, 25 pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal, or any com hydrate, N-oxide, prodrug, polymorph, impurity or crystal of bination thereof, in an amount effective to alter the body said compound, or any combination thereof. In another composition of the Subject. In one embodiment, altering the embodiment the compound is a compound of formula XI or body composition comprises altering the lean body mass, its analog, derivative, isomer, metabolite, pharmaceutically the fat free body mass of the subject, or a combination 30 acceptable salt, pharmaceutical product, hydrate, N-oxide, thereof. In another embodiment the compound is a com prodrug, polymorph, impurity or crystal of said compound, pound of formula I-XII or its analog, derivative, isomer, or any combination thereof. In another embodiment the metabolite, pharmaceutically acceptable salt, pharmaceuti compound is compound 12u, listed in Table 1. In another cal product, hydrate, N-oxide, prodrug, polymorph, impurity embodiment the compound is compound 12y, listed in Table or crystal of said compound, or any combination thereof. In 35 1. In another embodiment the compound is compound 12Z. another embodiment the compound is a compound of for listed in Table 1. In another embodiment the compound is mula XI or its analog, derivative, isomer, metabolite, phar compound 14m, listed in Table 1. maceutically acceptable salt, pharmaceutical product, In one embodiment, the present invention provides meth hydrate, N-oxide, prodrug, polymorph, impurity or crystal of ods for increasing lean mass in a Subject. In another embodi said compound, or any combination thereof. In another 40 ment, the present invention provides methods for preventing embodiment the compound is compound 12u, listed in Table decrease in lean mass in a subject. In one embodiment the 1. In another embodiment the compound is compound 12y, decrease in lean mass is related to high fat diet consumption. listed in Table 1. In another embodiment the compound is In another embodiment the decrease in lean mass is related compound 12Z, listed in Table 1. In another embodiment the to post-menopausal obesity. In another embodiment the compound is compound 14m, listed in Table 1. 45 decrease in lean mass is related to visceral obesity. In In another embodiment, the present invention provides another embodiment the decrease in lean mass is related to methods for reducing a fat mass in a subject. In another visceral obesity at andropause. In another embodiment the embodiment, the present invention provides methods for methods comprise administering a compound of this inven preventing fat mass formation in a subject. In one embodi tion. In another embodiment the compound is a compound ment the fat mass formation is related to high fat diet 50 of formula I-XII or its analog, derivative, isomer, metabolite, consumption. In another embodiment, the fat mass forma pharmaceutically acceptable salt, pharmaceutical product, tion is related to post-menopausal obesity. In one embodi hydrate, N-oxide, prodrug, polymorph, impurity or crystal of ment the fat mass formation is related to visceral obesity. In said compound, or any combination thereof. In another one embodiment the fat mass formation is related to visceral embodiment the compound is a compound of formula XI or obesity at andropause. In another embodiment the methods 55 its analog, derivative, isomer, metabolite, pharmaceutically comprise administering a compound of this invention. In acceptable salt, pharmaceutical product, hydrate, N-oxide, another embodiment the compound is a compound of for prodrug, polymorph, impurity or crystal of said compound, mula I-XII or its analog, derivative, isomer, metabolite, or any combination thereof. In another embodiment the pharmaceutically acceptable salt, pharmaceutical product, compound is compound 12u, listed in Table 1. In another hydrate, N-oxide, prodrug, polymorph, impurity or crystal of 60 embodiment the compound is compound 12y, listed in Table said compound, or any combination thereof. In another 1. In another embodiment the compound is compound 12Z. embodiment the compound is a compound of formula XI or listed in Table 1. In another embodiment the compound is its analog, derivative, isomer, metabolite, pharmaceutically compound 14m, listed in Table 1. acceptable salt, pharmaceutical product, hydrate, N-oxide, In another embodiment, this invention relates to methods prodrug, polymorph, impurity or crystal of said compound, 65 of increasing muscle weight. In another embodiment, this or any combination thereof. In another embodiment the invention relates to methods of preventing a decrease in compound is compound 12u, listed in Table 1. In another muscle weight. In one embodiment, the decrease is related US 9,623,021 B2 77 78 to high fat diet consumption. In another embodiment, the compound is compound 12Z, listed in Table 1. In another decrease is related to post-menopausal obesity. In another embodiment the compound is compound 14m, listed in embodiment, the decrease is related to visceral obesity. In Table 1. another embodiment, the decrease is related to visceral In another embodiment, this invention provides methods obesity at andropause. In one embodiment the muscle for increasing bone mineral content (BMC) in a subject. In weight is gastrocnemius muscle weight. In another embodi another embodiment, the present invention provides meth ment the methods comprise administering a compound of ods for preventing reduction in BMC in a subject. In one this invention. In another embodiment the compound is a embodiment the reduction in BMC is related to high fat diet. compound of formula I-XII or its analog, derivative, isomer, In another embodiment the reduction in BMC is related to metabolite, pharmaceutically acceptable salt, pharmaceuti 10 post-menopausal obesity. In another embodiment the reduc tion in BMC is related to visceral obesity. In another cal product, hydrate, N-oxide, prodrug, polymorph, impurity embodiment the reduction in BMC is related to visceral or crystal of said compound, or any combination thereof. In obesity at andropause. In another embodiment the methods another embodiment the compound is a compound of for comprise administering a compound of this invention. In mula XI or its analog, derivative, isomer, metabolite, phar 15 another embodiment the compound is a compound of for maceutically acceptable salt, pharmaceutical product, mula I-XII or its analog, derivative, isomer, metabolite, hydrate, N-oxide, prodrug, polymorph, impurity or crystal of pharmaceutically acceptable salt, pharmaceutical product, said compound, or any combination thereof. In another hydrate, N-oxide, prodrug, polymorph, impurity or crystal of embodiment the compound is compound 12u, listed in Table said compound, or any combination thereof. In another 1. In another embodiment the compound is compound 12y, embodiment the compound is a compound of formula XI or listed in Table 1. In another embodiment the compound is its analog, derivative, isomer, metabolite, pharmaceutically compound 12Z, listed in Table 1. In another embodiment the acceptable salt, pharmaceutical product, hydrate, N-oxide, compound is compound 14m, listed in Table 1. prodrug, polymorph, impurity or crystal of said compound, In another embodiment, this invention relates to a method or any combination thereof. In another embodiment the of altering lean body mass or fat free body mass of a Subject, 25 compound is compound 12u, listed in Table 1. In another comprising the step of administering to the Subject a com embodiment the compound is compound 12y, listed in Table pound as herein described and/or its analog, derivative, 1. In another embodiment the compound is compound 12Z. isomer, metabolite, pharmaceutically acceptable salt, phar listed in Table 1. In another embodiment the compound is maceutical product, hydrate, N-oxide, prodrug, polymorph, compound 14m, listed in Table 1. crystal, or any combination thereof, in an amount effective 30 In one embodiment, the present invention provides meth to alter the lean body mass or fat free body mass of the ods for treating, delaying the onset of reducing the inci Subject. In another embodiment the compound is a com dence of, or reducing the severity of osteoporosis. In another pound of formula or its analog, derivative, isomer, metabo embodiment, the present invention provides methods for lite, pharmaceutically acceptable salt, pharmaceutical prod preventing osteoporosis. In one embodiment, the osteopo 35 rosis is related to a post-menopausal obesity. In another uct, hydrate, N-oxide, prodrug, polymorph, impurity or embodiment the osteoporosis is related to a high fat diet crystal of said compound, or any combination thereof. In consumption. In another embodiment the osteoporosis is another embodiment the compound is a compound of for related to visceral obesity. In another embodiment the osteo mula XI or its analog, derivative, isomer, metabolite, phar porosis is related to visceral obesity at andropause. In maceutically acceptable salt, pharmaceutical product, 40 another embodiment the methods comprise administering a hydrate, N-oxide, prodrug, polymorph, impurity or crystal of compound of this invention. In another embodiment the said compound, or any combination thereof. In another compound is a compound of formula I-XII or its analog, embodiment the compound is compound 12u, listed in Table derivative, isomer, metabolite, pharmaceutically acceptable 1. In another embodiment the compound is compound 12y, salt, pharmaceutical product, hydrate, N-oxide, prodrug, listed in Table 1. In another embodiment the compound is 45 polymorph, impurity or crystal of said compound, or any compound 12Z, listed in Table 1. In another embodiment the combination thereof. In another embodiment the compound compound is compound 14m, listed in Table 1. is a compound of formula XI or its analog, derivative, In another embodiment, this invention relates to a method isomer, metabolite, pharmaceutically acceptable salt, phar of converting fat to lean muscle in a Subject, comprising the maceutical product, hydrate, N-oxide, prodrug, polymorph, step of administering to the Subject a compound as herein 50 impurity or crystal of said compound, or any combination described and/or its analog, derivative, isomer, metabolite, thereof. In another embodiment the compound is compound pharmaceutically acceptable salt, pharmaceutical product, 12u, listed in Table 1. In another embodiment the compound hydrate, N-oxide, prodrug, polymorph, crystal, or any com is compound 12y, listed in Table 1. In another embodiment bination thereof, in an amount effective to convert fat to lean the compound is compound 12Z, listed in Table 1. In another muscle in the Subject. In another embodiment the compound 55 embodiment the compound is compound 14m, listed in is a compound of formula I-XII or its analog, derivative, Table 1. isomer, metabolite, pharmaceutically acceptable salt, phar In another embodiment, this invention relates to methods maceutical product, hydrate, N-oxide, prodrug, polymorph, of reducing white adipose tissue (WAT) weight in a subject. impurity or crystal of said compound, or any combination In another embodiment, this invention relates to methods of thereof. In another embodiment the compound is a com 60 preventing an increase in white adipose tissue weight in a pound of formula XI or its analog, derivative, isomer, Subject. In one embodiment, the increase in white adipose metabolite, pharmaceutically acceptable salt, pharmaceuti tissue weight is related to high fat diet. In another embodi cal product, hydrate, N-oxide, prodrug, polymorph, impurity ment, the increase in white adipose tissue weight is related or crystal of said compound, or any combination thereof. In to post-menopausal obesity. In another embodiment, the another embodiment the compound is compound 12u, listed 65 increase in white adipose tissue weight is related to visceral in Table 1. In another embodiment the compound is com obesity. In another embodiment, the increase in white adi pound 12y, listed in Table 1. In another embodiment the pose tissue weight is related to visceral obesity at andro US 9,623,021 B2 79 80 pause. In another embodiment the methods comprise admin compound 12Z, listed in Table 1. In another embodiment the istering a compound of this invention. In another compound is compound 14m, listed in Table 1. embodiment the compound is a compound of formula I-XII In another embodiment, compounds of this invention are or its analog, derivative, isomer, metabolite, pharmaceuti co-administered with HDL-elevating agents. In another cally acceptable salt, pharmaceutical product, hydrate, embodiment, a compound of this invention is co-adminis N-oxide, prodrug, polymorph, impurity or crystal of said tered with an HDL-elevating agent. In another embodiment, compound, or any combination thereof. In another embodi HDL-elevating agents include niacin. In another embodi ment the compound is a compound of formula XI or its ment the HDL-elevating agents include fibrates including analog, derivative, isomer, metabolite, pharmaceutically gemfibrozil (Lopid), thiourea based gemfibrozil analogues, acceptable salt, pharmaceutical product, hydrate, N-oxide, 10 and fenofibrate (TriCor). In another embodiment, HDL prodrug, polymorph, impurity or crystal of said compound, elevating agents include statins. In another embodiment, or any combination thereof. In another embodiment the HDL-elevating agents include 1-hydroxyalkyl-3-phenylth compound is compound 12u, listed in Table 1. In another iourea, and analogs thereof. embodiment the compound is compound 12y, listed in Table In one embodiment atherosclerosis refers to a slow, com 1. In another embodiment the compound is compound 12Z. 15 plex disease that may begin with damage to the innermost listed in Table 1. In another embodiment the compound is layer of the artery. In another embodiment the causes of compound 14m, listed in Table 1. damage to the arterial wall may includea) elevated levels of Cholesterol, triacylglycerol and other lipids are trans cholesterol and in the blood; b) high blood pressure; c) ported in body fluids by lipoproteins which may be classified tobacco smoke d) diabetes. In another embodiment, the according to their density, for example, the very low density condition is treatable in a Smoker, despite the fact that lipoproteins (VLDL), intermediate density lipoproteins tobacco Smoke may greatly worsen atherosclerosis and (IDL), low density lipoproteins (LDL) and high density speed its growth in the coronary arteries, the aorta and lipoproteins (HDL). arteries in the legs. Similarly, in another embodiment, the It has been shown that high levels of LDL-Cholesterol in methods of this invention may be useful in treating Subjects the blood correlate with atherosclerosis which is a progres 25 with a family history of premature cardiovascular disease sive disease characterized in part by sedimentation of lipids who have an increased risk of atherosclerosis. in inner walls of arteries, particularly of coronary arteries. It In one embodiment, the present invention provides meth has also been shown that a high blood level of LDL ods for treating, delaying the onset of reducing the inci Cholesterol correlates with coronary heart disease. Also, a dence of, or reducing the severity of atherosclerosis. In negative correlation exists between blood levels of HDL 30 another embodiment, the present invention provides meth cholesterol and coronary heart disease. ods for preventing atherosclerosis. In one embodiment, the The level of total cholesterol in blood, which is the sum atherosclerosis is related to a post-menopausal obesity. In of HDL-Cholesterol, LDL-Cholesterol, VLDL-Cholesterol another embodiment the atherosclerosis is related to high fat and chylomicron-Cholesterol, is not necessarily predictive diet consumption. In another embodiment the atherosclero of the risk of coronary heart disease and atherosclerosis. 35 sis is related to visceral obesity. In another embodiment the The correlation between atherosclerosis and LDL choles atherosclerosis is related to visceral obesity at andropause. terol levels, however, is much higher than a similar corre In another embodiment the methods comprise administering lation between atherosclerosis and total serum cholesterol a compound of this invention. In another embodiment the levels. compound is a compound of formula I-XII or its analog, In another embodiment, this invention relates to methods 40 derivative, isomer, metabolite, pharmaceutically acceptable of reducing cholesterol levels in a Subject. In another salt, pharmaceutical product, hydrate, N-oxide, prodrug, embodiment, this invention relates to methods of lowering polymorph, impurity or crystal of said compound, or any LDL-cholesterol levels in a subject. In another embodiment, combination thereof. In another embodiment the compound this invention relates to methods of lowering total choles is a compound of formula XI or its analog, derivative, terol levels in a subject. In another embodiment, this inven 45 isomer, metabolite, pharmaceutically acceptable salt, phar tion relates to methods of preventing an increase in choles maceutical product, hydrate, N-oxide, prodrug, polymorph, terol levels in a subject. In one embodiment the increase in impurity or crystal of said compound, or any combination cholesterol levels is related to high fat diet. In another thereof. In another embodiment the compound is compound embodiment the increase in cholesterol levels is related to 12u, listed in Table 1. In another embodiment the compound post-menopausal obesity. In another embodiment the 50 is compound 12y, listed in Table 1. In another embodiment increase in cholesterol levels is related to visceral obesity. In the compound is compound 12Z, listed in Table 1. In another another embodiment the increase in cholesterol levels is embodiment the compound is compound 14m, listed in related to visceral obesity at andropause. In another embodi Table 1. ment the methods comprise administering a compound of In one embodiment, this invention provides a method of this invention. In another embodiment the compound is a 55 treating atherosclerosis and its associated diseases, such as, compound of formula I-XII or its analog, derivative, isomer, for example, cardiovascular disorders, cerebrovascular dis metabolite, pharmaceutically acceptable salt, pharmaceuti orders, peripheral vascular disorders, or intestinal vascular cal product, hydrate, N-oxide, prodrug, polymorph, impurity disorders in a subject, the method comprising the step of or crystal of said compound, or any combination thereof. In administering to the Subject compound of this invention or another embodiment the compound is a compound of for 60 its pharmaceutically acceptable salt, hydrate, N-oxide, or mula XI or its analog, derivative, isomer, metabolite, phar any combination thereof, or a composition comprising the maceutically acceptable salt, pharmaceutical product, same. In another embodiment the compound is a compound hydrate, N-oxide, prodrug, polymorph, impurity or crystal of of formula I-XII or its analog, derivative, isomer, metabolite, said compound, or any combination thereof. In another pharmaceutically acceptable salt, pharmaceutical product, embodiment the compound is compound 12u, listed in Table 65 hydrate, N-oxide, prodrug, polymorph, impurity or crystal of 1. In another embodiment the compound is compound 12y, said compound, or any combination thereof. In another listed in Table 1. In another embodiment the compound is embodiment the compound is a compound of formula XI or US 9,623,021 B2 81 82 its analog, derivative, isomer, metabolite, pharmaceutically bination thereof. In another embodiment the compound is a acceptable salt, pharmaceutical product, hydrate, N-oxide, compound of formula XI or its analog, derivative, isomer, prodrug, polymorph, impurity or crystal of said compound, metabolite, pharmaceutically acceptable salt, pharmaceuti or any combination thereof. In another embodiment the cal product, hydrate, N-oxide, prodrug, polymorph, impurity compound is compound 12u, listed in Table 1. In another 5 or crystal of said compound, or any combination thereof. In embodiment the compound is compound 12y, listed in Table another embodiment the compound is compound 12u, listed 1. In another embodiment the compound is compound 12Z. in Table 1. In another embodiment the compound is com listed in Table 1. In another embodiment the compound is pound 12y, listed in Table 1. In another embodiment the compound 14m, listed in Table 1. The method may further compound is compound 12Z, listed in Table 1. In another comprise co-administration, Subsequent or prior administra 10 tion with an agent or agents, which are known to be useful embodiment the compound is compound 14m, listed in in treating cardiovascular disorders, cerebrovascular disor Table 1. ders, peripheral vascular disorders, intestinal vascular dis In one embodiment, the subject for whom treatment is orders or combination thereof. sought via the methods of this invention is one with insulin resistance. Insulin resistance is a condition in which normal Hypercholesterolemia is a condition in which high levels 15 of cholesterol are present in the blood of a subject. It is not amounts of insulin are inadequate to produce a normal a disease but a metabolic derangement that can be secondary insulin response from fat, muscle and liver cells. Insulin to many diseases and can contribute to many forms of resistance in fat cells results in hydrolysis of stored triglyc disease, most notably cardiovascular disease. Elevated cho erides, which elevates free fatty acids in the blood plasma. lesterol in the blood is caused by abnormalities in the levels Insulin resistance in muscle reduces glucose uptake whereas of lipoproteins, the particles that carry cholesterol in the insulin resistance in liver reduces glucose storage, with both bloodstream. This may be related to diet, genetic factors effects serving to elevate blood glucose. High plasma levels (such as LDL receptor mutations in familial hypercholes of insulin and glucose due to insulin resistance often leads terolemia) and the presence of other diseases such as dia to the metabolic syndrome and type II diabetes. betes and an underactive thyroid. 25 In one embodiment, the present invention provides meth In one embodiment, this invention relates to methods of ods for treating, delaying the onset of reducing the inci alleviating hypercholesterolemia. In another embodiment, dence of, or reducing the severity of insulin resistance. In this invention relates to methods of preventing hypercho another embodiment, the present invention provides meth lesterolemia. In another embodiment the hypercholester ods for preventing insulin resistance. In one embodiment, olemia is related to high fat diet consumption. In another 30 the insulin resistance is related to post-menopausal obesity. embodiment the hypercholesterolemia is related to post In another embodiment, the insulin resistance related to menopausal obesity. In another embodiment hypercholes visceral obesity. In another embodiment, the insulin resis terolemia is related to visceral obesity. In another embodi tance related to visceral obesity at andropause. In another ment hypercholesterolemia is related to visceral obesity at embodiment the insulin resistance is related to a high fat diet andropause. In another embodiment the methods comprise 35 consumption. In another embodiment the methods comprise administering a compound of this invention. In another administering a compound of this invention. In another embodiment the compound is a compound of formula I-XII embodiment the compound is a compound of formula I-XII or its analog, derivative, isomer, metabolite, pharmaceuti or its analog, derivative, isomer, metabolite, pharmaceuti cally acceptable salt, pharmaceutical product, hydrate, cally acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, impurity or crystal of said 40 N-oxide, prodrug, polymorph, impurity or crystal of said compound, or any combination thereof. In another embodi compound, or any combination thereof. In another embodi ment the compound is a compound of formula XI or its ment the compound is a compound of formula XI or its analog, derivative, isomer, metabolite, pharmaceutically analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, impurity or crystal of said compound, 45 prodrug, polymorph, impurity or crystal of said compound, or any combination thereof. In another embodiment the or any combination thereof. In another embodiment the compound is compound 12u, listed in Table 1. In another compound is compound 12u, listed in Table 1. In another embodiment the compound is compound 12y, listed in Table embodiment the compound is compound 12y, listed in Table 1. In another embodiment the compound is compound 12Z. 1. In another embodiment the compound is compound 12Z. listed in Table 1. In another embodiment the compound is 50 listed in Table 1. In another embodiment the compound is compound 14m, listed in Table 1. compound 14m, listed in Table 1. In another embodiment, this invention relates to methods In one embodiment, the present invention provides meth of reducing leptin levels in a subject. In another embodi ods for improving insulin sensitivity in a subject. In another ment, the present invention provides methods for preventing embodiment the methods comprise administering a com an increase in leptin levels in a Subject. In one embodiment 55 pound of this invention. In another embodiment the com the increase in leptin levels is related to high fat diet pound is a compound of formula I-XII or its analog, deriva consumption. In another embodiment the increase in leptin tive, isomer, metabolite, pharmaceutically acceptable salt, levels is related to post-menopausal obesity. In another pharmaceutical product, hydrate, N-oxide, prodrug, poly embodiment the increase in leptin levels is related to visceral morph, impurity or crystal of said compound, or any com obesity. In another embodiment the increase in leptin levels 60 bination thereof. In another embodiment the compound is a is related to visceral obesity at andropause. In another compound of formula XI or its analog, derivative, isomer, embodiment the methods comprise administering a com metabolite, pharmaceutically acceptable salt, pharmaceuti pound of this invention. In another embodiment the com cal product, hydrate, N-oxide, prodrug, polymorph, impurity pound is a compound of formula I-XII or its analog, deriva or crystal of said compound, or any combination thereof. In tive, isomer, metabolite, pharmaceutically acceptable salt, 65 another embodiment the compound is compound 12u, listed pharmaceutical product, hydrate, N-oxide, prodrug, poly in Table 1. In another embodiment the compound is com morph, impurity or crystal of said compound, or any com pound 12y, listed in Table 1. In another embodiment the US 9,623,021 B2 83 84 compound is compound 12Z, listed in Table 1. In another compound is a compound of formula I-XII or its analog, embodiment the compound is compound 14m, listed in derivative, isomer, metabolite, pharmaceutically acceptable Table 1. salt, pharmaceutical product, hydrate, N-oxide, prodrug, In one embodiment, the present invention provides meth polymorph, impurity or crystal of said compound, or any ods for treating, halting the progression of, or treating combination thereof. In another embodiment the compound symptoms of delaying the onset of reducing the incidence is a compound of formula XI or its analog, derivative, of, or reducing the severity of diabetes. In another embodi isomer, metabolite, pharmaceutically acceptable salt, phar ment, the present invention provides methods for preventing maceutical product, hydrate, N-oxide, prodrug, polymorph, diabetes. In one embodiment, the diabetes is Type I diabetes. impurity or crystal of said compound, or any combination In another embodiment, the diabetes is Type II diabetes. In 10 thereof. In another embodiment the compound is compound a further embodiment, the diabetes is diabetes mellitus. In 12u, listed in Table 1. In another embodiment the compound one embodiment, the diabetes is related to post-menopausal is compound 12y, listed in Table 1. In another embodiment obesity. In another embodiment, the diabetes is related to the compound is compound 12Z, listed in Table 1. In another visceral obesity. In another embodiment, the diabetes is embodiment the compound is compound 14m, listed in related to visceral obesity at andropause. In another embodi 15 Table 1. ment the diabetes is induced by a high fat diet. In another Diabetic neuropathy is a family of nerve disorders caused embodiment the methods comprise administering a com by diabetes. Diabetic neuropathies cause numbness and pound of this invention. In another embodiment the com Sometimes pain and weakness in the hands, arms, feet, and pound is a compound of formula I-XII or its analog, deriva legs. Neurologic problems in diabetes may occur in every tive, isomer, metabolite, pharmaceutically acceptable salt, organ system, including the digestive tract, heart, and geni pharmaceutical product, hydrate, N-oxide, prodrug, poly talia. Diabetic neuropathies are classified as peripheral, morph, impurity or crystal of said compound, or any com autonomic, proximal, and focal. Peripheral neuropathy bination thereof. In another embodiment the compound is a causes pain or loss of feeling in the toes, feet, legs, hands, compound of formula XI or its analog, derivative, isomer, and arms. Autonomic neuropathy causes changes in diges metabolite, pharmaceutically acceptable salt, pharmaceuti 25 tion, bowel and bladder function, sexual response, and cal product, hydrate, N-oxide, prodrug, polymorph, impurity perspiration and can also affect the nerves that serve the or crystal of said compound, or any combination thereof. In heart and control blood pressure. Proximal neuropathy another embodiment the compound is compound 12u, listed causes pain in the thighs, hips, or buttocks and leads to in Table 1. In another embodiment the compound is com weakness in the legs. Focal neuropathy results in the Sudden pound 12y, listed in Table 1. In another embodiment the 30 weakness of one nerve, or a group of nerves, causing muscle compound is compound 12Z, listed in Table 1. In another weakness or pain. Any nerve in the body may be affected. embodiment the compound is compound 14m, listed in In another embodiment, this invention relates to treating Table 1. co-morbidities related to diabetes. These conditions include, In one embodiment, this invention provides a method of for example, hypertension (HTN), cerebrovascular disease, treating diabetic nephropathy comprising administering a 35 atherosclerotic coronary artery disease, macular degenera compound of this invention. In another embodiment the tion, diabetic retinopathy (eye disease) and blindness, cata compound is a compound of formula I-XII or its analog, racts—systemic inflammation (characterized by elevation of derivative, isomer, metabolite, pharmaceutically acceptable inflammatory markers such as erythrocyte sedimentation salt, pharmaceutical product, hydrate, N-oxide, prodrug, rate or C-reactive protein), birth defects, pregnancy related polymorph, impurity or crystal of said compound, or any 40 diabetes, pre-ecclampsia and hypertension in pregnancy, combination thereof. In another embodiment the compound kidney disease (renal insufficiency, renal failure etc.), nerve is a compound of formula XI or its analog, derivative, disease (diabetic neuropathy), Superficial and systemic fun isomer, metabolite, pharmaceutically acceptable salt, phar gal infections, congestive heart failure, gout/hyperuricemia, maceutical product, hydrate, N-oxide, prodrug, polymorph, obesity, hypertriglyceridemia, hypercholesterolemia, fatty impurity or crystal of said compound, or any combination 45 liver disease (non-alcoholic steatohepatitis, or NASH), and thereof. In another embodiment the compound is compound diabetes-related skin diseases such as Necrobiosis Lipoidica 12u, listed in Table 1. In another embodiment the compound Diabeticorum (NLD), Blisters of diabetes (Bullosis Diabeti is compound 12y, listed in Table 1. In another embodiment corum), Eruptive Xanthomatosis, Digital Sclerosis, Dis the compound is compound 12Z, listed in Table 1. In another seminated Granuloma Annulare and Acanthosis Nigricans. embodiment the compound is compound 14m, listed in 50 In one embodiment, the subject for whom treatment is Table 1. sought via the methods of this invention is one with hyper Diabetic nephropathy is a complication of diabetes that insulinemia. Hyperinsulinemia is a sign of an underlying evolves early, typically before clinical diagnosis of diabetes problem that is causing the pancreas to secrete excessive is made. The earliest clinical evidence of nephropathy is the amounts of insulin. The most common cause of hyperinsu appearance of low but abnormal levels (>30 mg/day or 20 55 linemia is insulin resistance, a condition in which your body ug/min) of albumin in the urine (microalbuminuria), fol is resistant to the effects of insulin and the pancreas tries to lowed by albuminuria (>300 mg/24 h or 200 ug/min) that compensate by making more insulin. Hyperinsulinemia is develops over a period of 10-15 years. In patients with type associated with type II diabetes 1 diabetes, diabetic hypertension typically becomes manifest In another embodiment, this invention relates to methods early on, by the time that patients develop microalbuminu 60 of alleviating hyperinsulinemia. In another embodiment, this ria. Once overt nephropathy occurs, the glomerular filtration invention relates to methods of preventing hyperinsuline rate (GFR) falls over a course of times, which may be mia. In one embodiment the hyperinsulinemia is related to several years, resulting in End Stage Renal Disease (ESRD) high fat diet consumption. In another embodiment the hyper in diabetic individuals. insulinemia is related to post-menopausal obesity. In another In one embodiment, this invention provides a method of 65 embodiment hyperinsulinemia is related to visceral obesity. treating diabetic neuropathy comprising administering a In another embodiment hyperinsulinemia is related to vis compound of this invention. In another embodiment the ceral obesity at andropause. In another embodiment the US 9,623,021 B2 85 86 methods comprise administering a compound of this inven The role of estrogen receptor and its ligands as therapy for tion. In another embodiment the compound is a compound inflammation has been under consideration. The effects are of formula I-XII or its analog, derivative, isomer, metabolite, regarded to be mediated by the isoform ER-B. Treatment of pharmaceutically acceptable salt, pharmaceutical product, rats with estradiol or SERMs such as raloxifene and tamox hydrate, N-oxide, prodrug, polymorph, impurity or crystal of 5 ifen has been shown to reduce the incidence of lipo-poly said compound, or any combination thereof. In another Sacharride induced inflammatory responses. One of the embodiment the compound is a compound of formula XI or pathways through which inflammatory responses are medi its analog, derivative, isomer, metabolite, pharmaceutically ated is through the activation of NFkB pathway. Nuclear acceptable salt, pharmaceutical product, hydrate, N-oxide, receptor ligands inhibit the NFKB activity through protein prodrug, polymorph, impurity or crystal of said compound, 10 protein interaction. Recently it was shown that SERMs or any combination thereof. In another embodiment the inhibit the inflammatory responses by inhibiting the NFKB compound is compound 12u, listed in Table 1. In another function without having estrogenic effects on other repro embodiment the compound is compound 12y, listed in Table ductive tissues. 1. In another embodiment the compound is compound 12Z. 15 In another embodiment, this invention relates to methods listed in Table 1. In another embodiment the compound is of treating preventing, inhibiting reducing the incidence of compound 14m, listed in Table 1. inflammation in a Subject. In one embodiment, the inflam In another embodiment, this invention relates to methods mation is related to increased levels of macrophage inflam of reducing glucose levels in a Subject. In another embodi matory protein-1B (MIP-1B). In one embodiment the inflam ment, this invention relates to methods of preventing an mation is related to high fat diet consumption. In another increase in the glucose levels in a Subject. In one embodi embodiment the inflammation is related to post-menopausal ment the increase in glucose levels is related to high fat diet obesity. In another embodiment the inflammation is related consumption. In another embodiment the increase in glucose to visceral obesity. In another embodiment the inflammation levels is related to post-menopausal obesity. In another is related to visceral obesity at andropause. In another embodiment the increase in glucose levels is related to 25 embodiment the methods comprise administering a com visceral obesity. In another embodiment the increase in pound of this invention. In another embodiment the com glucose levels is related to visceral obesity at andropause. In pound is a compound of formula I-XII or its analog, deriva another embodiment the methods comprise administering a tive, isomer, metabolite, pharmaceutically acceptable salt, compound of this invention. In another embodiment the pharmaceutical product, hydrate, N-oxide, prodrug, poly compound is a compound of formula I-XII or its analog, 30 morph, impurity or crystal of said compound, or any com derivative, isomer, metabolite, pharmaceutically acceptable bination thereof. In another embodiment the compound is a salt, pharmaceutical product, hydrate, N-oxide, prodrug, compound of formula XI or its analog, derivative, isomer, polymorph, impurity or crystal of said compound, or any metabolite, pharmaceutically acceptable salt, pharmaceuti combination thereof. In another embodiment the compound cal product, hydrate, N-oxide, prodrug, polymorph, impurity is a compound of formula XI or its analog, derivative, 35 isomer, metabolite, pharmaceutically acceptable salt, phar or crystal of said compound, or any combination thereof. In maceutical product, hydrate, N-oxide, prodrug, polymorph, another embodiment the compound is compound 12u, listed impurity or crystal of said compound, or any combination in Table 1. In another embodiment the compound is com thereof. In another embodiment the compound is compound pound 12y, listed in Table 1. In another embodiment the 12u, listed in Table 1. In another embodiment the compound 40 compound is compound 12Z, listed in Table 1. In another is compound 12y, listed in Table 1. In another embodiment embodiment the compound is compound 14m, listed in the compound is compound 12Z, listed in Table 1. In another Table 1. embodiment the compound is compound 14m, listed in In another embodiment, this invention relates to methods Table 1. of treating, preventing, inhibiting reducing the incidence of Inflammation is a common and potentially debilitating 45 increased macrophage inflammatory protein-1B (MIP-1B) condition that occurs when the white blood cells and endog levels in a subject. In another embodiment, this invention enous chemicals that can protect us from infection and relates to methods of preventing increased macrophage foreign Substances such as bacteria and viruses act on tissue inflammatory protein-13 (MIP-13) levels in a subject. In one Surrounding a wound or infection. In some diseases, how embodiment the increase is related to high fat diet consump ever, the body's defense system (immune system) triggers 50 tion. In another embodiment the increase is related to an inflammatory response when there are no foreign Sub post-menopausal obesity. In another embodiment the stances to fight off. In these diseases, called autoimmune increase is related to visceral obesity. In another embodi diseases, the body's normally protective immune system ment the increase is related to visceral obesity at andropause. causes damage to its own tissues. The body responds as if In another embodiment the methods comprise administering normal tissues are infected or somehow abnormal. Some, 55 a compound of this invention. In another embodiment the but not all types of arthritis are the result of misdirected compound is a compound of formula I-XII or its analog, inflammation. Arthritis is a general term that describes derivative, isomer, metabolite, pharmaceutically acceptable inflammation in joints and affects more than 2–4% of the salt, pharmaceutical product, hydrate, N-oxide, prodrug, world’s population. There are many available to polymorph, impurity or crystal of said compound, or any decrease Swelling and inflammation and hopefully prevent 60 combination thereof. In another embodiment the compound or minimize the progression of the inflammatory disease. is a compound of formula XI or its analog, derivative, The medications include non-steroidal anti-inflammatory isomer, metabolite, pharmaceutically acceptable salt, phar drugs (NSAIDs—such as aspirin, ibuprofen or naproxen), maceutical product, hydrate, N-oxide, prodrug, polymorph, corticosteroids (such as prednisone), anti-malarial medica impurity or crystal of said compound, or any combination tions (such as hydroxychloroquine), and other medications 65 thereof. In another embodiment the compound is compound including gold, methotrexate, Sulfasalazine, penicillamine, 12u, listed in Table 1. In another embodiment the compound cyclophosphamide and cyclosporine. is compound 12y, listed in Table 1. In another embodiment US 9,623,021 B2 87 88 the compound is compound 12Z, listed in Table 1. In another untreated, joint inflammation also can lead to destruction of embodiment the compound is compound 14m, listed in the joint synovium and the articular cartilage producing a Table 1. permanent debilitating condition. The edema, redness, and In one embodiment, the compound as described herein is pain that occur during inflammation are the result of physi useful in treating inflammation and related disorders such as: ological changes in the joint. For example, the permeability a) prevention, treatment, or reversal of arthritis; b) preven of the synovial membrane increases during inflammation tion, treatment, or reversal of an arthritic condition Such as allowing synovial fluid to leak into the tissues of the joint. Behcet’s disease (autoimmune vasculitis), bursitis, calcium Alterations in blood flow and pressure in the vascular system pyrophosphate dihydrate crystal (CPPD), deposition disease of the joint also occur during inflammation. In addition, the (or pseudogout), carpal tunnel syndrome, connective tissue 10 metabolic activity of the cells of the joint increases during disorders, Crohn's diseases, Ehlers-Danlos syndrome inflammation. (EDS), fibromyalgia, gout, infectious arthritis, inflammatory In another embodiment, the invention provides a method bowel disease (IBD), juvenile arthritis, systemic lupus ery of treating, preventing, inhibiting reducing the incidence of thematosus (SLE), Lyme’s disease, Marfan syndrome, myo joint inflammation in a Subject, comprising administering a sitis, osteoarthritis, polyarteritis nodosa, polymyalgia rheu 15 pharmaceutical composition comprising a NRBA of formula matica, psoriasis, psoriatic arthritis, Raynaud's (I)-(XII) or its prodrug, analog, isomer, metabolite, deriva phenomenon, reflex sympathetic dystrophy syndrome, Reit tive, pharmaceutically acceptable salt, pharmaceutical prod er's syndrome, rheumatoid arthritis, Scleroderma, Sjögrens uct, polymorph, crystal, impurity, N-oxide, ester, hydrate or syndrome, tendonitis or ulcerative colitis; c) preventing, any combination thereof, thereby treating, preventing, inhib treatment, or reversing an autoimmune disease; d) chronic iting reducing the incidence of joint inflammation in a kidney disease (CKD). Subject. In another embodiment the compound is a com In another embodiment, the invention provides a method pound of formula XI or its analog, derivative, isomer, of treating, preventing, inhibiting reducing the incidence of metabolite, pharmaceutically acceptable salt, pharmaceuti inflammatory diseases, disorders or conditions in a subject, cal product, hydrate, N-oxide, prodrug, polymorph, impurity comprising administering a pharmaceutical composition 25 or crystal of said compound, or any combination thereof. In comprising administering a compound of formula (I)-(XII) another embodiment the NRBA is compound 12u, listed in or its prodrug, analog, isomer, metabolite, derivative, phar Table 1. In another embodiment the NRBA is compound maceutically acceptable salt, pharmaceutical product, poly 12y, listed in Table 1. In another embodiment the NRBA is morph, crystal, impurity, N-oxide, ester, hydrate or any compound 12Z, listed in Table 1. In another embodiment the combination thereof, thereby treating, preventing, inhibiting 30 NRBA is compound 14m, listed in Table 1. reducing the incidence of inflammatory conditions in a In one embodiment, liver damage due to fat deposits refer subject. In some embodiments ER-B agonists are useful in to the build-up of fat in the liver cells forming a fatty liver treating, preventing, inhibiting reducing the incidence of which may be associated with or may lead to inflammation inflammatory diseases, disorders or conditions in a subject. of the liver. This can cause Scarring and hardening of the In another embodiment, ER-B agonist of this invention is 35 liver. When scarring becomes extensive, it is called cirrho compound 12b, listed in Table 1. In another embodiment, S1S. ER-B agonist of this invention is compound 12f, listed in In another embodiment, this invention relates to methods Table 1. In another embodiment, ER-B agonist of this of inhibiting fat accumulation in the liver of a subject. In invention is compound 12h, listed in Table 1. In another another embodiment, this invention relates to methods of embodiment, ER-B agonist of this invention is compound 40 reducing the amount of fat in the liver of a subject. In one 12p, listed in Table 1. In another embodiment, ER-Bagonist embodiment, the present invention provides methods for of this invention is compound 12s, listed in Table 1. In treating, delaying the onset of reducing the incidence of, or another embodiment, ER-3 agonist of this invention is reducing the severity of fatty liver condition. In another compound 12u, listed in Table 1. In another embodiment, embodiment, the present invention provides methods for ER-B agonist of this invention is compound 12Z, listed in 45 preventing fatty liver condition. In one embodiment, the Table 1. In another embodiment, ER-B agonist of this fatty liver condition is related to a post-menopausal obesity. invention is compound 12y, listed in Table 1. In another In another embodiment the fatty liver condition is related to embodiment, ER-B agonist of this invention is compound visceral obesity. In another embodiment the fatty liver 14m, listed in Table 1, or any combination thereof. condition is related to visceral obesity at andropause. In In some embodiments, ER-B agonists of this invention 50 another embodiment the fatty liver condition is related to inhibit stroma-epithelial proliferation (FIG. 23. Example 34) high fat diet consumption. In another embodiment the meth which can affect the development of anatomic obstruction, ods comprise administering a compound of this invention. In which can reduce inflammation and thereby, treat inflam another embodiment the compound is a compound of for mation. In one embodiment, ER-Bagonists of this invention mula I-XII or its analog, derivative, isomer, metabolite, relax Smooth muscle which can lower urine tract symptoms, 55 pharmaceutically acceptable salt, pharmaceutical product, affect the development of BPH, which can reduce inflam hydrate, N-oxide, prodrug, polymorph, impurity or crystal of mation and thereby, treat inflammation. said compound, or any combination thereof. In another In some embodiments, the inflammatory diseases disor embodiment the compound is a compound of formula XI or ders or conditions may comprise acute inflammation, its analog, derivative, isomer, metabolite, pharmaceutically arthropathies (in general), rheumatoid arthritis, systemic 60 acceptable salt, pharmaceutical product, hydrate, N-oxide, lupus erythema, asthma, acute inflammation, chronic prodrug, polymorph, impurity or crystal of said compound, inflammation, joint damage, joint Swelling, joint erosion, or any combination thereof. In another embodiment the sepsis, or any combination thereof. compound is compound 12u, listed in Table 1. In another Joint inflammation is one of the most common causes of embodiment the compound is compound 12y, listed in Table pain, lameness, and loss of physical activity, not only in 65 1. In another embodiment the compound is compound 12Z. humans but in animals, particularly horses. This debilitating listed in Table 1. In another embodiment the compound is condition is marked by edema, redness, heat and pain. If left compound 14m, listed in Table 1. US 9,623,021 B2 89 90 In one embodiment, “fatty liver condition” refers to a In some embodiments, the oxidative damage-related dis condition in which fat is accumulated in the liver. In another eases, disorders or conditions may comprise cancers; skin embodiment the fat accumulates in the liver as obesity. In disorders; neurodegenerative diseases Such as Alzheimer's another embodiment fatty liver is also associated with disease, Parkinson's disease, Huntington's disease, multiple diabetes mellitus, high blood triglycerides, and the heavy Sclerosis, and amytrophic lateral Sclerosis; vascular diseases use of alcohol. In another embodiment fatty Liver may occur Such as stroke and various age-related dementias, and ath with certain illnesses such as tuberculosis and malnutrition, erosclerosis; or age-related macular degeneration. intestinal bypass Surgery for obesity, excess vitamin A in the Oxidative damage can comprise damage to cells and body, or the use of certain drugs such as valproic acid (trade tissue, caused by oxidation of various cellular products, 10 which through the production of peroxides and free radicals names: Depakene/Depakote) and corticosteroids (cortisone, damage components of the cell and tissue, for example, prednisone). Sometimes fatty liver occurs as a complication damaging cell integrity, cell membranes, DNA, etc. of pregnancy. In one embodiment, this invention relates to methods of In one embodiment, this invention relates to methods of increasing uncoupling protein-a (UCP-1) levels in a Subject. altering the anti-oxidant pathways in a Subject. In another 15 In another embodiment, this invention relates to methods of embodiment, this invention relates to methods of reducing preventing a decrease in uncoupling protein-1 (UCP-1) glutathione peroxidase (GPx-3) levels in a subject. In levels in a subject. In one embodiment, the decrease is another embodiment, this invention relates to methods of related to high fat diet consumption. In another embodiment preventing an increase in glutathione peroxidase (GPx-3) the decrease is related to post-menopausal obesity. In levels in a subject. In one embodiment the increase is related another embodiment the decrease is related to visceral to high fat diet consumption. In another embodiment the obesity. In another embodiment the decrease is related to increase is related to post-menopausal obesity. In another visceral obesity at andropause. In another embodiment the embodiment the increase is related to visceral obesity. In methods comprise administering a compound of this inven another embodiment the increase is related to visceral obe tion. In another embodiment the compound is a compound sity at andropause. In another embodiment, this invention 25 of formula I-XII or its analog, derivative, isomer, metabolite, relates to methods of increasing the levels of DNA damage pharmaceutically acceptable salt, pharmaceutical product, inducible transcript III (Dalit3) in a subject. In another hydrate, N-oxide, prodrug, polymorph, impurity or crystal of embodiment, this invention relates to methods of preventing said compound, or any combination thereof. In another a decrease in the levels of DNA damage inducible transcript embodiment the compound is a compound of formula XI or III (Dalit?) in a subject. In one embodiment the decrease is 30 its analog, derivative, isomer, metabolite, pharmaceutically related to high fat diet consumption. In another embodiment acceptable salt, pharmaceutical product, hydrate, N-oxide, the decrease is related to post-menopausal obesity. In prodrug, polymorph, impurity or crystal of said compound, another embodiment the decrease is related to visceral or any combination thereof. In another embodiment the obesity. In another embodiment the decrease is related to compound is compound 12u, listed in Table 1. In another visceral obesity at andropause. In another embodiment the 35 embodiment the compound is compound 12y, listed in Table methods comprise administering a compound of this inven 1. In another embodiment the compound is compound 12Z. tion. In another embodiment the compound is a compound listed in Table 1. In another embodiment the compound is of formula I-XII or its analog, derivative, isomer, metabolite, compound 14m, listed in Table 1. pharmaceutically acceptable salt, pharmaceutical product, In another embodiment, this invention relates to methods hydrate, N-oxide, prodrug, polymorph, impurity or crystal of 40 of increasing energy expenditure in a Subject. In another said compound, or any combination thereof. In another embodiment, this invention relates to methods of preventing embodiment the compound is a compound of formula XI or a decrease in energy expenditure in a subject. In one its analog, derivative, isomer, metabolite, pharmaceutically embodiment the decrease in energy expenditure is related to acceptable salt, pharmaceutical product, hydrate, N-oxide, high fat diet consumption. In another embodiment the prodrug, polymorph, impurity or crystal of said compound, 45 decrease in energy expenditure is related to post-menopausal or any combination thereof. In another embodiment the obesity. In another embodiment the decrease in energy compound is compound 12u, listed in Table 1. In another expenditure is related to visceral obesity. In another embodi embodiment the compound is compound 12y, listed in Table ment the decrease in energy expenditure is related to visceral 1. In another embodiment the compound is compound 12Z. obesity at andropause. In another embodiment the methods listed in Table 1. In another embodiment the compound is 50 comprise administering a compound of this invention. In compound 14m, listed in Table 1. another embodiment the compound is a compound of for In another embodiment, the invention provides a method mula I-XII or its analog, derivative, isomer, metabolite, of treating, preventing, inhibiting reducing the incidence of pharmaceutically acceptable salt, pharmaceutical product, oxidative damage-related diseases, disorders or conditions hydrate, N-oxide, prodrug, polymorph, impurity or crystal of in a subject, comprising administering a pharmaceutical 55 said compound, or any combination thereof. In another composition comprising a compound of formula (I)-(XII) or embodiment the compound is a compound of formula XI or its prodrug, analog, isomer, metabolite, derivative, pharma its analog, derivative, isomer, metabolite, pharmaceutically ceutically acceptable salt, pharmaceutical product, poly acceptable salt, pharmaceutical product, hydrate, N-oxide, morph, crystal, impurity, N-oxide, ester, hydrate or any prodrug, polymorph, impurity or crystal of said compound, combination thereof, thereby treating, preventing, inhibiting 60 or any combination thereof. In another embodiment the reducing the incidence of oxidative damage-related diseases compound is compound 12u, listed in Table 1. In another in a subject. In another embodiment the compound is embodiment the compound is compound 12y, listed in Table compound 12u, listed in Table 1. In another embodiment the 1. In another embodiment the compound is compound 12Z. compound is compound 12y, listed in Table 1. In another listed in Table 1. In another embodiment the compound is embodiment the compound is compound 12Z, listed in Table 65 compound 14m, listed in Table 1. 1. In another embodiment the compound is compound 14m, In another embodiment, this invention relates to methods listed in Table 1. of reducing, inhibiting or preventing lipogenesis in a Subject. US 9,623,021 B2 91 92 In one embodiment the lipogenesis is related to decreased istering a NRBA of formula (I)-CXII) or its prodrug, ester, levels of genes promoting lipogenesis in a subject. These analog, isomer, metabolite, derivative, pharmaceutically genes include, but are not limited to: lipoprotein lipase acceptable salt, pharmaceutical product, polymorph, crystal, (LPL), fatty acid synthase (FASN), regulatory element bind impurity, N-oxide, hydrate or any combination thereof, or a ing protein-1 (SREBP-1), phospholipid transfer protein composition comprising the same, thereby improving the (PLTP) and dehydrocholesterol reductase (Dhcr24). In lipid profile in said subject. In some embodiments ER-B another embodiment, this invention relates to increasing the agonists are useful in improving a lipid profile in a Subject. levels of lipoprotein lipase (LPL) in a subject. In another In another embodiment, ER-B agonist of this invention is embodiment, this invention relates to increasing the levels of compound 12b, listed in Table 1. In another embodiment, fatty acid synthase (FASN) in a subject. In another embodi 10 ER-B agonist of this invention is compound 12f, listed in ment, this invention relates to increasing the levels of Table 1. In another embodiment, ER-B agonist of this regulatory element binding protein-1 (SREBP-1) in a sub invention is compound 12h, listed in Table 1. In another ject. In another embodiment, this invention relates to embodiment, ER-B agonist of this invention is compound increasing the levels of phospholipid transfer protein (PLTP) 12p, listed in Table 1. In another embodiment, ER-Bagonist in a Subject. In another embodiment, this invention relates to 15 of this invention is compound 12s, listed in Table 1. In increasing the levels of dehydrocholesterol reductase another embodiment, ER-B agonist of this invention is (Dhcr24) in a subject. In another embodiment, this invention compound 12u, listed in Table 1. In another embodiment, relates to preventing a decrease in the levels of lipoprotein ER-B agonist of this invention is compound 12y, listed in lipase (LPL) in a subject. In another embodiment, this Table 1. In another embodiment, ER-B agonist of this invention relates to preventing a decrease in the levels of invention is compound 12Z, listed in Table 1. In another fatty acid synthase (FASN) in a subject. In another embodi embodiment, ER-B agonist of this invention is compound ment, this invention relates to preventing a decrease in the 14m, listed in Table 1, or any combination thereof. levels of regulatory element binding protein-1 (SREBP-1) in In some embodiments, the phrase “improving a lipid a Subject. In another embodiment, this invention relates to profile' may refer to lowering pathogenic circulating lipid preventing a decrease in the levels of phospholipid transfer 25 levels, lowering plaque formation in vasculature, altering protein (PLTP) in a subject. In another embodiment, this circulating HDL/LDL ratios, ratios reducing the ratio of invention relates to preventing a decrease in the levels of LDL levels to HDL levels, lowering circulating cholesterol dehydrocholesterol reductase (Dhcr24) in a subject. In one levels, preventing lipid accumulation in vasculature, or any embodiment the lipogenesis is related to high fat diet combination thereof, or other therapeutic effects related consumption. In another embodiment the lipogenesis is 30 thereto, as will be appreciated by one skilled in the art. related to post-menopausal obesity. In another embodiment In one embodiment, this invention provides a method of the lipogenesis is related to visceral obesity. In another reducing circulating lipid levels in a subject, said method embodiment the lipogenesis is related to visceral obesity at comprising administering a compound of this invention or andropause. In another embodiment the methods comprise its pharmaceutically acceptable salt, hydrate, N-oxide, or administering a compound of this invention. In another 35 any combination thereof, or a composition comprising the embodiment the compound is a compound of formula I-XII same. In another embodiment the compound is a compound or its analog, derivative, isomer, metabolite, pharmaceuti of formula I-XII or its analog, derivative, isomer, metabolite, cally acceptable salt, pharmaceutical product, hydrate, pharmaceutically acceptable salt, pharmaceutical product, N-oxide, prodrug, polymorph, impurity or crystal of said hydrate, N-oxide, prodrug, polymorph, impurity or crystal of compound, or any combination thereof. In another embodi 40 said compound, or any combination thereof. In another ment the compound is a compound of formula XI or its embodiment the compound is a compound of formula XI or analog, derivative, isomer, metabolite, pharmaceutically its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, acceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, impurity or crystal of said compound, prodrug, polymorph, impurity or crystal of said compound, or any combination thereof. In another embodiment the 45 or any combination thereof. In another embodiment the compound is compound 12u, listed in Table 1. In another compound is compound 12u, listed in Table 1. In another embodiment the compound is compound 12y, listed in Table embodiment the compound is compound 12y, listed in Table 1. In another embodiment the compound is compound 12Z. 1. In another embodiment the compound is compound 12Z. listed in Table 1. In another embodiment the compound is listed in Table 1. In another embodiment the compound is compound 14m, listed in Table 1. 50 compound 14m, listed in Table 1. In one embodiment, the In one embodiment, this invention provides methods of Subject Suffers from atherosclerosis and its associated dis use of the compounds as herein described for improving the eases, premature aging, Alzheimer's disease, stroke, toxic lipid profile and/or reducing the circulating lipid levels in a hepatitis, viral hepatitis, peripheral vascular insufficiency, Subject. In some embodiments, according to this aspect of renal disease, hyperglycemia, or any combination thereof. the invention, the subject suffers from one or more condi 55 Hyperlipidemia is the presence of raised or abnormal tions selected from the group consisting of atherosclerosis levels of lipids and/or lipoproteins in the blood. Lipids (fatty and its associated diseases, premature aging, Alzheimer's molecules) are transported in a protein capsule, and the disease, stroke, toxic hepatitis, viral hepatitis, peripheral density of the lipids and type of protein determines the fate vascular insufficiency, renal disease, and hyperglycemia, of the particle and its influence on metabolism. Lipid and and the invention provides for the administration of a 60 lipoprotein abnormalities are extremely common in the compound or composition comprising the same, as herein general population, and are regarded as a highly modifiable described, which in some embodiments positively affects a risk factor for cardiovascular disease due to the influence of lipid profile in the subject, which is one means by which the cholesterol, one of the most clinically relevant lipid sub method is useful in treating the indicated diseases, disorders stances, on atherosclerosis. and conditions. 65 In one embodiment, the present invention provides meth In another embodiment, the invention provides a method ods for treating, delaying the onset of reducing the inci of improving a lipid profile in a Subject, comprising admin dence of, or reducing the severity of hyperlipidemia. In US 9,623,021 B2 93 94 another embodiment, the present invention provides meth or any combination thereof. In another embodiment the ods for preventing hyperlipidemia. In one embodiment, the compound is compound 12u, listed in Table 1. In another hyperlipidemia is related to a post-menopausal obesity. In embodiment the compound is compound 12y, listed in Table another embodiment the hyperlipidemia is related to high fat 1. In another embodiment the compound is compound 12Z. diet consumption. In another embodiment the hyperlipi listed in Table 1. In another embodiment the compound is demia is related to visceral obesity. In another embodiment compound 14m, listed in Table 1. the hyperlipidemia is related to visceral obesity at andro In one embodiment, this invention relates to a method of pause. In another embodiment the methods comprise admin inhibiting Peroxisome Proliferator Activated Receptor-y istering a compound of this invention. In another embodi (PPAR-Y) function. In another embodiment, this invention ment the compound is a compound of formula I-XII or its 10 relates to a method of inhibiting Peroxisome Proliferator analog, derivative, isomer, metabolite, pharmaceutically Activated Receptor-Y (PPAR-Y) function through indirectly acceptable salt, pharmaceutical product, hydrate, N-oxide, acting agents such as ER-B agonists. In another embodi prodrug, polymorph, impurity or crystal of said compound, ment, this invention relates to a method of inhibiting Per or any combination thereof. In another embodiment the oxisome Proliferator Activated Receptor-Y (PPAR-Y) func compound is a compound of formula XI or its analog, 15 tion without causing adverse side effects. In another derivative, isomer, metabolite, pharmaceutically acceptable embodiment the methods comprise administering a com salt, pharmaceutical product, hydrate, N-oxide, prodrug, pound of this invention. In another embodiment the com polymorph, impurity or crystal of said compound, or any pound is a compound of formula I-XII or its analog, deriva combination thereof. In another embodiment the compound tive, isomer, metabolite, pharmaceutically acceptable salt, is compound 12u, listed in Table 1. In another embodiment pharmaceutical product, hydrate, N-oxide, prodrug, poly the compound is compound 12y, listed in Table 1. In another morph, impurity or crystal of said compound, or any com embodiment the compound is compound 12Z, listed in Table bination thereof. In another embodiment the compound is a 1. In another embodiment the compound is compound 14m, compound of formula XI or its analog, derivative, isomer, listed in Table 1. metabolite, pharmaceutically acceptable salt, pharmaceuti In another embodiment, this invention relates to a method 25 cal product, hydrate, N-oxide, prodrug, polymorph, impurity of decreasing, Suppressing, inhibiting or reducing adipogen or crystal of said compound, or any combination thereof. In esis in a subject, comprising the step of administering to the another embodiment the compound is compound 12u, listed Subject a compound as herein described and/or its analog, in Table 1. In another embodiment the compound is com derivative, isomer, metabolite, pharmaceutically acceptable pound 12y, listed in Table 1. In another embodiment the salt, pharmaceutical product, hydrate, N-oxide, prodrug, 30 compound is compound 12Z, listed in Table 1. In another polymorph, crystal, or any combination thereof. In another embodiment the compound is compound 14m, listed in embodiment the compound is a compound of formula I-XII Table 1. or its analog, derivative, isomer, metabolite, pharmaceuti In one embodiment this invention provides a method of cally acceptable salt, pharmaceutical product, hydrate, treating a Subject Suffering from post menopausal condi N-oxide, prodrug, polymorph, impurity or crystal of said 35 tions, said method comprising the step of administering to compound, or any combination thereof. In another embodi said subject a NRBA and/or its pharmaceutically acceptable ment the compound is a compound of formula XI or its salt, hydrate, N-oxide, or any combination thereof. In analog, derivative, isomer, metabolite, pharmaceutically another embodiment the NRBA is compound 12u, listed in acceptable salt, pharmaceutical product, hydrate, N-oxide, Table 1. In another embodiment the NRBA is compound prodrug, polymorph, impurity or crystal of said compound, 40 12y, listed in Table 1. In another embodiment the NRBA is or any combination thereof. In another embodiment the compound 12Z, listed in Table 1. In another embodiment the compound is compound 12u, listed in Table 1. In another NRBA is compound 14m, listed in Table 1. In another embodiment the compound is compound 12y, listed in Table embodiment the NRBA is compound 15a, 15b, 15c, 15g, 1. In another embodiment the compound is compound 12Z. 15h, or 15i, listed in Table 1. listed in Table 1. In another embodiment the compound is 45 In another embodiment this invention provides a method compound 14m, listed in Table 1. of Suppressing, inhibiting or reducing the risk of post In another embodiment, this invention relates to increas menopausal conditions, said method comprising the step of ing the levels of Cell death inducing DNA fragmentation administering to said subject a NRBA and/or its pharma factor (CIDEA) in a subject. In another embodiment, this ceutically acceptable salt, hydrate, N-oxide, or any combi invention relates to preventing a decrease in the levels of 50 nation thereof. In another embodiment the NRBA is com Cell death inducing DNA fragmentation factor (CIDEA) in pound 12u, listed in Table 1. In another embodiment the a subject. In one embodiment, the decrease is related to high NRBA is compound 12y, listed in Table 1. In another fat diet consumption. In another embodiment the decrease is embodiment the NRBA is compound 12Z, listed in Table 1. related to post-menopausal obesity. In another embodiment In another embodiment the NRBA is compound 14m, listed the decrease is related to visceral obesity. In another embodi 55 in Table 1. In another embodiment the NRBA is compound ment the decrease is related to visceral obesity at andro 15a, 15b, 15c, 15g, 15h, or 15i, listed in Table 1. pause. In another embodiment the methods comprise admin In one embodiment, the present invention provides meth istering a compound of this invention. In another ods for treating, delaying the onset of reducing the inci embodiment the compound is a compound of formula I-XII dence of, or reducing the severity of a metabolic disorder, or its analog, derivative, isomer, metabolite, pharmaceuti 60 Such as obesity, metabolic syndrome, insulin resistance, cally acceptable salt, pharmaceutical product, hydrate, diabetes (e.g., Type I diabetes, Type II diabetes, diabetes N-oxide, prodrug, polymorph, impurity or crystal of said mellitus), atherosclerosis, hyperlipidemia, fatty liver, osteo compound, or any combination thereof. In another embodi porosis and/or leptin related disorders. In another embodi ment the compound is a compound of formula XI or its ment the methods comprise administering a compound of analog, derivative, isomer, metabolite, pharmaceutically 65 this invention. In another embodiment the compound is a acceptable salt, pharmaceutical product, hydrate, N-oxide, compound of formula I-XII or its analog, derivative, isomer, prodrug, polymorph, impurity or crystal of said compound, metabolite, pharmaceutically acceptable salt, pharmaceuti US 9,623,021 B2 95 96 cal product, hydrate, N-oxide, prodrug, polymorph, impurity hypertension (high blood pressure), cholesterol abnormali or crystal of said compound, or any combination thereof. In ties, and an increased risk for clotting. Patients are most another embodiment the compound is a compound of for often overweight or obese. mula XI or its analog, derivative, isomer, metabolite, phar In one embodiment, the present invention provides meth maceutically acceptable salt, pharmaceutical product, ods for treating, delaying the onset of reducing the inci hydrate, N-oxide, prodrug, polymorph, impurity or crystal of dence of, or reducing the severity of metabolic syndrome. In said compound, or any combination thereof. In another another embodiment, the present invention provides meth embodiment the compound is compound 12u, listed in Table ods for preventing metabolic syndrome. In one embodiment, 1. In another embodiment the compound is compound 12y, the metabolic syndrome is a post-menopausal metabolic listed in Table 1. In another embodiment the compound is 10 syndrome. In another embodiment the metabolic syndrome compound 12Z, listed in Table 1. In another embodiment the is related to high fat diet consumption. In another embodi compound is compound 14m, listed in Table 1. ment the metabolic syndrome is related to visceral obesity. In another embodiment, this invention relates to methods In another embodiment the metabolic syndrome is related to of treating an obesity-associated metabolic disorder in a visceral obesity at andropause. In another embodiment the Subject. In another embodiment, this invention relates to a 15 methods comprise administering a compound of this inven method of preventing, Suppressing, inhibiting or reducing an tion. In another embodiment the compound is a compound obesity-associated metabolic disorder in a subject. In one of formula I-XII or its analog, derivative, isomer, metabolite, embodiment the obesity-associated metabolic disorder is pharmaceutically acceptable salt, pharmaceutical product, related to high fat diet consumption. In another embodiment hydrate, N-oxide, prodrug, polymorph, impurity or crystal of the obesity-associated metabolic disorder is related to post said compound, or any combination thereof. In another menopausal obesity. In another embodiment the obesity embodiment the compound is a compound of formula XI or associated metabolic disorder is related to visceral obesity. its analog, derivative, isomer, metabolite, pharmaceutically In another embodiment the obesity-associated metabolic acceptable salt, pharmaceutical product, hydrate, N-oxide, disorder is related to visceral obesity at andropause. In prodrug, polymorph, impurity or crystal of said compound, another embodiment, this invention relates to a method of 25 or any combination thereof. In another embodiment the treating an obesity-associated metabolic disorder in a Sub compound is compound 12u, listed in Table 1. In another ject, comprising the step of administering to the Subject a embodiment the compound is compound 12y, listed in Table compound as herein described and/or its analog, derivative, 1. In another embodiment the compound is compound 12Z. isomer, metabolite, pharmaceutically acceptable salt, phar listed in Table 1. In another embodiment the compound is maceutical product, hydrate, N-oxide, prodrug, polymorph, 30 compound 14m, listed in Table 1. crystal, or any combination thereof, in an amount effective “Muscle wasting refers to the progressive loss of muscle to treat the obesity-associated metabolic disorder in the mass and/or to the progressive weakening and degeneration Subject. In another embodiment, this invention relates to a of muscles, including the skeletal or Voluntary muscles, method of preventing, Suppressing, inhibiting or reducing an which control movement, cardiac muscles, which control the obesity-associated metabolic disorder in a subject, compris 35 heart (cardiomyopathics), and Smooth muscles. Chronic ing the step of administering to the Subject a compound as muscle wasting is a chronic condition (i.e. persisting over a herein described and/or its analog, derivative, isomer, long period of time) characterized by progressive loss of metabolite, pharmaceutically acceptable salt, pharmaceuti muscle mass, weakening and degeneration of muscle. cal product, hydrate, N-oxide, prodrug, polymorph, crystal, Muscle wasting is associated with chronic, neurological, or any combination thereof, in an amount effective to 40 genetic or infectious pathologies, diseases, illnesses or con prevent, Suppress, inhibit or reduce the obesity-associated ditions. These include Muscular Dystrophies such as Duch metabolic disorder in the subject. In another embodiment the enne Muscular Dystrophy and Myotonic Dystrophy; Muscle compound is a compound of formula I-XII or its analog, Atrophies such as Post-Polio Muscle Atrophy (PPMA): derivative, isomer, metabolite, pharmaceutically acceptable Cachexias such as Cardiac Cachexia, AIDS Cachexia and salt, pharmaceutical product, hydrate, N-oxide, prodrug, 45 Cancer Cachexia, malnutrition, Leprosy, Diabetes, Renal polymorph, impurity or crystal of said compound, or any Disease, Chronic Obstructive Pulmonary Disease (COPD), combination thereof. In another embodiment the compound Cancer, end stage Renal failure, Sarcopenia, Emphysema, is a compound of formula XI or its analog, derivative, Osteomalacia, HIV Infection, AIDS, and Cardiomyopathy isomer, metabolite, pharmaceutically acceptable salt, phar In one embodiment, the present invention provides meth maceutical product, hydrate, N-oxide, prodrug, polymorph, 50 ods for treating, delaying the onset of reducing the inci impurity or crystal of said compound, or any combination dence of, or reducing the severity of muscle wasting. In thereof. In another embodiment the compound is compound another embodiment, the present invention provides meth 12u, listed in Table 1. In another embodiment the compound ods for preventing muscle wasting. In one embodiment, the is compound 12y, listed in Table 1. In another embodiment muscle wasting is a post-menopausal muscle wasting. In the compound is compound 12Z, listed in Table 1. In another 55 another embodiment the muscle wasting is due to high fat embodiment the compound is compound 14m, listed in diet consumption. In another embodiment the muscle wast Table 1. ing is due to visceral obesity. In another embodiment the In one embodiment, the obesity-associated metabolic muscle wasting is due to visceral obesity at andropause. In disorder is hypertension. In another embodiment, the disor another embodiment the methods comprise administering a der is osteoarthritis. In another embodiment, the disorder is 60 compound of this invention. In another embodiment the increased blood pressure. In another embodiment, the dis compound is a compound of formula I-XII or its analog, order is a stroke. In another embodiment, the disorder is derivative, isomer, metabolite, pharmaceutically acceptable heart disease. salt, pharmaceutical product, hydrate, N-oxide, prodrug, Metabolic syndrome refers to a cluster of metabolic risk polymorph, impurity or crystal of said compound, or any factors or medical disorders that together increase the risk of 65 combination thereof. In another embodiment the compound developing cardiovascular disease and diabetes. The main is a compound of formula XI or its analog, derivative, features of metabolic syndrome include insulin resistance, isomer, metabolite, pharmaceutically acceptable salt, phar US 9,623,021 B2 97 98 maceutical product, hydrate, N-oxide, prodrug, polymorph, In one embodiment, this invention provides: a) a method impurity or crystal of said compound, or any combination of treating endometriosis in a Subject; b) a method of treating thereof. In another embodiment the compound is compound breast cancer in a subject; c) a method of treating lung 12u, listed in Table 1. In another embodiment the compound cancer in a Subject; d) a method of reducing aggressive is compound 12y, listed in Table 1. In another embodiment behavior in a subject; e) a method of treating anxiety in a the compound is compound 12Z, listed in Table 1. In another Subject, f) a method of treating hot flashes in a Subject; g) a embodiment the compound is compound 14m, listed in method of treating post-menopausal osteoporosis in a Sub Table 1. ject, comprising administering a compound of this invention "Cachexia' is weakness and a loss of weight caused by a and/or an analog, derivative, isomer, metabolite, pharma disease or as a side effect of illness. Cardiac Cachexia, i.e. 10 ceutically acceptable salt, pharmaceutical product, hydrate, a muscle protein wasting of both the cardiac and skeletal muscle, is a characteristic of congestive heart failure. Cancer N-oxide, prodrug, polymorph, impurity or crystal of said Cachexia is a syndrome that occurs in patients with Solid compound, or any combination thereof, ER-B antagonists tumors and hematological malignancies and is manifested might be useful to treat various conditions such as anxiety, by weight loss with massive depletion of both adipose tissue 15 hot flashes and post-menopausal osteoporosis. Most of the and lean muscle mass. Acquired Immunodeficiency Syn above mentioned indications are mediated primarily by drome (AIDS). Cachexia is a Human Immunodeficiency ER-C. Mechanistically, it is a well known fact that ER-B is Virus (HIV) associated myopathy and/or muscle weakness/ a dominant negative inhibitor of ER-C. Hence, in these wasting that is a relatively common clinical manifestation of post-menopausal conditions, the binding and activation of AIDS. Individuals with HIV-associated myopathy or muscle even the limited amount of circulating estrogens to ER-C. is weakness or wasting typically experience significant weight inhibited by the binding and activation of ER-43. Inhibiting loss, generalized or proximal muscle weakness, tenderness, ER-B with antagonists will provide a way to relieve its and muscle atrophy. repressive effects on ER-C, leading to increase in ER-C. In one embodiment, the present invention provides meth function. Hence, ER-Bantagonists could be used to treat hot ods for treating, delaying the onset of reducing the inci 25 flashes, post-menopausal osteoporosis and anxiety. dence of, or reducing the severity of Cachexia. In another Endometriosis is a debilitating medical condition in embodiment, the present invention provides methods for females in which endometrial-like cells appear and flourish preventing Cachexia. In one embodiment, the Cachexia is a in areas outside the uterine cavity, most commonly on the post-menopausal Cachexia. In another embodiment the ovaries. The uterine cavity is lined by endometrial cells, Cachexia is due to high fat diet consumption. In another 30 which are under the influence of female hormones. These embodiment the Cachexia is due to visceral obesity. In endometrial-like cells in areas outside the uterus (endo another embodiment the Cachexia is due to visceral obesity metriosis) are influenced by hormonal changes and respond at andropause. In another embodiment the methods com similarly as do those cells found inside the uterus. Endo prise administering a compound of this invention. In another metriosis is typically seen during the reproductive years; it embodiment the compound is a compound of formula I-XII 35 has been estimated that it occurs in roughly 5% to 10% of or its analog, derivative, isomer, metabolite, pharmaceuti women. A major symptom of endometriosis is recurring cally acceptable salt, pharmaceutical product, hydrate, pelvic pain. Other symptoms may include nausea, vomiting, N-oxide, prodrug, polymorph, impurity or crystal of said fainting, dizzy spells, vertigo, frequent or constant menstrual compound, or any combination thereof. In another embodi flow, chronic fatigue, mood Swings, extreme pain in legs and ment the compound is a compound of formula XI or its 40 thighs, back pain, mild to extreme pain during intercourse analog, derivative, isomer, metabolite, pharmaceutically and others. acceptable salt, pharmaceutical product, hydrate, N-oxide, During endometriosis, ER-B is pathologically over-ex prodrug, polymorph, impurity or crystal of said compound, pressed resulting in inhibition of progestin and PR action. or any combination thereof. In another embodiment the Combining ER-B antagonist may improve the therapeutic compound is compound 12u, listed in Table 1. In another 45 efficacy of progestin. Alternatively, ER-B antagonist alone embodiment the compound is compound 12y, listed in Table may recover endogeneous progestin function. 1. In another embodiment the compound is compound 12Z. In one embodiment this invention relates to methods of listed in Table 1. In another embodiment the compound is treating, preventing, inhibiting, Suppressing, delaying the compound 14m, listed in Table 1. onset of reducing the incidence of, or reducing the severity In another embodiment, this invention relates to methods 50 of endometriosis comprising administering a compound of of increasing myoanabolism. In another embodiment the this invention. In another embodiment the compound is a methods comprise administering a compound of this inven compound of formula or its analog, derivative, isomer, tion. In another embodiment the compound is a compound metabolite, pharmaceutically acceptable salt, pharmaceuti of formula I-XII or its analog, derivative, isomer, metabolite, cal product, hydrate, N-oxide, prodrug, polymorph, impurity pharmaceutically acceptable salt, pharmaceutical product, 55 or crystal of said compound, or any combination thereof. In hydrate, N-oxide, prodrug, polymorph, impurity or crystal of another embodiment the compound is a compound of for said compound, or any combination thereof. In another mula XI or its analog, derivative, isomer, metabolite, phar embodiment the compound is a compound of formula XI or maceutically acceptable salt, pharmaceutical product, its analog, derivative, isomer, metabolite, pharmaceutically hydrate, N-oxide, prodrug, polymorph, impurity or crystal of acceptable salt, pharmaceutical product, hydrate, N-oxide, 60 said compound, or any combination thereof. In another prodrug, polymorph, impurity or crystal of said compound, embodiment the compound is an ER-Bantagonist. In another or any combination thereof. In another embodiment the embodiment the compound is compound 15a, 15b, 15c, 15g, compound is compound 12u, listed in Table 1. In another 15h, or 15i, listed in Table 1. embodiment the compound is compound 12y, listed in Table It has been shown that activation of ER-B leads to 1. In another embodiment the compound is compound 12Z. 65 increased proliferation in breast cancer and lung cancer. listed in Table 1. In another embodiment the compound is Accordingly, inhibition of ER-B may be useful for treating compound 14m, listed in Table 1. breast cancer and lung cancer. US 9,623,021 B2 99 100 In one embodiment this invention relates to methods of In one embodiment this invention relates to methods of treating, preventing, inhibiting, Suppressing, delaying the treating, preventing, inhibiting, Suppressing, delaying the onset of reducing the incidence of, or reducing the severity onset of reducing the incidence of, or reducing the severity of breast cancer comprising administering a compound of of hot flashes in a Subject comprising administering a this invention. In another embodiment the compound is a 5 compound of this invention. In another embodiment the compound of formula I-XII or its analog, derivative, isomer, compound is a compound of formula I-XII or its analog, metabolite, pharmaceutically acceptable salt, pharmaceuti derivative, isomer, metabolite, pharmaceutically acceptable cal product, hydrate, N-oxide, prodrug, polymorph, impurity salt, pharmaceutical product, hydrate, N-oxide, prodrug, or crystal of said compound, or any combination thereof. In polymorph, impurity or crystal of said compound, or any another embodiment the compound is a compound of for 10 combination thereof. In another embodiment the compound mula XI or its analog, derivative, isomer, metabolite, phar is a compound of formula XI or its analog, derivative, maceutically acceptable salt, pharmaceutical product, isomer, metabolite, pharmaceutically acceptable salt, phar hydrate, N-oxide, prodrug, polymorph, impurity or crystal of maceutical product, hydrate, N-oxide, prodrug, polymorph, said compound, or any combination thereof. In another impurity or crystal of said compound, or any combination embodiment the compound is an ER-Bantagonist. In another 15 thereof. In another embodiment the compound is an ER-B embodiment the compound is compound 15a, 15b, 15c, 15g, antagonist. In another embodiment the compound is com 15h, or 15i, listed in Table 1. pound 15a, 15b, 15c, 15g, 15h, or 15i, listed in Table 1. In one embodiment this invention relates to methods of In one embodiment this invention relates to methods of treating, preventing, inhibiting, Suppressing, delaying the treating, preventing, inhibiting, Suppressing, delaying the onset of reducing the incidence of, or reducing the severity onset of reducing the incidence of, or reducing the severity of lung cancer comprising administering a compound of this of post-menopausal osteoporosis in a subject comprising invention. In another embodiment the compound is an ER-B administering a compound of this invention. In another antagonist. In another embodiment the compound is a com embodiment the compound is an ER-Bantagonist. In another pound of formula or its analog, derivative, isomer, metabo embodiment the compound is a compound of formula I-XII lite, pharmaceutically acceptable salt, pharmaceutical prod 25 or its analog, derivative, isomer, metabolite, pharmaceuti uct, hydrate, N-oxide, prodrug, polymorph, impurity or cally acceptable salt, pharmaceutical product, hydrate, crystal of said compound, or any combination thereof. In N-oxide, prodrug, polymorph, impurity or crystal of said another embodiment the compound is a compound of for compound, or any combination thereof. In another embodi mula XI or its analog, derivative, isomer, metabolite, phar ment the compound is a compound of formula XI or its maceutically acceptable salt, pharmaceutical product, 30 analog, derivative, isomer, metabolite, pharmaceutically hydrate, N-oxide, prodrug, polymorph, impurity or crystal of acceptable salt, pharmaceutical product, hydrate, N-oxide, said compound, or any combination thereof. In another prodrug, polymorph, impurity or crystal of said compound, embodiment the compound is compound 15a, 15b, 15c, 15g, or any combination thereof. In another embodiment the 15h, or 15i, listed in Table 1. compound is compound 15a, 15b, 15c, 15g, 15h, or 15i, In one embodiment this invention relates to methods of 35 listed in Table 1. reducing aggressive behavior in a subject comprising admin In one embodiment, this invention provides: a) a method istering a compound of this invention. In another embodi of treating a bone-related condition in a Subject; b) a method ment the compound is an ER-B antagonist. In another of increasing a hone mass in a Subject; c) a method of embodiment the compound is a compound of formula I-XII improving the lipid profile in a Subject; d) a method of or its analog, derivative, isomer, metabolite, pharmaceuti 40 treating atherosclerosis and its associated diseases; e) a cally acceptable salt, pharmaceutical product, hydrate, method of improving dexterity and movement in a Subject; N-oxide, prodrug, polymorph, impurity or crystal of said f) a method of treating a Subject having dysmenorrheal compound, or any combination thereof. In another embodi comprising the step of administering to said Subject a ment the compound is a compound of formula XI or its compound of this invention and/or an analog, derivative, analog, derivative, isomer, metabolite, pharmaceutically 45 isomer, metabolite, pharmaceutically acceptable salt, phar acceptable salt, pharmaceutical product, hydrate, N-oxide, maceutical product, hydrate, N-oxide, prodrug, polymorph, prodrug, polymorph, impurity or crystal of said compound, impurity or crystal of said compound, or any combination or any combination thereof. In another embodiment the thereof. compound is compound 15a, 15b, 15c, 15g, 15h, or 15i, In one embodiment, the methods of this invention are listed in Table 1. 50 useful in treating diseases or disorders caused by, or asso In one embodiment this invention relates to methods of ciated with a hormonal disorder, disruption or imbalance. In treating, preventing, inhibiting, Suppressing, delaying the one embodiment, the hormonal disorder, disruption or onset of reducing the incidence of, or reducing the severity imbalance comprises an excess of a hormone. In another of anxiety in a Subject comprising administering a com embodiment, the hormonal disorder, disruption or imbalance pound of this invention. In another embodiment the com 55 comprises a deficiency of a hormone. In one embodiment, pound is a compound of formula I-XII or its analog, deriva the hormone is a steroid hormone. In another embodiment, tive, isomer, metabolite, pharmaceutically acceptable salt, the hormone is an estrogen. In another embodiment, the pharmaceutical product, hydrate, N-oxide, prodrug, poly hormone is an androgen. In another embodiment, the hor morph, impurity or crystal of said compound, or any com mone is a glucocorticoid. In another embodiment, the hor bination thereof. In another embodiment the compound is a 60 mone is a cortico-steroid. In another embodiment, the hor compound of formula XI or its analog, derivative, isomer, mone is Luteinizing Hormone (LH). In another embodiment, metabolite, pharmaceutically acceptable salt, pharmaceuti the hormone is Follicle Stimulating Hormone (FSH). In cal product, hydrate, N-oxide, prodrug, polymorph, impurity another embodiment, the hormone is any other hormone or crystal of said compound, or any combination thereof. In known in the art. In another embodiment, the hormonal another embodiment the compound is an ER-Bantagonist. In 65 disorder, disruption or imbalance is associated with meno another embodiment the compound is compound 15a, 15b, pause. In another embodiment, the hormonal disorder, dis 15c, 15g, 15h, or 15i, listed in Table 1. ruption or imbalance is associated with andropause, andro US 9,623,021 B2 101 102 pausal vasomotor symptoms, andropausal gynecomastia, comprise conditions characterized by elevated estrogen lev muscle strength and/or function, bone strength and/or func els, including hirsutism, infertility, polycystic ovarian Syn tion and anger. In another embodiment, hormone deficiency drome, endometrial carcinoma, breast cancer, male pattern is a result of specific manipulation, as a byproduct of treating baldness, prostate cancer, testicular cancer, and others, as a disease or disorder in the subject. For example, the will be known to one skilled in the art. For such conditions, hormone deficiency may be a result of androgen depletion in the Subject may be administered a compound as herein a Subject, as a therapy for prostate cancer in the Subject. described, alone or in combination with another therapeutic Each possibility represents a separate embodiment of the agent, as will be appreciated by one skilled in the art. present invention. In another embodiment, this invention provides a method In another embodiment of the present invention, a method 10 of treating a hormone dependent disease, disorder or con is provided for hormonal therapy in a patient (i.e., one dition, the method comprising administering to the Subject a Suffering from an androgen-dependent condition) which compound as herein described, and optionally chemothera includes contacting an nuclear hormone receptor of a patient peutics agents and therapies (methotrexate, cyclophosph with a compound and/or a non steroidal agonist of the amide, ifosfamide, adriamycin, doxorubicin, glucocorti present invention and/or its analog, derivative, isomer, 15 coids, cyclosporine, L-thyroxine, AI, , GnRH metabolite, pharmaceutically acceptable salt, pharmaceuti agents, ADT discontinuation of hormone replacement cal product, polymorph, crystal, impurity, hydrate, N-oxide therapy, cranial irradiation, peripheral irradiation, etc.; pro or any combination thereof, in an amount effective to bind lactinemia-inducing pharmacotherapeutics (serotonergic the compound to the receptor and effect a change in an antidepressants acting through 5HT2 receptors, selective hormone-dependent condition. In another embodiment the serotonin reuptake inhibitors, monoamine oxidase inhibi compound is a compound of formula I-XII or its analog, tors, tricyclic antidepressants, antihypertensives such as derivative, isomer, metabolite, pharmaceutically acceptable methyldopa, reserpine, clonidine, and Verapamil; antidop salt, pharmaceutical product, hydrate, N-oxide, prodrug, aminergic anti-emetics such as metoclopramide, H2 receptor polymorph, impurity or crystal of said compound, or any antagonists such as cimetidine and ranitidine, estrogens, combination thereof. In another embodiment the compound 25 amphetamines, AR partial antagonists (ketoconazole, is a compound of formula XI or its analog, derivative, , eplerenone). isomer, metabolite, pharmaceutically acceptable salt, phar In some embodiments, this invention provides for the use maceutical product, hydrate, N-oxide, prodrug, polymorph, of a compound as herein described, or its prodrug, analog, impurity or crystal of said compound, or any combination isomer, metabolite, derivative, pharmaceutically acceptable thereof. In another embodiment the compound is compound 30 salt, pharmaceutical product, polymorph, crystal, impurity, 12u, listed in Table 1. In another embodiment the compound N-oxide, hydrate or any combination thereof, for treating is compound 12y, listed in Table 1. In another embodiment reducing the severity of reducing the incidence of, or the compound is compound 12Z, listed in Table 1. In another reducing pathogenesis of cachexia and/or cachexia associ embodiment the compound is compound 14m, listed in ated with cancer in a Subject. In another embodiment, the Table 1. 35 cancer comprise adrenocortical carcinoma, anal cancer, In one embodiment of this invention, a method is pro bladder cancer, brain tumor, brain stem glioma, brain tumor, vided for hormone replacement therapy in a patient, which cerebellar astrocytoma, cerebral astrocytoma, ependymoma, includes administering a compound as herein described medulloblastoma, Supratentorial primitive neuroectodermal, and/or its analog, derivative, isomer, metabolite, pharma pineal tumors, hypothalamic glioma, breast cancer, carci ceutically acceptable salt, pharmaceutical product, poly 40 noid tumor, carcinoma, cervical cancer, colon cancer, endo morph, crystal, impurity, hydrate, N-oxide or any combina metrial cancer, esophageal cancer, extrahepatic bile duct tion thereof, to a Subject, in an amount Sufficient to effect a cancer, ewings family of tumors (Pnet), extracranial germ change in a hormone-dependent condition in the Subject. In cell tumor, eye cancer, intraocular melanoma, gallbladder another embodiment the compound is a compound of for cancer, gastric cancer, germ cell tumor, extragonadal, ges mula I-XII or its analog, derivative, isomer, metabolite, 45 tational trophoblastic tumor, head and neck cancer, pharmaceutically acceptable salt, pharmaceutical product, hypopharyngeal cancer, islet cell carcinoma, laryngeal can hydrate, N-oxide, prodrug, polymorph, impurity or crystal of cer, leukemia, acute lymphoblastic, leukemia, oral cavity said compound, or any combination thereof. In another cancer, liver cancer, lung cancer, non Small cell lung cancer, embodiment the compound is a compound of formula XI or Small cell, lymphoma, AIDS-related lymphoma, central ner its analog, derivative, isomer, metabolite, pharmaceutically 50 Vous system (primary), lymphoma, cutaneous T-cell, lym acceptable salt, pharmaceutical product, hydrate, N-oxide, phoma, Hodgkin’s disease, non-Hodgkin’s disease, malig prodrug, polymorph, impurity or crystal of said compound, nant mesothelioma, melanoma, Merkel cell carcinoma, or any combination thereof. In another embodiment the metasatic Squamous carcinoma, multiple myeloma, plasma compound is compound 12u, listed in Table 1. In another cell neoplasms, mycosis fungoides, myelodysplastic Syn embodiment the compound is compound 12y. listed in Table 55 drome, myeloproliferative disorders, nasopharyngeal can 1. In another embodiment the compound is compound 12Z. cer, neuroblastoma, oropharyngeal cancer, osteosarcoma, listed in Table 1. In another embodiment the compound is ovarian epithelial cancer, ovarian germ cell tumor, ovarian compound 14m, listed in Table 1. low malignant potential tumor, pancreatic cancer, exocrine, Hormone-dependent conditions which may be treated pancreatic cancer, islet cell carcinoma, paranasal sinus and with the compounds and/or compositions as herein 60 nasal cavity cancer, parathyroid cancer, penile cancer, described, comprising the methods of the present invention pheochromocytoma cancer, pituitary cancer, plasma cell include those conditions which are associated with aging, neoplasm, prostate cancer, rhabdomyosarcoma, rectal can hypogonadism, diminished erythropoiesis, osteoporosis, and cer, renal cell cancer, salivary gland cancer, Sezary Syn any other conditions dependent upon low estrogen levels. drome, skin cancer, cutaneous T-cell lymphoma, skin cancer, Hormone-dependent conditions which may be treated 65 Kaposi's sarcoma, skin cancer, melanoma, Small intestine with the compounds and/or compositions as herein cancer, soft tissue sarcoma, Soft tissue sarcoma, testicular described, and comprising a method of the invention, may cancer, thymoma, malignant, thyroid cancer, urethral cancer, US 9,623,021 B2 103 104 uterine cancer, sarcoma, unusual cancer of childhood, vagi composition comprising the compound of this invention. In nal cancer, Vulvar cancer, Wilms tumor, or any combination another embodiment the compound is compound 12u, listed thereof. in Table 1. In another embodiment the compound is com In another embodiment, this invention provides for the pound 12y, listed in Table 1. In another embodiment the use of a compound as herein described, or its prodrug, compound is compound 12Z, listed in Table 1. In another analog, isomer, metabolite, derivative, pharmaceutically embodiment the compound is compound 14m, listed in acceptable salt, pharmaceutical product, polymorph, crystal, Table 1. impurity, N-oxide, hydrate or any combination thereof, for In one embodiment, this invention provides for the use of treating reducing the severity of reducing the incidence of a compound as herein described, or its prodrug, analog, delaying the onset of lung cancer. In another embodiment 10 isomer, metabolite, derivative, pharmaceutically acceptable the compound is a compound of formula I-XII. salt, pharmaceutical product, polymorph, crystal, impurity, In another embodiment, this invention provides for the N-oxide, hydrate or any combination thereof, for a) treating use of a compound as herein described, or its prodrug, a bone related disorder; b) preventing a bone related disor analog, isomer, metabolite, derivative, pharmaceutically der; c) suppressing a bone related disorder; d) inhibiting a acceptable salt, pharmaceutical product, polymorph, crystal, 15 bone related disorder; e) increasing a strength of a bone of impurity, N-oxide, hydrate or any combination thereof, for a Subject: f) increasing a bone mass in a Subject, g) use for treating reducing the severity of reducing the incidence of osteoclastogenesis inhibition. delaying the onset of non Small cell lung cancer. In one embodiment, this invention provides for the use of Colon cancer is the second most frequently diagnosed a compound as herein described, or its prodrug, analog, malignancy in the United States, as well as the second most isomer, metabolite, derivative, pharmaceutically acceptable common cause of cancer death. Cholesterol-rich diets have salt, pharmaceutical product, polymorph, crystal, impurity, had a significant epidemiological association with cancers of N-oxide, hydrate or any combination thereof, for a) Accel the colon, which in turn may be influenced by the admin erate bone repair; b) treating bone disorders; c) treating bone istration of compounds which modulate nuclear hormone density loss; d) treating low bone mineral density (BMD); e) binding agents, in particular, compounds which modulate 25 treating reduced bone mass: f) treating metabolic bone receptors binding components of the steroidogenic pathway, disease; g) promoting bone growth or regrowth; h) promot in particular, as described herein. ing bone restoration: i) promoting bone fracture repair, j) In one embodiment, the invention provides a method of promoting bone remodeling, k) treating bone damage fol treating, preventing the recurrence, inhibiting, reducing the lowing reconstructive Surgery including of the face, hip, or incidence of delaying onset, reducing the recurrence of, or 30 joints; 1) enhancing of bone strength and function; m) reducing the severity of colon cancer in a subject, compris increasing cortical bone mass; n) increasing trabecular con ing administering a compound of formula (I)-(XII), or its nectivity. prodrug, analog, isomer, metabolite, derivative, pharmaceu In one embodiment, the invention provides a method of tically acceptable salt, pharmaceutical product, polymorph, treating, preventing, reducing the severity of delaying onset crystal, impurity, N-oxide, ester, hydrate or any combination 35 or reducing the recurrence of a bone-related disease or thereof, to the subject. In another embodiment the com disorder in a subject, comprising administering a NRBA of pound is a compound of formula (I)-(XII). In some embodi this invention to the subject. In one embodiment, the subject ments ER-B agonists are useful in treating, preventing the is administered a NRBA or composition comprising the recurrence, inhibiting, reducing the incidence of delaying same, wherein the NRBA is a of formula (I)-CXII) or its onset, reducing the recurrence of, or reducing the severity of 40 prodrug, ester, analog, isomer, metabolite, derivative, phar colon cancer in a subject. In another embodiment, ER-B maceutically acceptable salt, pharmaceutical product, poly agonist of this invention is compound 12b, listed in Table 1. morph, crystal, impurity, N-oxide, hydrate or any combina In another embodiment, ER-B agonist of this invention is tion thereof. In some embodiments ER-Bagonists are useful compound 12f, listed in Table 1. In another embodiment, in treating, preventing, reducing the severity of delaying ER-B agonist of this invention is compound 12h, listed in 45 onset, reducing the recurrence of a bone-related disease or Table 1. In another embodiment, ER-B agonist of this disorder in a subject. In another embodiment, ER-B agonist invention is compound 12p, listed in Table 1. In another of this invention is compound 12b, listed in Table 1. In embodiment, ER-B agonist of this invention is compound another embodiment, ER-B agonist of this invention is 12s, listed in Table 1. In another embodiment, ER-Bagonist compound 12f, listed in Table 1. In another embodiment, of this invention is compound 12u, listed in Table 1. In 50 ER-B agonist of this invention is compound 12h, listed in another embodiment, ER-3 agonist of this invention is Table 1. In another embodiment, ER-B agonist of this compound 12y, listed in Table 1. In another embodiment, invention is compound 12p, listed in Table 1. In another ER-B agonist of this invention is compound 12Z, listed in embodiment, ER-B agonist of this invention is compound Table 1, or any combination thereof. 12s, listed in Table 1. In another embodiment, ER-Bagonist In one embodiment, this invention provides methods of 1) 55 of this invention is compound 12u, listed in Table 1. In improving the lipid profile of a subject; 2) reducing the another embodiment, ER-B agonist of this invention is circulating lipid levels in a subject; 3) increasing high compound 12y, listed in Table 1. In another embodiment, density lipoprotein (HDL) cholesterol levels in a subject; 4) ER-B agonist of this invention is compound 12Z, listed in altering ratios of low density lipoprotein to high density Table 1. In another embodiment, ER-B agonist of this lipoprotein levels in a Subject; wherein said Subject has 60 invention is compound 14m, listed in Table 1, or any prostate cancer and is undergoing or has undergone ADT. combination thereof. wherein said method comprises administering to said subject In one embodiment, the bone related disorder is a genetic a compound of formula (I)-(XII) or its prodrug, ester, disorder, or in another embodiment, is induced as a result of analog, isomer, metabolite, derivative, pharmaceutically a treatment regimen for a given disease. acceptable salt, pharmaceutical product, polymorph, crystal, 65 In one embodiment, the bone-related disorder is osteopo impurity, N-oxide, hydrate or any combination thereof. In rosis. In another embodiment, the bone-related disorder is another embodiment, the method comprises administering a osteopenia. In another embodiment, the bone-related disor US 9,623,021 B2 105 106 der is increased bone resorption. In another embodiment, the reducing the incidence, inhibiting, Suppressing, and treating bone-related disorder is bone fracture. In another embodi osteoporosis, bone fractures and/or loss of bone mineral ment, the bone-related disorder is bone frailty. density (BMD) in a subject. In another embodiment, ER-B In another embodiment, the bone-related disorder is a loss agonist of this invention is compound 12b, listed in Table 1. of bone mineral density (BMD). In another embodiment, the In another embodiment, ER-B agonist of this invention is bone-related disorder is any combination of osteoporosis, compound 12f, listed in Table 1. In another embodiment, osteopenia, increased bone resorption, bone fracture, bone ER-B agonist of this invention is compound 12h, listed in frailty and loss of BMD. Each disorder represents a separate Table 1. In another embodiment, ER-B agonist of this embodiment of the present invention. invention is compound 12p, listed in Table 1. In another “Osteoporosis” refers, in one embodiment, to a thinning 10 of the bones with reduction in bone mass due to depletion of embodiment, ER-B agonist of this invention is compound calcium and bone protein. In another embodiment, osteo 12s, listed in Table 1. In another embodiment, ER-Bagonist porosis is a systemic skeletal disease, characterized by low of this invention is compound 12u, listed in Table 1. In bone mass and deterioration of bone tissue, with a conse another embodiment, ER-B agonist of this invention is quent increase in bone fragility and Susceptibility to fracture. 15 compound 12y, listed in Table 1. In another embodiment, In osteoporotic patients, bone strength is abnormal, in one ER-B agonist of this invention is compound 12Z, listed in embodiment, with a resulting increase in the risk of fracture. Table 1. In another embodiment, ER-B agonist of this In another embodiment, osteoporosis depletes both the cal invention is compound 14m, listed in Table for any combi cium and the protein collagen normally found in the bone, nation thereof. in one embodiment, resulting in either abnormal bone qual In one embodiment, the bone stimulating compound may ity or decreased bone density. In another embodiment, bones comprise a bone morphogenetic protein (BMP), a growth that are affected by osteoporosis can fracture with only a factor, such as epidermal growth factor (EGF), a fibroblast minor fall or injury that normally would not cause a bone growth factor (FGF), a transforming growth factor (TGF, an fracture. The fracture can be, in one embodiment, either in insulin growth factor (IGF), a platelet-derived growth factor the form of cracking (as in a hip fracture) or collapsing (as 25 (PDGF) hedgehog proteins such as Sonic, Indian and desert in a compression fracture of the spine). The spine, hips, and hedgehog, a hormone Such as follicle stimulating hormone, wrists are common areas of osteoporosis-induced bone parathyroid hormone, parathyroid hormone related peptide, fractures, although fractures can also occur in other skeletal activins, inhibins, follistatin, frizzled, frzb or frazzled pro areas. Unchecked osteoporosis can lead, in another embodi teins, BMP binding proteins such as chordin and fetuin, a ment, to changes in posture, physical abnormality, and 30 cytokine such as IL-3, IL-7, GM-CSF, a chemokine, such as decreased mobility. eotaxin, a collagen, osteocalcin, osteonectin and others, as In one embodiment, the osteoporosis results from andro will be appreciated by one skilled in the art. gen deprivation. In another embodiment, the osteoporosis In another embodiment, the compositions for use in follows androgen deprivation. In another embodiment, the treating a bone disorder of this invention may comprise a osteoporosis is primary osteoporosis. In another embodi 35 compound or compounds as herein described an additional ment, the osteoporosis is secondary osteoporosis. In another bone stimulating compound, or compounds, and osteogenic embodiment, the osteoporosis is postmenopausal osteopo cells. In one embodiment, an osteogenic cell may be a stem rosis. In another embodiment, the osteoporosis is juvenile cell or progenitor cell, which may be induced to differentiate osteoporosis. In another embodiment, the osteoporosis is into an osteoblast. In another embodiment, the cell may be idiopathic osteoporosis. In another embodiment, the osteo 40 an osteoblast. In another embodiment, nucleic acids which porosis is senile osteoporosis. encode bone-stimulating compounds may be administered In another embodiment, the primary osteoporosis is Type to the subject, which is to be considered as part of this I primary osteoporosis. In another embodiment, the primary invention. osteoporosis is Type II primary osteoporosis. Each type of In one embodiment, the methods of the present invention osteoporosis represents a separate embodiment of the pres 45 comprise administering the compound for treating osteopo ent invention. rosis. In another embodiment, the methods of this invention According to this aspect of the invention and in one comprise administering a compound in combination with embodiment, the bone-related disorder is treated with a SERMs for treating osteoporosis. In another embodiment, compound as herein described, or a combination thereof. In the SERMs are tamoxifen, 4-hydroxytamoxifene, idoxifene, another embodiment, other bone-stimulating compounds 50 toremifene, ospennifene, , raloxifene, arZoxifene, can be provided to the subject, prior to, concurrent with or baZedoxifene, PPT (1,3,5-tris(4-hydroxyphenyl)-4-propyl following administration of a compound or compounds as 1H-pyrazole), DPN, lasofoxifene, pipendoxifene, EM-800, herein described. In one embodiment, Such a bone stimu EM-652, nafoxidine, Zindoxifene, tesmilifene, miproxifene lating compound may comprise natural or synthetic mate phosphate, RU 58,688, EM 139, ICI 164,384, ICI 182,780, rials. 55 clomiphene, MER-25, diethylstibestrol, coumestrol, In another embodiment, the invention provides, a method genistein, GW5638, LY353581, Zuclomiphene, enclomi of reducing the incidence, inhibiting, Suppressing, and treat phene, delmadinone acetate, DPPE, (N,N-diethyl-2-4- ing osteoporosis, bone fractures and/or loss of bone mineral (phenylmethyl)-phenoxyethanamine), TSE-424, WAY-070, density (BMD) in a subject, comprising administering a WAY-292, WAY-818, cyclocommunol, prinaberel, ERB NRBA/of formula (I)-(XII), or its prodrug, ester, analog, 60 041, WAY-397, WAY-244, ERB-196, WAY-169122, isomer, metabolite, derivative, pharmaceutically acceptable MF-101, ERb-002, ERB-037, ERB-017, BE-1060, BE-380, salt, pharmaceutical product, polymorph, crystal, impurity, BE-381, WAY-358, 18FIFEDNP, LSN-500307, AA-102, N-oxide, hydrate or any combination thereof, or a compo Ban Zhilian, CT-101, CT-102, or VG-101. sition comprising the same, thereby reducing the incidence, In another embodiment, the methods of the present inven inhibiting, Suppressing, and treating osteoporosis, bone frac 65 tion comprise administering the compounds of this inven tures and/or loss of bone mineral density (BMD) in the tion, in combination with bisphosphonates Such as alendro Subject. In some embodiments ER-B agonists are useful in nate, tiludroate, clodroniate, pamidronate, etidronate, US 9,623,021 B2 107 108 alendronate, Zolendronate, cimadronate, neridronate, mino cephalitic syndrome. In some embodiments, the central dronic acid, ibandronate, risedronate, or homoresidronate nervous system disease is cystic fibrosis induced hypogo for treating osteoporosis. nadal state. In another embodiment, the methods of the present inven In some embodiments, cranial nerve diseases comprise tion comprise administering the compound, in combination bell palsy, cranial nerve diseases, facial hemiatrophy, facial with Calcitonin such as salmon, Elcatonin, SUN-8577 or neuralgia, glossopharyngeal nerve diseases, Moebius Syn TJN-135 for treating osteoporosis. drome, or trigeminal neuralgia. In another embodiment, the methods of treating osteopo In some embodiments, central nervous system diseases rosis of the present invention comprise administering the comprise injuries or damage to the central nervous system compound of this invention, in combination with a) vitamin 10 D or derivative such as ZK-156979; b) vitamin D receptor (CNS). In some embodiments, injuries or damage to the ligand and analogues such as calcitriol, topitriol, CNS may be associated with muscle wasting disorders. ZK-15O123, TEI-9647, BXL-628, Ro-26-9228, BAL-2299, Injuries or damage to the CNS can be, for example, caused Ro-65-2299 or DP-035; c) estrogen, estrogen derivative, or by diseases, trauma or chemicals. Examples are central ; d) , progestins, or Syn 15 nerve injury or damage, peripheral nerve injury or damage thetic estrogen/progestins; e) RANK ligand mAb Such as and spinal cord injury or damage. denosumab formerly AMG162 (Amgen); f) CVB3 Integrin Studies involving patients with spinal cord injuries (SCI) receptor antagonist, g) osteoclast vacuolar ATPase inhibitor, have shown that central neurotransmitters may be altered h) antagonist of VEGF binding to osteoclast receptors: i) after SCI causing hypothalamus-pituitary-adrenal axis dys calcium receptor antagonist, j) PTh (parathyroid hormone) function, whose disruption led to a significant decrease in and analogues, PTHrP analogues (parathyroid hormone testosterone and other hormone levels. SCI or other acute related peptide); k) Cathepsin K inhibitors (AAE581, etc.); illness or trauma characteristically includes heightened 1) strontium ranelate; m) ; n) HCT-1026, PSK3471; catabolism in conjunction with the lowered anabolic activity o) gallium maltolate; p) nutropin AQ: q) prostaglandins (for resulting in a condition that is prone to loss of lean body osteo); r) p38 protein kinase inhibitor, s) bone morphoge 25 tissue, which is often accompanied by disturbed nutrient netic protein; t) inhibitor of BMP antagonism; u) HMG-CoA utilization. The effects of the loss of lean body mass include reductase inhibitor; v) vitamin K or derivative: w) iprifla the development of wounds and impaired healing mecha vone: X) fluoride salts; y) dietary calcium Supplement, and Z) nisms, further compounding the problem. Because of poor osteoprotegerin. nutrition and protein combined with immobilization, In some embodiments, the present invention provides a 30 patients with spinal cord injury are at high risk for bed Sores. method for treating, reducing the incidence, delaying the In one embodiment, a wide variety of injuries of the CNS onset or progression, or reducing and/or abrogating the may be treated by the methods of the present invention. CNS symptoms associated with a nervous system disease in a injury may refer, in one embodiment, to a breakdown of the Subject. In one embodiment, the method comprises admin membrane of a nerve cell, or, in another embodiment, to the istering to a Subject a composition comprising a compound 35 inability of the nerve to produce and propagate nerve and an anti-cancer agent, an immunomodulating agent, an impulses, or in another embodiment, to the death of the cell. agent treating the central nervous system, an anti-infective An injury includes damage that directly or indirectly affects agent, an agent treating a metabolic disease, an agent the normal functioning of the CNS. The injury may be a treating a wasting disease, a gene therapy agent, an agent structural, physical, or mechanical impairment and may be treating the endocrine system, vitamins, or a combination 40 caused by physical impact, as in the case of a crushing, thereof. In some embodiments, nervous system diseases compression, or stretching of nerve fibers. Alternatively, the comprise autonomic nervous system diseases, central ner cell membrane may be destroyed by or degraded by an Vous system diseases, cranial nerve diseases, demyelinating illness, a chemical imbalance, or a physiological malfunc diseases, nervous system malformations, neurologic mani tion Such as anoxia (e.g., stroke), aneurysm, or reperfusion. festations, or neuromuscular diseases. 45 A CNS injury includes, for example and without limitation, In some embodiments, autonomic nervous system dis damage to retinal ganglion cells, a traumatic brain injury, a eases comprise causalgia, or reflex sympathetic dystrophy. stroke-related injury, a cerebral aneurism-related injury, a In some embodiments, central nervous system diseases spinal cord injury, including monoplegia, diplegia, paraple comprise Alzheimer's disease, arachnoiditis, brain abscess, gia, hemiplegia and quadriplegia, a neuroproliferative dis brain ischemia, central nervous system infections, cerebral 50 order, or neuropathic pain syndrome. palsy, cerebrovascular disorders, corticobasal ganglionic Injuries or damage to the central nervous system (CNS) degeneration (CBGD), Creutzfeldt-Jakob syndrome, are also associated with muscle wasting and other wasting Dandy-Walker syndrome, dementia, encephalitis, encepha disorders. Injuries or damage to the CNS can be, for lomyelitis, epilepsy, epilepsy induced hypogonadal and/or example, caused by diseases, trauma or chemicals. hypermetabolic state, essential tremor, Friedreich ataxia, 55 Examples are central nerve injury or damage, peripheral Gerstmann-Straussler-Scheinker disease, Hallervorden nerve injury or damage and spinal cord injury or damage. In Spatz syndrome, Huntington disease, hydrocephalus, one embodiment CNS damage or injury comprise Alzheim hypoxia, insomnia, ischemic attack, kuru, Landau-Kleffner er's diseases (AD); anger (mood); anorexia, anorexia ner syndrome, Lewy Body disease, Machado-Joseph disease, Vosa, anorexia associated with aging and/or assertiveness meige syndrome, meningitis, bacterial meningitis, viral, 60 (mood). migraine disorders, movement disorders, multiple system In another embodiment, the invention provides a method atrophy, myelitis, olivopontocerebellar atrophies, Parkin of treating, preventing, Suppressing, inhibiting, or reducing son's disease, parkinsonian disorders, poliomyelitis, post the incidence of central nervous system (CNS) disorder, poliomyelitis syndrome, prion diseases, pseudotumor cere disease or condition in a mammalian Subject comprising bri, Shy-Drager syndrome, spasms, infantile, spinal cord 65 administering a compound of formula (I)-(XII) or its prod diseases, Supranuclear palsy, syringomyelia, thalamic dis rug, ester, analog, isomer, metabolite, derivative, pharma eases, tic disorders, tourette syndrome, or uveomeningoen ceutically acceptable salt, pharmaceutical product, poly US 9,623,021 B2 109 110 morph, crystal, impurity, N-oxide, hydrate or any In another embodiment, the methods of treating eye combination thereof to the subject. diseases comprise administering a composition comprising In some embodiments, the present invention provides a the compounds of this invention to the subject, wherein the method for treating, reducing the incidence, delaying the composition is in the form of eye drops, eye wash, oint onset or progression, or reducing and/or abrogating the ments, conjunctival injections, or contact lens adsorbents. In symptoms associated with an ophthalmic disease in a Sub another embodiment, the methods of treating eye diseases ject. In one embodiment, the method comprises administer comprises administering a composition comprising the com ing to a subject a composition comprising a NRBA com pounds of this invention in the form of a tablet, capsule, pound. In one embodiment, the method comprises liquid, syrup, injection, hap, ointment, eye drops, and the administering to a Subject a composition comprising a 10 like, and administered orally, or non-orally such as injection, NRBA compound and an anti-cancer agent, an immuno locally Such as dropping to eye, etc. The effective ingredient modulating agent, an agent treating the cardiovascular sys may be vaporized and inhaled, for example through the tem, an anti-infective agent, an agent treating a wasting nose, mouth or trachea. disease, a gene therapy agent, an agent treating the endo 15 In some embodiment, the methods of treating eye diseases crine system, vitamins, or a combination thereof. In some comprise administering a composition comprising the com embodiments ophthalmic disease comprise acute Zonal pounds of this invention and any other compound, which is occult outer retinopathy, abnormal color vision, Adie Syn useful in treating the indicated conditions, as known in the drome, albinism, ocular-amaurosis, fugax, amblyopia, art. aniridia, anisocoria, anterior ischemic optic neuropathy, In some embodiment, eye drops and eye wash comprise anophthalmos, aphakia, asthenopia astigmatism, autoim water-solubilized compounds (I)-CXII) of this invention, mune disease blepharitis, blepharoptosis, blepharospasm, which are, in one embodiment, dissolved in sterilized dis blindness, cataract, senile cataract central chorioretinopathy tilled water, BSS Plus, and/or physiological saline. In chalazion, chorioretinitis, chorioretinal hemorrhage, choroi another embodiment, the compounds of this invention. In deremia, coloboma, color vision defects, conjunctivitis, cor 25 another embodiment, additives are added comprising excipi neal diseases, corneal dystrophies, corneal edema, corneal ents, carriers, pH controllers, isotonic agents, preservatives, ulcer, corneal opacity, corneal erosion, corneal endothelial glutathione, glucose, various kind of salt(s), stabilizers, cell degeneration and dystrophy or loss of endothelial cell, refrigerants, antioxidants, antiseptic agents, or any combi corneal dystrophy or degeneration, detachment of corneal nation thereof. In another embodiment, the eye drops and epithelium, epidemic keratoconjunctivitis, chalazion, central 30 eye wash comprise hydroxypropylmethyl cellulose, car nerve diseases, central retinal artery or vein occlusion, arteriosclerosis of retinal artery, photopsia, diabetic retin boxymethyl cellulose or its sodium salt, polypyrrolidone, opathy, chorioretinal atrophy, diabetic retinopathy, diplopia, polyvinylpyrrolidone (this is added and heated), or any distichiasis, dry eye syndromes, Duane retraction syndrome, combination thereof. ectropion, entropion, esotropia, exfoliation syndrome, 35 In some embodiments, the present invention provides a exotropia, eye hemorrhage, eye neoplasms, eyelid diseases, method for treating, reducing the incidence, delaying the floaters, general fibrosis syndrome, glaucoma, high tension onset or progression, or reducing and/or abrogating the glaucoma, normal tension glaucoma, gyrate atrophy, hemi symptoms associated with an endocrine disorder in a Sub anopsia, Hermanski-Pudlak syndrome, hordeolum, Homer ject. In one embodiment, the method comprises administer syndrome, hysteria hyperopia, hyphema, iridocyclitis iritis, 40 ing to a Subject a composition comprising a compound and Kearns-Sayer syndrome, keratitis, keratoconus, lacrimal anti-cancer agent, an immunomodulating agent, an antidi apparatus diseases, lacrimal duct obstruction, lens diseases, abetic agent, an agent treating the cardiovascular system, an lowering in dynamic visual activity, macular degeneration, agent treating the gastrointestinal system, an agent treating macular hole microphthalmos, myopia, nystagmus, narrow a dermatological disorder, an agent treating the central ing of visual field due to various kinds of diseases patho 45 nervous system, an anti-infective agent, an agent treating the logic, ocular motility disorders, oculomotor nerve diseases, liver, an agent treating the kidney, an agent treating a ophthalmoplegia, optic atrophies, optic nerve diseases, optic metabolic disease, an agent treating a wasting disease, a neuritis, optic neuropathy, optic nerve atrophy orbital cel gene therapy agent, an agent treating the endocrine system, lulitis, papilledema, peters anomaly, presbyopia, psychosis Vitamins, or a combination thereof. In some embodiments, pterygium, pupil disorders, refractive errors, retinal detach 50 endocrine disorders comprise acromegaly, Addison disease, ment, retinal diseases, retinal vein occlusion, retinal and adrenal gland diseases, adrenal hyperplasia, congenital, choroidal neovascular diseases, cataract due to removal of androgen-insensitivity syndrome, congenital hypothyroid ovary, cataract due to TGFB macular fibrosis, macular epiretinal membrane, refractive error retinal tear, retinitis ism, Cushing syndrome, diabetes insipidus, diabetes melli proliferans, pigmentary retinal degeneration retinitis pig 55 tus, diabetes mellitus-type 1, diabetes mellitus-type 2, dia mentosa, retinopathy of prematurity, retinoschisis, Scleritis, betic, ketoacidosis, empty Sella syndrome, endocrine gland senile macular degeneration Scotoma, Strabismus, Thy neoplasms, endocrine System diseases, gigantism, gonadal geson's Superficial punctate keratitis, trachoma, uveitis, disorders, graves disease, hermaphroditism, hyperaldoster white dot syndrome, vision disorders, or vitreous disorders, onism, hyperglycemic hyperosmolar nonketotic coma, diseases due to cerebral pituitary gland disorder and imbal 60 hyperpituitarism, hyperprolactinemia, hyperthyroidism, ance of hormones, diseases due to gene disorder and dis hypogonadism, hypopituitarism, hypothyroidism, Kallmann eases due to immune disorder, the method comprising syndrome, Nelson syndrome, parathyroid diseases, pituitary administering a NRBA of formula (I)-CXII) or its prodrug, diseases, polyendocrinopathies, autoimmune, puberty, analog, isomer, metabolite, derivative, pharmaceutically delayed, puberty, precocious, renal osteodystrophy, thyroid acceptable salt, pharmaceutical product, polymorph, crystal, 65 diseases, thyroid hormone resistance syndrome, thyroid neo impurity, N-oxide, ester. hydrate or any combination thereof plasms, thyroid nodule, thyroiditis, thyroiditis, autoimmune, to the subject. thyroiditis, subacute, or Wolfram syndrome. US 9,623,021 B2 111 112 In one embodiment, "Hypogonadism’ is a condition infection, or certain autoimmune disorders. In some embodi resulting from or characterised by abnormally decreased ments, menopause is a form of hypogonadism. Menopause functional activity of the gonads, with retardation of growth may cause, in some embodiments, amenorrhea, hot flashes, and sexual development. vaginal dryness, or irritability due to woman’s estrogen In some embodiments, the present invention provides a levels fall. In one embodiment, the method comprises method for treating, reducing the incidence, delaying the administering to a subject a composition comprising a onset or progression, or reducing and/or abrogating the compound of this invention and an anti-cancer agent, an symptoms associated with a liver disease in a Subject. In one immunomodulating agent, an antidiabetic agent, an agent embodiment, the method comprises administering to a Sub treating the cardiovascular system, an agent treating the ject a composition comprising a compound of this invention 10 gastrointestinal system, an agent treating the central nervous and anti-cancer agent, an immunomodulating agent, an system, an agent treating a metabolic disease, an agent agent treating the gastrointestinal system, an anti-infective treating a wasting disease, a gene therapy agent, an agent agent, an agent treating the liver, an agent treating a meta treating the endocrine system, an agent treating a dermato bolic disease, an agent treating a wasting disease, a gene logical disorder, an anti-infective agent, an agent treating the therapy agent, an agent treating the endocrine system, Vita 15 liver, an agent treating the kidney, Vitamins, or a combina mins, or a combination thereof. In some embodiments, liver tion thereof. diseases comprise liver cancer, primary biliary cirrhosis, In one embodiment, the term "hot flashes' refers to the autoimmune hepatitis, chronic liver disease, cirrhosis of the following: sudden feeling of heat in the upper part or all of liver, hepatitis, viral hepatitis (hepatitis a, hepatitis b, the body, face and neck flush, red blotches appearing on the chronic hepatitis b, hepatitis c, chronic hepatitis c, hepatitis chest, back and arms, heavy Sweating, cold shivering, etc. d, hepatitis e, hepatitis X), liver failure, jaundice, neonatal It is to be understood that any -dependent jaundice, hepatoma, liver cancer, liver abscess, alcoholic disease, disorder or condition may be treated via the meth liver disease, hemochromatosis, Wilson's disease, portal ods of this invention, using the compositions of this inven hypertension, primary Sclerosing cholangitis, Sarcoidosis, tion. tapeworms, alveolar hydatid disease, fascioliasis, Schistoso 25 In some embodiments, the present invention provides a miasis, gaucher disease, Zellweger syndrome, alcoholism, method for treating, reducing the incidence, delaying the food poisoning, pneumococcal pneumonia or vibrio Vul onset or progression, or reducing and/or abrogating the nificus. symptoms associated with osteopenic state in a Subject. In In some embodiments, the present invention provides a one embodiment, the present invention provides a method method for treating, reducing the incidence, delaying the 30 for treating, reducing the incidence, delaying the onset or onset or progression, or reducing and/or abrogating the progression, or reducing and/or abrogating the symptoms symptoms associated with nerve injury, neuropathy, diabetic associated with a pharmacotherapy induced osteopenic state neuropathy, alcoholic neuropathy, Subacute combined in a subject. In some embodiments, osteopenia is a mild degeneration of the spinal cord, diabetes, rheumatoid arthri thinning of the bone mass. In some embodiments, osteope tis. 35 nia is a precursor to osteoporosis. In some embodiments In another embodiment, the invention provides a method osteopenia is defined as a bone density between one standard of treating, preventing, Suppressing, inhibiting, or reducing deviation (SD) and 2.5 SD below the bone density of a the incidence of hot flashes, gynecomastia, and/or hair loss normal young adult. In one embodiment, the method com in female Subjects, or in another embodiment, in male prises administering to a subject a composition comprising human Subjects. In one embodiment, invention provides a 40 a compound of this invention and an anti-cancer agent, an method of treating, preventing, Suppressing, inhibiting, or immunomodulating agent, an antidiabetic agent, an agent reducing the incidence of hot flashes, gynecomastia, and/or treating the cardiovascular system, an agent treating the hair loss in a male Subject having prostate cancer, compris gastrointestinal system, an agent treating the central nervous ing administering a NRBA of formula (I)-(XII) or its pro system, an agent treating a metabolic disease, an agent drug, ester, analog, isomer, metabolite, derivative, pharma 45 treating a wasting disease, a gene therapy agent, an agent ceutically acceptable salt, pharmaceutical product, treating the endocrine system, an agent treating a dermato polymorph, crystal, impurity, N-oxide, hydrate or any com logical disorder, an anti-infective agent, an agent treating the bination thereof, or a composition comprising the same, liver, an agent treating the kidney, Vitamins, or a combina thereby treating, preventing, Suppressing, inhibiting, or tion thereof. reducing the incidence of hot flashes, gynecomastia, and/or 50 In some embodiments, the present invention provides a hair loss in said male human Subjects. method for treating, reducing the incidence, delaying the In some embodiments, the present invention provides a onset or progression, or reducing and/or abrogating the method for treating, reducing the incidence, delaying the symptoms associated with a combination of diseases and/or onset or progression, or reducing and/or abrogating the disorders in a subject as described hereinabove. In one symptoms associated with a hypogonadal state in a subject. 55 embodiment, the method comprises administering to a Sub In one embodiment, the present invention provides a method ject a composition comprising a compound of this invention for treating, reducing the incidence, delaying the onset or and an anti-cancer agent, an immunomodulating agent, an progression, or reducing and/or abrogating the symptoms antidiabetic agent, an agent treating the cardiovascular sys associated with a pharmacotherapy induced hypogonadal tem, an agent treating the gastrointestinal system, an agent state in a Subject. In some embodiments, hypogonadism is 60 treating the central nervous system, an agent treating a caused by treatments which alter the secretion of hormones metabolic disease, an agent treating a wasting disease, a from the sex glands in both women and men. In some gene therapy agent, an agent treating the endocrine system, embodiments, hypogonadism may be “primary or “cen an agent treating a dermatological disorder, an anti-infective tral'. In primary hypogonadism, the ovaries or testes them agent, an agent treating the liver, an agent treating the selves do not function properly. In some embodiments, 65 kidney, Vitamins, or a combination thereof. hypogonadism may be induced by Surgery, radiation, genetic It is to be understood that any method of this invention, and developmental disorders, liver and kidney disease, as herein described, encompasses the administration of a US 9,623,021 B2 113 114 compound as herein described, or a composition comprising pharmaceutically acceptable salt, pharmaceutical product, the same, to the subject, in order to treat the indicated polymorph, crystal, impurity, N-oxide, hydrate or any com disease, disorder or condition. The methods as herein bination thereof, or a pharmaceutical composition compris described each and/or all may further comprise administra ing the same. tion of an additional therapeutic agent as herein described, In one embodiment, the invention provides a method of and as will be appreciated by one skilled in the art. treating, preventing, reducing the risk of mortality from In one embodiment, the method comprises administering cardiovascular and/or cerebrovascular disease in a Subject, to a Subject a composition comprising a compound of this comprising administering a NRBA of formula (I)-(XII) or its invention and an anti-cancer agent, an immunomodulating prodrug, ester, analog, isomer, metabolite, derivative, phar agent, an antidiabetic agent, an agent treating the cardio 10 maceutically acceptable salt, pharmaceutical product, poly vascular system, an agent treating the gastrointestinal sys morph, crystal, impurity, N-oxide, hydrate or any combina tem, an agent treating the central nervous system, an agent tion thereof, or a composition comprising the same. In some treating a metabolic disease, an agent treating a wasting embodiments ER-B agonists are useful in treating, prevent disease, a gene therapy agent, an agent treating the endo ing, reducing the risk of mortality from cardiovascular crine system, an agent treating a dermatological disorder, an 15 and/or cerebrovascular disease in a Subject. In another anti-infective agent, an agent treating the liver, an agent embodiment, ER-B agonist of this invention is compound treating the kidney, vitamins, nutritional additives, hor 12b, listed in Table 1. In another embodiment, ER-Bagonist mones, each and/or all as herein described, or any other of this invention is compound 12f, listed in Table 1. In therapeutic agent as herein described, or a combination another embodiment, ER-B agonist of this invention is thereof. compound 12h, listed in Table 1. In another embodiment, In another embodiment, this invention provides methods ER-B agonist of this invention is compound 12p, listed in of treatment of cystic fibrosis and induced hypogonadal Table 1. In another embodiment, ER-B agonist of this states as a result of the same, epilepsy and induced hypogo invention is compound 12s, listed in Table 1. In another nadal and/or hypermetabolic states as a result of the same, embodiment, ER-B agonist of this invention is compound hereditary angioedema, lupus erythematosus and decreased 25 12u, listed in Table 1. In another embodiment, ER-Bagonist BMD as a result of the same, alcohol and smoking induced of this invention is compound 12y, listed in Table 1. In osteoporosis, in a Subject the methods comprising adminis another embodiment, ER-B agonist of this invention is tering a compound as herein described to the Subject. compound 12Z, listed in Table 1. In another embodiment, In another embodiment, this invention provides a method ER-B agonist of this invention is compound 14m, listed in of treating a nervous system disease, disorder or condition, 30 Table 1, or any combination thereof. the method comprising administering to the Subject a com In one embodiment, cardiovascular disease comprises, pound as herein described, and optionally anti-psychotics, inter alia, atherosclerosis of the coronary arteries, angina Such as, for example, Zotepine, haloperidol, amisulpride, pectoris, and myocardial infarction. In one embodiment, risperidone, other D2 dopamine receptor antagonists; anti cerebrovascular disease comprises, interalia, atherosclerosis epileptics, such as valproic acid, carbamazepine, oXcarbam 35 of the intracranial or extracranial arteries, stroke, Syncope, azepine, etc. or combinations thereof. and transient ischemic attacks. In one embodiment cardiovascular disorders comprise of Cardiovascular cells, as well as reproductive tissues, hypertension (HTN), coronary artery disease (CAD) or bone, liver, and brain, express both of the known estrogen myocardial perfusion. In another embodiment this invention receptors, estrogen receptor-C. (ER-C) and estrogen recep provides methods of use of the NRBA compounds as herein 40 tor-3 (ER-B). These receptors are important targets for described for promoting aortic Smooth muscle cell prolif endogenous estrogen, estrogen replacement therapy (ERT), eration. In another embodiment this invention provides and pharmacological estrogen agonists. Estrogen-estrogen methods of use of the compounds as herein described for receptor complexes serve as transcription factors that pro treating arteriosclerosis. In one embodiment this invention mote gene expression with a wide range of vascular effects, provides methods of use of the compounds as herein 45 including regulation of vasomotor tone and response to described in conjunction with vascular stents. In some injury, which may be protective against development of embodiments the compounds of this embodiment could be atherosclerosis and ischemic diseases. Estrogen receptors in incorporated onto the stent as a coating to retard vascular other tissues, such as the liver, may mediate both beneficial fibrosis and remodeling, vascular cell proliferation and effects (e.g., changes in apoprotein gene expression that migration, etc. that often cause stent failure or restenosis. In 50 improve lipid profiles) and adverse effects (e.g., increases in another embodiment this invention provides methods of use gene expression of coagulation proteins and/or decreases in of the compounds as herein described for lowering blood fibrinolytic proteins). Two general estrogen-mediated vas pressure. In another embodiment this invention provides cular effects are recognized. Rapid, transient vasodilation methods of use of the compounds as herein described for occurs within a few minutes after estrogen exposure, inde treating cardiac diseases and disorders comprising cardio 55 pendently of changes in gene expression. Longer-term myopathy, cardiac dysfunctions such as myocardial infarc effects of estrogen on the vasculature, such as those related tion, cardiac hypertrophy and cognitive heart failure. In to limiting the development of atherosclerotic lesions or another embodiment this invention provides methods of use vascular injury, occur over hours to days after estrogen of the compounds as herein described for cardioprotection treatment and have as their hallmark alterations in vascular comprising cardioprotection in insulin resistance; treating 60 gene expression. Progesterone and other hormonal receptors diabetes type I and II, metabolic syndrome, syndrome X are also expressed in the vasculature. and/or high blood pressure. In one embodiment, this invention provides a method of In one embodiment, the invention provides a method of improving the dexterity and movement in a Subject, for treating, preventing, reducing the risk of mortality from example, by treating arthritis in the Subject. cardiovascular and/or cerebrovascular disease in a subject, 65 The term “arthritis' refers, in another embodiment, to a comprising administering a compound of this invention or non-inflammatory degenerative joint disease occurring its prodrug, ester, analog, isomer, metabolite, derivative, chiefly in older people, characterized by degeneration of the US 9,623,021 B2 115 116 articular cartilage, hypertrophy of bones and the margins, In some embodiments, such activity results in Suppression changes in the synovial membrane, etc. It is accompanied, in of pathogenic apoptosis, for example, as occurs in various other embodiments, by pain and stiffness, particularly after disease states, such as neurodegenerative diseases or disor prolonged activity. ders, glaucoma, autoimmune disease, and others as will be The term “increased blood pressure' or “hypertension” appreciated by one skilled in the art. refers, in other embodiments, to a repeatedly high blood In some embodiments, the compounds of this invention, pressure above 140 over 90 mmHg. Chronically-elevated characterized by the structures of formulae I-XII, and blood pressure can cause blood vessel changes in the back including any embodiment thereof, localize within the cyto of the eye, thickening of the heart muscle, kidney failure, Sol of a cell, or within cytosolic organelles, such as mito 10 chondrion, wherein such compounds may affect cellular and brain damage. signaling pathways, and thereby effect the methods as The term "stroke' refers, in other embodiments, to dam described herein. For example, and in one embodiment, the age to nerve cells in the brain due to insufficient blood compounds may interact with cellular proteins and thereby supply often caused by a bursting blood vessel or a blood synergize a desired effect, in some embodiments, in signal clot. The term “heart disease', in other embodiments, refers 15 ing pathways within the cell, producing the desired effect. In to a malfunction in the heart normal function and activity, other embodiments, the compounds of formulae I-XII including heart failure. antagonize a particular response or pathway in the cell, In one embodiment, this invention provides a method of which otherwise produces an undesired effect, for example, treating vascular disease in a human Subject, comprising the exacerbating disease, and thus the compounds as described step of administering to said Subject a compound of this herein are effective in such methods by their ability to invention or its isomer, pharmaceutically acceptable salt, disrupt or interfere or antagonize pathogenic mechanisms in pharmaceutical product, hydrate, N-oxide, or any combina a cell or in a Subject. tion thereof. In some embodiments, the agents of this invention may In one embodiment, the NRBAs of this invention bind alter intracellar signaling pathways or responsiveness to their cognate receptor at the cell Surface, translocate to the 25 Such pathways or cascades. cell's nucleus, and exert their effects. In one embodiment, In some embodiments, downstream effects of the com Such effects may comprise, interalia, regulation of particular pounds of this invention, characterized by the structures of gene expression, and may in turn play a role in the inhibition formulae I-XII, and including any embodiment thereof, may of apoptosis, activation of protein kinase pathways, and be controlled by intracellular kinase signaling pathways others. 30 activated by growth factors. In some embodiments, the In another embodiment, the NRBAs of this invention bind compounds may affect signaling downstream of binding of cognate receptors and translocate within the mitochondria, a hormone to its receptor, for example, with the case of whereupon they associate with mitochondrial DNA, and in glycogen synthase kinase 3 (GSK3), an effector kinase of the turn play a role in the increased respiratory chain activity, phosphatidylinositol 3-kinase (PI3K) pathway, may be acti inhibition of TGFB-induced apoptosis and/or activation of 35 vated by administration of a compound of this invention and manganese Superoxide dismutase, and others. in turn affect ERalpha activity in specific cells, for example Superoxide dismutases (SODs) are key enzymes in the in neuroblastoma cells, and thereby effect some of the cellular defence against free radical oxidation. By catalyzing methods of this invention. In some embodiments, the com the degradation of the Superoxide free radical to water and pounds of this invention may result in greater expression of hydrogen peroxide, SODs, play an important role in reduc 40 GSK3, which in turn stimulates or increases ER-dependent ing the damage associated with, for example ischemic gene expression. injury, chronic lung disease, Alzheimer's disease, Down It is to be understood that any use of any of the com syndrome, inflammatory disorders, cardiovascular disease, pounds as herein described may be used in the treatment of immune-system decline, brain dysfunction, cataracts, and any disease, disorder or condition as described herein, and other aspects of aging and degenerative disease. 45 represents an embodiment of this invention. In one embodiment, this invention provides a method of In some embodiments, any of the compositions useful in treating, ameliorating and/or preventing reactive species the methods disclosed herein comprise a compound of this mediated damage in a subject, comprising the step of invention, in any form or embodiment as described herein. administering a NRBA of formula (I)-CXII) or its prodrug, In some embodiments, of the compositions of this invention analog, isomer, metabolite, derivative, pharmaceutically 50 will consist essentially of a compound of this invention, in acceptable salt, pharmaceutical product, polymorph, crystal, any form or embodiment as described herein. impurity, N-oxide, ester, hydrate or any combination thereof It is to be understood that any use of any of the com to the Subject. In one embodiment, the reactive species pounds as herein described may be used in the treatment of comprises reactive oxygen intermediates and the NRBA any disease, disorder or condition as described herein, and promotes or enhances the activity of cellular Superoxide 55 represents an embodiment of this invention. dismutase. In one embodiment, the reactive species com An “effective amount’ means the amount of a compound prises reactive nitrogen intermediates and the NRBA pro or composition according to the invention that, when admin motes or enhances the activity of cellular nitric oxide istered to a patient for treating a state, disorder or condition synthase. is sufficient to effect such treatment. The “effective amount In some embodiments, such damage is associated with a 60 will vary depending on the active ingredient, the state, variety of diseases, such as, but not limited to cardiovascular disorder, or condition to be treated and its severity, and the disease. Such as coronary heart disease and atherosclerosis, age, weight, physical condition and responsiveness of the neurodegenerative disease. Such as Alzheimer's disease and/ subject to be treated. or multiple sclerosis, infection, for example, HCV infection The terms “treat,” “treatment, and “treating” mean to and complications thereof, autoimmune disease, such as 65 relieve, alleviate, delay, reduce, reverse, improve, manage or lupus, cancer, and others, as appreciated by one skilled in the prevent at least one symptom of a condition in a Subject. The art. term “treating may also mean to arrest, delay the onset (i.e., US 9,623,021 B2 117 118 the period prior to clinical manifestation of a disease) and/or -continued OCH reduce the risk of developing or worsening a condition. OH O A subject or patient in whom administration of a thera 1. NaH peutic compound is an effective therapeutic regimen for a N 2. O disease or disorder is in Some embodiments, a human, but 5 HCO 2 3 can be any animal. Thus, as can be readily appreciated by F.C-( ) { C one of ordinary skill in the art, the compositions of the CF present invention are particularly Suited to administration to any animal, particularly a mammal, and including, but by no means limited to, humans, domestic animals, such as feline 10 or canine Subjects, farm animals, such as but not limited to bovine, equine, caprine, ovine, and porcine Subjects, wild NBS -es animals (whether in the wild or in a Zoological garden), OCH CH3CN research animals, such as mice, rats, rabbits, goats, sheep, 15 pigs, dogs, cats, etc., avian species. Such as chickens, turkeys, Songbirds, etc., i.e., for veterinary medical use. The following examples are presented in order to more fully illustrate the preferred embodiments of the invention. HCO C 2 They should in no way, however, be construed as limiting the broad scope of the invention. CF EXAMPLES Example 1: Chemical syntheses of 4-bromo-6,8- dihydroxy-2-(4-hydroxyphenyl)isoquinolin-1 (2H)- 25 HO one (12u) OCH HessBBr3 He Scheme and Procedures for Synthesis of 12u. O O O O 30 N OCH HCO 2

SOCl Br He OH 21 OH CHCl2 OH O H3CO O OCH 40 HO NaN He Br 21 C Dioxane/H2O H3CO 12u. O 45 OCH Synthesis of 6,8-dimethoxyisoquinolin-1-ol

Ph2O, BuN --- A mixture of trans-3,5-dimethoxycinnamic acid (15.30 g, 21 N 73.48 mmol) and thionyl chloride (13.11 g, 0.11 mol) were HCO placed in a 250 mL single-necked round-bottomed flask O fitted with a magnetic stirring bar and reflux condenser. Dry OCH methylene chloride (80.0 mL) was added to the above OCH, OH mixture. The resulted solution was heated to reflux for 3 55 hours. Then, the solvent was removed under reduced pres I1 Sure. The residue was dried under vacuum overnight to give CuIL-Proline a pale-yellow solid, trans-3,5-dimethoxycinnamic acid chlo DMSO, 120° C. ride. HCO C2 The pale-yellow solid acid chloride was dissolved in 20 OCH 60 mL of 1,4-dioxane and added drop wise over 1 hour to a 0° OMe O C. suspension of 14.33 g (0.22 mol) of sodium azide in 80 LiCl HCI mL of 1:1 (v/v) 1.4-dioxane?water. During the addition the He -e- temperature was maintained at 0°C. in an ice-bath. After N DMF complete addition of the acid chloride, the mixture was 65 stirred for 1 hour at 0°C., and then diluted with 75 mL of HCO 2 water. The mixture was extracted with methylene chloride (3x40 mL); the combined extracts were dried over anhy US 9,623,021 B2 119 120 drous magnesium sulfate followed by filtration and concen 7.06 (d. 2H, J=9.0 Hz), 6.70-6.67 (m, 2H), 6.45 (d. 1H, J=2.1 tration to ca. 100 mL. The solution was diluted with 20 mL HZ), 3.85 (s, 3H), 3.82 (s, 3H). of phenyl ether and further concentrated to remove the remaining methylene chloride (trans-3,5-dimethoxycin Synthesis of 6-methoxy-2-(4-methoxyphenyl)-1- namic acyl azide). oxo-1,2-dihydroisoquinolin-8-yl-4-(trifluoromethyl) A 500 mL three-necked round-bottomed flask fitted with benzoate a nitrogen inlet, reflux condenser, an addition funnel, inter nal thermometer and magnetic stirring bar was charged with Compound 8-hydroxy-6-methoxy-2-(4-methoxyphenyl) 29 mL of tributylamine and 80 mL of phenyl ether. The isoquinolin-1 (2H)-one (0.60 g, 2.02 mmol) was placed in a solution was heated to 230° C. and the acyl azide in 40 mL 10 dry 250 mL three-necked flask fitted with a stirring bar and of phenyl ether was added drop wise over 3 hours from an sealed with septa. Anhydrous DMF (15 mL) was added via addition funnel. During the addition, the reflux temperature a syringe under argon atmosphere. The Solution was cooled gradually decreased to about 200° C. Hence, after comple to 0° C. in an ice-bath. NaH (0.12 g, 3.03 mmol, 60% tion of the addition, the temperature was raised to 230° C. dispersion in mineral oil) was added. The reaction mixture After heating for an additional hour at 230° C., the mixture 15 was stirred at 0°C. for 30 minutes. Then, it was warmed to was cooled to room temperature. The mixture was poured to room temperature for 30 minutes. The mixture was cooled to 500 mL of hexanes with stirring. The solid was filtered and 0° C. again in an ice bath. 4-(Trifluoromethyl)benzoyl washed with hexanes (2x100 mL). The pale-yellow solid chloride was added via a syringe with stirring at 0°C. The was dried and recrystallized from ethyl acetate/methanol reaction mixture was stirred at 0° C. for 30 minutes and at mixture to give a pale-yellow crystalline material, 10.58 g. room temperature for additional 30 minutes. The reaction 70.2% yield. MS: m/z 228.2 M+Na". "H NMR (DMSO-d was quenched by adding 20 mL of saturated NHCl solution. 300 MHz): & 10.71 (s, 1H), 7.02 (d. 1H, J=6.9 Hz), 6.63 (d. The solution was diluted with 20 mL of water and stirred for 1H, J=2.4 Hz), 6.47 (d. 1H, J=2.4 Hz), 6.31 (d. 1H, J=6.9 one hour at room temperature. It was extracted with ethyl Hz), 3.83 (s, 3H), 3.79 (s.3H). acetate (3x20 mL). The extracts were washed with brine (20 25 mL) and dried over anhydrous MgSO. The solvent was Synthesis of 6,8-dimethoxy-2-(4-methoxyphenyl) removed under reduced pressure. The residue was subjected isoquinolin-1 (2H)-one to flash column chromatography (silica-gel, CH2Cl2) to give a white solid product, 0.93 g, 98.1% yield. MS: m/z 492.1 6,8-Dimethoxyisoquinolin-1-ol (1.59 g, 7.75 mmol), 4-io IM+Na". "H NMR (DMSO-d 300 MHz): 8 8.25 (d. 2H, doanisole (2.72, 11.62 mmol), copper(I) iodide (0.30 g, 1.55 30 J=8.7 Hz), 7.93 (d. 2H, J=8.4 Hz), 7.40 (d. 1H, J=7.5 Hz), mmol), L-proline (0.36 g., 3.10 mmol) and anhydrous potas 7.23 (d. 2H, J–8.7 Hz), 7.21 (d. 1H, J=2.4 Hz), 7.01 (d. 1H, sium carbonate (2.14 g. 15.50 mmol) were placed in a dry J=2.4 Hz), 6.98 (d. 2H, J=8.7 Hz), 6.67 (d. 1H, J=7.5 Hz), 250 mL three-necked round-bottomed flask fitted with a 3.93 (s, 3H), 3.76 (s, 3H). stirring bar and reflux condenser. The system was vacuumed and refilled with dry argon. Then, anhydrous methyl sulfox 35 Synthesis of 4-bromo-6-methoxy-2-(4-methoxyphe ide (50 mL) was added via a syringe under argon atmo nyl)-1-oxo-1,2-dihydroisoquinolin-8-yl-4-(trifluo sphere. The reaction solution was stirred and heated to 120° romethyl)benzoate C. for 20 hours. Water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (5x20 Compound 6-methoxy-2-(4-methoxyphenyl)-1-oxo-1,2- mL). The extracts were combined, washed with brine (3x10 40 dihydroisoquinolin-8-yl-4-(trifluoromethyl)benzoate (0.51 mL) and dried over anhydrous MgSO followed by filtration g, 1.09 mmol) and N-bromosuccinimide (0.23g, 1.30 mmol) and concentration to give a yellow residue. The yellow were placed in a dry, argon flushed 150 mL single-necked residue was purified by flash column chromatography flask fitted with a stirring bar and sealed with a septa. (silica-gel, CHCl2/Acetone=1971 V/v) to give a pale-yellow Acetonitrile (15 mL) was added via a syringe at room solid product, 2.12 g, 88.0% yield. MS: m/z. 312.9 M+H". 45 temperature under argon atmosphere. After the mixture was H NMR (DMSO-de, 300 MHz): 8 7.31-7.26 (m, 3H), 7.02 stirred at room temperature for 5 hours, the solvent was (d. 2H, J–8.7 Hz), 6.71 (d. 1H, J=2.4 Hz), 6.54 (d. 1H, J–2.4 removed under reduced pressure. The residue was purified Hz), 6.45 (d. 1H, J=7.8 Hz), 3.87 (s.3H), 3.81 (s.3H), 3.79 by flash column chromatography (silica-gel, CH2Cl2) to (s, 3H). give a white solid product, 0.54 g. 90.0% yield. MS: m/z. 50 572.1 M+Na". H NMR (DMSO-de, 300 MHz): 88.26 (d. Synthesis of 8-hydroxy-6-methoxy-2-(4-methoxy 2H, J=8.1 Hz), 7.93 (d. 2H, J=8.4 Hz), 7.28 (d. 2H, J=8.7 phenyl)isoquinolin-1 (2H)-one Hz), 7.21 (d. 1H, J–2.1 Hz), 7.20 (d. 1H, J=2.4 Hz), 6.97 (d. 2H, J=9.0 Hz), 3.98 (s, 3H), 3.76 (s, 3H). Compound 6,8-dimethoxy-2-(4-methoxyphenyl)isoqui nolin-1 (2H)-one (2.25 g, 7.23 mmol) and LiCl (6.12 g, 55 Synthesis of 4-bromo-6,8-dihydroxy-2-(4-hydroxy 144.54 mmol) were placed in a dry, argon flushed 150 mL phenyl)isoquinolin-1 (2H)-one (12u) three-necked flask fitted with a stirring bar and reflux condenser. Anhydrous DMF (30 mL) was added via a Compound 4-bromo-6-methoxy-2-(4-methoxyphenyl)-1- syringe. The reaction mixture was heated to 140°C. under oxo-1,2-dihydroisoquinolin-8-yl-4-(trifluoromethyl)benzo vacuum for 20 hours. Then, the reaction was quenched by 60 ate (2.46 g, 4.49 mmol) was placed in a dry 250 mL addition of 30 mL of 2N HCl solution. The solution was single-necked round-bottomed flask fitted with a stirring bar extracted with EtOAc (3x30 mL). The extracts were com and sealed with a rubber stopper. Anhydrous chlorobenzene bined and dried over anhydrous MgSO. The solvent was (60 mL) was added via a syringe at room temperature. BBr removed under reduced pressure. The residue was purified (6.74 g, 26.92 mmol) was added dropwise with stirring at by flash column chromatography (silica-gel, CH,Cl) to 65 room temperature. The resulted solution was heated to 100° give a white solid product, 1.80 g. 83.7% yield. "H NMR C. for 20 hours. 50 mL of water and 10 mL of methanol were (DMSO-d 300 MHz): & 12.98 (s, 1H), 7.42-7.35 (m, 3H), added to quench the reaction at 0°C. The solution was US 9,623,021 B2 121 122 stirred at room temperature for two hours. CHCl layer was Example 3: Synthesis of 4-chloro-6,8-dihydroxy-2- separated and the aqueous layer was extracted with EtOAC (4-hydroxyphenyl)isoquinolin-1 (2H)-one (12y) (3x20 mL). The organic layers were combined and dried over anhydrous MgSO. The solvent was removed under Scheme and Procedures for Synthesis of 12y. reduced pressure. The residue was purified by column 5 chromatography (silica-gel, CHCl2/MeOH=9/1 V/v) to give a white solid product, 1.32 g, 84.6% yield. MS: m/e 347.8 CF3 M-H. 'H NMR (DMSO-de, 300 MHz): 8 13.12 (s, 1H), 10.78 (s, 1H), 9.81 (s, 1H), 7.75 (s, 1H), 7.28 (d. 2H, J=8.7 Hz), 6.85 (d. 2H, J=8.7 Hz), 6.61 (d. 1H, J=2.1 Hz), 6.37 (d. 10 1H, J–2.1 Hz). NCS OCH3 CHCN Example 2: Synthesis of 6,8-dihydroxy-2-(4-hy O O O droxyphenyl)-1-oxo-1,2-dihydroisoquinoline-4-car 15 bonitrile (14m) N Scheme and Procedures for Synthesis of 14m. H3CO 2 CF OH OH O

N Zn(CN)2 25 Pd(dba)3(dppf OCH BBr3 HO DMF HO 21 O O O O MeOH Br N 12u. 30 HCO 21

C OH

OH 35 OH O N

N HO 2 40 HO 21 C 12y CN 14m Synthesis of 4-chloro-6-methoxy-2-(4-methoxyphe 45 nyl)-1-oxo-1,2-dihydroisoquinolin-8-yl-4-(trifluo 4-Bromo-6,8-dihydroxy-2-(4-hydroxyphenyl)isoquino romethyl)benzoate lin-1 (2H)-one (12u) (0.13 g, 0.37 mmol), Zn(CN), (53 mg, 0.45 mmol), tris(dibenzylideneacetone)dipalladium (34 mg. Compound 6-methoxy-2-(4-methoxyphenyl)-1-oxo-1,2- 0.037 mmol), and 1,1'-bis(diphenylphosphino) ferrocene (83 dihydroisoquinolin-8-yl-4-(trifluoromethyl)benzoate (0.55 mg, 0.15 mmol) were placed in a dry and argon flushed 150 50 g, 1.17 mmol) and N-bromosuccinimide (0.19 g, 1.41 mmol) mL three-necked round-bottomed flask fitted with a stirring were placed in a dry, argon flushed 150 mL single-necked bar, reflux condenser and an argon inlet. Then, anhydrous flask fitted with a stirring bar and sealed with a septa. Acetonitrile (15 mL) was added via a syringe at room dimethylformamide (10 mL) was added via a syringe under temperature under argon atmosphere. After the mixture was argon atmosphere. The reaction solution was stirred and 55 stirred and heated to 60° C. for 8 hours, the solvent was heated to 100° C. for 12 hours. Water (20 mL) was added to removed under reduced pressure. The residue was purified quench the reaction. The mixture was extracted with ethyl by flash column chromatography (silica-gel, hexanes/ acetate (2x25 mL). The extracts were combined, washed EtOAc=7/3 v/v) to give a white solid product, 0.56 g., 94.9% with brine (10 mL) and dried over anhydrous MgSO yield. MS: m/z 526.2 M+Nal". "H NMR (DMSO-de, 300 followed by filtration and concentration to give a yellow 60 MHz): 88.26 (d. 2H, J=8.1 Hz), 7.94 (d. 2H, J=8.4 Hz), 7.28 residue. The yellow residue was purified by flash column (d. 2H, J–8.7 Hz), 7.23 (d. 1H, J=2.1 Hz), 7.21 (d. 1H, J–2.4 chromatography (silica-gel, CH2Cl2/Acetone/MeCH=80/ Hz), 6.97 (d. 2H, J=9.0 Hz), 3.99 (s.3H), 3.76 (s, 3H). 17/3 V/v/v) to give a pale-yellow solid product, 80 mg. Synthesis of 4-chloro-6,8-dihydroxy-2-(4-hydroxy 72.7% yield. MS: m/z 3.07.0 M+Na". "H NMR (DMSO phenyl)isoquinolin-1 (2H)-one (12v) do, 300 MHz) & 12.43 (s, 1H), 10.92 (s, 1H), 9.86 (s, 1H), 65 8.37 (s, 1H), 7.29 (d. 2H, J=8.7 Hz), 6.86 (d. 2H, J=8.7 Hz), Compound 4-chloro-6-methoxy-2-(4-methoxyphenyl)-1- 6.57 (d. 1H, J–2.1 Hz), 6.40 (d. 1H, J–2.1 Hz). oxo-1,2-dihydroisoquinolin-8-yl-4-(trifluoromethyl)benzo US 9,623,021 B2 123 124 ate (0.24 g., 0.48 mmol) was placed in a dry 250 mL -continued single-necked round-bottomed flask fitted with a stirring bar CF3 and sealed with a rubber stopper. Anhydrous chlorobenzene (20 mL) was added via a syringe at room temperature. BBrs (0.71 g, 2.86 mmol) was added dropwise with stirring at CF room temperature. The resulted solution was heated to 100° O BBr C. for 20 hours. 50 mL of water and 10 mL of methanol were O1 O O OC He added to quench the reaction at 0°C. The solution was O stirred at room temperature for two hours. CHCl layer was N F separated and the aqueous layer was extracted with EtOAC 10 (3x20 mL). The organic layers were combined and dried HCO 21 Br over anhydrous MgSO. The solvent was removed under OH reduced pressure. The residue was purified by column OH O chromatography (silica-gel, CH,Cl/MeOH-9/1 V/v) to give 15 a white solid product, 0.11 g, 76.1% yield. MS m/e 301.9 (M-H). H NMR (DMSO-de, 300 MHz) & 13.09 (s, 1H), N F 10.77 (s, 1H), 9.81 (s, 1H), 7.70 (s, 1H), 7.27 (d. 2H, J=8.7 Hz), 6.85 (d. 2H, J=8.7 Hz), 6.62 (d. 1H, J=2.1 Hz), 6.38 (d. HO 2 1H, J–2.1 Hz). Br 12Z Example 4: Synthesis of 4-chloro-6,8-dihydroxy-2- (4-hydroxyphenyl)isoquinolin-1 (2H)-one (12Z) 25 Synthesis of 6,8-dimethoxy-2-(3-fluoro-4-methoxy phenyl)isoquinolin-1 (2H)-one 6.8-Dimethoxyisoquinolin-1-ol (0.70 g, 3.41 mmol), OCH, OH 4-bromo-2-fluoroanisole (1.05 g, 5.12 mmol), copper(I) 30 iodide (0.13 g, 0.68 mmol), L-proline (0.16 g, 1.36 mmol) Br rF and anhydrous potassium carbonate (0.94 g. 6.82 mmol) CuIL-Proline DMSO, 120° C. were placed in a dry 250 mL three-necked round-bottomed HCO C2 flask fitted with a stirring bar and reflux condenser. The system was vacuumed and refilled with dry argon. Then, OCH 35 anhydrous methyl sulfoxide (20 mL) was added via a OMe O Syringe under argon atmosphere. The reaction solution was BBr3 stirred and heated to 120° C. for 20 hours. Water (30 mL) N F s was added to quench the reaction. The mixture was extracted with ethyl acetate (5x20 mL). The extracts were combined, H3CO 2 40 washed with brine (3x10 mL) and dried over anhydrous MgSO followed by filtration and concentration to give a yellow residue. The yellow residue was purified by flash column chromatography (silica-gel, CH2Cl2/Acetone-1971 V/v) to give a pale-yellow solid product, 0.92 g, 82.1% yield. O 45 MS: m/z 330.3 M+H". "H NMR (DMSO-d,300 MHz): 8 737-7.13 (m, 4H), 6.72 (d. 1H, J=2.1 Hz), 6.55 (d. 1H, J=2.1 OH C Hz), 6.46 (d. 1H, J=7.5 Hz), 3.89 (s.3H), 3.87 (s.3H), 3.80 OH O (s, 3H). FC N F Synthesis of 2-(3-fluoro-4-hydroxyphenyl)-8-hy 21 droxy-6-methoxyisoquinolin-1 (2H)-one HCO Compound 2-(3-fluoro-4-hydroxyphenyl)-6,8-dime thoxyisoquinolin-1 (2H)-one (0.65 g, 1.97 mmol) was placed 55 in a dry 250 mL single-necked round-bottomed flask fitted CF with a stirring bar and sealed with a rubber stopper. Anhy drous methylene chloride (30 mL) was added via a syringe at room temperature. BBr (16.0 mL of 1M CHCL solu CF tion) was added dropwise with stirring at room temperature. 60 NBS The resulted mixture was stirred at room temperature for 3 O He days. Then, the reaction was quenched by adding 50 mL of O1 O O water and 10 mL of methanol at 0° C. The solution was O stirred at room temperature for two hours. CHCl layer was N F separated and the aqueous layer was extracted with EtOAC 65 (3x20 mL). The organic layers were combined and dried H3CO 2 over anhydrous MgSO. The solvent was removed under reduced pressure. The residue was purified by column US 9,623,021 B2 125 126 chromatography (silica-gel, CHCl2/MeOH=9/1 V/v) to give added dropwise with stirring at room temperature. The a white solid product, 0.45 g, 76.3% yield. MS: m/z 324.2 resulted solution was heated to 100° C. for 20 hours. 50 mL M+Na". "H NMR (DMSO-de, 300 MHz): & 12.91 (s, 1H), of water and 10 mL of methanol were added to quench the 10.27 (s, 1H), 741-7.35 (m, 2H), 7.13-7.03 (m, 2H), 6.69 reaction at 0°C. The solution was stirred at room tempera 6.65 (m, 2H), 6.44 (d. 1H, J–2.4 Hz), 3.85 (s, 3H). ture for two hours. CHCl layer was separated and the aqueous layer was extracted with EtOAc (3x20 mL). The Synthesis of 2-(3-fluoro-4-(4-(trifluoromethyl)ben organic layers were combined and dried over anhydrous Zoyloxy)phenyl)-6-methoxy-1-oxo-1,2-dihydroiso MgSO. The solvent was removed under reduced pressure. quinolin-8-yl-4-(trifluoromethyl)benzoate The residue was purified by column chromatography (silica 10 gel, CHCl/MeoH=9/1 V/v) to give a white solid product, Compound 2-(3-fluoro-4-hydroxyphenyl)-8-hydroxy-6- 82 mg, 48.2% yield. MS: m/e 363.9 M-H. 'H NMR methoxyisoquinolin-1 (2H)-one (0.32 g, 1.06 mmol) was (DMSO-d 300 MHz): 8 13.02 (s, 1H), 10.78 (s, 1H), 10.27 placed in a dry 250 mL three-necked flask fitted with a (s, 1H), 7.79 (s, 1H), 7.41 (dd. 1H, J-11.7 Hz, J-2.4 Hz), stirring bar. Anhydrous DMF (20 mL) was added via a 7.16-7.01 (m, 2H), 6.61 (d. 1H, J=2.1 Hz), 6.38 (d. 1H, J–2.1 Syringe under argon atmosphere. The Solution was cooled to 15 Hz). 0° C. in an ice-bath. NaH (0.13 g, 3.19 mmol. 60% disper sion in mineral oil) was added. The reaction mixture was Example 5: Synthesis of stirred at 0°C. for 30 minutes. Then, it was warmed to room 6-methoxyisoquinolinemethoxyisoquinoline-1-ol temperature for 30 minutes. The mixture was cooled to 0°C. again in an ice bath. 4-(Trifluoromethyl)benzoyl chloride A mixture of 17.82 g (0.10 mol) of trans-3-methoxycin (0.67 g, 3.19 mmol) was added via a syringe with stirring at namic acid and thionyl chloride (14.28 g., 0.12 mol) were 0° C. The reaction mixture was stirred at 0° C. for 30 placed in a 250 mL single-necked round-bottomed flask minutes and at room temperature for additional 30 minutes. fitted with a stirring bar and reflux condenser. 80 mL of dry The reaction was quenched by adding 20 mL of Saturated methylene chloride was added to the flask. The resulting NHCl solution. The solution was diluted with 20 mL of 25 mixture was heated to reflux for 3 hours and then the solvent water and stirred for one hour at room temperature. It was was removed under reduced pressure. The residue oil was extracted with ethyl acetate (3x20 mL). The extracts were dried under vacuum overnight. washed with brine (20 mL) and dried over anhydrous The pale-yellow solid acid chloride was dissolved in 20 MgSO. The solvent was removed under reduced pressure. mL of 1,4-dioxane and added dropwise with stirring to a 0° The residue was Subjected to flash column chromatography 30 C. suspension of 19.50 g (0.30 mol) of sodium azide in 80 (silica-gel, CHCl) to give a white solid product, 0.60 g, mL of 1,4-dioxane?water (1:1 mixture). During the addition 88.2% yield. MS: m/z 668.3 M+Nal". "H NMR (DMSO-d the temperature was maintained at 0° C. After complete 300 MHz): 8 8.34 (d. 2H, J=8.1 Hz), 8.27 (d. 2H, J=8.1 Hz), addition of the acid chloride, the mixture was stirred at 0°C. 8.01 (d. 2H, J=8.4 Hz), 7.95 (d. 2H, J=8.4 Hz), 7.64-7.53 (m, for an additional hour, and then diluted with 75 mL of water. 3H), 7.34 (d. 1H, J=8.7 Hz), 7.25 (d. 1H, J=2.4 Hz), 7.07 (d. 35 The mixture was extracted with methylene chloride (2x40 1H, J–2.4 Hz), 6.74 (d. 1H, J–7.5 Hz), 3.94 (s, 3H). mL). The combined extracts were dried over anhydrous magnesium Sulfate, filtered and concentrated to approxi Synthesis of 4-bromo-2-(3-fluoro-4-(4-(trifluorom mately 100 mL. The solution was diluted with 20 mL of ethyl)benzoyloxy)phenyl)-6-methoxy-1-oxo-1,2- phenyl ether and further concentrated to remove the remain dihydroisoquinolin-8-yl-4-(trifluoromethyl)benzoate 40 ing methylene chloride. A 500 mL 3-necked round-bottomed flask fitted with an argon inlet, reflux condenser, additional Compound 2-(3-fluoro-4-(4-(trifluoromethyl)benzoy funnel and an internal thermometer was charged with 29 mL loxy)phenyl)-6-methoxy-1-oxo-1,2-dihydroisoquinolin-8- of tributylamine and 80 mL of phenyl ether. The solution yl-4-(trifluoromethyl)benzoate (0.56 g. 0.87 mmol) and was heated to 23.0°C., and the acyl azide in 20 mL of phenyl N-bromosuccinimide (0.20 g, 1.13 mmol) were placed in a 45 ether was added dropwise with stirring over 3 hours from an dry, argon flushed 150 mL single-necked flask fitted with a addition funnel. During the addition, the reflux temperature stirring bar and sealed with a septa. Acetonitrile (20 mL) was gradually decreased to 200° C. After completion of the added via a Syringe at room temperature under argon atmo addition, the distillate was collected in the addition funnel sphere. After the mixture was stirred at room temperature for (15 mL of a 1:1 mixture of tributylamine/phenyl ether) until 5 hours, the solvent was removed under reduced pressure. 50 the temperature reached 23.0°C. After heating for an addi The residue was purified by flash column chromatography tional hour at 230° C., the mixture was cooled to room (silica-gel, CHCl) to give a white solid product, 0.35 g. temperature. The mixture was then combined with 500 mL 55.6% yield. MS: m/z 726.2 M+H". "H NMR (DMSO-d hexane with stirring. The solid was filtered and washed with 300 MHz): 8 8.35-8.27 (m, 4H), 8.06-7.90 (m, 5H), 7.69 hexanes (2x100 mL). The pale-yellow solid was recrystal 7.20 (m, 3H), 6.72 (d. 1H, J=2.4 Hz), 6.11 (d. 1H, J=2.4 Hz), 55 lized from ethyl acetate/methanol (9/1 V/v) to give a pure 3.99 (s.3H). pale-yellow crystalline material, 15.28 g., 87.2% yield. MS: 198.1 M+Na". H NMR (DMSO-d 300 MHz): 8 11.06 (s, Synthesis of 4-bromo-2-(3-fluoro-4-hydroxyphe 1H), 8.08 (d. 1H, J=8.5 Hz), 7.14-7.14 (m, 1H), 7.10 (d. 1H, nyl)-6,8-dihydroxyisoquinolin-1 (2H)-one (12Z) J=2.5 Hz), 705-7.03 (m. 1H), 7.04 (dd. 1H, J–9.0 Hz, 60 J–2.5 Hz), 6.47 (d. 1H, J–7.0 Hz), 3.86 (s, 3H). Compound 4-bromo-2-(3-fluoro-4-(4-(trifluoromethyl) benzoyloxy)phenyl)-6-methoxy-1-oxo-1,2-dihydroisoqui Example 6: Synthesis of nolin-8-yl-4-(trifluoromethyl)benzoate (0.34g, 0.47 mmol) 6-methoxy-2-(4-methoxyphenyl)isoquinolin-1 (2H)-one was placed in a dry 250 mL single-necked round-bottomed flask fitted with a stirring bar and sealed with a rubber 65 6-Methoxyisoquinoline-1-ol (2.00 g, 11.42 mmol), 4-io stopper. Anhydrous chlorobenzene (20 mL) was added via a doanisole (4.01 g, 17.13 mmol), copper (I) iodide (0.44 g. Syringe at room temperature. BBrs (0.71 g, 2.82 mmol) was 2.28 mmol). L-proline (0.53 g, 4.57 mmol) and anhydrous US 9,623,021 B2 127 128 potassium carbonate (3.16 g. 22.84 mmol) were placed in a (0.22 g, 0.91 mmol) were placed in a dry and argon flushed dry 250 mL three-necked round-bottomed flask fitted with a 150 mL three-necked round-bottomed flask fitted with a stirring bar and reflux condenser. The reaction flask was stirring bar and reflux condenser. Anhydrous 1, 2-dime vacuumed and refilled with dry argon. 50 mL of anhydrous thoxyethane (10 mL) and water (3 mL) were added via a methyl Sulfoxide was added via Syringe. The reaction mix Syringe under argon atmosphere. The reaction solution was ture was stirred and heated to 130° C. for 20 hours. 50 mL stirred and heated to reflux for 4 hours. The reaction was of water was added to quench the reaction, and yellow solid quenched by adding 20 mL of water at room temperature. precipitated out. The pale-yellow solid was filtered, washed The mixture was extracted with ethyl acetate/methanol (9/1 with water (2x20 mL) and dried in air. This pale-yellow V/v) (2x20 mL). The extracts were combined, washed with Solid was purified by flash column chromatography (silica 10 brine (2x10 mL) and dried over anhydrous MgSO, followed gel, ethyl acetate) to give a pale-yellow solid product, 2.90 by filtration and concentration to give a yellow residue. The g, 90.3% yield. MS: 282.2 M+H". "H NMR (DMSO-d yellow residue was purified by flash column chromatogra 300 MHz): b 8.14 (d. 1H, J=8.7 Hz), 7.39-7.34 (m,3H), 7.19 phy (silica-gel, CHCl/Me?oH=19/1 V/v) to give a white (d. 1H, J=2.4 Hz), 7.13-7.03 (m, 3H), 6.62 (dd. 1H, J–7.5 solid product, 0.44g, 87.0% yield. M. p. C. (decomposed). HZ), 3.89 (s, 3H), 3.81 (s, 3H). 15 MS: m/z 280.0 M+H". "H NMR (DMSO-d 300 MHz) & 10.43 (s, 1H), 9.71 (s, 1H), 8.13 (d. 1H, J=8.7 Hz), 7.41 (s, Example 7: Synthesis of 4-bromo-6-methoxy-2-(4- 1H), 7.24 (d. 2H, J=8.7 Hz), 7.10 (d. 1H, J=2.1 Hz), 7.01 methoxyphenyl)isoquinolin-1 (2H)-one (14a) (dd. 1H, J=8.7 Hz, J-2.1 Hz), 6.88 (dd. 1H, J, =17.4 Hz, J–10.8 Hz), 6.85 (d. 2H, J=8.7 Hz), 5.64 (dd. 1H, J, = 17.4 6-Methoxy-2-(4-methoxyphenyl)isoquinolin-1 (2H)-one Hz, J-1.2 Hz), 5.26 (dd. 1H, J-10.8 Hz, J-1.2 Hz). (0.50 g, 1.78 mmol) was placed in a dry 250 mL single necked round-bottomed flask fitted with a stirring bar and Example 10: Synthesis of 6-methoxy-2-(4-methoxy septa. Acetonitrile (10 mL) was added via a syringe under phenyl)-1-oxo-1,2-dihydroisoquinoline-4-carboni argon atmosphere at room temperature. N-Bromosuccinim trile (14g) ide or NBS (0.33 g, 1.87 mmol) was added portionwise 25 under argon atmosphere at room temperature. The reaction 4-Bromo-6-Methoxy-2-(4-methoxyphenyl)-isoquinolin-1 mixture was allowed to stir at room temperature for 2 hours. (2H)-one (0.80g, 2.22 mmol), Zn(CN) (0.40 g, 3.42 mmol), 20 mL of saturated sodium bicarbonate solution was then tris(dibenzylideneacetone)dipalladium (0.20 g, 0.22 mmol) added. The mixture was extracted with ethyl acetate (3x10 and 1,1'-bis(diphenylphosphino) ferrocene (0.49 g, 0.89 mL). Organic layers were separated, dried over anhydrous 30 mmol) were placed in a dry and argon flushed 150 mL magnesium sulfate and concentrated under vacuum. The three-necked round-bottomed flask fitted with a stirring bar residue was purified by flash column chromatography (silica and reflux condenser. Then, anhydrous dimethylformamide gel, hexanes/EtOAc=2/3 v/v) to give a white solid product, (30 mL) was added via a syringe under argon atmosphere. 0.55g, 85.9% yield. MS: 360.4 M+H". "H NMR (DMSO The reaction solution was stirred and heated to 100° C. for de 300 MHz): 8 8.14 (d. 1H, J=8.7 Hz), 7.39-7.34 (m, 3H), 35 5 hours. Water (30 mL) was added to quench the reaction. 7.19 (d. 1H, J=2.4 Hz), 7.13-7.03 (m, 3H), 6.62 (dd. 1H, The mixture was extracted with ethyl acetate (2x20 mL). J=7.5 Hz), 3.89 (s.3H), 3.81 (s, 3H). The extracts were combined, washed with brine (3x10 mL) and dried over anhydrous MgSO, followed by filtration and Example 8: Synthesis of 4-Bromo-6-hydroxy-2-(4- concentration to give a yellow residue. The yellow residue hydroxyphenyl)isoquinolin-1 (2H)-one (12b) 40 was purified by flash column chromatography (silica-gel, EtOAc/hexanes=1/1 V/v) to give a pale-yellow solid prod 4-Bromo-6-methoxy-2-(4-methoxyphenyl)isoquinolin-1 uct, 0.63 g, 92.6% yield. M.p. C. (decomposed). MS: m/z. (2H)-one (0.22 g, 0.61 mmol) was placed in a dry 150 mL 3.07.0 M+H". "H NMR (DMSO-d 300 MHz) & 8.48 (s, single-necked flask fitted with a stirring bar and septa. 1H), 8.22 (d. 1H, J=9.0 Hz), 7.43 (d. 2H, J=8.7 Hz), 7.27 Methylene chloride (30 mL) was added via a syringe. Boron 45 (dd. 1H, J, =8.7 Hz, J-24 Hz), 7.08 (d. 1H, J=2.4 Hz), 7.06 tribromide (1.83 mL of 1.0 M methylene chloride solution) (d. 2H, J=8.7 Hz), 3.97 (s, 3H), 3.82 (s, 3H). was added dropwise with stirring under argon atmosphere at room temperature. The reaction mixture was allowed to stir Example 11: Synthesis of 6-Hydroxy-2-(4-hydroxy at room temperature for 20 hours. Then, 20 mL of water was phenyl)-1-oxo-1,2-dihydroisoquinoline-4-carboni added to quench the reaction. The mixture was extracted 50 trile (14h) with 50 mL of ethyl acetate. The organic layer was sepa rated, dried over anhydrous magnesium sulfate and concen 6-Methoxy-2-(4-methoxyphenyl)-isoquinoline-4-carbo trated under vacuum. The residue was subjected to flash nitrile (0.45 g, 1.47 mmol) was placed in a dry and argon column chromatography (silica gel, CHCl/MeOH-9/1 flushed 150 mL single-necked round-bottomed flask fitted V/v) to give a white solid product, 0.10 g, 49.4% yield. MS: 55 with a stirring bar and an argon inlet. BBr (9.0 mL of 1.0M 334.2 M+H". "H NMR (DMSO-d 300 MHz): & 10.58 (s, CHC12 solution, 9.0 mmol) was added via a syringe with 1H), 9.83 (s, 1H), 8.12 (d. 1H, J=8.7 Hz), 7.71 (s, 1H), 7.22 stirring at room temperature. After stirred at room tempera (d. 2H, J=8.7 Hz), 7.09 (d. 1H, J–21. Hz), 7.04 (dd. 1H, J, ture for 24 hours, the reaction was quenched by adding 20 =8.7 Hz, J-24 Hz), 6.84 (d. 2H, J=8.7 Hz). mL of water. The solution was stirred at room temperature 60 for one hour, extracted with EtOAc (3x20 mL). The organic Example 9: Synthesis of 6-hydroxy-2-(4-hydroxy layers were separated, combined and dried over anhydrous phenyl)-4-vinylisoquinolin-1 (2H)-one (14f) MgSO. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica 4-Bromo-6-hydroxy-2-(4-hydroxyphenyl)-isoquinolin-1 gel, CHC1/MeoH=9/1 V/v) to give a white solid product, (2H)-one (0.60 g, 1.81 mmol), tetrakis(triphenylphosphine) 65 0.28g, 68.5% yield. M.p. C. (decomposed). MS: m/z 279.0 palladium (42 mg 0.036 mmol), potassium carbonate (0.25 M+H". "H NMR (DMSO-de, 300 MHz) & 10.86 (s, 1H), g, 1.81 mmol) and vinylboronic anhydride pyridine complex 9.80 (s, 1H), 8.38 (s, 1H), 8.13 (d. 1H, J=8.7 Hz), 7.25 (d. US 9,623,021 B2 129 130 2H, J=8.7 Hz), 7.09 (dd. 1H, J=8.7 Hz, J-2.4 Hz), 7.04 (d. N-bromosuccinimide (0.15g, 0.86 mmol) were placed in a 1H, J–2.4 Hz), 6.85 (d. 2H, J=8.7 Hz). dry, argon flushed 150 mL single-necked flask fitted with a stirring bar and sealed with a rubber stopper. Acetonitrile (10 Example 12: Synthesis of 6-methoxy-2-(4-methoxy mL) was added via a syringe at room temperature under phenyl)-1-oxo-1,2-dihydroisoquinolin-8-yl trifluo argon atmosphere. After the mixture was stirred at room romethanesulfonate (14d) temperature for 4 hours, the solvent was removed under reduced pressure. The residue was purified by flash column 8-Hydroxy-6-methoxy-2-(4-methoxyphenyl)isoquinolin chromatography (silica-gel, hexanes/EtOAc=2/3 v/v) to 1(2H)-one (2.10 g, 7.06 mmol) was dissolved in 30 mL of give a white solid product, 0.23 g, 83.3% yield. M.p. C. anhydrous dimethylformide in a 250 mL three-necked 10 (decomposed). MS: m/z 387.1 M+H". "H NMR (DMSO round-bottomed flask fitted with a magnetic stirring bar, an de 300 MHz) & 8.01 (s, 1H), 7.81 (d. 1H, J=2.4 Hz), 7.43 argon inlet and sealed with rubber stoppers. The solution (d. 1H, J=2.4 Hz), 7.42 (d. 2H, J=8.7 Hz), 7.07 (d. 2H, J=8.7 was cooled to 0°C. in an ice-bath. Sodium hydride (0.37g Hz), 4.02 (s, 3H), 3.82 (s, 3H). of 60% wt. in mineral oil, 9.18 mmol) was added in 4 portions under argon atmosphere. The reaction mixture was 15 Example 15: Synthesis of 4-bromo-6-hydroxy-2-(4- stirred at 0°C. for 30 minutes, than at room temperature for hydroxyphenyl)-1-oxo-1,2-dihydroisoquinoline-8- 30 minutes. After the solution was cooled to 0° C. again, carbonitrile (14k) N-phenyl-bis (trifluoromethanesulfonamide) (2.65 g, 7.41 mmol) was added in portions under argon protection. The 4-Bromo-6-methoxy-2-(4-methoxyphenyl)-1-oxo-1,2-di reaction mixture was stirred at 0° C. for 30 minutes and at hydroisoquinoline-8-carbonitrile (0.15 g, 0.39 mmol) was room temperature for one hour. The reaction was quenched placed in a dry and argon flushed 100 mL single-necked by adding 50 mL of Saturated ammonia chloride solution, round-bottomed flask fitted with a stirring bar, reflux con and diluted with 50 mL of water. The solution was extracted denser and an argon inlet. Anhydrous chlorobenzene (10 with ethyl acetate (3x50 mL). The organic layers were mL) was added via a syringe at room temperature. BBr separated, combined, washed with brine, dried over anhy 25 (0.59, 2.33 mmol) was added via a syringe with stirring at drous MgSO filtered and concentrated under reduced pres room temperature. The resulting solution was heated to 120° Sure. The residue was purified by flash column chromatog C. for 4 hours. 10 mL of water was added to quench the raphy (silica gel, hexanes/EtOAc=1/1 V/v) to give a white reaction. After stirred at room temperature for one hour, the solid product, 2.85g. 94.1% yield. M.p. C. (decomposed). solution was extracted with EtOAc (5x20 mL). The organic MS: m/z 452.1 M+Na)". "H NMR (DMSO-de, 300 MHz) 30 layers were combined and dried over anhydrous MgSO. & 7.52 (d. 1H, J–7.2 Hz), 7.38 (d. 1H, J=2.4 Hz), 7.34 (d. 2H, The solvent was removed under reduced pressure. The J=9.0 Hz), 7.07 (d. 2H, J=9.0 Hz), 7.02 (d. 1H, J=1.8 Hz), residue was purified by column chromatography (silica-gel, 6.72 (d. 1H, J–7.5 Hz), 3.94 (s, 3H), 3.82 (s, 3H). CHCl/Me?oH=9/1 V/v) to give a white solid product, 0.05g, 36.0% yield. M.p. C. (decomposed). MS: m/z,357.1 Example 13: Synthesis of 6-methoxy-2-(4-methoxy 35 M+H". "H NMR (DMSO-de, 300 MHz) & 11.40 (s, 1H), phenyl)-1-oxo-1,2-dihydroisoquinoline-8-carboni 9.79 (s, 1H), 7.91 (s, 1H), 7.48 (d. 1H, J=2.1 Hz), 7.38 (d. trile (14i) 1H, J=2.1 Hz), 7.26 (d. 2H, J=8.7 Hz), 6.86 (d. 2H, J=8.7 Hz). 6-Methoxy-2-(4-methoxyphenyl)-1-oxo-1,2-dihydroiso quinolin-8-yl trifluoromethanesulfonate (0.43 g, 1.00 40 Example 16: Synthesis of 4-bromo-6-hydroxy-2-(4- mmol), Zn(CN) (0.14g, 1.20 mmol), tris(dibenzylideneac hydroxyphenyl)isoquinolin-1 (2H)-one (12b) etone)dipalladium (92 mg, 0.1 mmol) and 1,1'-bis(diphenyl phosphino)ferrocene (0.22g, 0.40 mmol) were placed in a 4-Bromo-6-methoxy-2-(4-methoxyphenyl)isoquinolin-1 dry and argon flushed 150 mL three-necked round-bottomed (2H)-one (14q) was prepared as described above. 14q was flask fitted with a stirring bar and reflux condenser. Then, 45 placed in a dry 150 mL single-necked flask fitted with a anhydrous dimethylformide (20 mL) was added via a stirring bar and septa. Chlorobenzene (30 mL) was added via Syringe under argon atmosphere. The reaction solution was a syringe. Boron tribromide (6 equivalents, neat) was added stirred and heated to 100° C. for 4 hours. Water (20 mL) was dropwise with stirring under argon atmosphere at room added to quench the reaction. The mixture was extracted temperature. The reaction mixture was allowed to stir at with ethyl acetate (4x30 mL). The extracts were combined, 50 room temperature for 20 hours. Then, 20 mL of water was washed with brine (3x10 mL) and dried over anhydrous added to quench the reaction. The mixture was extracted MgSO, followed by filtration and concentration to give a with 50 mL of ethyl acetate. The organic layer was sepa yellow residue. The yellow residue was purified by flash rated, dried over anhydrous magnesium Sulfate and concen column chromatography (silica-gel, EtOAC/hexanes 3/2 trated under vacuum. The residue was subjected to flash V/v) to give a white solid product, 0.23 g, 75.2% yield. M.p. 55 column chromatography (silica gel, CHCl/MeOH=9/1 ° C. (decomposed). MS: m/z 3.07.2 M+H". "H NMR V/v) to give a white solid product, 0.10 g, 49.4% yield. MS: (DMSO-d 300 MHz) & 7.63 (d. 1H, J=2.1 Hz), 7.54 (d. 1H, 334.2 M+H. 'H NMR (DMSO-d 300 MHz): & 10.58 (s, J=2.1 Hz), 7.51 (d. 1H, J=7.5 Hz), 7.38 (d. 2H, J=8.7 Hz), 1H), 9.83 (s, 1H), 8.12 (d. 1H, J=8.7 Hz), 7.71 (s, 1H), 7.22 7.06 (d. 2H, J=8.7 Hz), 6.71 (d. 1H, J=7.5 Hz), 3.95 (s.3H), (d. 2H, J=8.7 Hz), 7.09 (d. 1H, J–21. Hz), 7.04 (dd. 1H, 3.82 (s, 3H). 60 J–8.7 Hz, J-2.4 Hz), 6.84 (d. 2H, J–8.7 Hz). Example 14: Synthesis of 4-bromo-6-methoxy-2-(4- Example 17: Synthesis of 4-bromo-2-(4-hydroxy methoxyphenyl)-1-oxo-1,2-dihydroisoquinoline-8- phenyl)-6-methoxy-isoquinolin-1 (2H)-one (12c) carbonitrile (14i) 65 4-Bromo-6-methoxy-2-(4-methoxyphenyl)isoquinolin-1 Compound 6-methoxy-2-(4-methoxyphenyl)-1-oxo-1,2- (2H)-one (14q) was prepared as described above. 14q was dihydroisoquinoline-8-carbonitrile (0.22 g, 0.72 mmol) and placed in a dry 150 mL single-necked flask fitted with a US 9,623,021 B2 131 132 stirring bar and septa. Chlorobenzene (30 mL) was added via Example 20: Synthesis of 1-(2-(piperidin-1-yl) a syringe. Boron tribromide (3 equivalents, neat) was added ethoxy)isoquinolin-6-ol (13a) dropwise with stirring under argon atmosphere at room temperature. The reaction mixture was allowed to stir at room temperature for 20 hours. Then, 20 mL of water was added to quench the reaction. The mixture was extracted with 50 mL of ethyl acetate. The organic layer was sepa SOCI rated, dried over anhydrous magnesium sulfate and concen 21 O - B - trated under vacuum. The residue was subjected to flash H3CO CHCl2 10 column chromatography (silica gel, CHCl2/MeCH=9/1 O V/v) to give a white solid product, 0.10 g, 49.4% yield. MS: 334.2 M+H". "H NMR (DMSO-d 300 MHz): & 10.58 (s, 21 C - N - 1H), 9.83 (s, 1H), 8.12 (d. 1H, J=8.7 Hz), 7.71 (s, 1H), 7.22 HCO Dioxane, H2O (d. 2H, J=8.7 Hz), 7.09 (d. 1H, J–21. Hz), 7.04 (dd. 1H, 15 J–8.7 Hz, J-2.4 Hz), 6.84 (d. 2H, J–8.7 Hz). O

Example 18: Synthesis of 6-methoxy-2-(4-methoxy 2 N PhO, BuN phenyl)-4-phenylisoquinolin-1 (2H)-one HCO 230° C. 4-Bromo-6-methoxy-2-(4-methoxyphenyl)-isoquinolin-1 O (2H)-one (0.52g, 1.44 mmol), tetrakis(triphenylphosphine) palladium (8.3 mg, 0.07 mmol), potassium carbonate (0.22g, O NH —Y\-Nus S 1.00 mmol) and phenylboronic acid (0.21 g, 1.73 mmol) 25 K2CO3/Acetone were placed in a dry and argon flushed 150 mL three-necked reflux round-bottomed flask fitted with a stirring bar and reflux HCO 21 condenser. 1,2-Dimethoxyethane (10 mL) and water (3 mL) were added via a syringe under argon atmosphere. The reaction solution was stirred and heated to reflux for 20 30 N hours. The reaction was quenched by adding 30 mL of water at room temperature. The mixture was extracted with ethyl ? BBr3 acetate (3x20 mL). The extracts were combined, washed O CHCl2 with brine (2x10 mL) and dried over anhydrous MgSO and 35 2 g of 3-(diethylenetriamino)propylfunctionalized silical gel N N followed by filtration and concentration to give a yellow residue. The yellow residue was purified by flash column chromatography (silica-gel, hexanes/ethyl acetate-2/3 V/v) H3CO 2 to give a white solid product, 0.50 g., 98.0% yield. MS: m/z. 358.3 M+H". "H NMR (DMSO-de, 300 MHz) & 8.30 (d. 40 2H, J=9.0 Hz), 7.55-7.40 (m, 8H), 7.29 (s. 7.21 (dd. 1H, J=9.0 Hz, J-2.4 Hz), 7.05 (d. 2H, J=9.0 Hz), 6.94 (d. 1H, J=2.4 Hz), 3.81 (s, 3H), 3.78 (s, 3H). ? N O 45 Example 19: Synthesis of 6-hydroxy-2-(4-hydroxy n N phenyl)-4-phenylisoquinolin-1 (2H)-one (15a) HO 2 6-Methoxy-2-(4-methoxyphenyl)-4-phenylisoquinolin-1 50 (2H)-one (0.36 g, 1.01 mmol) was placed in a dry 150 mL 13a single-necked flask fitted with a stirring bar and septa. Methylene chloride (30 mL) was added via a syringe. Boron tribromide (5.0 mL of 1.0 M methylene chloride solution) Synthesis of 6-methoxyisoquinoline-1-ol was added dropwise with stirring under argon atmosphere at 55 room temperature. The reaction mixture was allowed to stir A mixture of 17.82 g (0.10 mol) of trans-3-methoxycin at room temperature for 16 hours. Then, 20 mL of water was namic acid and thionyl chloride (14.28 g., 0.12 mol) were added to quench the reaction. The mixture was extracted placed in a 250 mL single-necked round-bottomed flask with ethyl acetate (3x20 mL). The organic layers were fitted with a stirring bar and reflux condenser. 80 mL of dry separated, dried over anhydrous magnesium sulfate and 60 methylene chloride was added to the flask. The resulted concentrated under vacuum. The residue was subjected to mixture was heated to reflux for 3 hours. Then, the solvent flash column chromatography (silica gel, CH2Cl2/ was removed under reduced pressure. The residue oil was MeOH=9/1 v/v) to give a white solid product, 0.29 g, 87.9% dried under vacuum overnight. The pale-yellow solid acid yield. MS: 330.2 M+H". "H NMR (DMSO-de, 300 MHz): chloride was dissolved in 20 mL of 1,4-dioxane and added & 10.31 (s, 1H), 9.69 (s, 1H), 8.19 (d. 1H, J=8.7 Hz), 65 dropwise with stirring to a 0° C. suspension of 19.50 g (0.30 7.52-7.39 (m, 5H), 7.28 (d. 2H, J=8.7 Hz), 7.18 (s, 1H), 7.00 mol) of sodium azide in 80 mL of 1,4-dioxane/water (1:1 (dd. 1H, J=8.7 Hz, J-2.4 Hz), 6.87-6.82 (m, 3H). mixture). During the addition the temperature was main