SELECTIVE ESTROGEN RECEPTOR DEGRADERS

Background

Selective estrogen receptor degraders (SERDs) bind to the estrogen receptor (ER) and downregulate ER-mediated transcriptional activity. This degradation and downregulation caused by SERDs can be useful in the treatment of cell proliferation disorders, such as cancer. Some small molecule examples of SERDs have been disclosed in the literature (see, e.g., W02005073204, WO2014205136, and W02016097071). However, known SERDs have not yet been as useful as is needed to effectively treat cancer. For example, finding SERDs with better pharmacokinetic (PK) and pharmacodynamic (PD) properties, higher efficiency in the clinic, and good oral bioavailability would be very helpful in treating cancer. A pure antagonist SERD with potent inhibition of ER-mediated transcription would be expressly beneficial in treating cancer. There is a need for new SERDs to treat cancers such as breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, and lung cancer as well as mutations due to emerging resistance. In particular there is a need for new SERDs to treat ER-positive breast cancer, gastric cancer, and/or lung cancer.

Summary

Compounds of the formula:

and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, are provided herein. In this formula either R1 or R2 is independently selected from Cl, F, -CF3, or -CH3, and the other is hydrogen.

Methods of using the compounds as described herein, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, to treat breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, or lung cancer are also provided. The methods include administering a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, to a patient in need.

Further provided are the compound as described herein, and a pharmaceutically acceptable salts thereof, for use in therapy. The compounds described herein, and

pharmaceutically acceptable salts thereof, can be used in the treatment of breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, or lung cancer.

The use of the compounds as described herein, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for treating breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, or lung cancer is further provided.

Detailed Description

Novel tetracyclic compounds and pharmaceutical salts thereof that act as SERDs are disclosed herein. The newly invented SERDs that are described herein provide inhibition of ER-mediated transcription that will be useful in treating cancers such as breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, and lung cancer as well as mutations due to emerging resistance. These SERDs can be used either as single agents or in combination with other classes of drugs including selective estrogen receptor modulators (SERMs), aromatase inhibitors, CDK4 inhibitors, CDK6 inhibitors, PI3K inhibitors, and mTOR inhibitors to treat hormone receptor-positive cancers such as breast cancer, gastric cancer, and/or lung cancer.

The novel compounds described herein are represented by Formula I:

and pharmaceutically acceptable salts thereof, wherein either R1 or R2 is independently selected from Cl, F, -CF3, or -CFl·,, and the other is hydrogen. One of skill in the art will appreciate that compounds as described by Formula I, or pharmaceutically acceptable salts thereof, contain a chiral center, the position of which is indicated by an * above. One of skill in the art will also appreciate that the Cahn-Ingold-Prelog (R) or (S) designations for chiral centers will vary depending upon the substitution patterns around a chiral center. The chiral center in the compound of Formula I provides an R-enantiomeric form shown by Formula II:

And an S-enantiomeric form shown by Formula III:

All individual stereoisomers, enantiomers, and diastereomers, as well as mixtures of the enantiomers and diastereomers of the compounds according to Formula I, Formula II, and Formula III including racemates are included within the scope of the compounds described herein. Compounds for pharmaceutical use that contain chiral centers are often isolated as single enantiomers or diastereomers and such isolated compounds of Formula I, Formula II, and Formula III are included within the scope of the compounds disclosed herein. One of

skill in the art will also appreciate that the compounds of Formula I, Formula II, and Formula III described herein, and pharmaceutically acceptable salts thereof, can be deuterated (where a hydrogen can be replaced by a deuterium) and such molecules are considered to be included within the scope of the compounds disclosed herein.

Specific examples of the compounds of Formula I (including IUPAC nomenclature names) are shown here:

5-(4-{2-[3-(fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-(trifluoromethyl)-5H-[ 1 ]benzopyrano[4, 3 -c] quinolin-2-ol ;

5-(4-{2-[3-(fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-7-(trifluoromethyl)-5H-[ 1 ]benzopyrano[4,3 -c]quinolin-2-ol;

8-chloro-5-(4-{2-[3-(fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-5H-[1 ]benzopyrano[4,3 -c]quinolin-2-ol;

7-chloro-5-(4-{2-[3-(fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-5H-[ 1 ]benzopyrano[4, 3 -c] quinolin-2-ol ;

8-fluoro-5 -(4- { 2- [3 -(fluoromethyl)azetidin- 1 -yl] ethoxy } phenyl)-5H-[ 1 ]benzopyrano[4,3 -c]quinolin-2-ol;

7 -fluoro-5 -(4- { 2- [3 -(fluoromethyl)azetidin- 1 -yl] ethoxy } phenyl)-5H-[ 1 ]benzopyrano[4,3 -c]quinolin-2-ol;

5-(4-{2-[3-(fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-8-methyl-5H- [ 1 ]benzopyrano[4,3 -c]quinolin-2-ol; and

5-(4-{2-[3-(fluoromethyl)azetidin-l-yl]ethoxy}phenyl)-7-methyl-5H- [ 1 ]benzopyrano[4,3 -c]quinolin-2-ol .

Due to the chiral center noted above, each of these specific examples of compounds of Formula I shown above have R- and S-enantiomeric forms (i.e., R-enantiomeric compounds of Formula II and S-enantiomeric compounds of Formula III) as shown in Table 1

Table 1: Enantiomeric forms of compounds of Formula I

Also described herein are pharmaceutical compositions including the compounds of Formula I, Formula II, and Formula III as described herein, or pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable excipient, carrier, or diluent. The pharmaceutical compositions described herein may be prepared using pharmaceutically acceptable additives. The term“pharmaceutically acceptable additive(s)” as used herein, refers to one or more carriers, diluents, and excipients that are compatible with the other additives of the compositions or formulations and not deleterious to the patient. The compounds of Formula I, Formula II, and Formula III, or pharmaceutically acceptable salts thereof, described herein can be formulated as pharmaceutical compositions administered by a variety of routes, such as oral or IV. Bioavailability is often a factor in cancer treatment and the ability to choose administration methods and pharmaceutical compositions to control or optimize the bioavailability of an active ingredient is useful. For example, an orally bioavailable SERD composition would be particularly useful. The compounds of Formula I, Formula II, and Formula III, or pharmaceutically acceptable salts thereof, as described herein are believed to have oral bioavailability. Examples of pharmaceutical compositions and processes for their preparation can be found in“Remington: The Science and Practice of Pharmacy”, L. V. Allen Jr, Editor, 22nd Ed., Mack Publishing Co., 2012. Non-limiting examples of pharmaceutically acceptable carriers, diluents, and excipients include the following: saline, water, starch, sugars, mannitol, and silica derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; kaolin and bentonite; and polyethyl glycols.

Further described herein are methods of treating a cancer. The methods described herein include administering to a patient in need of such treatment an effective amount of a compound of Formula I, Formula II, and Formula III as described herein, or a

pharmaceutically acceptable salt thereof. For example, the method of administering the effective amount of a compound of Formula I, Formula II, and Formula III as described herein, or a pharmaceutically acceptable salt thereof, can be oral administration. The cancer can be an estrogen responsive cancer. Additionally, the cancer can be breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, or lung cancer. For example, the cancer can be ER-positive breast cancer, ER-positive gastric cancer, or ER-positive lung cancer.

Also described herein are compounds of Formula I, Formula II, and Formula III as described herein, or pharmaceutically acceptable salts thereof, for use in therapy. Also provided herein are the compounds of Formula I, Formula II, and Formula III as described herein, or pharmaceutically acceptable salts thereof, for use in the treatment of breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, or lung cancer. In particular the breast cancer can be ER-positive breast cancer, ER-positive gastric cancer, or ER-positive lung cancer. For example, the compound of Formula I, Formula II, and Formula III, or pharmaceutically acceptable salt thereof, can be orally administered.

Additionally, the compounds of Formula I, Formula II, and Formula III as described herein, or pharmaceutically acceptable salts thereof, can be used in the manufacture of a medicament for the treatment of a cancer. For example, the medicament can be orally administered. The types of cancer the medicaments as described herein can be used to treat include breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, or lung cancer. In particular the cancer can be ER-positive breast cancer, ER-positive gastric cancer, or ER-positive lung cancer.

The compounds of Formula I, Formula II, and Formula III as described herein, and pharmaceutically acceptable salts thereof, may have clinical utility as a single agent or in combination with one or more other therapeutic agents (e.g., anti-cancer agents), for the treatment of cancers such as breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, or lung cancer. When used in combination with other therapeutic agents (such as anti-cancer agents), the compounds of Formula I, Formula II, and Formula III as described herein, or pharmaceutically acceptable salts thereof, can be used simultaneously, sequentially, or separately with other therapeutic agents. Examples of classes of drugs that the compounds of Formula I, Formula II, and Formula III as described herein, or pharmaceutically acceptable salts thereof, can be combined with include SERMs, aromatase inhibitors, CDK4 inhibitors, CDK6 inhibitors, PI3K inhibitors, and mTOR inhibitors to treat hormone receptor-positive breast cancer. More specific examples of drugs with which the compounds of Formula I, Formula II, and Formula III as described herein, or pharmaceutically acceptable salts thereof, can be combined include abemaciclib (CDK4/6 inhibitor), everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and 8-[5-(l -hydroxy -1 -methyl ethyl)pyridin-3-yl]- 1 -[(2S)-2-methoxypropyl]-3-methyl- 1 ,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (PI3K/mTOR inhibitor).

As used herein, the term“effective amount” refers to the amount or dose of a compound of Formula I, Formula II, and Formula III as described herein, or a

pharmaceutically acceptable salt thereof, which, upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment.

Preferably, a desired effect is inhibition of tumor cell proliferation, tumor cell death, or both. The compounds of Formula I, Formula II, and Formula III as described herein, or pharmaceutically acceptable salts thereof, are generally effective over a wide dosage range. For example, dosages per day normally fall within the daily range of about 100 mg to about 2000 mg.

As used herein,“treat”,“treating” or“treatment” refers to restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder.

As used herein, the term“patient” refers to a human which is afflicted with a particular disease, disorder, or condition.

The compounds of Formula I, Formula II, and Formula III as described herein, or pharmaceutically acceptable salts thereof, may be prepared by a variety of procedures known in the art, some of which are illustrated in the Preparations and Examples below. The specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different procedures, to prepare compounds of Formula I, Formula II, and Formula III as described herein, or pharmaceutically acceptable salts thereof. The products can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and

crystallization. The reagents and starting materials are readily available to one of ordinary skill in the art.

Intermediates and processes useful for the synthesis of the compounds of Formula I, Formula II, and Formula III as described herein are intended to be included in this description. Additionally, certain intermediates described herein may contain one or more protecting groups. The variable protecting group may be the same or different in each occurrence depending on the particular reaction conditions and the particular transformations to be performed. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature (See for example“Greene’s Protective Groups in Organic Synthesis”, Fourth Edition, by Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

Individual isomers, enantiomers, and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of Formula I, Formula II, and Formula III as described herein, by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al.,

“ Enantiomers , Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,“ Stereochemistry of Organic Compounds" , Wiley-Interscience, 1994).

While individual isomers, enantiomers, and diastereomers may be separated or resolved as noted, their Cahn-Ingold-Prelog (R) or (S) designations for chiral centers may not yet have been determined. Where Cahn-Ingold-Prelog (R) or (S) designations are not available, the identifiers“isomer 1” and“isomer 2” are used and are combined with the IUPAC name

without Cahn-Ingold-Prelog stereochemistry designation. The compounds of Formula I, Formula II, and Formula III being identified as“isomer 1” or“isomer 2” herein are isolated as defined in the specific experimental descriptions below. Whether an isomer is a“1” or a “2” refers to the order in which the compounds of Formula I, Formula II, and Formula III elute from a chiral chromatography column, under the conditions listed, i.e., an“isomer 1” is the first to elute from the column under the noted conditions. If chiral chromatography is initiated early in the synthesis, the same designation is applied to subsequent intermediates and compounds of Formula I, Formula II, and Formula III.

Unless specifically noted, abbreviations used herein are defined according to

Aldrichimica Acta, Vol. 17, No. 1, 1984. Other abbreviations are defined as follows:

“ACN” refers to acetonitrile;“BSA” refers to Bovine Serum Albumin;“cataCXium® A Pd G3” refers to [(di(l-adamantyl)-butylphosphine)-2-(2'-amino-l,l'-biphenyl)]palladium(II) methanesulfonate;“DCM” refers to dichloromethane or methylene chloride;“DMA” refers to dimethylacetamide;“DMEA” refers to dimethylethylamine;“DMEM” refers to

Dulbecco’s Modified Eagle’s Medium;“DMF” refers to N,N-dimethylformamide;“DMSO” refers to dimethyl sulfoxide;“DNA” refers to deoxyribonucleic acid;“cDNA” refers to complementary DNA;“DNase” refers to deoxyribonuclease;“DTT” refers to dithiothreitol; “EC50” refers to the concentration of an agent which produces 50 % response of the target activity compared to a predefined positive control compound (absolute EC50);“EDTA” refers to ethylenediaminetetraacetic acid;“ee” refers to enantiomeric excess;“ERa” refers to estrogen receptor alpha;“ERP” refers to estrogen receptor beta;“EtOAc” refers to ethyl acetate;“EtOH” refers to ethanol or ethyl alcohol;“FBS” refers to Fetal Bovine Serum; “HBSS” refers to Hank’s Balanced Salt Solution;“HEC” refers to hydroxy ethyl cellulose; “HEPES” refers to 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid;“HPLC” refers to high-performance liquid chromatography;“IC50” refers to the concentration of an agent which produces 50% of the maximal inhibitory response possible for that agent, (relative IC50), or the concentration of an agent which produces 50% inhibition of the target enzyme activity compared to placebo control (absolute IC50);“IP A” refers to isopropylamine;

“iPrOH” refers to isopropanol or isopropyl alcohol;“IV” refers to intravenous

administration;“K” refers to inhibition constant;“MEK” refers to methyl ethyl ketone; “MeOH” refers to methyl alcohol or methanol;“MTBE” refers to methyl /-butyl ether; “PBS” refers to Phosphate Buffered Saline;“PO” refers to oral administration;“PRa” refers to progesterone receptor alpha;“QD” refers to once a day dosing;“RNA” refers to ribonucleic acid;“RNase” refers to ribonuclease;“RT-PCR” refers to reverse transcription polymerase chain reaction;“RT-qPCR” refers to reverse transcription quantitative polymerase chain reaction;“SEC” refers to supercritical fluid chromatography;“TED50” refers to the effective dose to achieve 50% inhibition of the target in the tumors;“THF” refers to tetrahydrofuran;“t(R>” refers to retention time;“XantPhos Pd G2” refers to chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-l, 1 '-biphenyl)]palladium(II); and“XPhos Pd G2” refers to chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1 , 1 '-biphenyl)[2-(2'-amino- 1 , 1 '-biphenyl)]palladium(II).

The following preparations and examples further illustrate the invention.

Preparations and Examples

Scheme 1

I

Scheme 1 depicts the synthesis of compounds of Formula I.

In Step A, a Grignard reaction is accomplished. A Grignard reaction is well known in the art as a reaction for the formation of carbon-carbon bonds. The reaction involves an organometallic reaction in which an aryl magnesium halide, the Grignard reagent adds to a carbonyl group such as the acid chloride of compound 2 to give the compound of Step A.

For example, a 4-chloro-substituted quinolone, compound 1, is treated with a Grignard reagent such as isopropylmagnesium chloride to form a Grignard intermediate followed by the addition of an acid chloride, 4-fluorobenzoyl chloride, compound 2, in a solvent such as THF. At completion, the reaction can be quenched with water to give compound 3.

In Step B, the aryl methyl ether of compound 3 may be demethylated under a variety of conditions recognizable to the skilled artisan such as treatment with boron tribromide. For example, compound 3 is slowly treated with boron tribromide at a temperature of about 0 °C in a solvent such as DCM. The mixture is stirred at room temperature and quenched with dibasic potassium phosphate to give compound 4.

In Step C, the azetidine ether 6 may be formed by treatment of the corresponding p-fluorophenyl ketone 4 and the azetidine alcohol salt 5, or the corresponding free base with a suitable base, for example sodium hydride, sodium /-butoxide or potassium /-butoxide, in the appropriate polar aprotic solvent such as DMF or THF to give the ether compound 6.

Compound 6 is then alkylated with the appropriate substituted aryl boronic acid, compound 7, in a Suzuki cross coupling reaction to give compound 8 in Step D. The skilled artisan will recognize that there are a variety of conditions that may be useful for facilitating such cross-coupling reactions. Suitable palladium reagents may include XantPhos Pd G2, cataCXium® A Pd G3, bis(triphenylphosphine)palladium(II) chloride,

tris(dibenzylideneacetone)dipalladium (0) with tricyclohexylphosphine, (I, -bis(diphenylphosphino)ferrocene)palladium(II) chloride, palladium

tetrakistriphenylphosphine, or palladium(II) acetate. Suitable bases may include potassium fluoride, cesium carbonate, sodium carbonate, potassium carbonate, lithium t-butoxide, or potassium phosphate tribasic monohydrate. Compound 6, for example, can be reacted with the appropriate boronic acid, compound 7, such as 2-fluoro-4-(trifluoromethyl)phenylboronic acid in a solvent such as 2-methyl-2-butanol with a base such as potassium carbonate and a catalyst such as XPhos Pd G2 and heated to about 80 °C under microwave conditions to give compound 8.

One skilled in the art will recognize that Step D, the Suzuki cross coupling reaction, could be completed before the azetidine ether formation of Step C.

In Step E, one skilled in the art will recognize that compound 8 may be cyclized by the initial reduction of the ketone. This can be accomplished using a reducing agent, such as lithium tri ethyl borohydride in solvents such as l,4-dioxane and THF and at a temperature of about 0 °C to room temperature to give the corresponding secondary alcohol. This

intermediate alcohol can be carried on crude and be deprotonated with a suitable base such as cesium carbonate, sodium hydride, sodium /-butoxide or potassium /-butoxide in a solvent such as THF, DMSO, or DMF. The resulting alkoxide can cyclize into the aryl fluoride at room temperature, with heating to reflux, or at a temperature of about 60 °C. The substituted cyclic ether formed upon displacement of the fluoride can then be obtained to give compounds of Formula I.

Alternatively, the ketone, 8, can be reduced to the alcohol and chirally purified at Step F to give the chiral alcohol 9, and then cyclized in Step G as described above for Step E to give compounds of Formula I.

In another alternative reaction, the ketone can be reduced using a chiral reagent such as (R)-(+)-a.a-diphenyl-2-pyrrolidinemethanol along with trimethyl borate and borane-dimethyl sulfide to directly give the desired chiral alcohol, compound 9 which can then be cyclized in Step G as described above for Step E to give compounds of Formula I.

In an optional step, a pharmaceutically acceptable salt of a compound of Formula I, Formula II, and Formula III as described herein can be formed by reaction of an appropriate free base of a compound of Formula I, Formula II, and Formula III as described herein with an appropriate pharmaceutically acceptable acid in a suitable solvent under standard conditions. Additionally, the formation of such salts can occur simultaneously upon deprotection of a nitrogen-protecting group. The possible formation of pharmaceutically acceptable salts is well known. See, for example , Gould, P.L.,“Salt selection for basic drugs f International Journal of Pharmaceutics, 3_3: 201-217 (1986); Bastin, R.J., et al.“Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities,” Organic Process Research and Development, 4: 427-435 (2000); and Berge, S.M., et al.,

“Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66: 1-19, (1977). One of ordinary skill in the art will appreciate that a compound of Formula I, Formula II, and Formula III as described herein is readily converted to and may be isolated as a

pharmaceutically acceptable salt. Examples of useful salts include, but are not limited to, benzenesulfonic acid salts and 4-methybenzenesulfonic acid salts. 4-methylbenzenesulfonic acid salts are also known as tosylate salts.

WE CLAIM:

1. A compound of the formula:

wherein either R1 or R2 is independently selected from Cl, F, -CF3, or -CFE, and the other is hydrogen,

or a pharmaceutically acceptable salt thereof.

2. The compound according to Claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.

3. The compound according to Claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.

4. The compound according to Claim 2, wherein the compound is

or a pharmaceutically acceptable salt thereof.

5. The compound according to Claim 4, wherein the pharmaceutically acceptable salt is a benzenesulfonic acid salt.

6. The compound according to Claim 4, wherein the pharmaceutically acceptable salt is a 4-methylbenzenesulfonic acid salt.

The compound according to Claim 4, wherein the compound is

The compound according to Claim 3, wherein the compound is

or a pharmaceutically acceptable salt thereof.

9. The compound according to Claim 8, wherein the pharmaceutically acceptable salt is a benzenesulfonic acid salt.

10. The compound according to Claim 8, wherein the pharmaceutically acceptable salt is a 4-methylbenzenesulfonic acid salt.

11. The compound according to Claim 8, wherein the compound is

12. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof according to any one of Claims 1 to 11 in combination with a pharmaceutically acceptable excipient, carrier, or diluent.

13. The pharmaceutical composition according to Claim 12, comprising one or more other therapeutic agents.

14. A method of treating breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, or lung cancer, comprising administering to a patient in need of such treatment an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 11 or a pharmaceutical composition according to any one of Claims 12 to 13.

15. The method according to Claim 14, wherein the breast cancer is ER-positive breast cancer.

16. The method according to Claim 14, wherein the gastric cancer is ER-positive gastric cancer.

17. The method according to Claim 14, wherein the lung cancer is ER-positive lung cancer.

18. A compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of Claims 1 to 13 for use in therapy.

19. A compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 11 for use in the treatment of breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, or lung cancer.

20. The compound or the salt thereof for use according to Claim 19 in the treatment of ER-positive breast cancer.

21. The compound or the salt thereof for use according to Claim 19 in the treatment of ER-positive gastric cancer.

22. The compound or the salt thereof for use according to Claim 19 in the treatment of ER-positive lung cancer.