Novel substituted quinoline and tetrahydronaphthoic acid derivatives and therapeutic use thereof

Abstract

Disclosed herein is a compound or a pharmaceutically acceptable salt thereof, in particular a hydrochloride thereof, characterized in that the compound is selected from the group consisting of:-4-(4-((1-(3-fluoropropyl) azetidin-3-yl) oxy) benzoyl)-3-(4-(trifluoromethyl) phenyl) quinoline-7-carboxylic acid (1),-4-(4-(1-fluoropropyl) azetidin-3-yl) oxy) benzoyl)-3-(4-(trifluoromethyl) phenyl) quinoline-7-carboxylic acid (2); (2)-3-(2-fluoro-4-(trifluoromethyl) phenyl)-4-(4-(2-(3-(fluoromethyl) azetidine-1-yl) ethyoxyl) benzoyl) quinoline-7-formic acid, and (3)-6-(2-(ethyl (4-(2-(ethylamino) ethyl) benzyl) amino)-4-methoxyphenyl)-5, 6, 7, 8-tetrahydronaphthalene-2-formic acid. Further disclosed are processes for preparing the same, pharmaceutical compositions comprising the same and the compounds of formula (I) for use as inhibitors and degrading agents of estrogen receptors, in particular in the treatment of ovulation dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

Description

[0001] Disclosed herein are novel substituted quinoline and tetralincarboxylic acid derivatives, methods for their preparation, and their therapeutic uses, particularly as anticancer agents via selective antagonism and degradation of estrogen receptors.

[0002] Estrogen receptor (ER) belongs to the steroid / nuclear receptor superfamily involved in regulating eukaryotic gene expression, cell proliferation and target tissues. ER is in two forms: estrogen receptor α (ERα) and estrogen receptor β (ERβ) encoded by ESR1 and ESR2 genes, respectively. ERα and ERβ are ligand-activated transcription factors, which are activated by the hormone estrogen (the most potent estrogen produced in vivo is 17β-estradiol). In the absence of hormones, ER is mainly located in the cytosol of cells. When the hormone estrogen binds to ER, ER migrates from the cytosol of cells to the nucleus, forms a dimer, and then binds to a specific genomic sequence called an estrogen response element (ERE). DNA / ER complexes interact with co-regulators to regulate the transcription of target genes.

[0003] ERα is mainly expressed in reproductive tissues such as uterus, ovary, breast, bone and white adipose tissue. Abnormal ERα signaling leads to the development of a variety of diseases such as cancer, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammatory diseases and osteoporosis.

[0004] ERα is expressed in no more than 10% of normal breast epithelium, but is expressed in approximately 50%-80% of breast tumors. Such breast tumors with high levels of ERα are classified as ERα-positive breast tumors. The etiological role of estrogen in breast cancer is established, and regulation of ERα signaling remains an important approach to breast cancer treatment for most ERα-positive breast tumors. Currently, there are several strategies for inhibiting the estrogen axis in breast cancer, including: 1-Blocking estrogen synthesis through aromatase inhibitors for the treatment of early and late ERα-positive breast cancer patients; 2-Antagonizing estrogen ligand binding to ERα through tamoxifen for the treatment of ERα-positive breast cancer patients in both premenopausal and postmenopausal situations; 3-Antagonizing and downregulating ERα levels through Fulvestrant for the treatment of breast cancer in patients who have progressed despite endocrine therapy such as tamoxifen or aromatase inhibitors.

[0005] Although these endocrine therapies have greatly contributed to the reduction of breast cancer development, about more than one-third of ERα-positive patients show resistance to such existing therapies from the beginning or develop resistance over time. Several mechanisms have been described to explain resistance to such hormone therapies. For example, the hypersensitivity of ERα to low estrogen levels in the treatment with aromatase inhibitors, the switching of tamoxifen effects from antagonists to agonist effects or multiple growth factor receptor signaling pathways in tamoxifen treatment. ERα acquired mutations that occur after hormone therapy is initiated can also play a role in treatment failure and cancer progression. Certain mutations in ERα, particularly those identified in the ligand binding domain (LBD), lead to the ability to bind to DNA in the absence of a ligand and confer hormone independence in cells with such mutant receptors.

[0006] Most of the identified mechanisms of resistance to endocrine therapy rely on ERα-dependent activity. One of the new strategies to combat this resistance is to shut down ERα signaling by removing ERα from tumor cells using selective estrogen receptor degraders (SERDs). Clinical and preclinical data suggest that a number of resistance pathways can be circumvented by using SERDs.

[0007] There remains a need to provide SERDs with good degradation efficacy.

[0008] Documents WO 2017 / 140669 and WO 2018 / 091153 disclose some substituted 6,7-dihydro-5H-benzo[7]annulene compounds and substituted N-(3-fluoropropyl)-pyrrolidine derivatives that can be used as SERDs.

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

[0010] Disclosed herein is a compound or a pharmaceutically acceptable salt thereof, particularly a hydrochloride thereof, the compound being selected from:

[0011] -4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylic acid (1),

[0012] -3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)quinoline-7-carboxylic acid (2), and

[0013] -(R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (3).

[0014] Another embodiment is a compound or a pharmaceutically acceptable salt thereof, in particular a hydrochloride thereof, which compound is selected from:

[0015] -4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylic acid (1), and

[0016] -(R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (3).

[0017] The compounds (1), (2) or (3), in particular compounds (1) and (3), may contain one or more asymmetric carbon atoms and therefore, they may exist in the form of enantiomers.

[0018] The compound (1), (2) or (3), in particular the compounds (1) and (3), may also exist in the form of tautomers.

[0019] The compound (1), (2) or (3), in particular the compounds (1) and (3), may exist in the form of a base, an acid, a zwitterion or an addition salt with an acid or a base. Therefore, the present invention provides the compound or a pharmaceutically acceptable salt thereof.

[0020] These salts may be prepared with pharmaceutically acceptable acids or bases, although salts of other acids or bases useful, for example, in purifying or isolating the compounds are also provided.

[0021] Among suitable salts of said compounds, hydrochloride may be cited.

[0022] Another embodiment is a compound selected from the above list or a pharmaceutically acceptable salt thereof for use in therapy, especially as an inhibitor and degrader of estrogen receptors.

[0023] Another embodiment is a compound selected from the above list or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, especially breast cancer.

[0024] Another embodiment is a method of inhibiting and degrading estrogen receptors, which comprises administering a therapeutically effective amount of a compound selected from the above list or a pharmaceutically acceptable salt thereof to a subject, especially a human, in need thereof.

[0025] Another embodiment is a method for treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation, comprising administering to a subject, particularly a human, in need thereof a therapeutically effective amount of a compound selected from the above list or a pharmaceutically acceptable salt thereof.

[0026] 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 above list or a pharmaceutically acceptable salt thereof.

[0027] Another embodiment is a pharmaceutical composition comprising, as an active ingredient, an effective dose of a compound selected from the above list or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

[0028] The compounds as provided herein can be prepared by the following methods.

[0029] Compounds as provided herein can be synthesized using techniques and materials described below or known to those skilled in the art. In addition, the solvents, temperatures and other reaction conditions presented below can be varied as deemed appropriate by those skilled in the art.

[0030] The following abbreviations and empirical formulas are used:

[0031] NH4Cl Ammonium chloride

[0032] CO Carbon monoxide

[0033] DCM Dichloromethane

[0034] DIEA N,N-Diisopropylethylamine

[0035] DMF N,N-Dimethylformamide

[0036] DMAP dimethylaminopyridine

[0037] DMSO Dimethyl sulfoxide

[0038] LiOH Lithium Hydroxide

[0039] MeOH Methanol

[0040] MgSO4 Magnesium sulfate

[0041] NaH Sodium hydride

[0042] THF Tetrahydrofuran

[0043] RT Room temperature

[0044] At 400 and 500MHz 1H NMR spectra were performed on Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometers, respectively, with chemical shifts (δ, in ppm) in the solvent dimethyl sulfoxide-d6 (d6-DMSO) referenced to 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

[0045] Liquid chromatography / mass spectrometry (LC / MS) was obtained on a UPLC Acquity Waters instrument using UV detection DAD 210-400 nm and fast Acquity UPLC CSH C18 1.7 μm, size 2.1x30 mm, mobile phase H2O+0.1% HCO2H / CH3CN+0.1% HCO2H, light scattering detector Sedere and SQD Waters mass spectrometer.

[0046] Tables 1a and 1b below contain specific compounds (names and structures) as provided herein and their characterizations according to the present disclosure, respectively. 1 H NMR and LC / MS / MS).

[0047] Table 1a : (the first column "Example" corresponds to the compound and example number)

[0048]

[0049]

[0050] Table 1b:

[0051]

[0052]

[0053] In addition, the present invention provides a compound, or any pharmaceutically acceptable salt thereof, which is selected from

[0054]

[0055]

[0056] The following examples describe the preparation of compounds as provided herein. The quantities of the compounds exemplified below match those given in Table 1 above. Unless otherwise specified, all reactions were performed under an inert atmosphere.

[0057] In the following examples, when the origin of the starting product is not specified, it is understood that the product is a known compound.

[0058] Examples

[0059] Example 1 :4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylic acid

[0060]

[0061] Step 1: (4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)(7-hydroxy-3-(4-(trifluoromethyl)phenyl)quinolin-4-yl)methanone

[0062]

[0063] NaH 60% (0.23 g, 5.8 mmol) was added to a mixture of 3-[2-fluoro-4-(trifluoromethyl)phenyl]-4-(4-fluorobenzoyl)quinoline-7-ol (prepared according to WO 2020 / 014440) (0.5 g, 1.2 mmol) and 1-(3-fluoropropyl)azetidine-3-ol (commercially available) (0.33 g, 2.5 mmol) in DMF (6 ml). The mixture was heated at 40 ° C for 2 h. After cooling to RT, the crude mixture was concentrated under reduced pressure. DCM (20 ml) and water (10 ml) were added to the obtained residue. After decantation, the organic phase was dried over MgSO4, filtered and concentrated under reduced pressure, and the residue obtained was purified by flash chromatography eluting with a gradient of MeOH in DCM from 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.

[0064] LC / MS(m / z,MH+):543

[0065] Step 2: 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinolin-7-yl trifluoromethanesulfonate

[0066]

[0067] 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) cooled to -10°C. The reaction mixture was stirred at -10°C for 1 h. The crude mixture was quenched with an aqueous solution of NH4Cl (5 ml). After decantation, the organic phase was washed with water (5 ml), dried over MgSO4, 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 as is in the next step.

[0068] LC / MS(m / z,MH+):675

[0069] Step 3: Methyl 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylate

[0070]

[0071] In a stainless steel reactor, 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 acetate (29 mg, 0.13 mmol) and 1,3-bis(diphenylphosphino)propane (63 mg, 0.15 mmol) in MeOH (12 ml) was subjected to 20 bar of CO pressure and heated at 100° C. for 23 h. The crude solution was concentrated under reduced pressure and diluted in DCM (20 ml) and water (10 ml). After decantation, the organic phase was dried over MgSO, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of MeOH in DCM from 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.

[0072] LC / MS(m / z,MH+):585

[0073] Step 4: 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylic acid

[0074]

[0075] A mixture of 3-[2-fluoro-4-(trifluoromethyl)phenyl]-4-(4-{[1-(3-fluoropropyl)azetidin-3-yl]oxy}benzoyl)quinoline-7-carboxylic acid methyl ester (86 mg, 0.15 mmol) and LiOH (78 mg, 3.2 mmol) in a mixture of THF (4 ml) and water (4 ml) was stirred at 60 ° C for 30 minutes. After cooling to RT, acetic acid (0.18 mL, 3.18 mmol) was added and the mixture was concentrated under reduced pressure. The obtained residue was purified by flash chromatography eluting with a gradient of MeOH from 100 / 00 to 95 / 05 in DCM to give 45 mg (54%) of 4-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylic acid.

[0076] Example 2 :3-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)quinoline-7-carboxylic acid

[0077]

[0078] Step 1: 4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinolin-7-yl trifluoromethanesulfonate

[0079]

[0080] Step 1 of Example 2 was prepared according to a procedure similar to Step 2 of Example 1 from (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 to give 200 mg (crude) of 4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinolin-7-yl trifluoromethanesulfonate, which was used as is in the next step.

[0081] LC / MS(m / z,MH+):675

[0082] Step 2: 4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylic acid methyl ester

[0083]

[0084] In a stainless steel reactor, 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 subjected to 5 bar of CO pressure and heated at 70°C for 5 h. The crude solution was filtered through celite and the filtrate was concentrated under reduced pressure. DCM (10 ml) and water (10 ml) were added to the obtained residue. After decantation, the organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of MeOH in DCM from 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.

[0085] LC / MS(m / z,MH+):585

[0086] Step 3: 3-(2-Fluoro-4-(trifluoromethyl)phenyl)-4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)quinoline-7-carboxylic acid

[0087]

[0088] Step 3 of Example 2 was prepared according to a procedure similar to Step 4 of Example 1 from methyl 4-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)benzoyl)-3-(4-(trifluoromethyl)phenyl)quinoline-7-carboxylate 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.

[0089] Example 3:(R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid

[0090]

[0091] Step 1: (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate

[0092]

[0093] Step 1 of Example 3 was prepared according to a procedure similar to Step 2 of Example 1 from (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 to give 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 as is in the next step.

[0094] LC / MS(m / z,MH+):591

[0095] Step 2: (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester

[0096]

[0097] Step 2 of Example 3 was prepared from (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate 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-tetrahydronaphthalen-2-carboxylate.

[0098] LC / MS(m / z,MH+):501

[0099] Step 3: (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid

[0100]

[0101] Step 3 of Example 3 was prepared according to a procedure similar to Step 4 of Example 1 from (R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester 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.

[0102] The compounds according to Table 1 above were subjected to pharmacological testing for determining their degradation effect on estrogen receptors.

[0103] Test: Estrogen receptor degradation activity

[0104] The test involves measuring the in vitro degradation activity of the compounds of Table 1.

[0105] Degradation activity of ERα was measured using breast cancer cells in a cellular Western blot assay as described below.

[0106] MCF7 cells (ATCC) were seeded in red phenol-free MEMα medium (Invitrogen) containing 5% charcoal dextran-treated FBS at a concentration of 10,000 cells / 30 μL / well in 384-well microplates (collagen coated). The next day, 9 points of each compound were added to the cells in a final concentration ranging from 0.3-0.0000018 μM (Table 2) or 0.1 μM of Fulvestrant (used as a positive control) in 2.5 μL cells: 1:5 dilutions were added to the cells. 4 hours after compound addition, cells were fixed by adding 25 μL of formalin (5% formalin with a final concentration of 0.1% triton) for 10 minutes at room temperature, and then washed twice with PBS. Then, 50 μL of LI-COR blocking buffer containing 0.1% Triton was added to the plate for 30 minutes at room temperature. LI-COR blocking buffer was removed and 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. Wells treated with blocking buffer but without antibody were used as background controls. The wells were washed twice with PBS (0.1% tween-20) and incubated at 37°C for 60 minutes in LI-COR (0.1% tween-20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and Syto-64a DNA dye (2 μM final concentration). The cells were then washed 3 times in PBS and scanned in an ACUMEN detector (TTP-Labtech). The integrated intensity of green and red fluorescence was measured to determine the levels of ERα and DNA, respectively.

[0107] In this test, the degradation activity of estrogen receptor is determined by the concentration that degrades 50% of the estrogen receptor (or IC 50 ) is given in nM.

[0108] The % reduction in ERa levels was determined as follows: % inhibition = 100*(1-(sample - fulvestrant:DMSO-fulvestrant)).

[0109] The following Table 2 shows the estrogen receptor degradation activity results of the compounds of Table 1 tested at 0.3 μM, and demonstrates that the compounds have significant degradation activity on the estrogen receptor.

[0110] Table 2:

[0111]

[0112] Therefore, it is obvious that the test compound has degradation activity on estrogen receptor, IC50 is less than 1 μM and the degradation level is greater than 50%. Therefore, the compounds provided herein can be used to prepare drugs, especially drugs as degraders of estrogen receptor.

[0113] Therefore, also provided herein is a medicament comprising a compound as defined above or a pharmaceutically acceptable salt thereof.

[0114] Also provided herein is a compound as defined above, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0115] Also provided herein are compounds as defined above, or pharmaceutically acceptable salts thereof, for use in therapy, particularly as inhibitors and degraders of estrogen receptors.

[0116] Also provided herein is a compound as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.

[0117] A particular aspect is a compound as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0118] In embodiments, the cancer is a hormone-dependent cancer.

[0119] In another embodiment, the cancer is an estrogen receptor dependent cancer, in particular the cancer is an estrogen receptor alpha dependent cancer.

[0120] In another embodiment, the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, cervical cancer, and lung cancer, or metastases thereof.

[0121] In another embodiment, the metastasis is a brain metastasis.

[0122] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0123] In another embodiment, the cancer is resistant to anti-hormone therapy.

[0124] In further embodiments, the compounds provided herein are used as single agents or in combination with other agents such as CDK4 / 6, mTOR or PI3K inhibitors.

[0125] According to another aspect, provided herein is a method of treating the above indicated pathological conditions, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as provided herein or a pharmaceutically acceptable salt thereof. In an embodiment of this method of treatment, the subject is a human.

[0126] 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 for the treatment of any of the above indicated pathological conditions, more particularly useful for the treatment of cancer.

[0127] Also provided herein are pharmaceutical compositions comprising as active ingredients a compound as defined above. These pharmaceutical compositions comprise an effective dose of at least one compound as defined above or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

[0128] The excipients are selected from the customary excipients known to those skilled in the art, depending on the desired pharmaceutical form and method of administration.

[0129] In pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient or its base, acid, zwitterion or salt thereof as defined above can be administered to animals and humans in a unit administration form, in a mixture with conventional pharmaceutical excipients for the treatment of the above disorders or diseases.

[0130] Suitable unit administration forms include oral forms, such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, forms for inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration forms and implants. For topical use, the compounds as provided herein can be used in creams, gels, ointments or lotions.

[0131] As an example, a unit administration form of a compound as provided herein in the form of a tablet may contain the following components:

[0132]

[0133] There may be specific cases where higher or lower doses are appropriate. According to routine practice, the appropriate dose for each patient is determined by the physician according to the mode of administration and the weight and response of the patient.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, in particular 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).

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, in particular a hydrochloride thereof, which 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), and -(R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (3).

3. A compound or any pharmaceutically acceptable salt thereof, the compound being selected from 4. A drug, characterized in that The medicament comprises the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

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

7. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.

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

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