WO2018175965A1 - Anti-œstrogènes de thérapie du cancer du sein - Google Patents

Anti-œstrogènes de thérapie du cancer du sein Download PDF

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WO2018175965A1
WO2018175965A1 PCT/US2018/024144 US2018024144W WO2018175965A1 WO 2018175965 A1 WO2018175965 A1 WO 2018175965A1 US 2018024144 W US2018024144 W US 2018024144W WO 2018175965 A1 WO2018175965 A1 WO 2018175965A1
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Prior art keywords
methyl
adamantan
ylidene
hydroxyphenyl
phenyl
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PCT/US2018/024144
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English (en)
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John A. Katzenellenbogen
Benita KATZENELLENBOGEN
Jian MIN
Sung Hoon Kim
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The Board Of Trustees Of The University Of Illinois
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Publication of WO2018175965A1 publication Critical patent/WO2018175965A1/fr

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    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
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    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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    • C07C243/30—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
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    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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Definitions

  • antiestrogens are able to suppress the agonist activity of ERa is needed so that better compounds can be developed, and it is likely that new agents that are more potent and efficacious inhibitors of wild type ERa (WT-ERa) will also show greater effectiveness in inhibiting the growth of breast cancers driven by ERa with activating mutations and displaying resistance to current standard of care treatments.
  • WT-ERa wild type ERa
  • antiestrogens can be thought to consist of a ligand core element that is accommodated within the ligand-binding pocket (LBP) and provides robust binding affinity, onto which is appended a side chain that extends outward from the ligand binding domain (LBD) and whose function is to disrupt the agonist activity of the receptor by mispositioning helix-12 studied thoroughly.
  • LBP ligand-binding pocket
  • LBD ligand binding domain
  • Antiestrogens of the selective ER modulator (SERM) class like tamoxifen, raloxifene, lasofoxifene, and bazedoxifene, have structurally distinct aromatic-rich, non-steroidal cores but very similar positively charged basic side chains (FIG. 1). By forming strong charge- charge interactions with D351, these basic side chains displace hl2, causing it to be repositioned into the hydrophobic groove into which coactivators bind in ER-agonist complexes.
  • SERM selective ER modulator
  • FIG. 1 An alternative antiestrogen design, first exemplified in 1994 on the tamoxifen core structure in compounds from Glaxo-SmithKline (GSK), GW-5638 and GW-7604, has an acrylic acid as a functional side chain (FIG. 1) (11, 12). This side chain, which also moves hl2 to block the coactivator binding groove, has been replicated without any change in two orally active antiestrogens currently in clinical development, AZD-9496 and GDC-0810 (FIG. 1) (13, 14).
  • SERDs for selective ER downregulators
  • fulvestrant a steroid onto which is appended a long, largely hydrophobic side chain at the 7a position.
  • SERD activity is also found with the GSK, AZD, and GDC compounds mentioned above. Because of its very poor oral bioavailability, fulvestrant needs to be administered by painful intramuscular injection, and even this does not provide sufficiently high blood levels of drug to fully occupy ER in tumors.
  • the present invention provides compounds or a pharmaceutically acceptable salt thereof and the methods and compositions disclosed herein for treating breast cancer.
  • the invention provides compounds or compositions of formula (I), or a pharmaceutically acceptable salt thereof,
  • G is an optionally substituted polycycloalkylidene
  • Xi, X 2 , X 3 , and X 4 are each independently N, CH, or CR m , wherein at most two of Xi, X 2 , X 3 , and X 4 are N, and wherein at most one of Xi and X 4 is N;
  • Y is alkyl, -OR A , -COOR B , -N(R C )(R D ), -CON(R c )(R D ), -N(R c )-OH,
  • R p and R m at each occurrence are independently alkyl, alkoxy, halogen, -OH, -CN, haloalkyl, or hydroxyalkyl;
  • p O, 1, 2, 3, 4, or 5;
  • Q 1 and Q 2 are O, H, or S;
  • Q 3 is an optionally substituted cycloalkylene
  • R A , RB , RC ⁇ , and R D" at each occurrence are independently hydrogen, alkyl, cycloalkyl, aryl, heterocycle, heteroaryl, or alkyl substituted by one or more substituents selected from the group consisting of -OH, - H 2 , - H(Ci- 4 alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, phenyl, and -NHCO-R 2 , wherein the cycloalkyl, aryl, heterocycle, and heteroaryl are each optionally substituted;
  • R x and R y at each occurrence are independently hydrogen, alkyl, halogen, haloalkyl, or -CN;
  • R z is -OCi -4 alkyl, cycloalkyl or -Ci- 4 alkylene-cycloalkyl.
  • Another aspect of the present invention provides a compound or composition of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating or preventing breast cancer. Also provided is a compound or composition of formula (I), or a pharmaceutically acceptable salt thereof, for use in inhibiting or slowing the growth of estrogen receptor-positive, endocrine therapy-sensitive tumors or endocrine therapy resistant tumors driven by active estrogen receptors. Also provided is use of a compound or composition of formula (I), or a pharmaceutically acceptable salt thereof, for manufacturing a medicament for treating or preventing breast cancer.
  • Another aspect of the invention provides a method of treating breast cancer comprising administering to a subject in need thereof, a therapeutically effective amount of a compound or composition of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or medicament thereof.
  • Another aspect of the invention provides a method for inhibiting or slowing the growth of estrogen receptor-positive, endocrine therapy-sensitive tumors or endocrine therapy resistant tumors driven by active estrogen receptors comprising administering to a subject, in need thereof, a therapeutically effective amount of a compound or composition of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or medicament thereof.
  • FIG. 1 Evolutionary Design of Antiestrogen Cores and Side Chains. The direction upward from the GW-7604 structure is taken in the present disclosure; the direction downward is that taken by Genentech and AstraZeneca.
  • FIG. 2 Detail of Crystal Structure of GW-5638-ERa LBD Complex. This structure shows that one of the interactions between the carboxylate in GW-5638 and the N-terminus of hl2 is mediated through a water molecule. (PDB code: 1R5K).
  • FIG. 3 Binding affinities of isostructural esters and amines terminated either with a methyl, hydroxyl or amino group.
  • FIG. 4A Star plots of the antiproliferative efficacy (solid line) and ERa
  • FIG. 4B Star plots of the antiproliferative efficacy (solid line) and ERa
  • FIG. 4C Star plots of the antiproliferative efficacy (solid line) and ERa
  • FIG. 5 Dose Response Curves for Antiproliferative Activities of Selected
  • FIG. 6A Dose-response curves from in-cell Western blots of ERa downregulating activities of selected compounds. IC 50 values are extracted from this experiment.
  • FIG. 6B In-cell Western blots used for dose-response measurements of FIG. 6 A.
  • FIG. 7 A Dose-response suppression of E2-stimulated expression of GREB 1 by antiestrogen ligands.
  • FIG. 7B Dose-response suppression of E2-stimulated expression of PgR by antiestrogen ligands.
  • FIG. 7C Dose-response suppression of E2-stimulated expression of pS2 by antiestrogen ligands.
  • FIG. 8 Correlation between Suppression of Cellular Proliferation and ERa
  • FIG. 9 Conformational Preferences of Esters, and Secondary and Tertiary Amides. Both esters and secondary amides prefer an extended conformation due to ⁇ - ⁇ * or ⁇ - ⁇ * ⁇ - overlap, respectively. The tertiary amides have no such electronic preference.
  • FIG. 10A Structures of three Antiestrogens (AE), compounds 5(K-07), 21(K-09), and 32(K-62).
  • FIG. 10B Cell viability of T47D cells with WT-ERa, Y537S-ERa or D538G-ERa cultured in E2-deprived conditions and compounds 5, 21, and 32 at 3xl0 "6 M for 6 days. Values are the mean ⁇ SD of 3 determinations from 3 separate experiments.
  • FIG. IOC Cell viability of T47D cells with WT-ERa, Y537S-ERa or D538G-ERa cultured with E2 (3xl0 "9 M) and compounds 5, 21, and 32 at 3xl0 "6 M for 6 days. Values are the mean ⁇ SD of 3 determinations from 3 separate experiments.
  • FIG. 11 Dose-dependent inhibition of T47D cell proliferation by AEs: D538G-ERa is more effectively suppressed by AEs vs. Y537S-ERa.
  • T47D cells with WT- ERa, Y537S- ERa or D538G-ERa were cultured under estrogen-deprived conditions (in phenol red-free medium with 5% charcoal dextran-treated serum). They were treated with ligands at the concentrations indicated (3xl0 "u to 3xl0 "6 M) and cell proliferation was monitored after 6 days. Values are mean ⁇ SD of 3 determinations from 3 separate experiments.
  • FIG. 12A The results are mean ⁇ SD of 3 determinations from 3 separate experiments.
  • FIG. 12 B Effects of E2 ligands of the expression of the ER target gene PGR monitored after T47D cell treatments with Veh, E2 and ligands for 24 h followed by RNA extraction and qPCR analysis.
  • Solid line (set at 1) indicates mRNA expression in Veh-treated WT T47D cells, and dashed line indicates mRNA expression level in E2 -treated cells. Values are the mean ⁇ SD of 3 determinations from 2 separate experiments.
  • FIG. 13 Differences in the ability of compounds to induce the degradation of WT or mutant ERa protein in T47D cells.
  • T47D cells were treated with Control Vehicle, E2 or compounds alone for 24 h at the concentrations indicated, and cells were subjected to in cell Western (ICW) blot analysis for evaluation of ERa protein levels.
  • ICW cell Western
  • FIG. 14 A New AEs show good growth suppression of MCF7 xenograft tumors and inhibition of estrogen target gene expression.
  • FIG. 14B NSG mice were supplemented with E2 (0.36mg, 60-day release) pellets, injected with WT MCF7 cells to generate xenograft tumors, and dosed with 80mg/kg of Fulv, K- 07, K09 or K-62 by daily sc injection. On the final day of treatment, tumor volumes were compared.
  • Multiple plasma samples were collected from each mouse (n 4 for each experiment) over the course of 48 h after compounds were administered. Compounds were quantified using LC-MS/MS. The data were fitted to a non-compartment PK model.
  • FIG. 16A Antitumor efficacy of orally administered K-07 and suppression of estrogen target gene expression in tumors.
  • FIG. 16B Antitumor efficacy of orally administered K-07 and suppression of estrogen target gene expression in tumors.
  • FIG. 16C Antitumor efficacy of orally administered K-07 and suppression of estrogen target gene expression in tumors.
  • FIG. 17A Y537S- and D538G-containing tumors grow in the absence of estrogen and are arrested by K-07 treatment.
  • NSG mice were ovariectomized and 3 weeks later received MCF7 cells containing only wild type (WT) ER or MCF7 cells containing half Y537S ER or D538G ER and half wild type ER.
  • FIG. 17B Y537S- and D538G-containing tumors grow in the absence of estrogen and are arrested by K-07 treatment.
  • NSG mice were ovariectomized and 3 weeks later received MCF7 cells containing only wild type (WT) ER or MCF7 cells containing half Y537S ER or D538G ER and half wild type ER. Mice were then given daily sc injection with Vehicle or 80mg/kg of K-07 or Fulv. After 28 days, tumors were compared in size.
  • FIG. 17C Y537S- and D538G-containing tumors grow in the absence of estrogen and are arrested by K-07 treatment.
  • NSG mice were ovariectomized and 3 weeks later received MCF7 cells containing only wild type (WT) ER or MCF7 cells containing half Y537S ER or D538G ER and half wild type ER. Mice were then given daily sc injection with Vehicle or 80mg/kg of K-07 or Fulv. Animal body weights were monitored.
  • FIG. 17D Y537S- and D538G-containing tumors grow in the absence of estrogen and are arrested by K-07 treatment.
  • FIG. 18 Dose-dependent inhibition of the growth of T47D cells by antiestrogen compounds with WT or mutant-ERa in tissue culture medium with 5% fetal bovine serum and 3xl0 "10 M E2.
  • T47D cells with WT, Y537S- or D538G-ERa were cultured in E2-containing media, and were treated with E2 (3xl0 "9 M) or compounds at the concentrations indicated (3x10 " 11 to 3xl0 "6 M) for 6 days.
  • Cell viability values are mean ⁇ SD of 3 determinations from 3 separate experiments.
  • FIG. 19A Compounds suppress proliferation of breast cancer cells with heterozygous levels of mutant Y537S ERa.
  • MCF-7 or T47D cells containing 50% mutant ERa and 50% wild type ERa were treated with E2 or compounds alone for 6 days at the concentrations indicated and cell viability was measured. Values are mean ⁇ SD from 3 determinations from 3 separate experiments.
  • FIG. 19B Compounds suppress proliferation of breast cancer cells with heterozygous levels of mutant D538G ERa.
  • MCF-7 or T47D cells containing 50% mutant ERa and 50% wild type ERa were treated with E2 or compounds alone for 6 days at the concentrations indicated and cell viability was measured. Values are mean ⁇ SD from 3 determinations from 3 separate experiments.
  • FIG. 20 Compounds induce degradation of ERa in MCF-7 and T47D breast cancer cells containing half mutant and half wild type ERa.
  • ICW assay of ERa was performed in breast cancer cells treated for 24 h with Control Vehicle, E2 or compounds alone at the concentrations indicated.
  • FIG. 21 Suppression of ERa-regulated gene expressions in MCF-7 and T47D breast cancer cells containing half mutant and half wild type ERa. After 24 h of Control Vehicle, E2 or compound treatment, cells were harvested and processed for qPCR analysis of the ERa-regulated genes GREB 1 and PGR. Fold change of mRNA level was calculated relative to the vehicle treated cell samples, set at 1.
  • FIG. 23 Effect of certain disclosed compounds on MCF-7 cell proliferation at 3 ⁇ .
  • the activity in suppressing cell proliferation was calculated as a percent of vehicle control; maximum suppression is ca. 0% (corresponding to essentially no increase in cell number after 6 days). All assays were performed in triplicates, the values are the average of two to three independent experiments.
  • FIG. 24 In-cell western blotting for certain disclosed compounds at 3 ⁇ .
  • the value of 0% represents the ERa level after 24 h with 3 ⁇ fulvestrant treatment, the value of 100% represents the ERa level in vehicle control cells.
  • the values are the average from at least three independent experiments.
  • FIG. 25 Crystal structure of GW-5638-ERa LBD complex.
  • the left-side panel shows an overlay of the ERa LBD complex with hydroxytamoxifen (OHT; blue color for hi 2, OHT, and arrow) and with GW-5638 (yellow color for hl2, GW, and arrow).
  • OHT hydroxytamoxifen
  • GW-5638 yellow color for hl2, GW, and arrow
  • the differing orientation of hl2 is evident in the two structures.
  • the right-side panel shows the interaction of the carboxylate in GW-5638 with the N-terminus of hl2.
  • PDB code 1R5K One of the interactions between these two units is mediated through a structural water molecule.
  • FIG. 26 Fluorescence Resonance Energy Transfer (FRET) analysis of antiestrogen compounds 5(K-07), 21(K-09), and 32(K-62) and trans-hydroxy -tamoxifen (TOT) show dose dependent suppression of the binding of SRC3 to wild type ER, Y537S-ER, and D538G-ER.
  • FRET Fluorescence Resonance Energy Transfer
  • TOT trans-hydroxy -tamoxifen
  • FIG. 27A Western blot examination of GREB l and ERa protein in individual tumors, ⁇ -actin served as the loading control.
  • FIG. 27B Quantitation of ERa and GREB l protein in vehicle and K-07-treated tumors (t test, P ⁇ 0.0005; n 1 ⁇ 4 5 vehicle and n 1 ⁇ 4 6 K-07 tumors).
  • FIG. 28A Tumor volumes of ovariectomized NSG mice. Three weeks after ovariectomy, mice received MCF7 cells containing half D538G ER and half WT ER and daily subcutaneous injections with vehicle or 80 mg/kg of K-07 or fulvestrant. Two-way ANOVA, Bonferroni posttest, P ⁇ 0.0001; n 1 ⁇ 4 8 per group.
  • FIG. 28B Tumor volumes of ovariectomized NSG mice. Three weeks after ovariectomy mice received MCF7 cells containing half Y537S ER or D538G ER and half WT ER and daily treatments with oral vehicle or oral K-07 at 80 mg/kg. Two-way ANOVA,
  • Bonferroni post-test P ⁇ 0.0001; n 1 ⁇ 4 8 per group.
  • FIG. 28C Expression of the estrogen target genes GREBl and PGR in tumor harvested at day 26 from NSG mice ovariectomized 3 weeks prior to receiving MCF7 cells containing half D538G ER and half WT ER and daily subcutaneous injection with vehicle or 80 mg/kg of K-07 or fulvestrant.
  • FIG. 28D Expression of the estrogen target genes GREBl and PGR in tumor harvested at day 26 from NSG mice ovariectomized 3 weeks prior to receiving MCF7 cells containing half D538G ER and half WT ER and daily subcutaneous injection with vehicle or 80 mg/kg of K-07 or fulvestrant.
  • FIG. 28D One-way ANOVA, Tukey posttest; n 1 ⁇ 4 8 per group.
  • FIG. 28E Expression of ERa protein by Western blot analysis of tumor lysates from the harvested tumors in FIGS. 28C-28D.
  • FIG. 28F Expression of ERa protein by IHC for ERa in tumor tissue sections from the harvested tumors in FIGS. 28C-28D.
  • IVIS bioluminescence
  • IVIS bioluminescence
  • IVIS bioluminescence
  • FIG. 30B Metastasis growth after tail vein injection of NOD-SCID-gamma (NSG) female mice with 0.5 x 10 6 MCF-7 breast cancer cells expressing luciferase and Y537S ER (ca. 50% mutant ER and 50% wild type ER). Animals were treated 6-times per week with vehicle or K-07 (80 mg/kg orally for 30 days and then 40 mg/kg). Tumor metastasis growth was monitored after 57 days by bioluminescence (IVIS) imaging.
  • IVIS bioluminescence
  • FIG. 30C Animal survival after tail vein injection of NOD-SCID-gamma (NSG) female mice with 0.5 x 10 6 MCF-7 breast cancer cells expressing luciferase and Y537S ER (ca. 50%) mutant ER and 50% wild type ER). Animals were treated 6-times per week with vehicle or K-07 (80 mg/kg orally for 30 days and then 40 mg/kg). Animal survival was followed to 100 days.
  • Hazard Ratio Mantel-Haenszel
  • CI 1.396 to 74.28.
  • FIG. 31 A Metastasis growth after tail vein injection into NOD-SCID-gamma (NSG) female mice with 0.5 x 10 6 MCF-7 breast cancer cells expressing luciferase and D538G ER (ca. 50%) mutant ER and 50% wild type ER). Animals were treated 6-times per week with vehicle or K-07 (80 mg/kg orally for 30 days and then 40 mg/kg). Tumor metastasis growth was monitored with time by bioluminescence (IVIS) imaging.
  • IVIS bioluminescence
  • FIG. 32 Reversal of coactivator SRC3/A1B 1 binding to WT and mutant ERs.
  • compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
  • the variables in formula I encompass specific groups, such as, for example, alkyl and cycloalkyl.
  • combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • the modifier "about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity).
  • the modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4" also discloses the range “from 2 to 4.”
  • the term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1" may mean from 0.9-1.1. Other meanings of "about” may be apparent from the context, such as rounding off, so, for example "about 1” may also mean from 0.5 to 1.4.
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert- butoxy. [0081]
  • alkyl as used herein, means a straight or branched chain saturated hydrocarbon.
  • alkyl include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • alkylene means a divalent group derived from a straight or branched chain saturated hydrocarbon.
  • Representative examples of alkylene include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, and
  • aryl means phenyl or a bicyclic aryl.
  • the bicyclic aryl is naphthyl, dihydronaphthalenyl, tetrahydronaphthalenyl, indanyl, or indenyl.
  • the phenyl and bicyclic aryls are attached to the parent molecular moiety through any carbon atom contained within the phenyl or bicyclic aryl.
  • cycloalkyl as used herein, means a monovalent group derived from an all- carbon ring system containing zero heteroatoms as ring atoms, and zero double bonds.
  • the all- carbon ring system can be a monocyclic, bicylic, or tricyclic ring system, and can be a fused ring system, a bridged ring system, or a spiro ring system, or combinations thereof.
  • Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • cycloheptyl cyclooctyl
  • cyclooctyl cyclooctyl
  • the cycloalkyl groups described herein can be appended to the parent molecular moiety through any substitutable carbon atom.
  • cycloalkylene as used herein, means a divalent group derived from an all- carbon ring system containing zero heteroatoms as ring atoms and zero double bonds, which attaches to the parent molecule at two different ring carbons atoms.
  • the all-carbon ring system can be a monocyclic, bicylic, or tricyclic ring system, and can be a fused ring system, a bridged ring system, or a spiro ring system.
  • Representative examples of cycloalkylene include, but are
  • halogen means a chlorine, bromine, iodine, or fluorine atom.
  • haloalkyl means an alkyl, as defined herein, in which one, two, three, four, five, six, or seven hydrogen atoms are replaced by halogen.
  • representative examples of haloalkyl include, but are not limited to, 2-fluoroethyl,
  • heteroaryl means an aromatic heterocycle, i.e., an aromatic ring that contains at least one heteroatom selected from O, N, or S.
  • a heteroaryl may contain from 5 to 12 ring atoms.
  • a heteroaryl may be a 5- to 6-membered monocyclic heteroaryl or an 8- to 12-membered bicyclic heteroaryl.
  • a 5-membered monocyclic heteroaryl ring contains two double bonds, and one, two, three, or four heteroatoms as ring atoms.
  • 5-membered monocyclic heteroaryls include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, and triazolyl.
  • a 6-membered heteroaryl ring contains three double bonds, and one, two, three or four heteroatoms as ring atoms.
  • 6-membered monocyclic heteroaryls include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
  • the bicyclic heteroaryl is an 8- to 12-membered ring system having a monocyclic heteroaryl fused to an aromatic, saturated, or partially saturated carbocyclic ring, or fused to a second monocyclic heteroaryl ring.
  • bicyclic heteroaryl include, but are not limited to, benzofuranyl, benzoxadiazolyl, 1,3- benzothiazolyl, benzimidazolyl, benzothienyl, indolyl, indazolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine, quinolinyl, thienopyridinyl, 5 ,6, 7 ,8-tetrahydroquinolinyl, and 6, 7-dihydro- 5H-cyclopenta[b Jpyridinyl.
  • the heteroaryl groups are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the groups.
  • heterocycle refer generally to ring systems containing at least one heteroatom as a ring atom where the heteroatom is selected from oxygen, nitrogen, and sulfur. In some embodiments, a nitrogen or sulfur atom of the heterocycle is optionally substituted with oxo.
  • Heterocycles may be a monocyclic heterocycle, a fused bicyclic heterocycle, or a spiro heterocycle.
  • the monocyclic heterocycle is generally a 4, 5, 6, 7, or 8- membered non-aromatic ring containing at least one heteroatom selected from O, N, or S.
  • the 4- membered ring contains one heteroatom and optionally one double bond.
  • the 5-membered ring contains zero or one double bond and one, two or three heteroatoms.
  • the 6, 7, or 8-membered ring contains zero, one, or two double bonds, and one, two, or three heteroatoms.
  • Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, diazepanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl , 4,5-dihydroisoxazol-5-yl, 3,4- dihydropyranyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl
  • the fused bicyclic heterocycle is a 7-12-membered ring system having a monocyclic heterocycle fused to a phenyl, to a saturated or partially saturated carbocyclic ring, or to another monocyclic heterocyclic ring, or to a monocyclic heteroaryl ring.
  • fused bicyclic heterocycle include, but are not limited to, 1,3- benzodioxol-4-yl, 1,3-benzodithiolyl, 3-azabicyclo[3.1.0]hexanyl, hexahydro-lH-furo[3,4- c]pyrrolyl, 2,3-dihydro-l,4-benzodioxinyl, 2,3-dihydro-l-benzofuranyl, 2,3-dihydro-l- benzothienyl, 2,3-dihydro-lH-indolyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazinyl, and 1,2,3,4- tetrahydroquinolinyl.
  • Spiro heterocycle means a 4-, 5-, 6-, 7-, or 8-membered monocyclic heterocycle ring wherein two of the substituents on the same carbon atom form a second ring having 3, 4, 5, 6, 7, or 8 members.
  • Examples of a spiro heterocycle include, but are not limited to, l,4-dioxa-8-azaspiro[4.5]decanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6- azaspiro[3.3]heptanyl, and 8-azaspiro[4.5]decane.
  • the monocyclic heterocycle groups of the present invention may contain an alkylene bridge of 1, 2, or 3 carbon atoms, linking two nonadjacent atoms of the group.
  • Examples of such a bridged heterocycle include, but are not limited to, 2,5-diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 2- azabicyclo[2.2.2]octanyl, and oxabicyclo[2.2.1]heptanyl.
  • the monocyclic, fused bicyclic, and spiro heterocycle groups are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the group.
  • hydroxy as used herein, means an -OH group.
  • hydroxyalkyl as used herein means an alkyl, as defined herein, in which a hydrogen atom is replaced by -OH.
  • representative examples of hydroxyalkyl include, but are not limited to those derived from Ci -6 alkyls, such as -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, and the like.
  • oxo refers to an oxygen atom bonded to the parent molecular moiety.
  • An oxo may be attached to a carbon atom or a sulfur atom by a double bond.
  • an oxo may be attached to a nitrogen atom by a single bond, i.e., an N-oxide.
  • polycycloalkylidene refers to an all-carbon ring system having a divalent ring carbon atom that bonds to the parent molecular moiety through a carbon- carbon double bond.
  • the divalent ring carbon atom is formed by removal of two hydrogen atoms from the same ring carbon atom of a corresponding polycycloalkane.
  • a polycycloalkane refers to an all-carbon ring system having at least one alkylene bridge (i.e., an alkylene that connects two non-adjacent carbon atoms) and optionally having a fused ring (i.e., an alkylene connecting two adjacent carbon atoms) and/or a spirocyclic ring (i.e., an alkylene connected at either end to the same carbon atom).
  • alkylene bridge i.e., an alkylene that connects two non-adjacent carbon atoms
  • a fused ring i.e., an alkylene connecting two adjacent carbon atoms
  • a spirocyclic ring i.e., an alkylene connected at either end to the same carbon atom
  • polycycloalkane examples include, but are not limited to adamantane, noradamantane, norbornane, (3aR,4R,7S,7aS)-octahydro-lH- 4,7-methanoindene, bicyclo[2.2.2]octane, and (2R,3S,4S,5R)-
  • polycycloalkylidene etc. may be preceded by a designation indicating the number of atoms present in the group in a particular instance (e.g., "Ci-C 4 alkyl,” “C3- 6 cycloalkyl,” “Ci- 4 alkylene”). These designations are used as generally understood by those skilled in the art. For example, the representation “C” followed by a subscripted number indicates the number of carbon atoms present in the group that follows. Thus, “Csalkyl” is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl).
  • a non-hydrogen substituent group is in the place of hydrogen radical on a carbon or nitrogen of that group.
  • a substituted alkyl is an alkyl in which at least one non-hydrogen radical is in the place of a hydrogen radical on the alkyl.
  • monofluoroalkyl is alkyl substituted with a fluoro radical
  • difluoroalkyl is alkyl substituted with two fluoro radicals. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen radical may be identical or different (unless otherwise stated).
  • each substituent is selected independent of the other. Each substituent, therefore, may be identical to or different from the other substituent(s).
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric ( or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Thus, included within the scope of the invention are tautomers of compounds of formula I.
  • the structures also include zwitterioinc forms of the compounds or salts of formula I where appropriate.
  • E2 refers to estradiol
  • an “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a composition or combination of compositions being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study. The dose could be administered in one or more administrations.
  • the precise determination of what would be considered an effective dose may be based on factors individual to each patient, including, but not limited to, the patient's age, size, type or extent of disease, stage of the disease, route of administration of the regenerative cells, the type or extent of supplemental therapy used, ongoing disease process and type of treatment desired (e.g., aggressive vs. conventional treatment).
  • treat means a slowing, stopping or reversing of progression of cancer when provided a composition described herein to an appropriate control subject.
  • the term also means a reversing of the progression of such a disease or disorder to a point of eliminating or greatly reducing the cell proliferation.
  • “treating” means an application or administration of the compositions described herein to a subject, where the subject has a disease or a symptom of a disease, where the purpose is to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disease or symptoms of the disease.
  • subject or “patient” means an individual having symptoms of, or at risk for, cancer or other malignancy.
  • a patient may be human or non-human and may include, for example, animal strains or species used as "model systems" for research purposes, such a mouse model as described herein.
  • patient may include either adults or juveniles (e.g., children).
  • patient may mean any living organism, preferably a mammal (e.g., human or non-human) that may benefit from the administration of compositions contemplated herein.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • compositions of the disclosure are used interchangeably herein and refer to the placement of the compositions of the disclosure into a subject by a method or route which results in at least partial localization of the composition to a desired site.
  • the compositions can be administered by any appropriate route which results in delivery to a desired location in the subject.
  • a first aspect of the invention provides compounds or compositions of formula (I), or a pharmaceutically acceptable salt thereof,
  • G is an optionally substituted polycycloalkylidene
  • Xi, X 2 , X 3 , and X 4 are each independently N, CH, or CR m , wherein at most two of Xi, X 2 , X 3 , and X 4 are N, and wherein at most one of Xi and X 4 is N;
  • Y is alkyl, -OR A , -COOR B , -N(R C )(R D ), -CON(R c )(R D ), -N(R c )-OH,
  • R p and R m at each occurrence are independently alkyl, alkoxy, halogen, -OH, -CN, haloalkyl, or hydroxyalkyl;
  • p O, 1, 2, 3, 4, or 5;
  • Q 1 and Q 2 are O, H, or S;
  • Q 3 is an optionally substituted cycloalkylene
  • R A , RB , RC ⁇ , and R D" at each occurrence are independently hydrogen, alkyl, cycloalkyl, aryl, heterocycle, heteroaryl, or alkyl substituted by one or more substituents selected from the group consisting of -OH, - H 2 , - H(Ci- 4 alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, phenyl, and -NHCO-R 2 , wherein the cycloalkyl, aryl, heterocycle, and heteroaryl are each optionally substituted;
  • R x and R y at each occurrence are independently hydrogen, alkyl, halogen, haloalkyl, or -CN;
  • R z is -OCi -4 alkyl, cycloalkyl or -Ci- 4 alkylene-cycloalkyl.
  • G is a polycycloalkylidene group as defined herein.
  • G is a C 6 - 30 bicylic or tricyclic ring system, or a ring system with an even higher number of rings.
  • G is fused ring system, a bridged ring system, or a spiro ring systems.
  • G is a C 6-2 5, a C 6-2 o, a C 8-20 , or a Cio- 2 o ring system.
  • G is a C 6 , C 7 , C 8 , Cg, Cio, Cii, C 12 , Ci3, Ci4, Ci5, or Ci 6 polycycloalkylidene group as disclosed herein.
  • G may be substituted or unsubstituted.
  • G is substituted with Ci-ioalkyl, halogen, Ci-iohaloalkyl, Ci-iohydroxyalkyl, cyano, nitro, amino, or other substituent groups as disclosed herein.
  • G is unsubstituted. ments, G
  • Xi, X 2 , X 3 , and X 4 are each independently CH or CR m . In some embodiments, only one of Xi, X 2 , X 3 , and X 4 is N, with the others being independently CH or CR m . In some embodiments, X 1 and X 2 are N, and X 3 and X 4 are independently CH or CR m . In some embodiments, X 1 and X 3 are N, and X 2 and X 4 are independently CH or CR m .
  • the ring containing Xi, X 2 , X 3 , and X 4 together with Q is
  • one or two or three or four of Xi, X 2 , X 3 , and X 4 are inde n some embodiments, the ring containing Xi, X 2 , X 3 , and X 4 together with
  • R m at each occurrence is independently alkyl (such as Ci -4 alkyl), alkoxy (such as Ci -4 alkoxy), halogen, -OH, -CN, haloalkyl (such as Ci -4 haloalkyl), or hydroxyalkyl (such as Ci -4 hydroxy alkyl), and m is 0, 1, 2, 3, or 4.
  • R m at each occurrence is independently halogen, -OH, -CN, Ci -4 haloalkyl, or Ci -4 hydroxyalkyl.
  • R m at each occurrence is independently halogen, such as fluoro.
  • R P at each occurrence is independently alkyl (such as Ci. 4 alkyl), alkoxy (such as Ci -4 alkoxy), halogen, -OH, -CN, haloalkyl (such as Ci -4 haloalkyl), or hydroxyalkyl (such as Ci -4 hydroxyalkyl).
  • R P at each occurrence is independently halogen, -OH, -CN, or Ci -4 hydroxyalkyl.
  • R P at each occurrence is independently halogen (such as fluoro) or -OH.
  • R P is -OH.
  • p is 0, 1, 2, 3, 4, or 5. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 1, and R P is halogen, -OH, -CN, or Ci -4 hydroxyalkyl. In some
  • p is 1, and R P is -OH.
  • the ring containing R P is
  • Q is , wherein the C(O) group is attached to Y.
  • Q is in in the C(O) group is attached to Y.
  • Q is , wherein in the C(O) group is attached to Y.
  • the Y-Q group is in in the C(O) group is attached to Y.
  • ⁇ N-N CR X -
  • - - ⁇ N-N CR X -
  • - ⁇ ,N-N CH-
  • - - ⁇ N-N CR X -
  • the Y-Q group is Y-C(0)- H-
  • Q is -C(0)-Q 3 -, wherein the C(O) group is attached to Y.
  • Q 3 is an optionally substituted cycloalkylene derived from a C 3 . 10 ring system as disclosed herein.
  • Q 3 is an optionally substituted cycloalkylene which is monocyclic.
  • Q 3 is an optionally substituted cycloalkylene
  • Q 3 is unsubstituted. In some embodiments, Q 3 is substituted with one or more substituent groups disclosed herein. In some embodiments, Q3 is substituted with one or more substituents selected from the group consisting of -OH, - H 2 , -NH(C 1 - 4 alkyl), -N(Ci- 4 alkyl) 2 , halogen, Ci- 4 haloalkyl, and -CN.
  • the Y-Q group is
  • R x and R y at each occurrence are independently hydrogen, alkyl (such as halogen, haloalkyl (such
  • R x and R y are independently hydrog or -CN. In some embod iments, at least one of R x and R y is CN. For example, in some embodiments, R y is -CN, or halogen, and R x is hydrogen. In some embodiments, R x is -CN, or halogen, and R y is hydrogen. In some embodiments, R x and R y are both hydrogen.
  • -C(Q 2 )-NH-N CR X - -C(0)-NH- -C(0)-Q 3 -
  • -S0 2 -CR y CR z - as defined herein
  • Y is alkyl (such as Ci-i 0 alkyl), -OR A , -COOR B , -N(R C )(R D ), -CON(R c )(R D ), -N(R c )-OH, or -NH-N(R C )(R D ).
  • Q is , the C(O) group being attached to Y, and Y is -OR A ,
  • the Y-Q group is [00123]
  • Q is -C(0)- H- as defined herein.
  • the Y-Q group is R B OOC-C(0)- H- or (R c )(R D )NC(0)-C(0)- H- wherein R B , R c , and R D are as defined herein.
  • Q is -C(0)- H- as defined herein, and Y is -COOR B .
  • the Y-Q group is R B OOC-C(0)- H- wherein R B is hydrogen or Ci-i 0 alkyl.
  • the Y-Q group is HOOC-C(0)- H-.
  • Q is -C(0)-Q 3 - as defined herein. In some embodiments, the
  • Y-Q group is R A 0-C(0)-Q 3 -. In some embodiments, the Y-Q group is
  • R , R , R ⁇ , and R" at each occurrence are independently selected from hydrogen, alkyl (such as Ci-ioalkyl), cycloalkyl (such as C3-iocycloalkyl), aryl (such as C6-i 2 ryl), heterocycle (such as Cs- heterocycle), and heteroaryl (such as Cs- heteroaryl), wherein the alkyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each optionally substituted.
  • alkyl such as Ci-ioalkyl
  • cycloalkyl such as C3-iocycloalkyl
  • aryl such as C6-i 2 ryl
  • heterocycle such as Cs- heterocycle
  • heteroaryl such as Cs- heteroaryl
  • R , R , R , and R are unsubstituted. In some embodiments, each of R , R , R , and R D are independently substituted with one or more substituents disclosed herein.
  • R A is an alkyl optionally substituted with one or more substituents selected from the group consisting of -OH, - H 2 , - H(Ci- 4 alkyl), -N(C 1 - 4 alkyl) 2 , halogen, haloalkyl, phenyl, and - HCO-R 2 , wherein R z is cycloalkyl (such as C 3 . l ocycloalkyl), or -C 1 -4 alkylene-cycloalkyl (such as -C 1 -4 alkylene-C 3- iocycloalkyl).
  • an alkyl such as C 3 . l ocycloalkyl
  • -C 1 -4 alkylene-cycloalkyl such as -C 1 -4 alkylene-C 3- iocycloalkyl.
  • R A is hydrogen, Ci-ioalkyl, Ci-ioalkylene-OH, Ci-ioalkylene- H 2 , Ci.
  • Q is a bond
  • Y is -OR A
  • R A is an alkyl (such as Ci-ioalkyl) substituted with -NHCO-R 2 .
  • Q is a bond
  • Y is -OR A
  • R A is Ci. l oalkyl substituted with -NHCO-R 2 , wherein R 2 is C 3- iocycloalkyl or -Ci- 4 alkylene-C 3- l ocycloalkyl
  • R is an alkyl optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -NH(Ci- 4 alkyl), -N(Ci- 4 alkyl) 2 , halogen, haloalkyl, phenyl, and -NHCO-R 2 , wherein R 2 is -OCi -4 alkyl, cycloalkyl (such as C 3- l ocycloalkyl), or - - 4 alkylene-cycloalkyl (such as -Ci- 4 alkylene-C 3- iocycloalkyl).
  • substituents selected from the group consisting of -OH, -NH 2 , -NH(Ci- 4 alkyl), -N(Ci- 4 alkyl) 2 , halogen, haloalkyl, phenyl, and -NHCO-R 2 , wherein R 2 is -OCi -4 alkyl, cycl
  • R R is an alkyl
  • R is hydrogen, Ci-ioalkyl, Ci-ioalkylene-OH, Ci.ioalkylene-NH 2 , Ci.
  • R D is hydrogen, Ci- 4 alkyl, or Ci- 4 hydroxyalkyl.
  • formula (I) is formula (I-a)
  • n 0, 1, 2, 3, or 4;
  • G, Q, Y, R p , R m , and p are as defined herein.
  • formula (I) is formula (I-b)
  • n 0, 1, 2, 3, or 4;
  • formula (I) is formula (I-c)
  • Y is alkyl, -OR A , or -N(R C )(R D );
  • R x , R y , R A , R c , and R D are as defined herein.
  • formula (I) is formula (I-c), wherein R x and R y are
  • formula (I) is formula (I-c), wherein R y is Ci -4 alkyl, -CN, or halogen, and R x is hydrogen.
  • R x is Ci -4 alkyl, -CN, or halogen
  • R y is hydrogen. In some embodiments, R x and R y are both hydrogen.
  • formula (I-c) is formula (I-c-1),
  • Y is alkyl, -OR A , or -N(R C )(R D );
  • R A , R c , and R D are as defined herein.
  • formula (I-c) is formula (I-c-1), wherein Y is -OR A , R A is hydrogen, Ci-ioalkyl optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -NH(C 1 -C alkyl), -N(C 1 -C alkyl) 2 , halogen, phenyl, and
  • R z is C3-iocycloalkyl or -Ci- 4 alkylene- C3-iocycloalkyl.
  • formula (I-c) is formula (I-c-1), wherein Y is -N(R )(R ), R is hydrogen, Ci-ioalkyl optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -NH(Ci-C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , halogen, phenyl, and -NHCO-R 2 , wherein R z is C 3 -iocycloalkyl or -C 1 -4 alkylene-C 3 -iocycloalkyl, and R D is hydrogen, Ci- 4 alkyl, or Ci- 4 hydroxy alkyl
  • formula (I-c) is formula (I-c-1), wherein Y is -OR A or -N(R C )(R D );
  • R and R are hydrogen, Ci-ioalkyl, Ci-ioalkylene-OH, Ci-ioalkylene-NH2, Ci.
  • R D is hydrogen, C 1 -4 alkyl, or C 1 -4 hydroxyalkyl
  • R z is a -OCi -4 alkyl, C 3 .i 0 cycloalkyl, or -C 1 -4 alkylene-C 3 .i 0 cycloalkyl.
  • formula (I) is formula (I-d)
  • R A , R x , and R y are as defined herein.
  • formula (I) is formula (I-d), wherein Y is -OR A or
  • R A is Ci-i 0 alkyl substituted with -NHCO-R 2 ;
  • R x and R y is each independently hydrogen, Ci -4 alkyl, halogen, Ci -4 haloalkyl, or -CN; and
  • R 2 is C 3 -iocycloalkyl or -C 1 -4 alkylene-C 3 -iocycloalkyl.
  • formula (I) is formula (I-d), wherein Y is -OR A , and R A is Ci. l oalkyl substituted with -NHCO-R 2 , wherein R 2 is C 3 -iocycloalkyl or -Ci- 4 alkylene-C 3 - l ocycloalkyl.
  • formula (I) is formula I-d), wher -OR A , and R A is
  • Ci-ioalkyl substituted with -NHCO-R 2 wherein R z is or
  • formula (I) is formula (I-d), wherein Y is -OR A , and R A is an Ci-ioalkyl
  • Ri is selected from -CO(CH 2 ) 4 CH 3 , -COOCH 3 , -COOCH 2 CH 3 ,
  • R 2 is selected from -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -(CH 2 ) 4 CH 3 , -(CH 2 ) 2 OH, - (CH 2 ) 3 OH, -(CH 2 ) 4 OH, -(CH 2 ) 5 OH, -(CH 2 )CF 3 , -(CH 2 ) 2 N(CH 3 ) 2 , -(CH 2 ) 2 NHBoc, - (CH 2 ) 3 HBoc, and -(CH 2 ) 4 HBoc.
  • R 3 is selected from -(CH 2 ) 2 H 2 , -(CH 2 ) 3 N3 ⁇ 4 and -(CH 2 ) 4 H 2 .
  • R4 is selected from -CH 3 and -(CH 2 ) 2 OH
  • R 5 is selected from -(CH 2 ) 2 OH and -(CH 2 ) 3 CH 3 .
  • the compounds include isotope-labelled forms.
  • An isotope- labelled form of a compound is identical to the compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs in greater natural abundance.
  • isotopes which are readily commercially available and which can be incorporated into a compound by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 18 F and 36 C1.
  • SERMs such as tamoxifen and raloxifene
  • SERMs are effective in suppressing proliferation yet have no effect on ERa level or can even stabilize the receptor and upregulate cellular ERa levels, as observed in FIG. 7B for tamoxifen and as observed by others.
  • ERa When ERa is occupied by a SERM or a SERD, its overall effect on gene expression is not only a suppression of pro-proliferative and anti-apoptotic activity but also an upregulation of anti-proliferative and pro-apoptotic factors (36-38). The potential benefits of such effects would be lost in the complete absence of ERa (39, 40) and might, in fact, engender the development of more aggressive forms of breast cancer that are independent of ERa or fully resistant to ERa-targeted endocrine therapy agents (1).
  • the core element contributes to the drug-like attributes of the overall molecule that defines its pharmacokinetic behavior, such as oral bioavailability.
  • esters and secondary amides are notable in having an extended (Z or s-cis) conformation, which is energetically favored due to ⁇ - ⁇ * or ⁇ - ⁇ * ⁇ overlap, respectively (47, 48), that would project the single substituent directly outward, away from the ring and presumably in a functional direction, toward hl2 (FIG. 9).
  • the two possible geometries of tertiary amides are of essentially equal energy, so the smaller group could be extended.
  • mutant ERs that drive hormone-independent constitutive activity.
  • D538G or Y537S the nature of the mutant ER (D538G or Y537S), the cell background (T47D or MCF-7), and the chemical structure of the antiestrogens (K-07 vs. K-09 vs. K-62 vs. Fulv) all affected response to AE ligands.
  • these mutant ERs showed differential responsiveness to chemically distinct AEs with the mutant Y537S-ER being more resistant to the AEs compared to the mutant D538G receptor and requiring higher compound concentrations for growth suppression.
  • MCF-7 and T47D cells carry different mutant forms of PI3K.
  • GATA3 an important factor for ER activity, is often mutated in breast cancers and could influence responsiveness of WT and mutant ERs to antiestrogens.
  • mutant ER allele fraction is crucial in the extent of endocrine treatment resistance observed.
  • T47D cells with both alleles homozygous for the mutant ER showed greater resistance to antiestrogens than did cells with 50% mutant and 50% wild type ER.
  • 50% mutant ER conferred a dominant antiestrogen resistant phenotype. This is of importance because metastatic breast cancers usually contain a mixture of both mutant and wild type ERs.
  • Y537 and D538 are present at key locations in the activation function-2 region of the ligand binding domain that determines the three-dimensional structure of helix 12 of the ER that is key in interactions with co-activators.
  • These changes in ER structure result in ligand-independent interaction with co-activators that is normally seen in wild type receptor only in the presence of estrogenic hormones.
  • this disclosure shows that these changes in ER also reduce the receptor's affinity for binding of antiestrogen ligands. This reduced binding affinity likely contributes to the relative resistance of these ER mutant cells to antiestrogens.
  • Y537S-ER was always more resistant to suppressive effects of ligands compared to D538G-ER.
  • AZD9496 has shown some liver toxicity and GDC-0810 causes gastrointestinal problems including diarrhea in about one- third of patients.
  • RAD-0910 shows promise but clinical trials are at an earlier stage. Thus, there is an unmet need for orally active antiestrogens with an improved clinical profile and reduced side effects.
  • one or more compounds of the present invention, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as described herein can be used to inhibit the growth of a cell.
  • the cell is identified as having an estrogen receptor that mediates a growth characteristic of the cell. Growth of a cell can be inhibited by contacting the cell with an effective amount of at least one of the compounds described herein, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as described elsewhere herein.
  • Such contacting of the one or more compounds, or pharmaceutically acceptable salts thereof, can take place in various ways and locations, including without limitation away from a living subject (e.g., in a laboratory, diagnostic and/or analytical setting) or in proximity to a living subject (e.g., within or on an exterior portion of an animal, e.g., a human).
  • Another embodiment provides a use of one or more compounds of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition (as described elsewhere herein), in the manufacture of a medicament for the treatment of a disease or condition that is estrogen receptor alpha dependent and/or estrogen receptor alpha mediated.
  • a method of treating or preventing breast cancer in a subject comprising administering to a subject a therapeutically effective amount of a compound or composition of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.
  • the breast cancer is primary, metastatic, or recurrent breast cancer.
  • a method of preventing breast cancer recurrence in a subject with prior breast cancer comprising administering to a subject a therapeutically effective amount of a compound or composition of formula (I), or a
  • a method of inhibiting or slowing the growth of estrogen receptor-positive, endocrine therapy-sensitive tumors or endocrine therapy resistant tumors driven by active estrogen receptors in a subject comprising administering to a subject a therapeutically effective amount of a compound or composition of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.
  • the compounds and pharmaceutical compositions as disclosed herein may be used for treating or preventing breast cancer or inhibiting the growth of tumors as disclosed herein, wherein the tumor is driven by wild type, constitutively active estrogen receptors, and combinations thereof.
  • the compounds of the present invention have several potential benefits as therapeutic drugs for treating or ameliorating diseases or conditions that are estrogen receptor alpha dependent and/or estrogen receptor alpha mediated.
  • Compounds of the invention show ability to downregulate ERa with robust correlation with suppression of cell proliferation.
  • the compounds of the present invention have antiproliferative and ERa
  • K-07 displayed the best pharmacokinetic properties by either subcutaneous or oral routes. It was also the most effective growth inhibitor in breast tumor xenografts in vivo, despite the fact that other antiestrogens showed good anti-proliferative and target gene inhibitory activities in cells in culture. K-07 appears to be a potential alternative orally effective antiestrogen. Although in the initial studies no impact on overall animal health was observed with this compound, or with K-09 or K-62, further investigations and ultimate safety and effectiveness studies will be needed with K-07 or related antiestrogens.
  • Compounds of the invention also have efficacy in suppressing growth of breast cancer cells and tumors containing WT ERs and that, at higher concentrations, these compounds can also inhibit ER-regulated gene expression and proliferation of breast cancer cells containing constitutively active mutant ERs.
  • Compounds of the present invention are effective growth inhibitors in breast tumor xenografts in vivo, and show good anti-proliferative and target gene inhibitory activities in cells in culture.
  • Three antiestrogen compounds with novel chemical structures of the present disclosure were shown to have efficacy in suppressing growth of breast cancer cells and tumors containing WT ERs and that, at higher concentrations, these compounds can also inhibit ER-regulated gene expression and proliferation of breast cancer cells containing constitutively active mutant ERs.
  • Non-limiting examples of diseases or conditions that are estrogen receptor alpha dependent and/or estrogen alpha receptor mediated and thus suitable for treatment using the compounds, compositions and methods described herein include breast cancers, gynecological cancers and pituitary cancers.
  • diseases or conditions may include one or more of the following: breast cancer, endometrial cancer, ovarian cancer and cervical cancer.
  • An embodiment provides a use of one or more compounds of the present invention, or a
  • a pharmaceutically acceptable salt thereof or a pharmaceutical composition (as described elsewhere herein), in the manufacture of a medicament for the treatment of breast cancers and gynecological cancers, including for example one or more of the following: breast cancer, endometrial cancer, ovarian cancer and cervical cancer.
  • An embodiment provides the use of the compounds herein for the treatment of primary, metastatic, or recurrent breast cancer.
  • Primary breast cancer is breast cancer that hasn't spread beyond the breast or the lymph nodes under the arm.
  • Metastatic breast cancer also called stage IV or advanced breast cancer
  • Metastatic breast cancer is not a specific type of breast cancer, but rather the most advanced stage of breast cancer.
  • Metastatic breast cancer is breast cancer that has spread beyond the breast to other organs in the body (most often the bones, lungs, liver or brain). Although metastatic breast cancer has spread to another part of the body, it's considered and treated as breast cancer. When breast cancer comes back, it's called recurrence.
  • Breast cancer can recur at any time or not at all, but most recurrences happen in the first 5 years after breast cancer treatment.
  • Breast cancer can come back as a local recurrence (meaning in the treated breast or near the mastectomy scar) or somewhere else in the body.
  • Some of the most common sites of recurrence outside the breast are the lymph nodes, bones, liver, lungs, and brain.
  • compounds of the invention are used to inhibit or slow the growth of estrogen receptor-positive, endocrine therapy-sensitive tumors or endocrine therapy resistant tumors driven by active estrogen receptors.
  • the cancer cell or tumor growth may be driven by wild type, constitutively active estrogen receptors, and combinations thereof.
  • Another aspect of the present invention provides a compound or composition of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating or preventing breast cancer.
  • a compound or composition of formula (I), or a pharmaceutically acceptable salt thereof for use in treating or preventing breast cancer.
  • disclosed are compounds or compositions of formula (I), or pharmaceutically acceptable salts thereof, for use in treating or preventing primary, metastatic, or recurrent breast cancer.
  • such tumors are driven by wild type, constitutively active estrogen receptors, and combinations thereof.
  • the breast cancer is primary, metastatic, or recurrent breast cancer.
  • compounds of the present invention can be administered to such subjects by a variety of methods.
  • administration can be by various routes known to those skilled in the art, including without limitation oral, inhalation, intravenous, intramuscular, topical, subcutaneous, systemic, and/or intraperitoneal administration to a subject in need thereof.
  • the amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature and/or symptoms of the estrogen receptor dependent and/or estrogen receptor mediated disease or condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • dosages may be calculated as the free base.
  • the compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as disclosed herein may be administered by inhalation, oral administration, or intravenous administration.
  • a suitable dose will often be in the range of from about 0.01 mg/kg to about 100 mg/kg, such as from about 0.05 mg/kg to about 10 mg/kg.
  • a suitable dose may be in the range from about 0.10 mg/kg to about 7.5 mg/kg of body weight per day, such as about 0.10 mg/kg to about 0.50 mg/kg of body weight of the recipient per day, about 0.10 mg/kg to about 1.0 mg/kg of body weight of the recipient per day, about 0.15 mg/kg to about 5.0 mg/kg of body weight of the recipient per day, about 0.2 mg/kg to 4.0 mg/kg of body weight of the recipient per day.
  • the compound may be administered in unit dosage form; for example, containing 1 to 100 mg, 10 to 100 mg or 5 to 50 mg of active ingredient per unit dosage form.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed.
  • the determination of effective dosage levels can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies and in vitro studies.
  • useful dosages of a compound of the present invention, or pharmaceutically acceptable salts thereof can be determined by comparing their in vitro activity, and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as fulvestrant.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vivo and/or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, FIPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
  • the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
  • the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the estrogen receptor dependent and/or estrogen receptor mediated disease or condition to be treated and to the route of administration. The severity of the estrogen receptor dependent and/or estrogen receptor mediated disease or condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose, and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
  • the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • a cell line such as a mammalian, and preferably human, cell line.
  • the results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity of particular compounds in an animal model such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods.
  • the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.
  • compositions as disclosed herein may be administered alone or in combination with a therapeutically effective amount of at least one additional anti-cancer therapeutic agents.
  • the compounds or pharmaceutical compositions as disclosed herein are administered in combination with at least one additional anti-cancer therapeutic agents.
  • the at least one additional anti-cancer therapeutic is administered prior to or following administration of the compounds or pharmaceutical compositions as disclosed herein.
  • compositions comprising any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or vehicles.
  • compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate,
  • benzenesulfonate benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl (e.g., phenyl/substituted phenyl) sulfonate.
  • the pharmaceutically acceptable compositions of the invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and
  • any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
  • pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,
  • polyethylenepolyoxypropylene-block polymers wool fat, sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; com oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar;
  • buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen- free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen- free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, pre
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease being treated.
  • compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate) and suitable mixtures thereof.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable
  • composition can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the active compound can be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such
  • Solid compositions of a similar type may also be employed as fillers in soft and hardfilled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in microencapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Dosage forms for topical or trans dermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • the invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • Compounds described herein can be administered as a pharmaceutical composition comprising the compounds of interest in combination with one or more pharmaceutically acceptable carriers. It is understood, however, that the total daily dosage of the compounds and compositions can be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient can depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health and prior medical history, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well-known in the medical arts.
  • compositions described herein may be administered with additional compositions to prolong stability, delivery, and/or activity of the compositions, or combined with additional therapeutic agents, or provided before or after the administration of additional therapeutic agents.
  • Combination therapy includes administration of a single pharmaceutical dosage formulation containing one or more of the compounds described herein and one or more additional pharmaceutical agents, as well as administration of the compounds and each additional pharmaceutical agent, in its own separate pharmaceutical dosage formulation.
  • a compound described herein and one or more additional pharmaceutical agents can be administered to the patient together, in a single oral dosage composition having a fixed ratio of each active ingredient, such as a tablet or capsule; or each agent can be administered in separate oral dosage formulations.
  • the present compounds and one or more additional pharmaceutical agents can be administered at essentially the same time (e.g., concurrently) or at separately staggered times (e.g., sequentially).
  • the doses are generally from about 0.01 to about 100 mg/kg, desirably about 0.1 to about 1 mg/kg body weight per day by inhalation, from about 0.01 to about 100 mg/kg, desirably 0.1 to 70 mg/kg, more desirably 0.5 to 10 mg/kg body weight per day by oral administration, and from about 0.01 to about 50 mg/kg, desirably 0.1 to 1 mg/kg body weight per day by intravenous administration.
  • the ligand core was selected based on the well-known SERM cyclofenil, in which the monocyclic cyclohexane was replaced with the much bulkier tricyclic adamantane, generating a series of ER ligands that we term "adamantyls" (FIG. 1). This adamantane-based core was identified from an earlier exploration of substitutions for the cyclohexane ring of cyclofenil (19).
  • the adamantyl core system 3 was easily prepared by a McMurray coupling between 4,4'-dihydroxybenzophenone (compound 1) and 2-adamantanone (compound 2) (Scheme 1) (25).
  • the monotriflate 4 could be obtained efficiently by treatment with /?-nitrophenyl trifluoromethanesulfonate (26), and then various acryloyl groups were appended by a Heck reaction (25).
  • the acrylic acid 5 was obtained by hydrolysis of the ethyl ester 8, and then the secondary amides 17-27, 31 and tertiary amides 28-30 were prepared by HATU- mediated coupling (27) of the primary and secondary amines (Scheme 2A) (28), respectively, with the acrylic acid core structure 5, the couplings with secondary amines requiring somewhat elevated temperatures (50 °C) (Scheme 2B).
  • Scheme 2A primary and secondary amines
  • Scheme 2B somewhat elevated temperatures
  • Reaction conditions and reagents a) TiCl 4 /Zn, THF, reflux; b) K 2 C0 3 , DMF, r.t.; c) Pd(PPh 3 ) 2 Cl 2 , TEA, DMF, 120°C; d) KOH, CH 3 OH; e) i) Isobutyl chloroformate, DMAP, Et 3 N, DCM, propane-l,3-diol, -15°C to 0°C, 3 h; and ii) piperidine, 1 h, r.t.
  • Reaction conditions and reagents a) HATU, DMF, r. ; b) TFA/DCM, 0°C; c) HATU, DMF, 50 °C.
  • ERa levels ERa, shown in red
  • 20% is the ERa level after 3 ⁇ fulvestrant treatment, with 100% being the ERa level in vehicle control cells.
  • Representative compounds were also screened in ERa-negative MDA-MB-231 breast cancer cells, and they had no effect on proliferation of cells lacking ERa (not shown).
  • Example 4 Comparison of the Antiproliferative and ERa Downregulating Efficacies of Core Structures and of Ketone, Ester, and Other Variant Side Chains.
  • the ketone compound 6 prepared herein showed reduced efficacy in terms of antiproliferative and ER downregulating activities; hence, further ketone analogs were not explored.
  • the series of acrylate esters 7-10 and co- hydroxyl esters 11-13 showed a broad span in both dimensions of efficacy. The best in terms of antiproliferative activity was 9 at 40%, but none were better than 5.
  • FIGS. 4B-4C The activities of a significant number of adamantyl carboxamides are displayed in two separate star plots (FIGS. 4B-4C).
  • the amides presented in FIG. 4B are all secondary amides except for the primary amide 16.
  • the alkyl amides 17-19 and co-hydroxyalkyl amides 20- 23 all showed relatively comparable antiproliferative efficacies, with the best two (21 and 23) being equivalent to that of the parent acid 5; the ER downregulating activities of these two were also good and similar to that of the parent 5.
  • FIGS. 6 and 7. Much more variable were the activities of the primary amide 16, the co-aminoalkyl amides 24-26, and the
  • FIG. 4C Comparisons between sets of related compounds in these two structural series are illustrated in FIG. 4C.
  • the good efficacies of the N-butyl secondary amide 18 can be contrasted with the very poor efficacies of the N-methyl tertiary amide analog 28.
  • the impressive efficacies of the hydroxyethyl secondary amide 20 are markedly better than those of the N-methyl analog 29 and the bis-hydroxy ethyl analog 30.
  • the symmetrically substituted tertiary amide 30 showed the highest ER binding affinity of the compounds we have studied, yet it was relatively unimpressive in both antiproliferative and ER downregulating activities. Similar comparisons can be made between the 2-aminoethyl secondary amide 24 and the trimethyl tertiary amide analog 31.
  • Example 6 Antiproliferative and ERa Downregulating Potencies, and Suppression of Estrogen Target Gene Expression, of the Most Efficacious Adamantyl Compounds.
  • the initial examination of compounds in the adamantyl series was based on their efficacies at a single, high concentration of 3 ⁇ . Therefore, to identify from among the best compounds those that would also be most potent in terms of their antiproliferative and ERa downrelating activities, dose-response assays were conducted on a number of compounds that had excellent anti-proliferative efficacies as well as a few others for comparison.
  • Reaction progress was monitored using analytical thin-layer chromatography (TLC) on 0.25 mm Merck F-254 silica gel glass plates. Visualization was achieved by either UV light (254 nm) or potassium permanganate indicator spray. Flash chromatography was performed with Woelm silica gel (0.040-0.063 mm) packing.
  • Zinc powder (8.0 eq.) was suspended in dry THF at 0 °C in a three-neck round bottom flask under a nitrogen atmosphere. Titanium tetrachloride (4.0 eq.) was added dropwise via a syringe while stirring. The reaction mixture was then refluxed for 2 h. After cooling to r. t, a THF solution containing 4,4'-dihydroxy benzophenone (1, 1.0 eq.) and 2-Adamantanone (2, 1.0 eq.) was added dropwise to the slurry. The mixture was refluxed for an additional two hours and then was cooled, poured into NaHC0 3 solution, and kept stirring until the dark color
  • reaction mixture was poured into 1 N HC1 (4.0 mL) and extracted from the aqueous phase with ethyl acetate. The organic layer was dried with anhydrous Na 2 S0 4 and concentrated in vacuo. Flash column chromatography (10% CH 3 0H/CH 2 C1 2 ) gave the acid product 5.
  • HATU 0-(7-Azabenzotriazole-l-yl)-N,N,N,N'-tetramethyluronium hexafluorophosphate
  • DIPEA diisopropylethylamine
  • 17p-Estradiol (E2), 4-hydroxytamoxifen (4-OHT) and fulvestrant (ICI 182,780, Fulv) were from Sigma-Aldrich. Tritiated estradiol was obtained from Perkin Elmer and purified, full- length human estrogen receptor a from Invitrogen. MCF7 cells from the ATCC were maintained and cultured as described (Sengupta et. al. Breast Cancer Res Treat 2009, 117, 243-51). Cells were cultured in phenol -red free media supplemented with 5% charcoal stripped FBS for 5 days to be in an E2-deprived condition for some western blot and gene regulation studies. All cells were tested for mycoplasma using Real-Time PCR Mycoplasma Detection Kit (Akron Biotech, Boca Raton, FL).
  • Binding Assays were performed on 96-well microtiter filter plates (Millipore), using full length human estrogen receptor a, with tritiated estradiol as tracer, as previously described (Carlson et. al. Biochemistry 1997, 36, 14897-905). After incubation on ice for 18-24 h, ERa-bound tracer was absorbed onto hydroxyapatite (BioRad), washed with buffer, and measured by scintillation counting. RBA values are the average ⁇ SD of 2-3 determinations.
  • WST-1 assay (Roche, Basel, Switzerland) was used to quantify cell viability after a 6- day exposure to compounds, as described (Gong et. al Molecular and cellular endocrinology 2016, 437, 190-200). Absorbance was measured at 450 nm using a VICTOR X5 PerkinElmer 2030 Multilabel Plate Reader, and cell proliferation values represent signal from compound- treated samples relative to vehicle-treated controls. All assays were performed in triplicate, and the values shown in FIGS. 4A-4C are the average of 2-3 independent experiments.
  • FIGS. 4A-4C are the average from at least three independent experiments.
  • Example 8 Structurally Novel Antiestrogens Suppress Growth of Breast Cancer Cells with Constitutively Active Mutant ERa
  • FIG. 10A Three new antiestrogens disclosed herein were first examined for their effects in T47D cells containing all wild type ER or all mutant ER (Y537S or D538G) (FIG. 10A).
  • the mutant ERs were introduced by knockin using CRISPR-Cas9 technology (Mao et. al. Scientific reports 2016, 6:34753).
  • the mutants examined are two of the most commonly occurring mutant ERa's in humans with breast cancer, namely Y537S and D538G.
  • the mutants showed high constitutive activity in the absence of estrogen, having 11 -times and four-times higher proliferative activity than that of cells containing wild type (WT) ER.
  • Treatments with the known antiestrogens fulvestrant (Fulv) or AZD9496 resulted in marked suppression of this constitutive activity in both mutants.
  • All three of the new compounds disclosed herein fully suppressed proliferative activity of the D538G cells, whereas in Y537S cells, good suppression was brought about by K-62 but to only a more limited extent by the K-07 and K-09 compounds.
  • E2 FIG. 10B
  • Fluorescence Resonance Energy Transfer (FRET) analysis indicated that antiestrogen compounds K-07, K-09, K-62 and trans-hydroxy-tamoxifen (TOT) suppress the binding of SRC3 to wild type ER, Y537S-ER, and D538G-ER, in a dose dependent fashion (FIG. 26).
  • FRET Fluorescence Resonance Energy Transfer
  • E2 increased the interaction of ER and SRC3, and show increased FRET
  • K-07, K-09, K-62 and TOT reduced the interaction of E2-ER and SRC3 and, as such, show reduced FRET
  • WT and mutant ERs required different E2 concentrations to be primed to ca. 50% activity (shown in brackets), reflecting their differing levels of constitutive activities and differing affinities for E2.
  • Table 2 summarizes the binding affinity of these ligands to WT, Y537S and D538G ERs.
  • antiestrogens bound about 10-40x less well to these mutant ERs vs. WT ER.
  • E2 was also found to bind 7x less well to the mutants.
  • Example 11 Antiestrogenic Compounds Differentially Downregulate WT and Mutant ERa Proteins in Cells
  • K-07 and K-09 worked more effectively as growth suppressors in MCF7 cells with mutant ERs, whereas Fulv was somewhat more potent in T47D cells with mutant ERs (FIG. 19).
  • the present compounds and Fulv could reduce the ER protein level in these MCF-7 and T47D cells, with Fulv generally eliciting a somewhat greater magnitude of down-regulation (FIG. 20).
  • Example 13 Structurally Novel Compounds Inhibit Tumor Growth of Wild Type and Mutant ER-containing Breast Cancer Cells In Vivo
  • mice were injected with cells sc into the mammary fat pad and compounds or Fulv were then administered daily sc at 80 mg/kg per day (FIG. 14). All compounds reduced tumor growth, with K-09 and K-62 being as effective as Fulv, and K-07 being the most effective in growth suppression (FIGS. 14A-14B). All compounds greatly reduced expression of the GREBl and PGR genes monitored in tumors harvested at day 26 (FIG. 14C).
  • K-09 and K-62 had long half-lives after sc injection, their blood levels were much lower compared with those of compound K-07. Because of its especially high blood levels and long half-life (97.2 h) after oral administration, K-07 was used by oral gavage in subsequent tumor growth experiments.
  • Example 15 K-07 is a Potent Oral Inhibitor of Tumor Progression In Vivo
  • Example 16 Y537S-ER and D538G-ER-containing Cells Form Tumors in the Absence of Estrogen that are Arrested by K-07 Treatment
  • Y537S-ER and D538G-ER-containing cells form tumors in the absence of estrogen and are arrested by K-07 treatment to mirror the low estrogen environment in postmenopausal women
  • tumor xenograft studies with Y537S and D538G-containing MCF7 cells were conducted in ovariectomized NSG mice in the absence of any added E2.
  • Y537S and D538G tumors grew well under these conditions, and growth of these constitutively active tumors was acutely arrested by subcutaneous treatment with K-07, as effectively as by fulvestrant (FIGS. 17 A, 17B and 28A).
  • oral K-07 was also very effective in arresting growth of the mutant ER tumors (FIG.
  • Example 17 Additional Compounds and Their Biological Activities
  • K t ( rf [estradiol]/RBA) ⁇ 100.
  • K d for estradiol is 0.2 nM.
  • A1 2 0 3 was added to the CH 2 C1 2 solution of methyl 2-cyanoacetate and benzaldehyde.
  • the reaction mixture was kept strirring at 65 °C until dry. Purified by silica column. Then add 1M NaOH and MeOH, until TLC analysis indicated the end of the reaction, neutralized with HCl (10% aq.), washed with water and dried, providing the cyanoacrylic acid 34.
  • a THF suspension of Zn metal and TMSC1 was stirred under a nitrogen atmosphere for about 15 min at 50°C.
  • a mixture of trichloroacetate and benzaldehyde was dissolved in THF and then was slowly added to the suspended solution.
  • the reaction mixture was then stirred for about 3h.
  • the mixture was poured into saturated aqueous ammonium chloride solution, then purified by silica column. Then add 1M NaOH and MeOH, until TLC analysis indicated the end of the reaction, neutralized with HC1 (10% aq.), washed with water and dried, providing the chloroacrylic acid product 35.
  • R 3 is selected from -H, -Me, and -isopropyl.
  • Ethyl (E)-3-(4-(((lr,3r,5R,7S)-adamantan-2-ylidene)(4- hydroxyphenyl)methyl)phenyl) acrylate was dissolved in CH2CI2 and methanol (1 :2). The resulting solution was cooled to 0 °C, and hydroxylamine (30 equiv) was added, followed by sodium hydroxide (10.0 equiv). The reaction was warmed to room temperature and kept stirring for 12 h. After complete consumption of starting material, ethyl acetate was added, and the resulting solution was washed with brine. The organic layer was dried with anhydrous Na 2 SC"4 and concentrated under vacuum.
  • Lawesson' s reagent (3.0 equiv) was added to a toluene solution of (E)-3-(4- (((lr,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl) phenyl)-N-butylacrylamide (1.0 equiv).
  • the reaction mixture was kept stirring at 90 °C overnight.
  • the resulting residue was purified by flash chromatography (10-80% ethyl acetate/hexane gradient) on silica gel to give 47 as brown solid.
  • the compound 54 was obtained from the (5R,7R,E)-2-((4-bromo-2,6- difluorophenyl)(4-methoxyphenyl)methylene)adamantine and ethyl acrylate and subsequently deprotecting reaction as described to make compound 53.
  • the o-fluorophenyl acrylic acid dervative 55 was obtained from the Heck coupling reaction using (5R, 7R,i!r)-2-((4-bromo-3-fluorophenyl)(4-methoxyphenyl)methylene)adamantane and ethyl acrylate and subsequently deprotecting reaction as described to make compound 53.
  • the o-trifluoromethylphenyl aldehyde derivative was prepared from the reaction of (5R,7R,E)-2-((4-bromo-3-(trifluoromethyl)phenyl)(4-methoxyphenyl)methylene)adamantine (60 mg, 0.13 mmol), n-BuLi (157 ⁇ ⁇ , 1.6 M n-hexane), and DMF (20 mg, .28 mmol) as described to prepare for 4-((E)-((5R,7R)-adamantan-2-ylidene)(4-methoxyphenyl)methyl)-3- fluorobenzaldehyde.
  • the picolinic acid derivative 58 was obtained from the Heck coupling reaction using 5-((E)-((5R,7R)-adamantan-2-ylidene)(4-methoxyphenyl)methyl)-2-bromopyridine and ethyl acrylate and subsequently deprotecting reaction as described to make compound 53.
  • Step 1 The corresponding triflate was reacted with ethyl acrylate following the general Heck reaction procedure.
  • the reaction mixture was cooled and extracted with ethyl acetate and washed with water and brine. The organic layer was dried with anhydrous Na 2 S0 4 and concentrated under vacuum.
  • Step 2 The crude product was dissolved in methanol. A 2M NaOH solution (2 mL) was added dropwise. The reaction was monitored by TLC and quenched by 1 N HCl/ice water. After stirring for 10 min, the mixture was extracted with ethyl acetate. The organic layers were collected and purified by flash column chromatography to give compound 59 as a yellow powder.
  • Step 1 The mixture of bromo compound (111 mg, 0.27 mmol), potassium vinyltrifluoroborate (40 mg, 0.3 mmol), Pd(PPh 3 ) 2 Cl 2 (5 mg, 7.1 ⁇ ), Cs 2 C0 3 (100 mg, 0.31 mmol) in THF (2 mL) and H 2 0 (100 ⁇ .) under argon was heated up in a 5 mL sealed vial at 80 °C for 8 hr. The reaction mixture was loaded Si02 column directly. Eluent with 10% EtOAv in n-Hexane (v/v) afforded the styrene compound (75 mg) of which TLC spot monitored as blue fluorescence and slightly lower Rf than a starting material.
  • Step 2 To the mixture of styrene (71 mg, 0.20 mmol) and catalytic amount of Rhodium(II) acetate dimer in DCM (500 ⁇ .) was add dropwise an ethyl diazoacetate (13 wt.% DCM, 300 ⁇ g) at 0 °C. Once bubbling was stopped from solution, the reaction mixture was loaded on the Si0 2 preparative TLC (Analtech, 1000 micron) and developed with 10% ethyl acetate/n-Hexane to separate cis (30 mg) and trans (30 mg) isomer.
  • ethyl diazoacetate 13 wt.% DCM, 300 ⁇ g
  • Step 3 Each isomer (20 mg, 0.05 mmol) was dissolved into DCM (500 ⁇ .) and treated with BF 3 -SMe 2 (200 ⁇ .) at rt. After stirring the reaction mixture for 3 h, the solvent was evaporated, followed by addition of 25 wt.% aqueous NaOH (100 ⁇ .), sonication for 20 min, and an adjustment of pH to ⁇ 3 with 6N HCI to collect each 66 (15 mg) and 67 (13 mg).
  • the compounds were initially screened in ERa-positive MCF-7 breast cancer cells for their suppression of cell proliferation (CP) and for their effects on ERa levels, using a single, saturating concentration of 3 ⁇ , as shown in FIGS. 23 and 24.
  • the antiestrogen and SERD, fulvestrant (Fulv) was included for comparison.
  • the levels of suppression of proliferation and downregulation of ERa were plotted on percent scales.
  • the activity in suppressing cell proliferation (CP, FIG. 23) was calculated as a percent of vehicle control; maximum suppression is ca. 0% (corresponding to essentially no increase in cell number after 6 days).
  • 0% is the ERa level after 24 h with 3 ⁇ fulvestrant treatment, with 100% being the ERa level in vehicle control cells.
  • WST-1 assay (Roche, Basel, Switzerland) was used to quantify cell viability after a 6 day exposure to compounds, as described. Absorbance was measured at 450 nm using a VICTOR X5 PerkinElmer 2030 Multilabel Plate Reader, and cell proliferation values represent signal from compound-treated samples relative to vehicle-treated controls.
  • 926-41090 were diluted (1 :600) for incubation with cells. Plates were washed, and ERa staining signals were quantified and normalized with Cell Tag signals using LI-COR Odyssey infrared imaging system. The ERa protein levels were calculated relative to the vehicle-treated samples.
  • results in FIG 23 show that certain compounds (38, 39, and 44) are very effective in suppressing proliferation, whereas others (36, 40, 45, 46, 51, 53, 54, and 58) show more moderate proliferation suppression; some (37, 42, 43, 48, 49, 50, 52, 60, 61, and 62) are only minimally suppressive.
  • results in FIG 24 show that compounds 53, 54, and 58 are most effective in downregulating ERa levels, and compounds 36, 37, 38, 39-46, and 59-62 are moderately effective in ERa downregulation.
  • Example 18 Suppression of breast cancer metastasis and extension of host animal survival by K-07 in a pre-clinical breast cancer metastasis model driven by constitutively active mutant estrogen receptors
  • mice after intracardiac injection into NOD-SCID-gamma (NSG) female mice with 0.5 x 10 6 MCF-7 breast cancer cells expressing luciferase and D538G ER (ca. 50% mutant ER and 50% wild type ER). Following injection mice were treated 6-times per week with vehicle or K-07 (80 mg/kg orally for 30 days and then 40 mg/kg). The reduced tumor burden in K-07 treated animals is evident from the reduce bioluminescence signal observed at Day 25 (FIG. 29B). As shown in FIG. 29C, shows animal survival increased with K-07 treatment.
  • MCF-7 breast cancer cells expressing luciferase and Y537S ER or D538G ER were also injected i.v. by the tail vein into NOD-SCID- gamma (NSG) female mice.
  • NSG NOD-SCID- gamma
  • the constitutively active ER-containing breast cancer cells established metastases in liver, bone and brain that increased in number and size over time (day zero - 80 days) as monitored by IVIS imaging and immunohistochemical (IHC) analysis (FIGS. 30A, 30B and 31 A).

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Abstract

Les 1,1-diarylméthylcycloalcanylidiènes sont des anti-œstrogènes ayant une utilité dans le traitement du cancer, y compris le cancer du sein récurrent et les tumeurs positives au récepteur des œstrogènes, sensibles à l'endocrinothérapie ou les tumeurs résistant à l'endocrinothérapie.
PCT/US2018/024144 2017-03-24 2018-03-23 Anti-œstrogènes de thérapie du cancer du sein WO2018175965A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019199863A1 (fr) 2018-04-10 2019-10-17 The Board Of Trustees Of The University Of Illinois Compositions à base d'un inhibiteur de foxm1 et procédés d'utilisation correspondantes
CN112218845A (zh) * 2018-04-10 2021-01-12 伊利诺伊大学理事会 Foxm1抑制剂组合物及其使用方法
JP2021521164A (ja) * 2018-04-10 2021-08-26 ザ・ボード・オブ・トラスティーズ・オブ・ザ・ユニバーシティ・オブ・イリノイＴｈｅ Ｂｏａｒｄ Ｏｆ Ｔｒｕｓｔｅｅｓ Ｏｆ Ｔｈｅ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｉｌｌｉｎｏｉｓ Ｆｏｘｍ１阻害剤組成物およびこれを使用する方法

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