WO2018130123A1 - Composé pentacyclique utilisé en tant que régulateur sélectif du récepteur des œstrogènes et son utilisation - Google Patents

Composé pentacyclique utilisé en tant que régulateur sélectif du récepteur des œstrogènes et son utilisation Download PDF

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WO2018130123A1
WO2018130123A1 PCT/CN2018/071699 CN2018071699W WO2018130123A1 WO 2018130123 A1 WO2018130123 A1 WO 2018130123A1 CN 2018071699 W CN2018071699 W CN 2018071699W WO 2018130123 A1 WO2018130123 A1 WO 2018130123A1
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group
alkyl
acyl
compound
amino
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PCT/CN2018/071699
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王勇
赵立文
张小猛
刘奇
徐岩
雷时海
王小伟
张雁
庞司林
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南京圣和药业股份有限公司
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07B2200/07—Optical isomers

Definitions

  • the compound of Formula I of the present invention is a compound of Formula Id, or an isomer thereof, a pharmaceutically acceptable salt, a solvate, a crystal, an isostere or a prodrug,
  • alkyl group of the present invention means a linear or branched saturated aliphatic hydrocarbon group, preferably a linear or branched group having 1 to 6 carbon atoms, further preferably a linear or branched having 1 to 3 carbon atoms.
  • Chain groups non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, and the like.
  • the alkyl group can be substituted or unsubstituted, and when substituted, the substituent can be at any point of attachment that can be used.
  • the "aryl” of the present invention means an aromatic system which may comprise a monocyclic or fused polycyclic ring, preferably a monocyclic or fused bicyclic aromatic system containing from 6 to 18 carbon atoms, preferably from about 6 to about 12 carbon atoms.
  • Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, anthracenyl, indanyl.
  • the aryl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any available point of attachment.
  • heteroaryl group of the present invention is preferably composed of 5 to 18 atoms (abbreviated as "5-18 membered heteroaryl group” or "C 5-18 membered heteroaryl group” in the present invention), further preferably A heteroaryl group having 5-12 atoms and at least one atom being a hetero atom.
  • Suitable five- to twelve-membered heteroaryl groups include, but are not limited to, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidopyrazolyl, pyrimidoimidazolyl, and the like.
  • the heteroaryl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be at any point of attachment that can be used.
  • the "isomer” of the present invention is a compound having the same molecular formula but differing in nature or on the bond sequence of its atom or in the spatial arrangement of its atoms.
  • Stereoisomers are isomers whose atoms are spatially distinct.
  • Stereoisomers that are not mirror images of each other are diastereomers and that the stereoisomers that are non-overlapping mirror images of each other are enantiomers.
  • a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • Enantiomers are characterized by the absolute configuration of their asymmetric centers and are described by Rahn and S-sequence rules of Cahn and Prelog, or by methods of rotating the plane of polarized light by molecules and designated as right-handed or left-handed ( That is, as (+) or (-)-isomers, respectively.
  • the chiral compound can exist as a single enantiomer or a mixture thereof.
  • An equal proportion of mixtures comprising enantiomers is referred to as a "racemic mixture".
  • the in vivo action of a compound of formula (I) can be exploited, in part, by one or more metabolites formed in the human or animal body following administration of a compound of formula (I).
  • the in vivo action of the compound of formula (I) can also be exerted via metabolism of the precursor compound ("prodrug").
  • the "prodrug” of the present invention refers to a compound which is converted into a compound of the formula (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in a living body, that is, a compound converted by oxidation, reduction, hydrolysis or the like of an enzyme.
  • the bioisostere of the present invention (or simply "e-isostere") is used to define that one or more of the atoms (or radicals) have been similarly spatially and/or electronically characterized by those atoms to which they are substituted.
  • a generally recognized term in the art of a drug analog substituted with an atom (or a group of atoms), such as an isostere of a carboxyl group of the present invention, may be an aminoacyl group, in particular, the isostere of the -COOH of the present invention may Is -CH 2 NH 2 .
  • the "pharmaceutically acceptable carrier” of the present invention means a carrier which does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes all solvents, diluents or other excipients, dispersing agents, Surfactant isotonicity agent, thickener or emulsifier, preservative, solid binder, lubricant, and the like. Unless any conventional carrier medium is incompatible with the compounds of the invention.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound.
  • Excipients can include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols.
  • the "use in a medicament for treating and/or preventing an estrogen receptor-associated disease" of the present invention means that an estrogen receptor-related disease can be improved, and growth, development and/or inhibition of an estrogen receptor-related disease can be suppressed. Or transferring, or reducing the risk of an estrogen receptor-related disease, primarily administering a therapeutically and/or prophylactically effective amount of a compound of the invention to a human or animal in need thereof to inhibit, slow or reverse the estrogen receptor in the subject
  • a body-related disease that improves or reduces the risk of estrogen receptor-related diseases, including diseases associated with estrogen receptor alpha and Diseases associated with estrogen receptor beta, such as cancers associated with estrogen receptor dysfunction (eg, bone cancer, breast cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, and uterine cancer), smoothing Fibroids (eg uterine leiomyoma, etc.), central nervous system (CNS) defects (eg alcoholism, migraine, etc.), cardiovascular system
  • CNS central
  • Serious depressive disorder, mental illness, etc. and reproductive defects (such as abnormal menarche age, endometriosis, infertility, etc.).
  • Step c Synthesis of (S)-2-amino-3-(1H-indol-3-yl)propan-1-ol
  • Step d Synthesis of (S)-benzyl-(1-hydroxy-3-(1H-indol-3-yl)propan-2-yl)carbamate
  • Step e Synthesis of (S)-2-(((benzyloxy)carbonyl)amino)-3-(1H-indol-3-yl)propyl-4-methylbenzenesulfonate
  • step b In a 250 mL reaction flask, the product obtained in step b was added 2-fluoro-2-methylpropyltrifluoromethanesulfonate (2 g, 30 mmol), (R)-1-(1H-indol-3-yl)propene 2-Amine (4.3g, 25mmol) and diisopropylethylamine (8.7mL, 50mmol), dissolved in 50mL dioxane, reacted under argon at 90 ° C for 2h, stop the reaction, concentrate, and purify by column chromatography The title compound was obtained. ESI-Ms m/z: 249.1 [M+H] + .
  • Step h Synthesis of 3',5'-difluoro-4'-formyl-[1,1'-biphenyl]-4-carboxylic acid methyl ester
  • the preparation method was similar to the preparation method of Example 1, except that the starting material 4-bromo-2,6-difluorobenzaldehyde was replaced with 4-bromo-2-chloro-6-fluorobenzaldehyde to give the title compound.
  • the preparation method was similar to the preparation method of Example 1, except that the starting material (4-(methoxycarbonyl)phenyl)boronic acid was replaced by (3-(methoxycarbonyl)phenyl)boronic acid to give the title compound.
  • 1 H NMR (400MHz, DMSO- d 6) ⁇ : 12.98 (s, 1H), 10.63 (s, 1H), 8.23-8.21 (d, 1H), 7.99-7.97 (m, 2H), 7.62-7.58 (m , 1H), 7.46 - 7.41 (d, 3H), 7.21 - 7.19 (d, 1H), 7.02 - 6.94 (d, 2H), 5.28 (s, 1H), 3.58 - 3.52 (m, 1H), 2.94 - 2.90 (m, 2H), 2.62 - 2.46 (m, 2H), 1.26 - 1.07 (m, 9H).
  • Step b Synthesis of (S)-1-fluoro-3-(1H-indol-3-yl)propan-2-amine
  • Step c Synthesis of (S)-2-fluoro-N-(1-fluoro-3-(1H-indol-3-yl)propan-2-yl)-2-methylpropan-1-amine
  • Example 12 3',5'-Difluoro-4'-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9 Synthesis of tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3-methoxy-[1,1'-biphenyl]-4-carboxylic acid
  • the preparation method is similar to the preparation method of Example 1, except that the starting material (4-(methoxycarbonyl)phenyl)boronic acid is replaced by (3-methoxy-4-(methoxycarbonyl)phenyl)boronic acid.
  • the title compound was obtained.
  • the preparation method is similar to the preparation method of Example 1, except that the starting material (4-(methoxycarbonyl)phenyl)boronic acid is replaced by (3-methoxy-4-(methoxycarbonyl)phenyl)boronic acid. And the starting material 4-bromo-2,6-difluorobenzaldehyde was replaced with 4-bromo-2,6-dichlorobenzaldehyde to give the title compound.
  • Example 18 3',5'-Difluoro-4'-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9 -tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-[1,1'-biphenyl]-4-carboxamide
  • the preparation method is similar to the preparation method of Example 1, except that the starting material (4-(methoxycarbonyl)phenyl)boronic acid is replaced by (3-methoxy-4-(methoxycarbonyl)phenyl)boronic acid. And the starting material 4-bromo-2,6-difluorobenzaldehyde was replaced with 4-bromo-2-chloro-6-fluorobenzaldehyde to give the title compound.
  • Example 20 6-(3-Fluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro -1H-pyrido[3,4-b]indol-1-yl)-5-methoxyphenyl)nicotinic acid
  • the preparation method is similar to the preparation method of Example 1, except that the starting material (4-(methoxycarbonyl)phenyl)boronic acid is replaced with 5-(methoxycarbonyl)-2-pyridineboronic acid, and the starting material is 4- The bromine-2,6-difluorobenzaldehyde was replaced with 4-bromo-2-methoxy-6-fluorobenzaldehyde to give the title compound.
  • Example 21 2-Chloro-3',5'-difluoro-4'-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3 ,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-6-methoxy-[1,1'-biphenyl]-4-carboxylic acid
  • the preparation method is similar to the preparation method of Example 1, except that the starting material (4-(methoxycarbonyl)phenyl)boronic acid is replaced by (3-methoxy-6-chloro-4-(methoxycarbonyl). Phenyl)boronic acid to give the title compound.
  • the preparation method was similar to the preparation method of Example 1, except that the starting material (4-(methoxycarbonyl)phenyl)boronic acid was replaced with 5-(methoxycarbonyl)-2-pyrimidineboronic acid to give the title compound.
  • 1 H NMR (400MHz, DMSO- d 6) ⁇ : 13.50 (s, 1H), 10.65 (s, 1H), 9.32 (s, 1H), 8.00-7.98 (m, 1H), 7.44-7.18 (m, 4H ), 7.08–6.88 (m, 2H), 5.30 (s, 1H), 3.55 (m, 1H), 2.96–2.91 (m, 2H), 2.63–2.59 (m, 1H), 2.41-2.37 (m, 1H) ), 1.30–1.25 (m, 9H).
  • methyl (S)-3-fluoro-2-methylpropanoate (2.3 g, 19.15 mmol) was added, dissolved in 100 mL of anhydrous tetrahydrofuran, and the reactor was cooled to about 0 ° C in a low temperature reactor.
  • Lithium aluminum hydride (0.78 g, 20.53 mmol) was slowly added. After the addition was completed, the reaction mixture was stirred at 0 ° C and room temperature for 1 h each. After the reaction was completed, sodium sulfate decahydrate was added portionwise, and the mixture was stirred for 1 hr.
  • reaction was carried out at 90 ° C for 2 h under argon. The reaction was quenched, concentrated and purified by column chromatography ESI-Ms m/z: 249.1 [M+H] + .
  • the preparation method is the same as the preparation method of the step cd of Example 23, except that the raw material (S)-3-fluoro-2-methylpropanol is replaced with 2,2-difluoro-2-methylpropyl-1-ol.
  • the title compound was obtained.
  • the preparation method was similar to the preparation method of the procedure of Example 23, except that the starting material (S)-N-((R)-1-(1H-indol-3-yl)propan-2-yl)-3- Replacement of fluoro-2-methylpropyl-1-amine with (R)-N-(1-(1H-indol-3-yl)propan-2-yl)-2,2-difluoropropyl-1 -Amine to give the title compound.
  • the control compound is the chemical name (E)-3-(3,5-difluoro-4-((1R,3R)-2-)) disclosed in Example 1 of WO 2014/191726 (PCT/GB2014/051607). -fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid
  • the compound (AZD9496) was prepared by the method described in WO 2014/191726 and identified by hydrogen spectroscopy and mass spectrometry.
  • phosphate buffer (DPBS), trypan blue, PolarScreen ER Alpha competitor Assay purchased from Invitrogen;
  • DMSO dimethyl sulfoxide
  • activated carbon Trimethyl sulfoxide (DMSO), activated carbon, Formaldehyde solution, purchased from Sigma;
  • Estrogen Receptor alpha (D8H8) Rabbit mAb, purchased from CST;
  • Tween 20 purchased from EIA GRADE.
  • Vortex mixer purchased from IKA;
  • Preparation of cell culture medium 50 mL of FBS, 5 mL of penicillin-streptomycin was added to 445 mL of DMEM, and mixed for use. Serum-free FBS was used in the preparation of serum-free cell culture media.
  • the cell-discarded culture medium in the logarithmic growth phase of the T75 cell culture flask was washed once with 10 mL of DPBS. Add 2 mL of trypsin-digested cells, and place at 37 ° C for 2 minutes. Observe most of the cells in a round shape under microscope. Add 5 mL of serum-free cell culture solution to stop digestion. Pipette repeatedly and digest the cells to make cell suspension. Add 10 mL of cell culture solution, mix and count, dilute to 1500 cells/40 ⁇ L of cell suspension, and place the cells into a 384-well cell culture plate with a Multiflow instrument, 40 ⁇ L/well; equilibrate at room temperature for 20 min. Incubate in a 37 ° C cell culture incubator for 24 h.
  • the compound was added to the cell culture plate with Acho instrument at a final concentration of 0.3% DMSO; it was centrifuged at 1000 rpm for 1 min at room temperature, and then cultured in a 37 ° C cell culture incubator for 24 h.
  • the cell culture medium was aspirated, the cells were washed once with PBS, and the cells were fixed with a final concentration of 3.7% paraformaldehyde solution (diluted in PBS) for 20 min at room temperature; the cells were washed twice with PBS and diluted with a final concentration of 0.5% Tween-20 (PBS).
  • the compounds of the present invention have a good inhibitory activity against ER levels based on cellular levels.
  • Test compound The compound of the present invention and the control compound prepared in the above examples, each compound was formulated into 10 mM with DMSO, and then diluted 3 times to 100.00 nM, 33.33 nM, 11.11 nM, 3.70 nM, 1.23 nM, 0.41 nM, 0.14 nM, 0.045 nM, 0.015 nM.
  • the breast cancer cell line MCF-7 was purchased from Nanjing Kaiji Biotechnology Co., Ltd.
  • MEM MEM, FBS, Trypsin-EDTA, Penicillin-Streptomycin, purchased from GIBCO, USA; Luminescent Cell Viability Assay Kit, purchased from Progema, USA; Paclitaxel, purchased from Sichuan Tai Chi Pharmaceutical Company.
  • Cultured expanded MCF-7 cells were trypsinized, resuspended in fresh medium and counted. The resuspended cells were adjusted to 2 ⁇ 10 4 cells/mL, and 96-well cell culture plates were added, and 100 ⁇ L of each well was added to each well. Incubate for 24 h at 37 ° C, 5% CO 2 .
  • the compound was formulated into 200 ⁇ working solution in DMSO, diluted to 2 ⁇ working solution with the culture solution, and then transferred to 100 ⁇ L to the test well, and incubated at 37° C. under 5% CO 2 for 96 h.
  • the compounds of the present invention showed good inhibitory activity against MCF-7 breast cancer cells.
  • Test compound The compound of the present invention and the control compound prepared in the above examples were prepared in an amount of 2 mg/kg for oral administration and 1 mg/kg for the test sample.
  • Balb/c mice were purchased from Beijing Weitong Lihua Experimental Animal Co., Ltd.
  • mice were orally administered with 2 mg/kg, and after a single dose of 1 mg/kg intravenously, blood was collected from the orbital venous plexus at 2 min, 5 min, 15 min, 30 min, 1 h, 2 h, 6 h, 10 h, 24 h, and centrifuged for plasma treatment.
  • the LC-MS/MS was used for the detection, and the measured blood concentration at each time point was plotted as a drug concentration-time curve, and the pharmacokinetic parameters were calculated.
  • Table 4 The experimental results are shown in Table 4.
  • MCF-7 breast cancer cells purchased from KGI were cultured in an MEM medium containing 10% fetal calf serum, 100 U/ml penicillin and 100 ⁇ g/ml streptomycin in a 37 ° C, 5% CO 2 incubator.
  • the initial concentration of the cell culture was 1 ⁇ 10 6 /mL, and the cells were subcultured every 3 to 4 days after the cells were over. Tumor cells in the logarithmic growth phase are used for inoculation of tumors in vivo.
  • a beta-estradiol sustained release tablet (Estradiol-17 ⁇ 60 days SE121 0.72 mg, purchased from Innovative Research of America) was inoculated into the left back of each mouse.
  • a beta-estradiol sustained release tablet (Estradiol-17 ⁇ 60 days SE121 0.72 mg, purchased from Innovative Research of America) was inoculated into the left back of each mouse.
  • the animals were urinated three times a week, and if necessary, the animals were urinated daily.
  • a PBS containing 10 ⁇ 10 6 cells was mixed with 100 ⁇ L of Matrigel (final volume 200 ⁇ L) to inoculate the right rear side of the mouse. 3.
  • Test compound The compound of the present invention and the control compound prepared in the above examples.
  • the compound of the present invention and the control compound were administered once daily (QD) for three weeks (3 W).
  • the experimental indicator is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameters were measured with vernier calipers three times a week.
  • the experimental results of the antitumor efficacy evaluation of the test compound on the human breast cancer cell line MCF-7 subcutaneous xenograft model are shown in Table 5.
  • the corresponding T/C (%) values of the compounds of the examples in the table are the respective examples.
  • the T/C (%) mean of the tumor volume calculated on the 21st day after administration of the animals in each dose group of the compound.
  • the experimental results show that, unexpectedly, the compound of the present invention has a significantly better antitumor effect against breast cancer than the positive drug AZD9496.
  • the compounds of Example 1, Example 5 and Example 24 of the present invention were significantly more effective than the same dose of AZD9496 at a dose of 0.6 mg/kg, and were more effective at a dose of 2 mg/kg than AZD9496 at a dose of 6 mg/kg. Drug effect.
  • Some of the compounds of the present invention produced an effect equivalent to the positive drug AZD9496 (0.6 mg/kg VS 6 mg/kg) at a tenth dose.

Abstract

La présente invention se rapporte au domaine de la chimie médicale et concerne un composé pentacyclique utilisé en tant que régulateur sélectif du récepteur des œstrogènes et son utilisation. La présente invention concerne particulièrement, un composé tel que représenté par la formule I ou un isomère, un sel pharmaceutiquement acceptable, un solvate, un cristal ou un promédicament de celui-ci. L'invention concerne également des procédés de préparation du composé, des compositions pharmaceutiques contenant ledit composé et une utilisation de ce composé ou de ces compositions pour le traitement et/ou la prévention de maladies associées au récepteur des œstrogènes. Le composé de la présente invention présente une meilleure activité antitumorale, un intervalle de dosage plus long et moins d'effets secondaires et semble être très prometteur en tant qu'agent thérapeutique contre le cancer du sein.
PCT/CN2018/071699 2017-01-11 2018-01-08 Composé pentacyclique utilisé en tant que régulateur sélectif du récepteur des œstrogènes et son utilisation WO2018130123A1 (fr)

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US11339162B1 (en) 2020-12-23 2022-05-24 Recurium Ip Holdings, Llc Estrogen receptor modulators

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WO2004030629A2 (fr) * 2002-10-01 2004-04-15 Predix Pharmaceuticals Nouveaux antagonistes de la neurokinine et leurs procedes d'utilisation
CN105229004A (zh) * 2013-05-28 2016-01-06 阿斯利康(瑞典)有限公司 化合物
WO2016097072A1 (fr) * 2014-12-18 2016-06-23 F. Hoffmann-La Roche Ag Modulateurs des récepteurs des oestrogènes tétrahydro-pyrido[3,4-b]indole et utilisations associées

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US11241418B2 (en) 2018-12-24 2022-02-08 InventisBio Co., Ltd. Salts of selective estrogen receptor degraders
US11903931B2 (en) 2018-12-24 2024-02-20 InventisBio Co., Ltd. Salts of selective estrogen receptor degraders
US11339162B1 (en) 2020-12-23 2022-05-24 Recurium Ip Holdings, Llc Estrogen receptor modulators

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