(19) & (11) EP 2 455 362 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 23.05.2012 Bulletin 2012/21 C07C 233/65 (2006.01) A61K 31/165 (2006.01) C07D 221/12 (2006.01) A61K 31/55 (2006.01) (2006.01) (2006.01) (21) Application number: 12150818.8 A61K 31/445 A61K 31/40 A61K 31/138 (2006.01) (22) Date of filing: 28.11.2006 (84) Designated Contracting States: • Hong, Seoung-Soo AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Collierville, Tennessee 38017 (US) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • Miller, Duane, D. SK TR Germantown, Tennessee 38139 (US) Designated Extension States: • Mohler, Michael, L. AL BA HR MK RS Memphis, Tennessee 38134 (US) • Narayanan, Ramesh (30) Priority: 28.11.2005 US 73989805 P Cordova, Tennessee 38018 (US) • Wu, Zhongzhi (62) Document number(s) of the earlier application(s) in Memphis, Tennessee 38107 (US) accordance with Art. 76 EPC: 06838432.0 / 1 954 670 (74) Representative: Lord, Hilton David Marks & Clerk LLP (71) Applicant: GTX, Inc. 90 Long Acre Memphis, TN 38163 (US) London WC2E 9RA (GB) (72) Inventors: • Dalton, James, T. Remarks: Upper Arlington, Ohio 43220 (US) This application was filed on 11-01-2012 as a • Barrett, Christina divisional application to the application mentioned Oakland, Tennessee 38060 (US) under INID code 62. • He, Yali Germantown, Tennessee 38139 (US) (54) Nuclear receptor binding agents (57) The present invention relates to a novel class of as prostrate and breast cancer, osteoporosis, hormone- selective estrogen receptor modulators (SERMs). The related diseases, hot flashes or vasomotor symptoms, SERM compounds are applicable for use in the preven- neurological disorders, cardiovascular disease and tion and/or treatment of a variety of diseases and condi- obesity. tions including prevention and treatment of cancers such EP 2 455 362 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 455 362 A1 Description FIELD OF THE INVENTION 5 [0001] The present invention relates to a novel class of nuclear receptor binding agents (NRBAs). The NRBA com- pounds are applicable for use in the prevention and/or treatment of a variety of diseases and conditions including, inter alia, prevention and treatment of hormone-related diseases, cancers, inflammation, osteoporosis, peripheral vascular disease, neurological disorders, ocular disorders, cardiovascular disease and obesity. 10 BACKGROUND OF THE INVENTION [0002] The nuclear hormone receptor superfamily of ligand activated transcription factors is present in various tissues, and responsible for a multitude of effects in these tissues. [0003] The nuclear receptor (NR) superfamily presently comprises approximately 48 different proteins, most of which 15 are believed to function as ligand activated transcription factors, exerting widely different biological responses by regu- lating gene expression. Members of this family include receptors for endogenous small, lipophilic molecules, such as steroid hormones, retinoids, vitamin D and thyroid hormone. [0004] The nuclear receptor (NR) superfamily includes the steroid nuclear receptor subfamily, such as the mineralo- corticoid receptor (MR) (or aldosterone receptor), the estrogen receptors (ER), ER alpha and ER beta, the androgen 20 receptor (AR), the progesterone receptors (PR), glucocorticoid receptors (GR) and others. Also closely related in structure are the estrogen related receptors (ERRs) ERR-alpha, ERR-beta and ERR-gamma. The steroid nuclear receptors perform important functions in the body some of which are related to the transcriptional homeostasis of electrolyte and water balance, growth, development and wound healing, fertility, stress responses, immunological function, and cognitive functioning. The effects may be mediated by cytosolic or nuclear events. The effects may be mediated by cytosolic or 25 nuclear events. Accordingly, compounds that modulate (i.e. antagonize, agonize, partially antagonize, partially agonize) the activity of steroid nuclear receptors are important pharmaceutical agents that have specific utility in a number of methods, as well as for the treatment and prevention of a wide range of diseases and disorders modulated by the activity of steroid nuclear receptors. [0005] Members of the steroid nuclear receptor sub-family exhibit significant homology to each other and possess 30 closely related DNA and ligand binding domains. [0006] Given the close similarity in ligand binding domains of the steroid nuclear receptors, it is not surprising that many naturally occurring and synthetic molecules possess the ability to modulate the activity of more than one steroid nuclear receptor. 35 SUMMARY OF THE PRESENT INVENTION [0007] In one embodiment, this invention provides a nuclear receptor binding agent (NRBA), which in one embodiment is a selective estrogen receptor modulator (SERM) compound or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, N-oxide, ester, hydrate or any 40 combination thereof, represented by the structure of formula I: 45 50 wherein 55 X is CO, CS, (CH2)q, branched alkyl, branched alkyl with haloalkyl side chain, haloalkyl, C(O)(CH2)q, SO, or SO2; R1, R2 and R 3 are independently, hydrogen, halogen, aldehyde, COOH, CHNOH, CH=CHCO 2H, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, 3CF, NH2, NHR, NHCOR, N(R)2, sulfonamide, SO2R, alkyl, aryl, protected hydroxyl, OCH2CH2NR4R5, Z-Alk-Q, Z-Alk-NR4R5, Z-Alk-heterorycle or OCH2CH2-heterocycle in which the heterocycle is a 3-7 2 EP 2 455 362 A1 membered substituted or unsubstituted heterocyclic ring, optionally aromatic, or R 1 R2 or R 3 together with the benzene ring to which the R- group is attached comprises a fused ring system represented by structure A 5 10 wherein; R6 and R7 are independently R1, R2 or R3; R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, CN, 15 NO2, or OH; R4 and R5 are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 membered heterocycloalkyl, or a 3 to 7 membered heteroaryl group; Z is O, NH, CH2 or 20 25 Q is SO3H, CO2H, CO2R, NO2, tetrazole, SO2NH2 or SO2NHR; j, k, l are independently 1-5; q is 1-5; Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons; and if X is (CH2)q, CO or C(O)(CH2)q, and R2 is OCH2CH2NR4R5, or OCH2CH2-heterocycle when k is 1, then R1 or R3 is 30 not hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino; if X is (CH2)q, CO or C(O)(CH2)q, aud R3 is OCH2CH2NR4R5, or OCH2CH2-heterocycle when 1 is one, then R1 or R2 is not hydrogen, lower alkyl (1-4 carbons), lower alkoxy (1-4 carbons), halogen, nitro or amino. [0008] In one embodiment, this invention provides a NRBA, which in one embodiment is a SERM compound or its prodrug, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, 35 crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula I: 40 45 wherein 50 X is CS, branched alkyl, branched alkyl with haloalkyl side chain, haloalkyl, SO, or SO2; R1, R2 and R 3 are independently, hydrogen, halogen, aldehyde, COOH, CHNOH, CH=CHCO 2H, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, 3CF, NH2, NHR, NHCOR, N(R)2, sulfonamide, SO2R, alkyl, aryl, protected hydroxyl, OCH2CH2NR4R5, Z(CH2)qQ, Z-Alk-NR4R5, Z-Alk-heterocycle or OCH2CH2-heterocycle in which the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic; 55 or R 1, R 2 or R 3 together with the benzene ring to which the R- group is attached comprises a fused ring system represented by structure A 3 EP 2 455 362 A1 5 wherein R6 or R7 are independently R1, R2 or R3; R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, halogen, alkenyl, CN, 10 NO2, or OH; R4 and R5 are independently hydrogen, phenyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 membered cycloalkyl, a 3 to 7 membered heterocycloalkyl, or a 3 to 7 membered heteroaryl group; Z is O, NH, CH2, or 15 Q is SO3H, CO2H, CO2R, NO2, tetrazole, SO2NH2, or SO2NHR; 20 j, k, 1 are independently 1-5; q is 1-5; Alk is linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons or cyclic alkyl of 3-8 carbons. [0009] In one embodiment this invention provides a NRBA, which in one embodiment is a SERM compound or its prodrug, analog, isomer, metabolite, derivative, Pharmaceutically acceptable salt, pharmaceutical product, polymorph, 25 crystal, impurity, N-oxide, ester, hydrate or any combination thereof, represented by the structure of formula II: 30 35 40 X is CO, CS, (CH2)q, branched alkyl, branched alkyl with haloalkyl side chain, haloalkyl, C(O)(CH2)q, SO, or SO2; R1, R2 and R 3 are independently, hydrogen, halogen, aldehyde, COOH, CHNOH, CH=CHCO 2H, hydroxyalkyl, hydroxyl, alkoxy, cyano, nitro, 3CF, NH2, NHR, NHCOR, N(R)2, sulfonamide, SO2R, alkyl, aryl, protected hydroxyl, OCH2CH2NR4R5, Z-Alk-Q, Z-Alk-NR4R5, Z-Alk-heterocycle or OCH2CH2-heterocycle in which the heterocycle is a 3-7 membered substituted or unsubstituted heterocyclic ring, optionally aromatic, 45 or R 1, R 2 or R 3 together with the benzene ring to which the R- group is attached comprises a fused ring system represented by structure A 50 55 wherein R6 and R7 are independently R1, R2 or R3; R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl,