Novel substituted quinoline and tetrahydronaphthalenecarboxylic acid derivatives and their therapeutic uses

Abstract

Disclosed herein is a compound or a pharmaceutically acceptable salt thereof, particularly a hydrochloride thereof, characterized in that the compound is selected from the following compounds: 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylic acid (1), 3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)quinoline-7-carboxylic acid (2), and (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (3). Further disclosed are processes for their preparation, pharmaceutical compositions containing them and said compounds of formula (I) for use as inhibitors and degraders of estrogen receptors, particularly in the treatment of ovulation disorders, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

Description

[Technical Field]

[0001] Disclosed herein are novel substituted quinoline and tetrahydronaphthalenecarboxylic acid derivatives, processes for their preparation and their therapeutic use, particularly as anti-cancer agents through selective antagonism and degradation of estrogen receptors. [Background technology]

[0002] Estrogen receptors (ERs) belong to the steroid / nuclear receptor superfamily, which are involved in the regulation of eukaryotic gene expression and cell proliferation in target tissues. There are two types of ERs: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), encoded by the ESR1 and ESR2 genes, respectively. ERα and ERβ are ligand-activated transcription factors activated by the hormone estrogen (17β-estradiol is the most potent estrogen produced in the body). In the absence of hormone, ERs reside primarily in the cytosol of cells. Upon binding of the hormone estrogen, ERs translocate from the cytosol to the cell nucleus, where they form dimers and then bind to specific genomic sequences called estrogen response elements (EREs). The DNA / ER complex interacts with coregulators to regulate the transcription of target genes.

[0003] ERα is mainly expressed in reproductive tissues such as the uterus, ovaries, and breast, as well as in bone and white adipose tissue. Aberrant ERα signaling contributes to the development of various diseases, including cancer, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammatory diseases, and osteoporosis.

[0004] ERα is expressed in less than 10% of normal breast epithelium, but approximately 50–80% of breast tumors. Breast tumors with such high levels of ERα are classified as ERα-positive breast tumors. The pathogenic role of estrogen in breast cancer is well documented, and modulating ERα signaling remains the mainstay of breast cancer treatment for the majority of ERα-positive breast tumors. Currently, several strategies exist to inhibit the estrogen pathway in breast cancer, including: 1) blockade of estrogen synthesis with aromatase inhibitors, which are used to treat patients with early-stage and advanced ERα-positive breast cancer; 2) antagonism of estrogen ligand binding to ERα with tamoxifen, which is used to treat patients with ERα-positive breast cancer in both premenopausal and postmenopausal settings; and 3) antagonism of ERα and downregulation of ERα levels with fulvestrant, which is used to treat patients whose breast cancer has progressed despite endocrine therapy, such as tamoxifen or aromatase inhibitors.

[0005] Although these endocrine therapies have contributed significantly to the prevention of breast cancer, approximately one-third of ERα-positive patients develop de novo resistance or acquire resistance over time to these existing therapies. Several mechanisms have been described to explain resistance to such hormone therapy, including the hypersensitivity of ERα to reduced estrogen levels following aromatase inhibitor treatment, the switch from antagonistic to agonistic effects of tamoxifen during tamoxifen treatment, and the presence of multiple growth factor receptor signaling pathways. Acquired mutations in ERα after the initiation of hormone therapy may also contribute to treatment failure and cancer progression. Certain mutations in ERα, particularly those identified in the ligand-binding domain (LBD), confer the ability to bind DNA even in the absence of ligand, rendering cells bearing such mutated receptors hormone independent.

[0006] Most identified mechanisms of endocrine therapy resistance are based on ERα-dependent activity. One novel strategy to combat such resistance is to block ERα signaling by removing ERα from tumor cells using selective estrogen receptor degraders (SERDs). Clinical and preclinical data indicate that the use of SERDs can circumvent a significant number of resistance pathways.

[0007] There remains a need to provide SERDs with good decomposition efficiency.

[0008] Documents WO 2017 / 140669 and WO 2018 / 091153 disclose several substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)-pyrrolidine derivatives useful in SERDs. Summary of the Invention [Means for solving the problem]

[0009] The present inventors have now discovered novel compounds capable of selectively antagonizing and degrading estrogen receptors (SERD compounds) for use in cancer therapy.

[0010] In this specification, 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylic acid (1), 3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)quinoline-7-carboxylic acid (2), and - (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (3) or a pharmaceutically acceptable salt thereof, particularly the hydrochloride salt thereof.

[0011] Other embodiments include: 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylic acid (1), and - (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (3) or a pharmaceutically acceptable salt thereof, particularly the hydrochloride salt thereof.

[0012] The compounds (1), (2) or (3), particularly the compounds (1) and (3), may contain one or more asymmetric carbon atoms and therefore may exist in enantiomeric forms.

[0013] The compounds (1), (2) or (3), particularly the compounds (1) and (3), may also exist in the form of tautomers.

[0014] The compounds (1), (2), or (3), particularly the compounds (1) and (3), can exist in the form of a base, an acid, a zwitterion, or an addition salt with an acid or a base. Accordingly, the present invention provides the compounds or pharmaceutically acceptable salts thereof.

[0015] These salts can be prepared with pharmaceutically acceptable acids or bases, although other acid or base salts useful, for example, in the purification or isolation of the compounds are also provided.

[0016] Among the suitable salts of said compounds, mention may be made of the hydrochloride salts.

[0017] Another embodiment is a compound selected from the list above, or a pharmaceutically acceptable salt thereof, for use in therapy, particularly as an inhibitor and degrader of the estrogen receptor.

[0018] Another embodiment is a compound selected from the list above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, particularly breast cancer.

[0019] Another embodiment is a method of inhibiting and degrading estrogen receptors, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharmaceutically acceptable salt thereof.

[0020] Another embodiment is a method for treating ovulatory disorders, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above or a pharmaceutically acceptable salt thereof.

[0021] Another embodiment is a method of treating cancer, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the list above, or a pharmaceutically acceptable salt thereof.

[0022] Another embodiment is a pharmaceutical composition comprising, as an active ingredient, an effective dose of a compound selected from the list above or a pharmaceutically acceptable salt thereof, as well as at least one pharmaceutically acceptable excipient.

[0023] The compounds provided herein can be prepared by the following process.

[0024] The compounds provided herein are synthesized using the techniques and materials described below or other techniques and materials known to those skilled in the art. Additionally, the solvents, temperatures, and other reaction conditions shown below can be varied as deemed appropriate by those skilled in the art. DETAILED DESCRIPTION OF THE INVENTION

[0025] The following abbreviations and empirical formulas are used: NH4Cl Ammonium chloride CO Carbon monoxide DCM dichloromethane DIEA N,N-Diisopropylethylamine DMF N,N-dimethylformamide DMAP dimethylaminopyridine DMSO dimethyl sulfoxide LiOH Lithium hydroxide MeOH Methanol MgSO4 Magnesium Sulfate NaH sodium hydride THF tetrahydrofuran RT room temperature

[0026] 1 H NMR spectra were acquired at 400 and 500 MHz using a Bruker Avance DRX-400 and a Bruker Avance DPX-500 spectrometer, respectively. Dimethylsulfoxide-d6 (d6-DMSO) was used as the solvent, and chemical shifts (δ in ppm) were referenced to 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0027] Liquid chromatography / mass spectra (LC / MS) were acquired on a UPLC Acquity Waters instrument, a Sedere light scattering detector, and an SQD Waters mass spectrometer. UV detection (210–400 nm) was performed using a DAD. A flash Acquity UPLC CSH C18 (1.7 μm, dimensions 2.1 × 30 mm) was used with the mobile phases HO + 0.1% HCOH / CHCN + 0.1% HCOH.

[0028] Tables 1a and 1b below each list specific compounds (names and structures) provided herein in accordance with the present disclosure, along with their characterization ( 1 H NMR and liquid chromatography / mass spectrometry).

[0029] [Table 1]

[0030] [Table 2]

[0031] In this specification, [ka] Further provided is a compound selected from: or any pharmaceutically acceptable salt thereof.

[0032] The following examples describe the preparation of compounds provided herein. The numbers of the compounds exemplified below correspond to the numbers shown in Table 1 above. Unless otherwise specified, all reactions are carried out in an inert atmosphere.

[0033] In the following examples, unless the source of a starting product is specified, it is to be understood that said product is a known compound. [Example]

[0034] Example 1: 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylic acid [ka] Step 1: (4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)(7-hydroxy-3-(4-(trifluoromethyl)phenyl)quinolin-4-yl)methanone [ka] 60% NaH (0.23 g, 5.8 mmol) was added to a mixture of 3-[2-fluoro-4-(trifluoromethyl)phenyl]-4-(4-fluorobenzoyl)quinolin-7-ol (prepared according to WO 2020 / 014440) (0.5 g, 1.2 mmol) and 1-(3-fluoropropyl)azetidin-3-ol (commercially available) (0.33 g, 2.5 mmol) in DMF (6 ml). The mixture was heated at 40° C. for 2 hours. After cooling to RT, the crude mixture was concentrated under reduced pressure. To the resulting residue were added DCM (20 ml) and water (10 ml). After decantation, the organic phase was dried over MgSO, filtered and concentrated under reduced pressure, and the resulting residue was purified by flash chromatography eluting with MeOH / DCM with a gradient of 100 / 00 to 98 / 02 to give 231 mg (37%) of (4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)(7-hydroxy-3-(4-(trifluoromethyl)phenyl)quinolin-4-yl)methanone. LC / MS(m / z,MH+):543

[0035] Step 2: 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinolin-7-yl trifluoromethanesulfonate [ka] Trifluoromethanesulfonic anhydride (144 mg, 86 μL, 0.51 mmol) was added to a mixture of (4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)(7-hydroxy-3-(4-(trifluoromethyl)phenyl)quinolin-4-yl)methanone (231 mg, 0.43 mmol) and DMAP (104 mg, 0.85 mmol) in DCM (15 ml) and cooled to −10° C. The reaction mixture was stirred at −10° C. for 1 h. The crude mixture was quenched with aqueous NH4Cl (5 ml). After decantation, the organic phase was washed with water (5 ml), dried over MgSO, filtered and concentrated under reduced pressure to give 171 mg (crude) of 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinolin-7-yl trifluoromethanesulfonate, which was used directly in the next step. LC / MS(m / z,MH+):675

[0036] Step 3: methyl 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylate [ka] In a stainless steel pressure vessel, a mixture of 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinolin-7-yl trifluoromethanesulfonate (171 mg, 0.25 mmol), DMAP (93 mg, 0.76 mmol), palladium diacetate (29 mg, 0.13 mmol), and 1,3-bis(diphenylphosphino)propane (63 mg, 0.15 mmol) in MeOH (12 ml) was exposed to CO at 20 bar pressure and heated at 100 °C for 23 h. The crude solution was concentrated under reduced pressure and diluted with DCM (20 ml) and water (10 ml). After decantation, the organic phase was dried over MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with MeOH / DCM with a gradient of 100 / 00 to 98 / 02 to give 86 mg (58%) of methyl 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylate. LC / MS(m / z,MH+):585

[0037] Step 4: 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylic acid [ka] A mixture of methyl 3-[2-fluoro-4-(trifluoromethyl)phenyl]-4-(4-{[1-(3-fluoropropyl)azetidin-3-yl]oxy}benzoyl)quinoline-7-carboxylate (86 mg, 0.15 mmol) and LiOH (78 mg, 3.2 mmol) in THF (4 mL) and water (4 mL) was stirred at 60 °C for 30 min. After cooling to RT, acetic acid (0.18 mL, 3.18 mmol) was added and the mixture was concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with MeOH / DCM with a gradient of 100 / 00 to 95 / 05 to give 45 mg (54%) of 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylic acid.

[0038] Example 2: 3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)quinoline-7-carboxylic acid [ka] Step 1: 4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinolin-7-yl trifluoromethanesulfonate [ka] Step 1 of Example 2 was prepared according to a procedure similar to that of Step 2 of Example 1, to obtain 200 mg (crude) of 4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)(7-hydroxy-3-(4-(trifluoromethyl)phenyl)quinolin-4-yl)methanone (prepared according to WO 2020 / 014440) and trifluoromethanesulfonic anhydride, which was used directly in the next step. LC / MS(m / z,MH+):675

[0039] Step 2: methyl 4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylate [ka] In a stainless steel pressure vessel, a mixture of 4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinolin-7-yl trifluoromethanesulfonate (200 mg, 0.30 mmol), DIEA (79 mg, 0.61 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg, 0.02 mmol), and 1,3-bis(diphenylphosphino)propane (63 mg, 0.15 mmol) in MeOH (2 mL) and DMF (4 mL) was exposed to CO at 5 bar pressure and heated at 70 °C for 5 h. The crude solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. To the resulting residue were added DCM (10 mL) and water (10 mL). After decantation, the organic phase was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with MeOH / DCM with a gradient of 100 / 00 to 95 / 05 to give 95 mg (55%) of methyl 4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylate). LC / MS(m / z,MH+):585

[0040] Step 3: 3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)quinoline-7-carboxylic acid [ka] Step 3 of Example 2 was prepared according to a procedure similar to that of Step 4 of Example 1 to give 71 mg (77%) of 3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)quinoline-7-carboxylic acid from methyl 4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)quinoline-7-carboxylate.

[0041] Example 3: (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid [ka] Step 1: (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate [ka] Step 1 of Example 3 was prepared according to a procedure similar to that of Step 2 of Example 1, whereby (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (prepared according to EP 1557288) and trifluoromethanesulfonic anhydride was used to obtain 330 mg (crude) of (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate, which was used directly in the next step. LC / MS(m / z,MH+):591

[0042] Step 2: (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate methyl [ka] Step 2 of Example 3 was prepared according to a procedure similar to that of Step 2 of Example 2 to give 27 mg (9%) of methyl (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate from (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-yl trifluoromethanesulfonate. LC / MS(m / z,MH+):501

[0043] Step 3: (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid [ka] Step 3 of Example 3 was prepared according to a procedure similar to that of Step 4 of Example 1, to give 25 mg (98%) of (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid from methyl (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate.

[0044] The compounds according to Table 1 above were subjected to pharmacological testing to determine their degrading effect on the estrogen receptor.

[0045] Test: Estrogen receptor degrading activity The test involves measuring the in vitro degradation activity of the compounds of Table 1.

[0046] The degradation activity was measured using ERα from breast cancer cells by the in cell western assay described below.

[0047] MCF7 cells (ATCC) were seeded in 384-well microplates (collagen-coated) at a concentration of 10,000 cells / 30 μL per well in phenol red-free MEM alpha medium (Invitrogen) containing 5% charcoal dextran-stripped FBS. The following day, 2.5 μL of each compound was added to the cells in nine 1:5 serial dilutions to final concentrations ranging from 0.3 to 0.0000018 μM (Table 2) or 0.1 μM fulvestrant (used as a positive control). Four hours after compound addition, cells were fixed for 10 minutes at room temperature by adding 25 μL of formalin (final concentration 5% formalin, containing 0.1% Triton) and then washed twice with PBS. Next, 50 μL of LI-COR blocking buffer containing 0.1% Triton was added to the plate and allowed to stand at room temperature for 30 minutes. The LI-COR blocking buffer was removed, and the cells were incubated overnight in a cold room with 50 μL of anti-ER rabbit monoclonal antibody (Thermo Scientific MA1-39540) diluted 1:1000 in LI-COR blocking buffer containing 0.1% Tween-20. Antibody-free wells treated with blocking buffer were used as background controls. The wells were washed twice with PBS (0.1% Tween-20) and incubated for 60 minutes at 37°C in LI-COR (0.1% Tween-20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and DNA stain Syto-64 (final concentration 2 μM). The cells were then washed three times with PBS and scanned using an ACUMEN explorer (TTP-Labtech). The integrated intensity of green and red fluorescence was measured to determine ERα and DNA concentrations, respectively.

[0048] In this test, the degrading activity against estrogen receptors was measured as the concentration at which 50% of the estrogen receptors were degraded (or IC 50 ) (in nM).

[0049] The decrease (%) in ERα concentration was calculated as follows: inhibition rate (%)=100×(1−(sample−fulvestrant:DMSO−fulvestrant)).

[0050] Table 2 below shows the estrogen receptor degrading activity of the compounds in Table 1 tested at 0.3 μM, and the results show that the compounds have significant degrading activity against the estrogen receptor.

[0051] [Table 3]

[0052] Therefore, it is clear that the test compound has the decomposition activity against estrogen receptor, with IC50 of less than 1 μM and the decomposition rate of more than 50%.Therefore, the compounds provided herein can be used as medicines, particularly medicines that are decomposing agents of estrogen receptors.

[0053] Therefore, there is also provided herein a medicament comprising a compound as defined above or a pharmaceutically acceptable salt thereof.

[0054] There is also provided herein a compound as defined above, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

[0055] There is also provided herein a compound as defined above, or a pharmaceutically acceptable salt thereof, for use in therapy, in particular as an inhibitor and degrader of the estrogen receptor.

[0056] There is also provided herein a compound as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulatory disorders, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

[0057] A particular embodiment is a compound as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0058] In one embodiment, the cancer is a hormone-dependent cancer.

[0059] In other embodiments, the cancer is an estrogen receptor dependent cancer, and in particular, the cancer is an estrogen receptor alpha dependent cancer.

[0060] In other embodiments, the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, cervical cancer, and lung cancer or metastases thereof.

[0061] In another embodiment, the metastasis is a cerebral metastasis.

[0062] In other embodiments, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0063] In other embodiments, the cancer is antihormone refractory.

[0064] In further embodiments, the compounds provided herein are used alone or in combination with other agents, such as CDK4 / 6, mTOR, or PI3K inhibitors.

[0065] According to another aspect, also provided herein is a method of treating the above-noted pathological conditions, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof. In one embodiment of this method of treatment, the subject is a human.

[0066] Also provided herein is the use of a compound as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in the treatment of any of the pathological conditions indicated above, more particularly useful in the treatment of cancer.

[0067] Also provided herein are pharmaceutical compositions containing the compounds defined above as active ingredients, which contain an effective dose of at least one compound defined above or a pharmaceutically acceptable salt thereof, as well as at least one pharmaceutically acceptable excipient.

[0068] The excipients are selected from conventional excipients known to those skilled in the art according to the desired dosage form and method of administration.

[0069] The active ingredient as defined above or its base, acid, zwitterion or salt thereof in unit dosage form in a mixture with conventional pharmaceutical excipients in pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration can be administered to animals and humans for the treatment of the above-mentioned disorders or diseases.

[0070] Suitable unit dosage forms include oral forms such as tablets, soft or hard gel capsules, powders, granules, and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular, intranasal dosage forms, forms for inhalation, topical, transdermal, subcutaneous, intramuscular, intravenous administration, rectal dosage forms, and indwelling agents. For topical application, the compounds provided herein can be used as creams, gels, ointments, or lotions.

[0071] As an example, a unit dosage form of a tablet of the compounds provided herein may contain the following ingredients: 50.0 mg of a compound provided herein Mannitol 223.75mg Croscarmellose sodium 6.0mg Corn starch 15.0mg Hydroxypropyl methylcellulose 2.25mg Magnesium stearate 3.0mg

[0072] There may be particular cases in which higher or lower dosages are appropriate. According to practice, the dosage appropriate for each patient is determined by the physician according to the mode of administration and the weight and response of said patient.

Claims

1. In the compound or a pharmaceutically acceptable salt thereof, particularly the hydrochloride salt thereof, said compound is the following compound: 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylic acid (1), 3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)quinoline-7-carboxylic acid (2), and (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (3) or a pharmaceutically acceptable salt thereof, in particular the hydrochloride thereof, characterized in that it is selected from:

2. The following compounds: 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylic acid (1), and (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (3) 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, in particular the hydrochloride salt thereof, selected from: 【Request 3】 【Chemical 1】 or any pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof.

5. 3. A pharmaceutical composition comprising the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

6. 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for use as an inhibitor and degrader of estrogen receptors.

7. 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulation disorders, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

8. 7. The compound or a pharmaceutically acceptable salt thereof for use according to claim 6 for use in the treatment of cancer.

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