Novel substituted 6,7-dihydro-5H-benzo[7]annulene compounds, methods for their preparation and therapeutic uses

Abstract

The present invention relates to a compound of formula (I) [Case 1] TIFF2022552132000205.tif6997 [wherein Ar represents a phenyl or a 6-membered heteroaryl group; R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3 represents (1) a -COR4 group, (2) a -BOR5OR6 group, (3) a -XZ group, (4) a (C1-C6) alkyl group or a (C1-C6) alkenyl group, (5) a -XS(O) n (R7) p (R8) q (6) a halogen atom, a -NH or -CN group, (7) a -O-R group, (8) a -NH-COR group, (9) a -C(=NH)NHOH group, (10) a -NH-C(NH)-R group, or (11) a -NHCOCOOR group or a -NHCOCONR'R'" group; X represents a bond, a -NH- group, a -CONH- group, or a -CO- group; and Z represents a 4- or 5-membered cycloalkyl, a 4- or 5-membered heterocycloalkyl group, a 4- or 5-membered heteroaryl group, or a phenyl group, or a pharmaceutically acceptable salt thereof. The present invention further relates to a pharmaceutical agent comprising said compound of formula (I), and to said compound of formula (I) for use as an estrogen receptor inhibitor and degrader.

Description

[Technical field]

[0001] The present invention relates to novel substituted 6,7-dihydro-5H-benzo[7]annulene compounds, methods 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 (ER) belong to the steroid / nuclear receptor superfamily that are involved in the regulation of eukaryotic gene expression, cell growth and differentiation in target tissues. ER exists in two forms, 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 that are activated by the hormone estrogen (the most potent estrogen produced in the body is 17β-estradiol). In the absence of hormone, ER is located mostly in the cytosol of cells. When the hormone estrogen binds to ER, ER translocates from the cytosol of cells to the nucleus, forms dimers, and then binds to specific genomic sequences called estrogen response elements (EREs). The DNA / ER complex interacts with coregulators to modulate the transcription of target genes.

[0003] ERα is primarily expressed in reproductive tissues such as the uterus and ovaries, breast, bone and white adipose tissue. Aberrant 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 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 established, and modulating ERα signaling remains the mainstay of breast cancer treatment for the majority of ERα-positive breast tumors. Currently, there are several strategies to inhibit the estrogen axis in breast cancer, including: 1-blocking estrogen synthesis with aromatase inhibitors, used to treat patients with early and advanced ERα-positive breast cancer; 2-antagonism of estrogen ligand binding to ERα with tamoxifen, used to treat patients with ERα-positive breast cancer in both pre- and postmenopausal status; 3-antagonism and downregulation of ERα levels with fulvestrant, used to treat breast cancer in patients who have progressed despite endocrine therapy such as tamoxifen or aromatase inhibitors.

[0005] Although these endocrine therapies have contributed greatly to the reduction of breast cancer incidence, approximately more than one-third of ERα-positive patients show de-novo resistance to such existing therapies or resistance over time. Several mechanisms have been described to explain resistance to such hormone therapy, such as hypersensitivity of ERα to low estrogen levels in aromatase inhibitor treatment, switching of tamoxifen action from antagonist to agonist action in tamoxifen treatment, or multiple growth factor receptor signaling pathways. More recently, acquired mutations in ERα that occur after the initiation of hormone therapy may contribute to treatment failure and cancer progression. Certain mutations in ERα, specifically identified in the ligand-binding domain (LBD), result in the ability to bind DNA in the absence of ligand, conferring hormone independence in cells carrying such mutant receptors.

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

[0007] There remains a need to provide a SERD with good degradation efficiency.

[0008] The document US Pat. No. 5,399,633 discloses several substituted 6,7-dihydro-5H-benzo[7]annulene compounds useful as SERDs. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] WO2017 / 140669 Summary of the Invention [Problem to be solved by the invention]

[0010] It is an object of the present invention to provide novel compounds capable of selectively antagonizing and degrading estrogen receptors (SERD compounds) for use in the treatment of cancer. [Means for solving the problem]

[0011] The present invention relates to compounds of formula (I): [ka] [In the formula, -Ar represents a phenyl or 6-membered heteroaryl group, and the phenyl or 6-membered heteroaryl group is not limited to a halogen atom, an -OH group, (C 1 ~C 3 ) alkyl group, (C 1 ~C 3)alkoxy groups, such as trifluoromethoxy (C 1 ~C 3 ) optionally substituted with 1 to 3 groups selected from perfluoroalkoxy groups and oxooxazolidinyl groups, such as 2-oxooxazolidin-3-yl; - R1 and R2 independently represent a hydrogen atom or a deuterium atom; -R3 is -(1)-COR4 groups, -(2)-BOR5OR6 groups, -(3)-XZ group, -(4) optionally substituted with 1 to 8 groups selected from a fluorine atom, a -OH group, and a -COOH group; 1 ~C 6 ) alkyl group or (C 1 ~C 6 ) an alkenyl group, -(5)-XS(O) n (R7) p (R8) q basis, -(6) Halogen atom, -NH 2 group or -CN group, -(7)-O-R11 groups, -(8)-NH-COR9 groups, -(9)-C(=NH)NHOH group, -(10)-NH-C(NH)-R9' group, -(11) -NHCOCOOR12 group or -NHCOCONR12'R12'' group represents R4 is (C 1 ~C 6 ) alkyl group, -NRR' group, -NHNH 2 Group, -NHNHCONH 2 group, -NHNHCS-1H-imidazolyl group or -NHSO 2 CH 3 R and R′ are independently a hydrogen atom, an —OH group, (C 1 ~C 6 ) alkoxy group or (C 1 ~C 6 ) an alkyl group; R5 and R6 are independently a hydrogen atom, (C 1 ~C 6 ) alkyl groups, optionally together with the boron atom to which they are attached, forming a 4- or 5-membered ring, said ring containing 1 to 4 (C 1 ~C 4 ) optionally substituted with alkyl groups; R7 and R8 are independently optionally partially or fully substituted with fluorine atoms (C 1 ~C 6 ) alkyl group, -NH 2 represents a group or a =NH group, R9 is a hydrogen atom, 1 ~C 6 ) alkoxy group, (C 1 ~C 6 ) alkyl group or (C 3 ~C 6 ) represents a cycloalkyl group, 1 ~C 6 ) alkoxy group, (C 1 ~C 6 ) alkyl group or (C 3 ~C 6 ) Cycloalkyl groups are those which contain 1 to 3 fluorine atoms, -OH groups or (C 1 ~C 4 ) optionally substituted with alkyl groups; R9' is (C 1 ~C 6 ) alkyl group or (C 3 ~C 6 ) represents a cycloalkyl group, R11 is optionally substituted with 1 to 6 fluorine atoms (C 1 ~C 6 ) an alkyl group; R12 is (C 1 ~C 6 ) an alkyl group; R12' and R12'' are independently a hydrogen group or (C 1 ~C 6 ) an alkyl group; X represents a bond, an -NH- group, a -CONH- group or a -CO- group; Z is (i) 4- or 5-membered cycloalkyl, (ii) a 4- or 5-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur; (iii) a 4- or 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein the cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted by 1 to 3 groups selected from -OH, oxo, =NR12'R12'' and thiooxo; or (iv) Hydroxy group, COOR12' group, -CONH 2 group, -NO 2 group, -NH 2 The group or itself is optionally substituted by a hydroxy group (C 1 ~C 6 ) a phenyl group optionally substituted by an alkyl group represents n is an integer and means 1 or 2; p+q is an integer and means 1 or 2, p and q are each an integer and mean 0, 1, or 2, if n is 1, then p+q is 2, if n is 2, then p+q is 1, and the sulfur atom remains pentavalent; When n is 1 and p+q is 2, the two groups R7 and R8 on the sulfur atom, together with the sulfur atom to which they are attached, further comprise (C 1 ~C 6 ) a 5-membered ring optionally substituted with 1 to 3 groups selected from an alkyl group and an oxo group; or a pharma- ceutically acceptable salt thereof.

[0012] The compounds of formula (I) contain one or more asymmetric carbon atoms, more particularly one asymmetric carbon atom on the pyrrolidinyl group. They can therefore exist in the form of enantiomers. These enantiomers form part of the present invention.

[0013] As far as carbon 3 of the pyrrolidinyl group linked to the oxygen atom of formula (I) is concerned, this may be in the absolute configuration (R) or (S). Within the framework of the present invention, said carbon 3 of the pyrrolidinyl group is in the absolute configuration (S).

[0014] Compounds of formula (I) can also exist in tautomeric forms and are part of the invention. This is true, for example, for compounds containing heteroaryl groups.

[0015] The compounds of formula (I) can exist in the form of bases, acids, zwitterions or addition salts with acids or bases. Such addition salts, bases, acids and zwitterions form part of the present invention. Thus, the present invention relates inter alia to compounds of formula (I) or pharma- ceutically acceptable salts thereof.

[0016] These salts can be prepared with pharma-ceutically acceptable acids or bases, but also salts of other acids or bases which are useful, for example, in the purification or isolation of the compounds of formula (I), also form part of the invention.

[0017] Among the suitable salts that form part of the invention there may be mentioned: trifluoroacetates, hydrochlorides and formates.

[0018] In the context of the present invention, the following terms, as used throughout this specification, have the following definitions, unless otherwise stated: - halogen atoms: fluorine, chlorine, bromine or iodine atoms, in particular fluorine and chlorine atoms; -Oxo: the "=O" group; -thioxo: "=S" group; -Cyano group: "-C≡N" group; -Amine group: unsubstituted or one or more (C 1 ~C 6 ) a nitrogen atom substituted with an alkyl group; -Alkyl group: unless otherwise specified, contains 1 to 6 carbon atoms ("(C 1 ~C 6) linear or branched saturated hydrocarbon-based aliphatic groups, described as "alkyl." Examples include, but are not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl groups; - optionally partially or completely substituted by fluorine atoms (C 1 ~C 6 ) alkyl groups are each substituted with at least one fluorine atom or each hydrogen atom is replaced by a fluorine atom (C 1 ~C 6 ) alkyl. In the latter case, the group may be designated as a perfluoroalkyl group. Examples of perfluoroalkyl groups are the trifluoromethyl group or the perfluoropropyl group; -Alkenyl group: contains at least one unsaturation and, unless otherwise specified, contains 1 to 6 carbon atoms ("(C 1 ~C 6 )-alkenyl) straight or branched chain aliphatic hydrocarbon radicals; -Alkoxy group: -O-alkyl group, where the alkyl group is as defined above. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, isobutoxy, pentoxy or hexoxy groups, etc.; - Perfluoroalkoxy group: an alkoxy group in which all hydrogen atoms are replaced by fluorine atoms. Examples include the trifluoromethoxy group; - Cycloalkyl group: unless otherwise stated, a cyclic alkyl group containing 4 to 5 carbon atoms (described as a "4- or 5-membered cycloalkyl group"), saturated or partially unsaturated, unsubstituted or substituted. Examples include, but are not limited to: cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl groups, etc.; - Heterocycloalkyl group: unless otherwise stated, a monocyclic alkyl group containing 4 to 5 carbon atoms (described as a "4- or 5-membered heterocycloalkyl group") and containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur. Such heterocycloalkyl groups are saturated or partially saturated, unsubstituted or substituted. Examples of heterocycloalkyl groups include, but are not limited to, azetidine, oxetane, thietane, 2H-pyrrole, 1H-, 2H- or 3H-pyrroline, pyrrolidine, THF, tetrahydrothiophene, oxadiazole, more particularly 1,3,4-oxadiazole or 1,3,5-oxadiazole, thiadiazole, more particularly 1,3,4-thiadiazole, isoxazoline, 2- or 3-pyrazoline, more particularly 3-pyrazoline, pyrroline, pyrazolidine, imidazoline, imidazolidine, thiazolidine, isoxazoline, isoxazolidine, dioxalane, oxathiazole, oxathiadiazole, dioxazole groups, and the like. - 4- or 5-membered heteroaryl group means: a cyclic aromatic group containing between 4 and 5 carbon atoms and containing between 1 and 4 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of 4- or 5-membered heteroaryl groups include, but are not limited to: pyrrole, furan, thiophene, oxazole, isoxazole, triazole, tetrazole, oxadiazole, furazan, thiazole, isothiazole, thiadiazole, pyrazole, imidazole groups, etc.; -6-membered heteroaryl group means a cyclic aromatic group containing 6 carbon atoms and containing between 1 and 4 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of 6-membered heteroaryl groups include, but are not limited to: pyridine, pyrimidine, pyridazine, triazine groups, etc. - Zwitterion means: an overall neutral molecule that carries a positive and negative charge and has acidic and basic groups.

[0019] In one embodiment, in the compound of formula (I), R1 and R2 represent a hydrogen atom.

[0020] In another embodiment, in the compound of formula (I), R1 and R2 represent deuterium atoms.

[0021] In another embodiment, in the compound of formula (I), Ar represents a phenyl or pyridinyl group, in particular a 3-pyridinyl group, said phenyl or pyridinyl group being optionally substituted by one or two groups selected from among chlorine, fluorine, hydroxy, methyl, trifluoromethoxy, 2-oxooxazolidin-3-yl and ethoxy. or a pharma- ceutically acceptable salt thereof.

[0022] In another embodiment, in the compounds of formula (I), the phenyl or 6-membered heteroaryl group is optionally substituted by one or two groups selected from halogen atoms, hydroxy, methyl or ethyl groups, methoxy or ethoxy groups, trifluoromethoxy and oxooxazolidinyl groups, such as 2-oxooxazolidin-3-yl.

[0023] In another embodiment, in the compound of formula (I), Ar is: [ka] represents a group selected from

[0024] In another embodiment, in the compound of formula (I), R3 represents a -COR4 group, wherein: R4 is (C 1 ~C 6 ) alkyl group, -NRR' group, -NHNH 2 Group, -NHNHCONH 2 group, -NHNHCS-1H-imidazolyl group or -NHSO 2 CH 3 represents a group, R and R' are independently a hydrogen atom, an -OH group, (C 1 ~C 6) alkoxy group or (C 1 ~C 6 ) an alkyl group; or a pharma- ceutically acceptable salt thereof.

[0025] In another embodiment, in the compound of formula (I), R3 represents a -BOR5OR6 group, wherein: R5 and R6 are independently a hydrogen atom or (C 1 ~C 6 ) alkyl groups, optionally together with the boron atom to which they are attached, forming a 5-membered ring, said ring being optionally substituted with 1 to 4 methyl groups; or a pharma- ceutically acceptable salt thereof.

[0026] In another embodiment, in the compound of formula (I), R3 is -B(OH) 2 Group or [ka] group, where Ra, Rb, Rc and Rd are independently selected from the group consisting of 1 ~C 4 ) alkyl, in particular methyl.

[0027] In another embodiment, in the compound of formula (I), R3 represents a -XZ group, wherein: X represents a bond, an -NH- group, a -CONH- group or a -CO- group; Z is (i) 4- or 5-membered cycloalkyl, more particularly selected from cyclobutenyl and cyclopentenyl; (ii) 4- or 5-membered heterocycloalkyl groups containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, more particularly selected from azetidinyl, oxetanyl, dihydropyrazolyl, dihydroisoxazolyl, dihydropyrrolyl, more particularly 1,5-dihydro-2H-pyrrolyl, oxazolidinyl, imidazolidinyl, dioxazolyl, even more particularly 1,2,4-dioxazolyl, oxathiazolyl, even more particularly 1,3,4-oxathiazolyl, oxathiadiazolyl and pyrrolidinyl; (iii) 4- or 5-membered heteroaryl groups containing from 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, more particularly selected from triazolyl, even more particularly 1,2,4-triazolyl, isoxazolyl, thiazolyl, oxadiazolyl, even more particularly 1,3,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4- or 1,2,5-oxadiazolyl, thiadiazolyl, even more particularly 1,3,5-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5- or 1,3,4-thiadiazolyl, tetrazolyl and pyrazolyl. wherein the cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted by 1 to 3 groups selected from -OH, oxo, =NR12'R12'' and thiooxo; or (iv) Hydroxy group, COOR12' group, -CONH 2 group, -NO 2 group, -NH 2 The group or itself is optionally substituted by a hydroxy group (C 1 ~C 6 ) a phenyl group optionally substituted by an alkyl group R12' and R12" each independently represent a hydrogen group or (C 1 ~C 6 ) alkyl group; or a pharma- ceutically acceptable salt thereof.

[0028] In another embodiment, in the compound of formula (I), R3 is [ka] represents a group selected from

[0029] In another embodiment, in the compound of formula (I), R3 is (i) 4- or 5-membered cycloalkyl, more particularly selected from cyclopentenyl; (ii) 4- or 5-membered heterocycloalkyl groups containing from 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, more particularly selected from dihydropyrazolyl, dihydroisoxazolyl, dihydropyrrolyl, more particularly 1,5-dihydro-2H-pyrrolyl, oxazolidinyl, imidazolidinyl, dioxazolyl, even more particularly 1,2,4-dioxazolyl, oxathiazolyl, even more particularly 1,3,4-oxathiazolyl, oxathiadiazolyl and pyrrolidinyl; (iii) 4- or 5-membered heteroaryl groups containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, more particularly selected from triazolyl, even more particularly 1,2,4-triazolyl, isoxazolyl, thiazolyl, oxadiazolyl, even more particularly 1,3,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4- or 1,2,5-oxadiazolyl, thiadiazolyl, even more particularly 1,3,5-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5- or 1,3,4-thiadiazolyl, tetrazolyl, and pyrazolyl. wherein the cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted by 1 to 3 groups selected from -OH, oxo, =NR12'R12'' and thiooxo; or (iv) Hydroxy group, COOR12' group, -CONH 2 group, -NO 2 group, -NH 2 The group or itself is optionally substituted by a hydroxy group (C1 ~C 6 ) a phenyl group optionally substituted by an alkyl group R12' and R12" each independently represent a hydrogen group or (C 1 ~C 6 ) alkyl group; or a pharma- ceutically acceptable salt thereof.

[0030] In another embodiment, in the compound of formula (I), R3 is (i) 4- or 5-membered cycloalkyl, more particularly selected from cyclobutenyl; (ii) a 4- or 5-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, more particularly selected from azetidinyl and oxetanyl, or (iii) 4- or 5-membered heteroaryl groups containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, more particularly tetrazolyl wherein the cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted with 1 to 3 groups selected from -OH and oxo groups; or a pharma- ceutically acceptable salt thereof.

[0031] In another embodiment, in the compound of formula (I), R3 is optionally substituted with 1 to 4 groups selected from a fluorine atom, a -OH group, and a -COOH group. 1 ~C 6 ) alkyl group or (C 1 ~C 6 ) an alkenyl group; or a pharma- ceutically acceptable salt thereof.

[0032] In another embodiment, in the compound of formula (I), R3 is -SO 2 NHCO(CH 3 ) group, -CONHSO 2 (CH 3 ) group, -SO 2 NH 2Group, -SO(CH 3 )NH group, -SO 2 CH 3 group, -NHSO 2 (CH 3 ) group or -NHSO 2 (CF 3 ) groups, or a pharma- ceutically acceptable salt thereof.

[0033] In another embodiment, in the compound of formula (I), R3 is a halogen atom, in particular a bromine atom, -NH 2 represents a group, or a -CN group, or a pharma- ceutically acceptable salt thereof.

[0034] In another embodiment, in the compound of formula (I), R3 represents a -O-R11 group, wherein: R11 is optionally substituted with 1 to 6 fluorine atoms, preferably with 1 to 3 fluorine atoms (C 1 ~C 6 ) an alkyl group; or a pharma- ceutically acceptable salt thereof.

[0035] In another embodiment, in the compound of formula (I), R3 represents a -NH-COR9 group, wherein: R9 is (C 1 ~C 6 ) alkoxy group, (C 1 ~C 6 ) alkyl group or (C 3 ~C 6 ) represents a cycloalkyl group, 1 ~C 6 ) alkyl group or (C 3 ~C 6 ) Cycloalkyl groups are those which contain 1 to 3 fluorine atoms, -OH groups or (C 1 ~C 4 ) optionally substituted with an alkyl group; or a pharma- ceutically acceptable salt thereof.

[0036] In another embodiment, in the compound of formula (I), R3 represents a -NH-C(NH)-R9' group, wherein: R9' is (C 1 ~C 6 ) alkyl group or (C 3 ~C 6 ) a cycloalkyl group, or a pharma- ceutically acceptable salt thereof.

[0037] In another embodiment, in the compound of formula (I), R3 represents a -NHCOCOOR12 group or a -NHCOCONR12'R12'' group, wherein: R12 is (C 1 ~C 6 ) an alkyl group; R12' and R12'' are independently a hydrogen group or (C 1 ~C 6 ) an alkyl group; or a pharma- ceutically acceptable salt thereof.

[0038] In another embodiment, in the compound of formula (I), Ar represents a phenyl or pyridinyl group, in particular a 3-pyridinyl group, said phenyl or pyridinyl group being optionally substituted by one or two radicals selected from among chlorine, fluorine, hydroxy, methyl, trifluoromethoxy, 2-oxooxazolidin-3-yl and ethoxy, R1 and R2 independently represent a hydrogen atom; R3 is, -(1) a -COR group, where R is (C 1 ~C 6 ) alkyl group, -NRR' group, -NHNH 2 Group, -NHNHCONH 2 group, -NHNHCS-imidazol-1-yl group or -NHSO 2 CH 3 R and R′ are independently a hydrogen atom, an —OH group, (C 1 ~C 6 ) alkoxy groups and (C 1 ~C 6 ) represents an alkyl group, -(2) 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl or -B(OH) 2 basis, -(3) Cyclopentenyl, -NH-Z group, where Z is cyclobutenyl, -CO-Z group, where Z is azetidinyl, 4- or 5-membered heterocycloalkyl groups containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, more particularly selected from azetidinyl, dihydropyrazolyl, dihydroisoxazolyl, dihydropyrrolyl, more particularly 1,5-dihydro-2H-pyrrolyl, oxazolidinyl, imidazolidinyl, dioxazolyl, even more particularly 1,2,4-dioxazolyl, oxathiazolyl, even more particularly 1,3,4-oxathiazolyl, oxathiadiazolyl and pyrrolidinyl, -CO-NH-Z group, where Z is oxetanyl, 4- or 5-membered heteroaryl groups containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, more particularly selected from triazolyl, even more particularly 1,2,4-triazolyl, isoxazolyl, thiazolyl, oxadiazolyl, even more particularly 1,3,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4- or 1,2,5-oxadiazolyl, thiadiazolyl, even more particularly 1,3,5-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5- or 1,3,4-thiadiazolyl, tetrazolyl and pyrazolyl -CO-NH-Z group (where Z is tetrazolyl) wherein the cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted with 1 to 3 groups selected from -OH, oxo, =NR12R12' and thiooxo; or Hydroxy group, COOR12' group, -CONH 2 group, -NO 2 group, -NH2 The group or itself is optionally substituted by a hydroxy group (C 1 ~C 6 ) a phenyl group optionally substituted by an alkyl group (R12' and R12" are independently a hydrogen group or (C 1 ~C 6 ) an alkyl group, -(4) optionally substituted with 1 to 8 groups selected from a fluorine atom, a -OH group, and a -COOH group; 1 ~C 6 ) alkyl group or (C 1 ~C 6 ) an alkenyl group, -(5)-CONHSO 2 CH 3 group, -NH-SO 2 CH 3 group, -NHSO 2 -CF 3 group or -NHSO 2 CH 3 basis, -(6) Halogen atom, -NH 2 group or -CN group, -(7)OCF 2 H group, -(8) -NH-COR9 group, where R9 is (C 1 ~C 6 ) alkoxy group, (C 1 ~C 6 ) alkyl group or (C 3 ~C 6 ) represents a cycloalkyl group, 1 ~C 6 ) alkyl group or (C 3 ~C 6 ) Cycloalkyl groups are those which contain 1 to 3 fluorine atoms, -OH groups or (C 1 ~C 4 ) optionally substituted with alkyl groups, -(9)-C(=NH)NHOH group, -(10) -NH-C(NH)-R' group, where R' is (C 1 ~C 3 ) represents an alkyl group, -(11) a -NHCOCOOR12 group or a -NHCOCONR12'R12'' group, R12 is (C 1 ~C 6 ) an alkyl group; R12 and R12' are independently a hydrogen group or (C 1 ~C 6 ) represents an alkyl group Represents, or a pharma- ceutically acceptable salt thereof.

[0039] Among the compounds of formula (I) that are the subject of the present invention, in particular the following compounds: -(S)-3-(4-(8-(2,4-dichlorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine (1) -(S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)boronic acid (2) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (3) -(S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)isoxazol-3-ol (4) -1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2-difluoroethan-1-ol (5) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide (6) -(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazole (7) -(S)-3-(4-(8-(2,4-dichlorophenyl)-3-(difluoromethyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine (8) -(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-thiadiazole (9) -1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroethan-1-ol (10) -(S)-3-(4-(3-bromo-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine (11) -(S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2-dihydro-3H-pyrazol-3-one (12) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)isoxazol-5(4H)-one (13) -(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl)hydrazine-1-carboxamide (14) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-(methylsulfonyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (15) -(S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2H-tetrazole (16) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-(2H-tetrazol-5-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (17) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (18) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (19) -(S,E)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acrylic acid (20) -(S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole (21) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile (22) -(S)-4-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole (23) -(S)-3-(4-(3-(difluoromethoxy)-8-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine (24) -Methyl (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate (25) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboximidamide (26) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-oxadiazol-5(4H)-one (27) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine (28) -4-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3H-1,2,3,5-oxathiadiazole 2-oxide hydrochloride (29) -(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanesulfonamide (30) -(S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazol-2(3H)-one (31) -tert-butyl (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate (32) -(S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxathiazol-2-one (33) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-oxadiazole-5(4H)-thione (34) -(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,1,1-trifluoromethanesulfonamide (35) -(S)-3-((8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-4-hydroxycyclobut-3-ene-1,2-dione (36) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-thiadiazol-5(4H)-one (37) -(S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-methoxy-1,5-dihydro-2H-pyrrol-2-one (38) -(S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-one (39) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxazolidin-2-one (40) -(S)-3-(8-(2-chloro-4-(2-oxooxazolidin-3-yl)phenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxazolidin-2-one (41) -(S)-4-(3-amino-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-8-yl)-3-chlorophenol (42) -5-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)imidazolidine-2,4-dione (43) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (44) -(S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazole-2(3H)-thione (45) -(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetimidamide (46) -(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroacetamide (47) -(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetamide (48) -1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-ol (49) -(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)propan-2-ol (50) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole (51) -(S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol (52) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol (53) -(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol (54) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid (55) -Methyl (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate (56) -Methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate (57) -(S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)pyrrolidin-2-one (58) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N'-(1H-imidazole-1-carbonothioyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide (59) -(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)cyclopropanecarboxamide (60) -(S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)thiazol-2-amine (61) -(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)pivalamide (62) -(S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (63) -(S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile 2,2,2-trifluoroacetate (64) -1-(8-(2-chloro-3-fluorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroethan-1-ol (65) -(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1-fluorocyclopropane-1-carboxamide (66) -(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1-methylcyclopropane-1-carboxamide (67) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2-hydroxycyclopent-2-en-1-one (68) -(S,Z)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-N,3-dimethylthiazol-2(3H)-imine hydrochloride (69) -(S)-5-(8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2H-tetrazole 2,2,2-trifluoroacetate (70) -tert-Butyl (S)-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate (71) -(S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid (72) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazol-5-amine (73) -(S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)(3-hydroxyazetidin-1-yl)methanone (74) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-(oxetan-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (75) -Ethyl (S)-2-((8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-2-oxoacetate (76) -(S)-N1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxalamide (77) -(S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine (78) -(S)-8-(6-ethoxy-2-fluoropyridin-3-yl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (79) -(S)-8-(6-ethoxy-2-fluoropyridin-3-yl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile 2,2,2-trifluoroacetate (80) -(S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzamide (81) -(S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanol (82) -Methyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate (83) -(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1-hydroxycyclopropane-1-carboxamide formate (84) -(S)-1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-4-hydroxypyrrolidin-2-one (85) -(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid (86) -N-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2-difluorocyclopropane-1-carboxamide (87) -(S)-3-((8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-4-hydroxycyclobut-3-ene-1,2-dione (88) -(S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine (89) -(S)-N-(8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanesulfonamide (90) -(S)-1-(3-fluoropropyl)-3-(4-(8-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine (91) -(S)-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-yl)boronic acid (92) -(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetic acid (93) -(S)-2-(3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)propan-2-ol (94) -(S)-2-(4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)propan-2-ol (95) -(S)-3-(4-(8-(2-chloro-3-fluorophenyl)-3-(3-nitrophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine (96) -(S)-3-(8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)aniline (97) (S)-2-(4-(8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)propan-2-ol (98) or a pharma- ceutically acceptable salt thereof.

[0040] Among the aforementioned listed compounds, specific examples include the following compounds: (2), (3), (5), (8), (10), (21), (28), (31), (42), (43), (45), (46), (49), (63), (64), (78), (80), (82), (89) and (92).

[0041] Another subject of the invention is a compound selected from the list above, or a pharma- ceutically acceptable salt thereof, for use in therapy, in particular as an inhibitor and degrader of the estrogen receptor.

[0042] Another subject of the invention is a compound selected from the list above, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer, and in particular breast cancer.

[0043] Another subject of the invention is a method for treating cancer, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound selected from the list above, or a pharma- ceutically acceptable salt thereof.

[0044] Another subject of the invention is a pharmaceutical composition comprising, as active ingredient, an effective dose of a compound selected from the above list, or a pharma- ceutical acceptable salt thereof, and also at least one pharma- ceutical acceptable excipient. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] According to the present invention, the compound of formula (I) can be prepared by the following process.

[0046] Compounds of formula (I) and other related compounds having different substituents are synthesized using the techniques and materials described below or otherwise known to those skilled in the art. In addition, the solvents, temperatures and other reaction conditions presented below may be varied as deemed appropriate by those skilled in the art.

[0047] The following general methods for preparing the compounds of the invention are optionally modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in formula (I) below.

[0048] The following abbreviations and empirical formulas are used: AIBN 2,2'-Azobisisobutyronitrile CDI 1,1'-Carbonyldiimidazole Cs 2 CO 3 Cesium Carbonate DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DIPEA N,N-Diisopropylethylamine DPA Diphenylphosphoryl azide EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOH Ethanol EtOAc Ethyl acetate HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HCl Hydrochloric acid iPrOH Isopropyl Alcohol K 2 CO 3Potassium carbonate LiAlH 4 Lithium Aluminum Hydride MeCN Acetonitrile MeOH Methanol MgCl 2 Magnesium chloride MgSO 4 Magnesium sulfate NaBH 4 Sodium borohydride NaHCO 3 Sodium bicarbonate Na 2 CO 3 Sodium carbonate NaIO 4 Sodium Periodate NaOAc Sodium Acetate NaOH Sodium hydroxide Na 2 SO 4 Sodium sulfate NBS N-Bromosuccinimide NH 4 CO 3 Ammonium carbonate NH 4 HCO 3 Ammonium bicarbonate NMP N-Methyl-2-pyrrolidone P4-T-BU N'''-(1,1-dimethylethyl)-N,N',N''-tris[tris(dimethylamino)phosphoranylidene]phosphorimidic acid triamide Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl 2 1,1'-Bis(diphenylphosphino)ferrocene Pd(PPh 3 ) 2 Cl 2 Bis(triphenylphosphine)palladium(II) chloride PIDA Phenyl iodine diacetate PTAB Phenyltrimethylammonium perbromide TBAF Tetrabutylammonium fluoride tBuXPhos 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate TCDI 1,1'-Thiocarbonyldiimidazole TEA Triethylamine TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride THF Tetrahydrofuran THPO-NH 2 O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine

[0049] Scheme 1a: Preparation of Compounds of Formula (I) - General Method [ka]

[0050] According to scheme 1a, where Ar is defined as above, compound 1A (prepared according to WO2017140669) can be converted in step 1 to the corresponding compound 1B by treatment with triflic anhydride in the presence of a base such as pyridine in an aprotic solvent such as DCM. This intermediate can be converted in step 2 to the corresponding compound 1B by treatment with triflic anhydride in the presence of a base such as NaOAc in a sealed tube in a microwave apparatus at reflux temperature or above in a solution in 1,4-dioxane, for example, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) in the presence of a base such as NaOAc, and a palladium catalyst such as bis(triphenylphosphine)palladium(II) chloride Pd(PPh 3 ) 2 Cl 2 Compound 1C can be converted to compound 1C in step 3 by treatment with NaIO as a solution in THF and water at room temperature for, e.g., 35 minutes. 4 to afford compound 1D.

[0051] Said route furthermore makes it possible to prepare, for example, the following compounds: [ka]

[0052] Scheme 1b: Preparation of Compounds of Formula (I) - General Method [ka]

[0053] According to scheme 1b, where Ar is defined as above, compound 1B can be converted in step 1 to compound 1E by treatment with tert-butyl acrylate in the presence of a catalyst such as bis(triphenylphosphine)palladium(II) chloride using TEA as base in DMF under HECK conditions at a temperature around 120° C. for 1 hour, which can be converted in step 2 to compound 1F in the presence of an acid such as hydrochloric acid as a solution in 1,4-dioxane.

[0054] Scheme 1c: Preparation of Compounds of Formula (I) - General Method [ka]

[0055] According to scheme 1c, where Ar is defined as above, compound 1A (prepared according to WO2017140669) can be converted to compound 1G in step 1 by treatment with diethyl(bromodifluoromethyl)phosphonate in the presence of potassium hydroxide, for example in a mixture of MeCN and water, at a temperature around 0° C. for 1 hour.

[0056] Scheme 1d: Preparation of Compounds of Formula (I) - General Method [ka]

[0057] According to scheme 1d, where Ar is defined as above, compound 1B can be prepared in step 1 by reacting 2-oxazolidone or pyrrolidinone, tBuXphos, Pd 2 (dba) 3 , can be converted to compound 1H using sodium tert-butylate.

[0058] Scheme 1e: Preparation of Compounds of Formula (I) - General Method [ka]

[0059] According to Scheme 1e, where Ar is defined as above, compound 1B can be prepared in step 1 by reacting 2-oxazolidone, tBuXphos, Pd 2 (dba) 3 , can be converted to compound 1I using sodium tert-butylate.

[0060] Scheme 1f: Preparation of Compounds of Formula (I) - General Method [ka]

[0061] According to scheme 1f, where Ar is defined as above, compound 1J (prepared according to WO2017140669) can be prepared in step 1 by reacting, for example, (1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)boronic acid, Pd(dppf)Cl in a mixture of, for example, 1,4-dioxane and water at 100° C. in a microwave apparatus. 2 , Cs 2 CO 3Compound 1K can be converted to compound 1K in step 2 by bromination with pyridinium tribromide in THF at room temperature to compound 1L in step 3. Compound 1L can be converted to compound 1K in step 4 by bromination with boronic acid derivative, Pd(dppf)Cl in a mixture of 1,4-dioxane and water at 100° C. in a microwave apparatus under Suzuki conditions. 2 , Cs 2 CO 3 can be converted to compound 1M using

[0062] The above procedure can be used to obtain further compounds of formula (I) in which R3 is a -XZ group, where X is a bond, by using alternative starting materials in step 1, i.e. alternative boronic acid derivatives, and corresponding adaptations are within the skill of the art.

[0063] Scheme 1g: Preparation of Compounds of Formula (I) - General Method [ka]

[0064] According to scheme 1g, where Ar is defined as above, compound 1B (prepared according to WO2017140669) can be converted to compound 1N in step 1 using 3-pyrazoleboronic acid under Suzuki conditions. Compound 1B can be converted to compound 1O in step 2 using hydroxyphenylboronic acid under Suzuki conditions. Compound 1B can be converted to compound 1P in step 3 using methoxycarbonylphenylboronic acid under Suzuki conditions. Compound 1P can be converted to compound 1Q in step 4 using NaOH in a mixture of MeOH and THF at 60° C. Compound 1Q can be converted to compound 1Q in step 5 using NaOH in a mixture of MeOH and THF at room temperature or higher in the presence of a base such as pyridine, for example NH 4 HCO 3and di-tert-butyl dicarbonate to give compound 1R. Compound 1B can be converted to compound 1S in step 6 using the corresponding boronic acid under Suzuki conditions.

[0065] Scheme 1h: Preparation of Compounds of Formula (I) - General Method [ka]

[0066] According to Scheme 1h, where Ar is defined as above, compound 1C (Scheme 1a) can be converted to the corresponding compound 1T in step 1 by treatment with 3-bromo-2-((tert-butyldimethylsilyl)oxy)cyclopent-2-en-1-one under Suzuki conditions. This intermediate can be converted to compound 1U in step 2 by treatment with TBAF in THF at room temperature.

[0067] Scheme 1i: Preparation of Compounds of Formula (I) - General Method [ka]

[0068] According to scheme 1i, where Ar is defined as above, compound 1B (prepared according to WO2017140669) can be converted to compound 1V in step 1 under Suzuki conditions, for example, with nitroboronic acid. Compound 1V can be converted to compound 1V in step 2 by reaction with, for example, zinc powder and NH in iPrOH at reflux. 4 Cl can be used to convert to compound 1W.

[0069] Scheme 2a: Preparation of Compounds of Formula (I) - General Method [ka]

[0070] In the formula, -CO-NRaRb includes both (1) the -COR4 group (wherein R4 is as defined above) and (3) the XZ group (wherein X represents a -CO- group and Z is as defined above).

[0071] According to scheme 2a, where Ar is defined as above, compound 2A (prepared according to WO2017140669) can be reacted in step 1, for example, as a solution in 1,4-dioxane at room temperature or above, in the presence of a base such as pyridine, for example with NH 4 HCO 3 and di-tert-butyl dicarbonate to give compound 2B. Compound 2A can also be converted to compound 2B' using the corresponding NHRaRb amine, where Ra and Rb are defined as shown above, in the presence of a coupling agent such as HBTU. Compound 2B can be converted to compound 2C using TFA and TEA in DCM at room temperature for 16 hours as in step 2. Compound 2C can be converted to compound 2D using azidotrimethylsilane in 1,4-dioxane at 100° C. for 11 hours in a microwave as in step 3.

[0072] Scheme 2b: Preparation of Compounds of Formula (I) - General Method [ka]

[0073] According to Scheme 2b, where Ar is defined as above, compound 2A (prepared according to WO2017140669) can be prepared in step 1 by reacting, for example, CDI, potassium methyl malonate, and MgCl in THF under reflux for 24 hours. 2 In step 2, compound 2E can be converted to compound 2E by treatment with THPO-NH in NMP at 120 °C for 2.5 h in a microwave apparatus. 2(O-(tetrahydro-2H-pyran-2-yl)hydroxylamine). Compound 2F can be converted to compound 2G in step 3 using concentrated HCl in MeOH at room temperature. Compound 2E can also be converted to compound 2H in step 4 using NaOH 1N in THF at 50° C. Compound 2E can also be converted to compound 2I in step 5 using, for example, hydrazine hydrate in THF at 80° C. in a microwave apparatus. Compound 2E can further be converted to compound 2J in step 6 using, for example, hydroxylamine hydrochloride in refluxing EtOH.

[0074] Scheme 2c: Preparation of Compounds of Formula (I) - General Method [ka]

[0075] According to scheme 2c, where Ar is defined as above, compound 2A (prepared according to WO2017140669) can be converted to the corresponding compound 2K in step 1 using, for example, N,O-dimethylhydroxylamine hydrochloride, DIPEA, HBTU in DMF at room temperature for 4 hours. Compound 2K can be converted to the corresponding compound 2K in step 2 using, for example, LiAlH 4 Compound 2L can be converted to compound 2M in step 3 using, for example, (difluoromethyl)trimethylsilane and P4-T-BU in DMF at room temperature for 45 minutes. Compound 2K can be converted to compound 2H in step 4 using a Grignard reagent such as methylmagnesium bromide in THF at 0° C. Compound 2L can also be converted to compound 2H in step 5 using, for example, NH in THF and water at 70° C. 4 CO 3and potassium cyanide to compound 2N. Compound 2L can similarly be converted to compound 2O in step 6 using, for example, deoxofluor (bis(2-methoxyethyl)aminosulfur trifluoride) in DCM at room temperature for 24 hours. Compound 2L can further be converted to compound 2P in step 7 using, for example, trifluoromethyltrimethylsilane and cesium fluoride in THF at room temperature.

[0076] Scheme 2d: Preparation of Compounds of Formula (I) - General Method [ka]

[0077] According to scheme 2d, where Ar is defined as above, compound 2Q can be obtained in step 1 from compound 2A (prepared according to WO2017140669) using, for example, DPA in refluxing tert-butanol for 16 hours. Compound 2Q can also be obtained in step 2 from compound 2A using, for example, tert-butyl carbamate, potassium tert-butoxide, tBuXPhos, Pd 2 (dba) 3 Compound 2Q can be obtained from compound 1B using, for example, DBU, NBS, in a mixture of solvents such as MeOH and DCM at room temperature. Compound 2R can be obtained from compound 2B in step 4 by first reacting with PIDA, 2-(trimethylsilyl)ethanol in DCM at 35° C., and then with TBAF and potassium fluoride in MeCN at 55° C. Compound 2B can also be obtained from compound 1B in step 5 using, for example, DBU, NBS, in a mixture of solvents such as MeOH and DCM at room temperature. Compound 2S can be obtained from compound 2R in step 6 using, for example, potassium hydroxide in refluxing MeOH.

[0078] Scheme 2e: Preparation of Compounds of Formula (I) - General Method [ka]

[0079] In the formula, the -NH-COY group encompasses the meanings of both (3) the XZ group (wherein X represents -NHCO and Z is as defined above) and (8) the -NH-COR9 group (wherein R9 is as defined above).

[0080] According to scheme 2e, where Ar is defined as above, compound 2R can be converted in step 1 to compound 2T, for example, with trifluoromethanesulfonic anhydride in DCM at room temperature in the presence of TEA. Compound 2R can be converted in step 2 to compound 2U, for example, with sulfonic acid chloride in DCM at room temperature in the presence of TEA. Compound 2R can be converted in step 3 to compound 2V, for example, with squaric acid in DMF at 130° C. in a microwave. Compound 2R can be converted in step 4 to compound 2W, for example, with methyl acetimidate hydrochloride in MeCN at room temperature in the presence of TEA. Compound 2R can be converted in step 5 to compound 2X, for example, with alcoyl chloride in DCM at room temperature in the presence of TEA (where Z and R9 are defined as above), or with a carboxylic acid in the presence of a tertiary amine, HATU, or EDAC in DMF (where Z and R9 are defined as above). Compound 2R can be converted to compound 2Y in step 6 using, for example, trifluoroacetic anhydride in the presence of TEA in THF at room temperature.

[0081] Scheme 2f: Preparation of Compounds of Formula (I) - General Method [ka]

[0082] According to scheme 2f, where Ar is defined as above, compound 2C can be converted to compound 2Z in step 1 using hydroxylamine hydrochloride in EtOH at 80° C. Compound 2Z can be converted to compound 2AA in step 2 using DBU and CDI in refluxing 1,4-dioxane. Compound 2Z can be converted to compound 2AB in step 3 by first treating with DBU and TCDI in THF at room temperature, then adding boron trifluoride-diethyl etherate. Compound 2Z can be converted to compound 2AC in step 4 by treating with DBU and TCDI in refluxing MeCN. Compound 2Z can be converted to compound 2AD in step 5 by treating with thionyl chloride in the presence of pyridine in THF at room temperature.

[0083] Scheme 2g: Preparation of Compounds of Formula (I) - General Method [ka]

[0084] According to scheme 2g, where Ar is defined as above, compound 2A (prepared according to WO2017140669) can be converted to compound 2AE in step 1 using tert-butyl carbazate, TBTU, and DIPEA in MeCN at room temperature. Compound 2AE can be converted to compound 2AF in step 2 using Lawesson's reagent in 1,4-dioxane at 110° C. in a microwave. Compound 2AF can be converted to compound 2AG in step 3 using hydrochloric acid 4N in 1,4-dioxane at room temperature. Compound 2AG can be converted to compound 2AH in step 4 using triethyl orthoformate in a microwave at 100° C.

[0085] Scheme 2h: Preparation of Compounds of Formula (I) - General Method [ka]

[0086] According to scheme 2h, where Ar is defined as above, compound 2A (prepared according to WO2017140669) can be converted to compound 2AI in step 1 by first reacting with O-benzylhydroxylamine, HATU, and DIPEA in DMF for 16 hours, and hydrogenating with palladium on carbon in MeOH at room temperature. Compound 2A can be converted to compound 2AJ in step 2 with O-methylhydroxylamine hydrochloride, HATU, and DIPEA in DMF at room temperature. Compound 2A can be converted to compound 2AK in step 3 with DMAP and EDCI in DCM at room temperature. Compound 2A can be converted to compound 2AL in step 4 with aminotetrazole, HATU, and DMAP in DMF at room temperature.

[0087] Scheme 2i: Preparation of Compounds of Formula (I) - General Method [ka]

[0088] According to scheme 2i, where Ar is defined as above, compound 2A (prepared according to WO2017140669) can be converted to compound 2AM in step 1 using Barton conditions by first reacting with thionyl chloride at room temperature for 3 hours, followed by reacting with 2-mercaptopyridine N-oxide sodium salt and AIBN (2,2'-azobisisobutyronitrile) in a mixture of bromotrichloromethane and carbon tetrachloride at reflux temperature for 3 hours. Compound 2AM can be converted to compound 2AN in step 2 under Ullmann conditions using 4-methoxy-3-pyrrolin-2-one, potassium phosphate, copper iodide, N,N'-dimethylethylenediamine in a mixture of 1,4-dioxane and DMF at 110°C in a microwave apparatus.

[0089] Scheme 2j: Preparation of Compounds of Formula (I) - General Method [ka]

[0090] According to Scheme 2j, where Ar is defined as above, compound 2B can be converted in step 1 to compound 2AO using chlorocarbonylsulfenyl chloride in refluxing toluene.

[0091] Scheme 2k: Preparation of Compounds of Formula (I) - General Method [ka]

[0092] According to Scheme 2k, where Ar is defined as above, compound 2H (Scheme 2c) can be prepared in step 1 by reacting NaBH 4 Compound 2H (Scheme 2c) can be converted to the corresponding compound 2AQ in step 2 using MeMgBr in THF at room temperature. Compound 2H (Scheme 2c) can be converted to the corresponding compound 2AR in step 3 by first treating with PTAB in THF at room temperature, followed by reaction with thiourea in refluxing MeOH.

[0093] Scheme 2l: Preparation of Compounds of Formula (I) - General Method [ka]

[0094] According to Scheme 21, where Ar is defined as above, compound 2R (Scheme 2d) can be converted to the corresponding compound 2AS in step 1 using ethyl oxalyl chloride and TEA in DCM at room temperature. Compound 2AS can be converted to the corresponding compound 2AT in step 2 using ammonia in MeOH at room temperature.

[0095] Scheme 2m: Preparation of Compounds of Formula (I) - General Method [ka]

[0096] According to Scheme 2m, where Ar is defined as above, compound 2H (Scheme 2c) can be converted in step 1 to the corresponding compound 2AU by first treating with benzyltrimethylammonium dichloroiodate in refluxing DCM for 16 hours, and then with N,N'-dimethylthiourea in refluxing EtOH for 3 hours.

[0097] Scheme 2n: Preparation of Compounds of Formula (I) - General Method [ka]

[0098] According to Scheme 2n, where Ar is defined as above, compound 2AM (Scheme 2i) can be converted in step 1 to compound 2AV using (S)-4-hydroxy-2-pyrrolidinone, (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine, cuprous iodide, potassium carbonate in refluxing toluene for 16 hours.

[0099] Scheme 3a: Preparation of Compounds of Formula (I) - General Method [ka]

[0100] According to scheme 3a, where Ar is defined as above, compound 3A (prepared according to WO2017140669) can be converted to the corresponding compound 3B in step 1 using hydrazine hydrate in EtOH at reflux for 4 hours. Compound 3B can be converted to the corresponding compound 3B in step 2 using sodium cyanate and acetic acid in a solvent such as chloroform at 50° C. for 24 hours. Compound 3B can be converted to compound 3D in step 3 using triethyl orthoformate as a solution in acetic acid in a microwave at 160° C. for 20 minutes. Compound 3B can be converted to compound 3E in step 4 using DBU and CDI in 1,4-dioxane at 160° C. for 20 minutes in a microwave. Compound 3B can be converted to compound 3F and compound 3G in step 5 using DBU and TCDI in 1,4-dioxane at 160° C. for 20 minutes in a microwave.

[0101] Scheme 3b: Preparation of Compounds of Formula (I) - General Method [ka]

[0102] According to scheme 3b, where Ar is defined as above, compound 3A can be converted to compound 3G in step 1 using MeCN and sodium hydride in DMSO at room temperature. Compound 3G can be converted to compound 3H using hydrazine hydrate in EtOH at reflux.

[0103] Scheme 4: Preparation of compounds of formula (I) - General method [ka]

[0104] According to Scheme 4, where Ar is defined as above, compound 4A can be prepared in step 1 by the reaction of zinc chloride and Pd(dib) in DMF at 135° C. for 3 hours in a microwave oven. 2 / P(t-Bu) 3 In the presence of 3 , it can be converted to the corresponding compound 4B using 1-(tert-butyldimethylsilyloxy)-1-methoxyethene. Compound 4B can be converted to compound 4C using trifluoroacetic anhydride and pyridine in DCM at room temperature. Compound 4C can be converted to compound 4E using compound 4D (prepared according to WO2017140669) under Suzuki conditions. Compound 4E can be converted to compound 4F using pyridinium tribromide in DCM at room temperature. Compound 4F can be converted to compound 4G using arylboronic acid under Suzuki conditions. Compound 4G can be converted to compound 4H using NaOH in MeOH under reflux.

[0105] For the examples in which the numbers in Table 1 are shown in bold, they will be described in more detail later.

[0106] At 400 and 500 MHz 1 The 1H NMR spectra were performed on a Bruker Avance DRX-400 and a Bruker Avance DPX-500 spectrometer, respectively. The chemical shifts (δ in ppm) in the solvent dimethyl sulfoxide-d6 (d6-DMSO) were referenced to 2.5 ppm at a temperature of 303 K. The coupling constants (J) are shown in Hertz.

[0107] Liquid chromatography / mass spectrometry (LC / MS) was obtained using a UPLC Acquity Waters instrument, a Sedere light scattering detector and a SQD Waters mass spectrometer, with UV detection DAD 210 <l < 400 nm and a column Acquity UPLC CSH C18 1.7 μm, dimensions 2.1×30 mm, and a mobile phase H 2 O + 0.1% HCO 2 H / CH 3 CN + 0.1% HCO 2 H.

[0108]

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

[0109] The following examples describe the preparation of some compounds according to the invention. The compound numbers exemplified below correspond to those shown in Table 1 above. All reactions are carried out under an inert atmosphere unless otherwise specified.

[0110] In the following examples, unless the source of a starting product is specified, said product is to be understood as a known compound. EXAMPLES

[0111] (S)-3-(4-(8-(2,4-dichlorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [ka]

[0112] Step 1: (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate. [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol [WO2017140669] (141 mg, 267.82 μmol) in DCM (2 ml) and pyridine (35 μl, 429 μmol) was added trifluoromethanesulfonic anhydride (96 μl, 568 μmol). The reaction mixture was stirred at room temperature for 15 min. Cold water (5 ml) and DCM (10 ml) were added. After decantation, the organic phase was washed with MgSO 4 The extract was dried at 40° C., filtered, and evaporated under reduced pressure to give 203 mg of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate.

[0113] LC / MS(m / z, MH+): 558

[0114] Step 2: (S)-3-(4-(8-(2,4-dichlorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [ka] A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (89 mg, 81 μmol), 1,4-dioxane (0.9 ml), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (55 mg, 216.59 μmol), bis(triphenylphosphine)palladium(II) chloride (7 mg, 10 μmol) and sodium acetate (45 mg, 543 μmol) was heated in a microwave at 130° C. for 5 hours. Water (5 ml) and DCM (10 ml) were added. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 95 / 05, v / v) to give 18 mg (34%) of tert-butyl (S)-3-(4-(8-(2,4-dichlorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine. EXAMPLES

[0115] (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)boronic acid [ka] THF (1.6 ml), water (0.4 ml) and NaIO 4A mixture of tert-butyl (S)-3-(4-(8-(2,4-dichlorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [Example 1] (159 mg, 250 μmol) in (160 mg, 749 μmol) was stirred at room temperature for 35 minutes. Hydrochloric acid 1M (0.17 ml, 170 μmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Water (10 ml) and DCM (10 ml) were added. After hydrophobic column decantation, the organic phase was evaporated under reduced pressure and the residue was purified by reverse phase HPLC to give 23 mg (17%) of (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)boronic acid. EXAMPLES

[0116] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [ka] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (511 mg, 921.58 μmol), pyridine (0.05 ml, 594.68 μmol), di-tert-butyl dicarbonate (105 mg, 460.79 μmol) and NH 4 HCO 3A mixture of (112 mg, 1.38 mmol) was stirred at 40 °C for 5 h and at room temperature for 18 h. Water (10 ml) and DCM (10 ml) were added. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 90 / 10, v / v) to give (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide 236 mg (46%). EXAMPLES

[0117] (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)isoxazol-3-ol [ka]

[0118] Step 1: Methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopropanoate [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (300 mg, 541.04 μmol) in THF (10 ml) was added CDI (164.50 mg, 811.57 μmol) and the reaction mixture was heated at reflux for 3 h. A suspension of potassium 3-methoxy-3-oxopropanoate (352.08 mg, 2.16 mmol) and magnesium chloride (208.12 mg, 2.16 mmol) in THF (4 ml) was added and the resulting reaction mixture was heated at reflux for 16 h. The solvent was evaporated under reduced pressure, the residue was partitioned between EtOAc and water, the organic phase was washed with water and diluted with MgSO 4 The mixture was dried at 40° C., filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM, EtOAc, and MeOH (50 / 45 / 5, v / v / v) to give 0.56 g (85%) of methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopropanoate.

[0119] LC / MS(m / z, MH+): 610

[0120] Step 2: 3-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxo-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide. [ka] A mixture of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopropanoate (100 mg, 163.79 μmol), o-(tetrahydro-2h-pyran-2-yl)hydroxylamine (60.59 mg, 491.36 μmol) and 4-dimethylaminopyridine (54 mg, 442.23 μmol) in 1-methyl-2-pyrrolidinone (2 ml) was heated in a microwave at 120° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water, brine and diluted with MgSO. 4 The residue was purified by flash chromatography eluting with a mixture of DCM, EtOAc, and MeOH (50 / 45 / 5, v / v / v) to give 42 mg (37%) of 3-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxo-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide.

[0121] LC / MS(m / z, MH+): 695

[0122] Step 3: (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)isoxazol-3-ol [ka] To a solution of 3-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxo-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide (42 mg, 60.37 μmol) in MeOH (2 ml) was added concentrated HCl (0.5 ml, 6.25 mmol) and the reaction mixture was stirred at room temperature for 40 min.

[0123] Saturated NaHCO 3 solution and EtOAc were added, and the organic phase was washed with water and MgSO 4 The residue was purified by flash chromatography eluting with a mixture of DCM, EtOAc, and MeOH (50 / 45 / 5, v / v / v) to give 21 mg (59%) of (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)isoxazol-3-ol. EXAMPLES

[0124] 1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2-difluoroethan-1-ol [ka]

[0125] Step 1: (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde [ka] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 44] (3.3 g, 5.52 mmol) in THF (150 ml) cooled at -40°C, LiAlH 4 (4.14 ml, 8.28 mmol) was added dropwise. The reaction mixture was stirred at -30°C for 30 min and quenched with water (4 ml), NaOH 5N (4 ml) and again with water (12 ml). The formed precipitate was filtered and washed with EtOAc, then the organic layer was washed with brine. The organic phase was diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 95 / 05, v / v) to give 2.7 g (91%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde.

[0126] LC / MS (m / z, M-H + ):538.

[0127] Step 2: 1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2-difluoroethan-1-ol [ka] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde (100 mg, 185.71 μmol) in DMF (3 ml) was added (difluoromethyl)trimethylsilane (34.60 mg, 278.56 μmol) and phosphazene base P4-t-Bu 0.8M in hexane (46.43 μl, 37.14 μmol). The reaction mixture was stirred at room temperature for 1 h. Water (2 ml) was then added, followed by a solution of HCl 5N until a pH of 2 was reached. The reaction mixture was stirred at room temperature for 1 h. Water (5 ml) was added, followed by K 2 CO 3 A saturated aqueous solution of was added until a pH of 10 was reached. The mixture was extracted twice with EtOAc, the organic layers were collected and washed with brine. The organic phase was washed with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 95 / 05, v / v) to give 20 mg (18%) of 1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2-difluoroethan-1-ol. EXAMPLES

[0128] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide [ka] To a solution of methyl (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl]oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [WO2017140669] (849 mg, 1.49 mmol) in EtOH (15 ml) was added hydrazine hydrate (724.94 μl, 14.93 mmol). The reaction mixture was heated at reflux for 16 h and partitioned between EtOAc and water. The organic phase was washed with water and brine and diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (95 / 05, v / v) to give 200 mg (23.6%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide. EXAMPLES

[0129] (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazole [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide [Example 6] (160 mg, 281.44 μmol) in acetic acid (1 ml) was added triethyl orthoformate (1 ml, 5.83 mmol). The reaction mixture was heated in a microwave at 160° C. for 20 minutes and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (98 / 02, v / v) to give 127 mg (78%) of (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazole. EXAMPLES

[0130] (S)-3-(4-(8-(2,4-dichlorophenyl)-3-(difluoromethyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [ka] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde [Example 5, step 1] (300 mg, 557.12 μmol) in DCM (5 ml) was added bis(2-methoxyethyl)aminosulfur trifluoride 2.7M in toluene (2.06 ml, 5.57 mmol). The reaction mixture was stirred at room temperature for 72 h. Water was added and the mixture was extracted with DCM. The organic layer was washed with brine. The organic phase was diluted with MgSO 4The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 95 / 05, v / v) to give 80 mg (26%) of (S)-3-(4-(8-(2,4-dichlorophenyl)-3-(difluoromethyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine. EXAMPLES

[0131] (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-thiadiazole [ka]

[0132] Step 1: tert-Butyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl)hydrazine-1-carboxylate [ka] To a suspension of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (400 mg, 721.39 μmol) in MeCN (10 ml) was added DIPEA (377.99 μl, 2.16 mmol), tert-butyl carbazate (129 mg, 937.81 μmol), and TBTU (354.53 mg, 1.08 mmol). The reaction mixture was stirred at room temperature for 3 h, partitioned between water and EtOAc, the organic phase was washed with water and diluted with MgSO 4The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (95 / 5, v / v) to give 450 mg (93%) of tert-butyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl)hydrazine-1-carboxylate.

[0133] LC / MS(m / z, MH+):668

[0134] Step 2: tert-Butyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonothioyl)hydrazine-1-carboxylate [ka] To a solution of tert-butyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl)hydrazine-1-carboxylate (100 mg, 149.56 μmol) in 1,4-dioxane (1.5 ml) was added Lawesson's reagent (62 mg, 149.56 μmol) and the reaction mixture was microwaved at 100° C. for 10 min. The reaction mixture was partitioned between water and EtOAc and the organic phase was washed with water, brine and diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (95 / 5; v / v) to give 40 mg (39%) of tert-butyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonothioyl)hydrazine-1-carboxylate.

[0135] LC / MS(m / z, MH+):684

[0136] Step 3: (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbothiohydrazide [ka] A mixture of tert-butyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonothioyl)hydrazine-1-carboxylate (225 mg, 328.61 μmol) and HCl 4N in 1,4-dioxane (1 ml, 4.00 mmol) was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure to give crude (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbothiohydrazide 150 mg (78%).

[0137] LC / MS(m / z, MH+):584

[0138] Step 4: (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazole [ka] A suspension of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbothiohydrazide (150 mg, 256.59 μmol) in triethyl orthoformate (1.5 ml) was heated in a microwave at 100° C. for 10 min. The reaction mixture was partitioned between water and EtOAc and the organic phase was washed with water, brine and diluted with MgSO. 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM, EtOAc and MeOH (50 / 45 / 5; v / v / v) to give 43.7 mg (33%) of (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazole. EXAMPLES

[0139] 1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroethane-1-ol [ka] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde [Example 5, step 1] (160 mg, 297.13 μmol) in THF (5 ml) was added (trifluoromethyl)trimethylsilane (58 μl, 0.392 mmol) and cesium fluoride (22 mg, 0.145 mmol). The reaction mixture was stirred at room temperature for 1 h. Water (2 ml) was then added, followed by a solution of HCl 5N until a pH of 2 was reached. The reaction mixture was stirred at room temperature for 1 h. Water (5 ml) was added, followed by K 2 CO3 A saturated aqueous solution of was added until a pH of 10 was reached. The mixture was extracted twice with EtOAc, the organic layer was collected and washed with brine. The organic phase was washed with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography using a gradient of MeOH in DCM (100 / 0 to 95 / 05, v / v) to give 44 mg (25%) of 1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroethan-1-ol. EXAMPLES

[0140] (S)-3-(4-(3-bromo-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [ka]

[0141] Step 1: (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl chloride [ka] To (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (300 mg, 541 μmol) was added thionyl chloride (3 mL) at 0° C. under an inert atmosphere, and the reaction mixture was stirred at room temperature for 3 hours. The thionyl chloride was evaporated under reduced pressure to give (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl chloride 308 mg (99.4%), which was used in the next step without further purification.

[0142] Step 2: (S)-3-(4-bromo-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [ka] To a suspension of 2-mercaptopyridine N-oxide sodium salt (136 mg, 876 μmol) in refluxing bromotrichloromethane (5 mL) at 105° C. under an inert atmosphere was added dropwise (5 min) a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl chloride (308 mg, 537 μmol) and AIBN (22.5 mg, 134 μmol) in bromotrichloromethane (8 mL). After heating for 3 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc to give 134 mg (42%) of (S)-3-(4-bromo-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine. EXAMPLES

[0143] (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2-dihydro-3H-pyrazol-3-one [ka] A solution of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopropanoate [Example 4, step 1] (117 mg, 191.63 μmol) in EtOH (10 ml), THF (1 ml), and hydrazine hydrate (12 mg, 191.63 μmol) was heated in a microwave at 80° C. for 20 min. The reaction mixture was partitioned between water and EtOAc, and the organic phase was washed with water, brine, and diluted with MgSO. 4 The residue was purified by flash chromatography eluting with a mixture of DCM, EtOAc, and MeOH (50 / 45 / 5, v / v / v) to give 19 mg (16%) of (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2-dihydro-3H-pyrazol-3-one. EXAMPLES

[0144] (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)isoxazol-5(4H)-one [ka] EtOH (4 ml), hydroxylamine hydrochloride (23.47 mg, 327.57 μmol) and NaHCO 3A mixture of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopropanoate [Example 4, step 1] (80 mg, 131.03 μmol) in (22 mg, 262.06 μmol) was heated under reflux for 3 h. The reaction mixture was partitioned between water and EtOAc, and the organic phase was washed with water, brine, and MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (95 / 5, v / v) to give 20.8 mg (27%) of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)isoxazol-5(4H)-one. EXAMPLES

[0145] (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl)hydrazine-1-carboxamide [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide [Example 6] (200 mg, 351.79 μmol) in chloroform (10 ml) was added acetic acid (20.74 μl, 351.79 μmol), and sodium cyanate (35.36 mg, 529.69 μmol). The reaction mixture was heated at 50° C. for 24 h and the solvent was removed under reduced pressure. The residue was partitioned between DCM and water, the organic phase was washed with water and brine, and MgSO 4The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (90 / 10, v / v) to give 47.5 mg (22.1%) of (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl)hydrazine-1-carboxamide. EXAMPLES

[0146] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-(methylsulfonyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide. [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl]oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (150 mg, 270 μmol) in DCM (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (108 mg, 541 μmol), 4-dimethylaminopyridine (68.85 mg, 541 μmol), and methanesulfonamide (53 mg, 541 μmol). The reaction mixture was stirred at room temperature for 16 h and partitioned between DCM and water. The organic phase was washed with water and brine and diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (95 / 05, v / v) to give 17.6 mg (10.3%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-(methylsulfonyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide. EXAMPLES

[0147] (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2H-tetrazole [ka] A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile [Example 22] (43 mg, 66 μmol), dibutyltin oxide (5 mg, 20.47 μmol) and azidotrimethylsilane (36 μl, 260 μmol) in 1,4-dioxane (0.6 ml) was microwaved at 100° C. for 6 h. After cooling and LCMS preparation, dibutyltin oxide (5 mg, 20.47 μmol) and azidotrimethylsilane (36 μl, 260 μmol) were added and the mixture was microwaved at 100° C. for a further 5 h. After cooling, water (5 ml) and DCM (10 ml) were added. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by supercritical fluid chromatography (SFC), phase: 2-ethylpyridine (Princeton), 5 μm, 250 × 30 mm; eluent: CO for 3 min. 2 65% / MeOH (+0.1% TEA) 35%, then CO 2 Purification by 60% / MeOH (+0.1% TEA) 40%; flow rate: 120 ml / min; P inlet: 160 bar; P outlet: 100 bar; oven temperature: 40° C.; λ=254 nm gave (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2H-tetrazole 20 mg (53%). EXAMPLES

[0148] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-(2H-tetrazol-5-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide. [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl]oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (150 mg, 270 μmol) in DMF (15 ml), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- Oxidohexafluorophosphate (HATU, 114.29 mg, 5297.57 μmol), 4-dimethylaminopyridine (1.72 mg, 13.53 μmol), TEA (112.1 μl, 811.57 μmol), and aminotetrazole (23 mg, 270.52 μmol) were added. The reaction mixture was stirred at room temperature for 16 h and partitioned between DCM and water. The organic phase was washed with water and brine and diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (95 / 05; v / v) to give 22.5 mg (13.4%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-(2H-tetrazol-5-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide. EXAMPLES

[0149] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [ka]

[0150] Step 1: (S)-N-(benzyloxy)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [ka] To a solution of (R)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (277 mg, 500 μmol) in DMF (6 ml) was added O-benzylhydroxylamine (96 mg, 90.94 μmol), HATU (333 mg, 850 μmol) and DIPEA (464 μl, 2.5 mmol). The reaction mixture was stirred at room temperature for 4 h. Cold water (25 ml) and a mixture of DCM / MeOH 80 / 20 (30 ml) were added. After decantation, the organic phase was diluted with MgSO 4 It was dried at 40° C., filtered, evaporated under reduced pressure and the residue was purified by flash chromatography eluting with DCM, MeOH, and MeCN (96 / 2 / 2, v / v / v) to give 230 mg (69%) of (S)—N-(benzyloxy)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide.

[0151] LC / MS(m / z, MH+): 659

[0152] Step 2: (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [ka] In an autoclave, a mixture of (S)-N-(benzyloxy)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (150 mg, 227 μmol) and Pd / C 10% (15 mg) in MeOH (6 ml) was hydrogenated at 20° C. for 2.5 h (H 2 , 2 bar). The reaction mixture was filtered, the filtrate was evaporated under reduced pressure, and the residue was purified by flash chromatography eluting with DCM, MeOH, and MeCN (98 / 1 / 1, v / v / v) to give 69 mg (53%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide. EXAMPLES

[0153] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [ka] To a solution of (R)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (110 mg, 198 μmol) in DMF (2.5 ml) was added O-methylhydroxylamine hydrochloride (25 mg, 297 μmol), HATU (132 mg, 337 μmol) and DIPEA (184 μl, 992 μmol). The reaction mixture was stirred at room temperature for 4 h. Cold water (25 ml) and a mixture of DCM / MeOH 80 / 20 (30 ml) were added. After decantation, the organic phase was diluted with MgSO 4The mixture was dried at 40° C., filtered, evaporated under reduced pressure and the residue was purified by flash chromatography eluting with DCM / MeOH / MeCN (96 / 2 / 2, v / v / v) to give (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide 63 mg (54%). EXAMPLES

[0154] (S,E)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acrylic acid [ka]

[0155] Step 1: tert-Butyl (S,E)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acrylate [ka] A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, step 1] (203 mg, 308 μmol), DMF (3 ml), ter-butyl acrylate (305 μl, 308 μmol), bis(triphenylphosphine)palladium(II) chloride (48 mg, 68 μmol) and TEA (382 μl, 308 μmol) was heated in a microwave at 120° C. for 1 h. Water (5 ml) and EtOAc (10 ml) were added. After decantation, the organic phase was washed with MgSO 4The mixture was dried at 40° C., filtered, evaporated under reduced pressure and the residue was purified by flash chromatography eluting with DCM / MeOH (99 / 1, v / v) to give 83 mg (42%) of tert-butyl (S,E)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acrylate.

[0156] Step 2. (S,E)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acrylic acid [ka] A mixture of tert-butyl (S,E)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acrylate (83 mg, 130 μmol) and hydrochloric acid (2.2 ml, 4N in 1,4-dioxane) was stirred at room temperature for 6 hours. The reaction mixture was evaporated under reduced pressure and the residue was run on an SCX (strong cation exchange) column to give 39 mg (52%) of (S,E)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acrylic acid. EXAMPLES

[0157] (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole [ka]

[0158] Step 1: (S)-4-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole [ka] (S)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [WO2017140669] (500 mg, 973 μmol), 1,4-dioxane (12 ml), water (2 ml), Cs 2 CO 3 (666 mg, 2.04 mmol) and (1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)boronic acid (207 mg, 974 μmol), and Pd(dppf)Cl 2 (43 mg, 58.42 μmol) was heated in a microwave at 100° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue were added DCM (50 ml) and water (50 ml). After decantation, the organic phase was washed with MgSO 4 The mixture was dried at 40° C., filtered, evaporated under reduced pressure and the residue was purified by flash chromatography eluting with DCM / MeOH / MeCN (94 / 3 / 3, v / v / v) to give 275 mg (66%) of (S)-4-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole.

[0159] LC / MS(m / z, MH+): 432

[0160] Step 2: (S)-4-(8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole [ka] A mixture of (S)-4-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole (170 mg, 394 μmol), THF (15 ml) and pyridinium bromide perbromide (133 mg, 414 μmol) was stirred at room temperature for 2 h. Water (20 ml) and DCM (100 ml) were added, followed by NaHCO 3 A saturated solution of MgSO was added until a pH of 7 was reached. After decantation, the organic phase was diluted with MgSO 4 Drying at 40° C., filtration and evaporation under reduced pressure gave 160 mg (80%) of (S)-4-(8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole.

[0161] LC / MS(m / z, MH+): 510

[0162] Step 3: (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole [ka] (S)-4-(8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole (90 mg, 176 μmol), 1,4-dioxane (8 ml), Pd(dppf)Cl 2 (9mg, 11μmol), water (1.5ml), Cs 2 CO 3A mixture of (121 mg, 370 μmol) and (2,4-dichlorophenyl)boronic acid (37 mg, 194 μmol) was microwaved at 100 °C for 50 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between DCM (50 ml) and water (50 ml). After decantation, the organic phase was washed with MgSO 4 The mixture was dried at 40° C., filtered, evaporated under reduced pressure and the residue was purified by flash chromatography eluting with DCM / MeOH / MeCN (90 / 5 / 5, v / v / v) to give 55 mg (52%) of (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole. EXAMPLES

[0163] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile [ka] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 3] (100 mg, 180.67 μmol) in THF (1 ml) cooled at 0° C., TEA (33 μl, 235 μmol) and TFAA (28 μl, 199 μmol) were added. The reaction mixture was stirred at 0° C. for 15 min and at room temperature for 45 min. NH 4Cl solution (5 ml) and DCM (10 ml) were added. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 95 / 05, v / v) to give 97 mg (85%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile as the trifluoroacetate salt. EXAMPLES

[0164] (S)-4-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole [ka] tert-Butyl (S)-4-(8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole [Example 21, Step 2] (160 mg, 285 μmol), 1,4-dioxane (8 ml), Pd(dppf)Cl 2 (14mg, 17μmol), water (1.5ml), Cs 2 CO 3 A mixture of (195 mg, 599 μmol) and (4-trifluoromethoxy)phenyl)boronic acid (65 mg, 314 μmol) was microwaved at 100° C. for 50 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue were added DCM (50 ml) and water (50 ml). After decantation, the organic phase was washed with MgSO 4The mixture was dried at 40° C., filtered, evaporated under reduced pressure and the residue was purified by flash chromatography eluting with DCM / MeOH / MeCN (90 / 5 / 5, v / v / v) to give 43 mg (26%) of (S)-4-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole. EXAMPLES

[0165] (S)-3-(4-(3-(difluoromethoxy)-8-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [ka] To a solution of (S)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol [WO2017140669] (100 mg, 184.64 μmol) in MeCN (1.5 ml) cooled at 0° C. was added KOH (122 mg, 1.85 mmol) and diethyl(bromodifluoromethyl)phosphonate (54 μl, 295 μmol) as a solution in water (0.5 ml). The reaction mixture was stirred at 0° C. for 2 h. Water (10 ml) and DCM (25 ml) were added. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with DCM / MeOH (95 / 05, v / v) to give 17 mg (16%) of (S)-3-(4-(3-(difluoromethoxy)-8-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine. EXAMPLES

[0166] Methyl (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 3] (200 mg, 361.34 μmol) in DCM (5 ml) and MeOH (5 ml) at −78° C., 1,8-diazabicycloundec-7-ene (170.65 μl, 1.08 mmol) and N-bromosuccinimide (65.63 mg, 361.34 μmol) were added. The reaction mixture was allowed to reach room temperature overnight and the solvent was removed under reduced pressure. The residue was partitioned between DCM and water and the organic phase was washed with water and brine and diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (90 / 10; v / v) to give 47.5 mg (22.1%) of (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate. EXAMPLES

[0167] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboximidamide [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile [Example 22] (526 mg, 809.84 μmol) in EtOH (10 ml) was added hydroxylamine hydrochloride (84.41 mg, 1.21 mmol), and DIPEA (418.68 mg, 3.24 mmol). The reaction mixture was heated at 80° C. for 4 h and the solvent was removed under reduced pressure to give 344 mg (74.7%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboximidamide. EXAMPLES

[0168] (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-oxadiazol-5(4H)-one. [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboximidamide [Example 26] (175 mg, 307.82 μmol) in 1,4-dioxane (5 ml) was added 1,8-diazabicycloundec-7-ene (53.30 μl, 338.60 μmol), and CDI (76.40 mg, 461.73 μmol). The reaction mixture was heated at reflux for 1 h and the solvent was removed under reduced pressure. The residue was partitioned between DCM and water, the organic phase was washed with water and brine, and MgSO 4The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (95 / 05; v / v) to give 102.5 mg (56%) of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-oxadiazol-5(4H)-one. EXAMPLES

[0169] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [ka] To a solution of (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate [Example 25] (70 mg, 119.96 μmol) in MeOH (5 ml) was added a 7N solution of potassium hydroxide in MeOH (2 ml, 14 mmol). The reaction mixture was heated at reflux overnight and diluted with EtOAc. The organic phase was washed with water and brine and diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (95 / 05, v / v) to give 14 mg (22.2%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine. EXAMPLES

[0170] 4-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3H-1,2,3,5-oxathiadiazole 2-oxide hydrochloride. [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboximidamide [Example 26] (1.2 g, 2.11 mmol) in THF (5 ml) was added pyridine (343.49 μl, 4.22 mmol) as a solution in DCM (1 ml), and thionyl chloride (230 μl, 3.17 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight and the solvent was removed under reduced pressure. The residue was partitioned between DCM and water, the organic phase was washed with water and brine, and diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (95 / 05, v / v) to give 173.8 mg (13%) of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride. EXAMPLES

[0171] (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanesulfonamide. [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (200 mg, 380.60 μmol) in DCM (10 ml) was added methanesulfonyl chloride (33 μl, 418.66 μmol), and TEA (59 μl, 418.66 μmol). The reaction mixture was stirred at room temperature overnight, washed with water and brine, and diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (98 / 02; v / v) to give 67.3 mg (22.2%) of (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanesulfonamide. EXAMPLES

[0172] (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazol-2(3H)-one [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide [Example 6] (141 mg, 248.01 μmol) in 1,4-dioxane (5 ml) was added 1,8-diazabicycloundec-7-ene (43.72 mg, 272.82 μmol), and CDI (61.56 mg, 372.02 μmol). The reaction mixture was microwaved at 160° C. for 20 minutes and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (98 / 02, v / v) to give 27 mg (18.3%) of (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazol-2(3H)-one. EXAMPLES

[0173] tert-Butyl (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate. [ka] Triethylamine (5.59 ml, 39.68 mmol) was added to solid (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (10 g, 18.03 mmol) and the mixture was stirred at room temperature for 1 h. Diphenylphosphoryl azide (DPPA) (4.81 ml, 21.64 mmol) was added to the slurry, followed by tert-butyl alcohol (27 ml). The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was poured onto ice (250 g) and stirred at room temperature overnight. The white fine solid that formed was filtered on a Buchner, rinsed with water and dried. The crude compound was purified by flash chromatography eluting with EtOAc to give 5.8 g (51%) of tert-butyl (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate.

[0174] Alternative method: To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (500 mg, 0.85 mmol), tert-butyl carbamate (127 mg, 1.06 mmol), and sodium tert-butoxide (147 mg, 1.51 mmol) in anhydrous toluene (5 ml) was added under argon tBuXPhos (2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, 151 mg, 0.31 mmol), and Pd 2 (dba) 3 (tris(dibenzylideneacetone)dipalladium(0), 108 mg, 0.13 mmol) was added. The reaction mixture was heated in a sealed tube at 110° C. for 3 h, diluted with EtOAc, washed with water, and brine, and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of heptane and EtOAc (70 / 30; v / v) to give 50 mg (52.6%) of tert-butyl (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate. EXAMPLES

[0175] (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxathiazol-2-one [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 3] (200 mg, 361.34 μmol) in toluene (5 ml) was added chlorocarbonylsulfenyl chloride (57 mg, 433.60 μmol). The reaction mixture was refluxed for 1 h, diluted with EtOAc, washed with water, brine, and diluted with MgSO. 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified first by flash chromatography eluting with a mixture of DCM and MeOH (99 / 01; v / v) and then by reverse phase HPLC to give 121.5 mg (55%) of (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazole. EXAMPLES

[0176] (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-oxadiazole-5(4H)-thione [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboximidamide [Example 26] (218 mg, 383.46 μmol) in 1,4-dioxane (5 ml) was added 1,8-diazabicycloundec-7-ene (482 μl, 3 mmol), and TCDI (108 mg, 575.18 μmol). The reaction mixture was heated at reflux for 2 h and the solvent was removed under reduced pressure. The residue was partitioned between DCM and water, the organic phase was washed with water and brine, and MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified first by flash chromatography eluting with a mixture of DCM and MeOH (98 / 02; v / v) and then by reverse phase HPLC to give 124 mg (53%) of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-oxadiazole-5(4H)-thione. EXAMPLES

[0177] (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,1,1-trifluoromethanesulfonamide [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (200 mg, 380.60 μmol) in DCM (10 ml) was added trifluoromethanesulfonic anhydride (70 μl, 418.66 μmol), and TEA (59 μl, 418.66 μmol). The reaction mixture was stirred at room temperature for 2 h, washed with water and brine, and diluted with MgSO 4 The residue was purified by flash chromatography eluting first with a mixture of DCM and MeOH (98 / 02; v / v) and then by reverse phase HPLC to give 52 mg (20.8%) of (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,1,1-trifluoromethanesulfonamide. EXAMPLES

[0178] (S)-3-((8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-4-hydroxycyclobut-3-ene-1,2-dione [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (200 mg, 380.60 μmol) in DMF (10 ml) was added 3,4-dihydrocyclobut-3-ene-1,2-dione (48 mg, 418.66 μmol). The reaction mixture was stirred at room temperature for 1 h and microwaved at 130 °C for 7 h. The residue was diluted with EtOAc, washed with water and brine, and diluted with MgSO 4The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting first with a mixture of DCM and MeOH (98 / 02, v / v) and then by reverse phase HPLC to give 52 mg (20.8%) of (S)-3-((8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-4-hydroxycyclobut-3-ene-1,2-dione. EXAMPLES

[0179] (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-thiadiazol-5(4H)-one [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboximidamide [Example 26] (324 mg, 569.91 μmol) in THF (10 ml) was added TCDI (128 mg, 683.89 μmol). The reaction mixture was stirred at room temperature for 1 h, partitioned between EtOAc and water, the organic phase was washed with water and brine, and diluted with MgSO 4 The mixture was dried over 100 ml, filtered and evaporated under reduced pressure. The residue was dissolved in THF (10 ml), cooled to 0° C. and boron trifluoride diethyl etherate (412.68 mg; 2.85 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, partitioned between EtOAc and water, the organic phase was washed with water and brine and concentrated with MgSO 4The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified first by flash chromatography eluting with a mixture of DCM and MeOH (95 / 05; v / v) and then by reverse phase HPLC to give 180 mg (53%) of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-thiadiazol-5(4H)-one. EXAMPLES

[0180] (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-methoxy-1,5-dihydro-2H-pyrrol-2-one [ka] To a solution of (S)-3-(4-(3-bromo-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [Example 11] (50 mg, 0.084 mmol) in 1,4-dioxane (1.5 ml) and DMF (0.25 ml) was added 4-methoxy-3-pyrrolin-2-one (30 mg, 0.25 mmol), potassium phosphate (22 mg, 0.11 mmol), cuprous iodide (25 mg, 0.14 mmol), and N,N'-dimethylethylenediamine (0.02 ml, 0.17 mmol) under argon. The reaction mixture was heated in a microwave at 100 °C for 5 h, diluted with EtOAc, washed with water, and brine, and diluted with MgSO. 4The residue was purified by flash chromatography eluting first with EtOAc and then by reverse phase HPLC to give (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-methoxy-1,5-dihydro-2H-pyrrol-2-one 6 mg (6%). EXAMPLES

[0181] (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-one [ka] To a solution of methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopropanoate [Example 4, Step 1] (300 mg, 491.36 μmol) in THF (10 ml) was added NaOH solution (1N, 3 ml). The reaction mixture was stirred at 50° C. for 16 h, poured into water, extracted with EtOAc and diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under pressure to give 229 mg (84%) of (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-one.

[0182] Alternative method: To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 44] (500 mg, 836.75 μmol) in THF (10 ml) was added a 2.5 M solution of methylmagnesium bromide in THF (1.7 ml, 5 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 hours. NH 4 A saturated solution of Cl was added, the mixture was extracted with EtOAc, and the organic phase was washed with water, brine and MgSO 4 Drying at 40° C., filtering, and evaporating under reduced pressure gave 350 mg (76%) of (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-one. EXAMPLES

[0183] (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxazolidin-2-one [ka] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (100 mg, 0.151 mmol), 2-oxazolidone (27.3 mg, 0.30 mmol), and sodium tert-butoxide (30 mg, 0.304 mmol) in anhydrous toluene (2 ml) was added tBuXPhos (2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, 20 mg, 0.050 mmol), and Pd 2 (dba) 3(tris(dibenzylideneacetone)dipalladium(0), 29 mg, 0.030 mmol) was added. The reaction mixture was stirred at room temperature in a sealed tube for 48 h, diluted with EtOAc, washed with water, and diluted with MgSO 4 The mixture was dried at 40° C., filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of EtOAc, heptane, and MeOH (75 / 20 / 5, v / v / v) to give 45 mg (50%) of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxazolidin-2-one. EXAMPLES

[0184] (S)-3-(8-(2-chloro-4-(2-oxooxazolidin-3-yl)phenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxazolidin-2-one [ka] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (100 mg, 0.151 mmol), 2-oxazolidone (19 mg, 0.212 mmol), and sodium tert-butoxide (43 mg, 0.432 mmol) in anhydrous toluene (2 ml) was added tBuXPhos (2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, 20 mg, 0.050 mmol), and Pd 2 (dba) 3 (tris(dibenzylideneacetone)dipalladium(0), 29 mg, 0.030 mmol) was added. The reaction mixture was stirred in a sealed tube at 110 °C for 48 h, diluted with EtOAc, washed with water, and diluted with MgSO 4The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting first with a mixture of EtOAc and MeOH (97 / 3; v / v) and then by reverse phase HPLC to give 8 mg (8.2%) of (S)-3-(8-(2-chloro-4-(2-oxooxazolidin-3-yl)phenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxazolidin-2-one. EXAMPLES

[0185] (S)-4-(3-amino-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-8-yl)-3-chlorophenol [ka]

[0186] Step 1: tert-Butyl (S)-(8-(2-chloro-4-hydroxyphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (500 mg, 0.85 mmol), tert-butyl carbamate (127 mg, 1.06 mmol), and sodium tert-butoxide (147 mg, 1.51 mmol) in anhydrous toluene (5 ml) was added under argon tBuXPhos (2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, 151 mg, 0.31 mmol), and Pd 2(dba) 3 (tris(dibenzylideneacetone)dipalladium(0), 108 mg, 0.13 mmol) was added. The reaction mixture was heated in a sealed tube at 110° C. for 16 h, diluted with EtOAc, washed with water, and brine, and diluted with Na 2 SO 4 The mixture was dried at 400° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of heptane and EtOAc (70 / 30, v / v) to give 400 mg (86.8%) of tert-butyl (S)-(8-(2-chloro-4-hydroxyphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate.

[0187] LC / MS(m / z, MH+):607

[0188] Step 2: (S)-4-(3-amino-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-8-yl)-3-chlorophenol [ka] To a solution of tert-butyl (S)-(8-(2-chloro-4-hydroxyphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate (100 mg, 0.16 mmol) in anhydrous DCM (2 ml) was added TFA (trifluoroacetic acid, 0.2 ml). The reaction mixture was stirred for 16 h, diluted with EtOAc, washed with saturated sodium bicarbonate solution and diluted with Na 2 SO 4 The extract was dried at 40° C. for 1 hour, filtered, and evaporated under reduced pressure to give (S)-4-(3-amino-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-8-yl)-3-chlorophenol 70 mg (86.4%). EXAMPLES

[0189] 5-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)imidazolidine-2,4-dione [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde [Example 5, Step 1] (200 mg, 371.41 μmol) in MeOH (2 ml) was added NH 4 CO 3 (107.06 mg, 1.11 mmol), potassium cyanide (26.60 mg, 408.55 μmol), water (2 ml), and THF (1 ml) were added. The reaction mixture was heated in a sealed tube at 70° C. for 20 h, poured into water, and extracted with EtOAc. The organic phase was washed with water, brine, and diluted with Na 2 SO 4 The residue was purified by reverse phase HPLC to give 16 mg (7%) of 5-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)imidazolidine-2,4-dione. EXAMPLES

[0190] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (3 g, 5.41 mmol) in DMF (100 ml) was added DIPEA (2.83 ml, 16.23 mmol), HBTU (3 g, 7.75 mmol) and N,O-dimethylhydroxylamine hydrochloride (604.71 mg, 5.95 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and then EtOAc was added. The organic layer was washed twice with water and once with brine. The organic layer was collected and diluted with MgSO 4 The crude product was purified by flash chromatography eluting with a gradient of EtOAc in heptane (5% EtOAc to 100% EtOAc, v / v) to give 3.2 g (99%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide. EXAMPLES

[0191] (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazole-2(3H)-thione [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide [Example 6] (386 mg, 678.96 μmol) in 1,4-dioxane (10 ml) was added DBU (120 mg, 746.86 μmol), and TCDI (191 mg, 178.03 μmol). The reaction mixture was refluxed for 1 h and evaporated under reduced pressure. The residue was partitioned between DCM and water, and the organic phase was washed with brine and MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (90 / 10, v / v) to give 28 mg (6.8%) of (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazole-2(3H)-thione. EXAMPLES

[0192] (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetimidamide [ka] To a mixture of methyl acetimidate hydrochloride (375.26 mg, 3.43 mmol) in MeCN (10 ml) was added TEA (480.94 μl, 3.43 mmol). The reaction mixture was stirred at room temperature for 15 min. Then (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (600 mg, 1.14 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solid was filtered off and washed with EtOAc (200 ml). The organic phase was washed twice with water, once with brine and diluted with MgSO 4 The crude product was first eluted with a gradient of MeOH in DCM (100 / 0 to 90 / 10, v / v) and then with (MeOH / 10%NH 3 -MeOH 2N) gradient (90 / 10 to 75 / 25, v / v) to give 200 mg (31%) of (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetimidamide. EXAMPLES

[0193] (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroacetamide [ka] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (180 mg, 342.54 μmol) in THF (5 ml) was added TEA (57.71 μl, 411.05 μmol) and TFAA (57.75 μl, 411.05 μmol). The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted twice with EtOAc. The organic layer was collected, washed with brine and diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 90 / 10, v / v) to give 200 mg (79%) of (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroacetamide. EXAMPLES

[0194] (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetamide [ka] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (100 mg, 190.30 μmol) in DCM (5 ml) was added TEA (58.94 μl, 418.66 μmol) and acetyl chloride (33.26 μl, 456.72 μmol) at 0° C. The reaction mixture was stirred at room temperature for 48 h. Water was added and the mixture was extracted twice with DCM. The organic layer was collected, washed with brine and diluted with MgSO 4The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 90 / 10, v / v) to give 86 mg (80%) of (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetamide. EXAMPLES

[0195] 1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-ol [ka] To a mixture of (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-one [Example 39] (200 mg, 361.98 μmol) in EtOH (20 ml) was added NaBH 4 (27.39 mg, 723.97 μmol) was added. The reaction mixture was stirred at room temperature for 2 h. Then water was added and the mixture was extracted twice with EtOAc. The organic layer was collected, washed with brine and diluted with MgSO 4 The residue was purified twice by flash chromatography, first eluting with a gradient of EtOAc in heptane (95 / 5 to 0 / 100, v / v) and then with a solution of EtOAc in MeOH (95 / 5, v / v) to give 140 mg (70%) of 1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-ol. EXAMPLES

[0196] (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)propan-2-ol [ka] To a mixture of (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-one [Example 39] (200 mg, 361.98 μmol) in anhydrous THF (10 ml) was added methylmagnesium bromide (361.98 μl, 1.09 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. Water was then added and the mixture was extracted twice with EtOAc. The organic layer was collected, washed with brine and diluted with MgSO 4 The mixture was dried at 70° C., filtered and evaporated under reduced pressure. The residue was purified twice by flash chromatography, first eluting with a gradient of EtOAc in heptane (95 / 5 to 0 / 100, v / v) and then with a solution of EtOAc in MeOH (95 / 5, v / v) to give 70 mg (22%) of (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)propan-2-ol. EXAMPLES

[0197] (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole [ka] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (350 mg, 478.34 μmol), 1,4-dioxane (13 ml), Pd(dppf) 2 Cl 2 (21mg, 28.70μmol), water (3ml), Cs 2 CO 3 A mixture of 1H-pyrazole-3-boronic acid pinacol ester (389.63 mg, 1.20 mmol) and 1H-pyrazole-3-boronic acid pinacol ester (136.78 mg, 669.67 μmol) was heated in a microwave at 90 °C for 30 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted twice with EtOAc. The organic layer was collected, washed with brine and diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography using a gradient of MeOH in DCM (100 / 0 to 90 / 10, v / v) to give 140 mg (51%) of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole. EXAMPLES

[0198] (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol [ka] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (300 mg, 410 μmol), 1,4-dioxane (13 ml), Pd(dppf) 2 Cl 2 (18mg, 24.60μmol), water (3ml), Cs 2 CO 3 A mixture of (333.97 mg, 1.03 mmol) and (4-hydroxyphenyl)boronic acid (71.43 mg, 492.01 μmol) was heated in a microwave at 90 °C for 45 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted twice with EtOAc. The organic layer was collected, washed with brine and diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of EtOAc in heptane (95 / 5 to 0 / 100, v / v) to give 140 mg (57%) of (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol. EXAMPLES

[0199] (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol [ka] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (300 mg, 410 μmol), 1,4-dioxane (13 ml), Pd(dppf) 2Cl 2 (18mg, 24.60μmol), water (3ml), Cs 2 CO 3 A mixture of (333.97 mg, 1.03 mmol) and (3-hydroxyphenyl)boronic acid (79.17 mg, 574.01 μmol) was heated in a microwave at 90 °C for 45 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted twice with EtOAc. The organic layer was collected, washed with brine and diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with a gradient of EtOAc in heptane (95 / 5 to 0 / 100, v / v) to give 150 mg (61%) of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol. EXAMPLES

[0200] (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol [ka] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (300 mg, 410 μmol), 1,4-dioxane (13 ml), Pd(dppf) 2 Cl 2 (18mg, 24.60μmol), water (3ml), Cs 2 CO 3A mixture of (333.97 mg, 1.03 mmol) and (2-hydroxyphenyl)boronic acid (67.86 mg, 492.01 μmol) was heated in a microwave at 90 °C for 45 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted twice with EtOAc. The organic layer was collected, washed with brine and diluted with MgSO 4 The mixture was dried at 70° C., filtered and evaporated under reduced pressure. The crude product was purified twice by flash chromatography, first eluting with a gradient of EtOAc in heptane (95 / 5 to 0 / 100, v / v) and then with a solution of EtOAc in MeOH (95 / 5, v / v) to give 170 mg (69%) of (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol. EXAMPLES

[0201] (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid [ka] To a mixture of methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate [Example 57] (280 mg, 434.37 μmol) in MeOH (20 ml) and THF (10 ml) was added a solution of NaOH 2M (10 ml, 434.37 μmol). The reaction mixture was stirred at 60° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added, followed by a solution of HCl 5N until pH 5. The mixture was extracted twice with EtOAc, the organic layer was collected and washed with brine. The organic phase was diluted with MgSO 4The extract was dried at 40° C., filtered, and evaporated under reduced pressure to give 175 mg (64%) of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid. EXAMPLES

[0202] Methyl (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate [ka] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (400 mg, 546.67 μmol), 1,4-dioxane (13 ml), Pd(dppf) 2 Cl 2 (24mg, 32.80μmol), water (3ml), Cs 2 CO 3 A mixture of (445.29.63 mg, 1.37 mmol) and 4-methoxycarbonylphenylboronic acid (142 mg, 765.34 μmol) was heated in a microwave at 90 °C for 30 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted twice with EtOAc. The organic layer was collected, washed with brine and diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with a gradient of EtOAc in heptane (95 / 5 to 0 / 100, v / v) to give 220 mg (62%) of methyl (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate. EXAMPLES

[0203] Methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate [ka] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (400 mg, 546.67 μmol), 1,4-dioxane (13 ml), Pd(dppf) 2 Cl 2 (24mg, 32.80μmol), water (3ml), Cs 2 CO 3 A mixture of (445.29 mg, 1.37 mmol) and 3-methoxycarbonylphenylboronic acid (118 mg, 656.01 μmol) was heated in a microwave at 90 °C for 30 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted twice with EtOAc. The organic layer was collected, washed with brine and diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with a gradient of EtOAc in heptane (95 / 5 to 0 / 100, v / v) to give 310 mg (88%) of methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate. EXAMPLES

[0204] (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)pyrrolidin-2-one [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoro-methanesulfonate [Example 1, Step 1] (100 mg, 0.216 mmol), 2-oxazolidone (27 mg, 0.302 mmol), and sodium tert-butoxide (43 mg, 0.432 mmol) in anhydrous toluene (2 ml) in a microwave vessel under argon was added t-Bu-XPhos (28 mg, 0.065 mmol), and Pd 2 (dba) 3 (41 mg, 0.043 mmol) was added. After degassing with argon for 5 min, the tube was sealed and stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and the organic phase was washed with water and brine, and Na 2 SO 4 The mixture was dried at 4° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of EtOAc and MeOH (97 / 03, v / v) to give 30 mg of crude product. elution was performed using a CSH 50×250 mm, 5 μm column at 20° C. with A:H 2 O / 0.1% formic acid and B:CH 3 Further purification by preparative reversed-phase high performance liquid chromatography by applying the following gradient with CN / 0.1% formic acid: 30% B at t=0 min, 30% B at t=5 min, 50% B at t=25 min, followed by lyophilization gave 5 mg (4%) of (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)pyrrolidin-2-one as a white solid. EXAMPLES

[0205] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N'-(1H-imidazole-1-carbonothioyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide [ka] The procedure followed is described in Example 45. The residue was further purified by flash chromatography eluting with a mixture of DCM and MeOH (90 / 10, v / v) to give 238 mg (51.7%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N'-(1H-imidazole-1-carbonothioyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide. EXAMPLES

[0206] (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)cyclopropanecarboxamide [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (600 mg, 1.14 mmol) in DCM (60 ml) was added TEA (138.65 mg, 1.37 mmol) and cyclopropanecarbonyl chloride (127.09 μl, 1.37 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and then EtOAc was added. The organic layer was extracted with K 2 CO 3The organic layer was collected and washed twice with a saturated aqueous solution of MgSO 4 The crude product was purified by flash chromatography eluting with a gradient of EtOAc in heptane (5% EtOAc to 100% EtOAc, v / v) to give 480 mg (71%) of (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)cyclopropanecarboxamide. EXAMPLES

[0207] (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)thiazol-2-amine [ka] To a mixture of (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-one [Example 39] (150 mg, 271.49 μmol) in anhydrous THF (20 ml) was added phenyltrimethylammonium tribromide (244.94 mg, 651.58 μmol) and the reaction mixture was stirred at room temperature for 7 h. The precipitate formed was filtered, washed three times with THF, the organic phase was collected and evaporated under reduced pressure. The crude residue was dissolved in MeOH (30 ml) and thiourea (22.73 mg, 298.64 μmol) was added. The reaction mixture was stirred at reflux for 4 h. The reaction mixture was evaporated under reduced pressure and the crude residue was diluted with EtOAc. The organic layer was washed twice with brine and diluted with MgSO 4The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography, eluting a first time with a gradient of EtOAc in heptane (95 / 5 to 0 / 100, v / v) and a second time with a solution of EtOAc in MeOH (95 / 5, v / v) to give 45 mg (27%) of (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)thiazol-2-amine. EXAMPLES

[0208] (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)pivalamide [ka] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (600 mg, 1.14 mmol) in DCM (60 ml) was added TEA (138.65 mg, 1.37 mmol) and pivaloyl chloride (165.21 mg, 1.37 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 h. Water was added and the mixture was extracted twice with DCM. The organic layer was collected, washed with brine and diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography using a gradient of EtOAc in heptane (95 / 5 to 0 / 100, v / v) to give 500 mg (72%) of (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)pivalamide. EXAMPLES

[0209] (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [ka] Obtained in 81% yield from (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] by a method similar to Example 3. EXAMPLES

[0210] (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile, 2,2,2-trifluoroacetate [ka] Obtained in 44% yield from (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 63] by a method similar to Example 22. EXAMPLES

[0211] 1-(8-(2-chloro-3-fluorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroethane-1-ol [ka]

[0212] Step 1: (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [ka] This compound was prepared as described in Example 44 starting from (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (440 mg, 818 μmol) to give (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide 300 mg (63%).

[0213] LC / MS (m / z, M-H + ):581

[0214] Step 2: (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde [ka] This compound was prepared as described in Example 5, step 1 starting from (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (300 mg, 516 μmol) to give 240 mg (89%) of (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde.

[0215] LC / MS (m / z, M-H + ):522

[0216] Step 3: 1-(8-(2-chloro-3-fluorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroethan-1-ol [ka] This compound was prepared as described in Example 10 starting from (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde (240 mg, 459.74 μmol) to give 1-(8-(2-chloro-3-fluorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroethan-1-ol 120 mg (44%). EXAMPLES

[0217] (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1-fluorocyclopropane-1-carboxamide [ka] To a solution of 1-fluorocyclopropane-1-carboxylic acid (10.01 mg, 91.34 μmol) in DCM (5 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.87 mg, 91.34 μmol) and 4-dimethylaminopyridine (11.27 mg, 91.34 μmol). The reaction mixture was stirred at room temperature for 10 minutes and (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (40 mg, 76.12 μmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and EtOAc was added. The organic layer was extracted with K 2 CO 3 The organic layer was collected and washed twice with a saturated aqueous solution of MgSO 4 The crude product was purified by flash chromatography eluting with a gradient of EtOAc in heptane (5% EtOAc to 100% EtOAc, v / v) to give 42 mg (90%) of (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1-fluorocyclopropane-1-carboxamide. EXAMPLES

[0218] (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1-methylcyclopropane-1-carboxamide [ka] To a solution of 1-methylcyclopropane-1-carboxylic acid (58.32 mg, 570.90 μmol) in DCM (5 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (111.68 mg, 570.90 μmol) and 4-dimethylaminopyridine (70.45 mg, 570.90 μmol) were added. The reaction mixture was stirred at room temperature for 10 minutes and (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (100 mg, 190.30 μmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and EtOAc was added. The organic phase was diluted with K 2 CO 3 The organic phase was washed twice with a saturated aqueous solution of MgSO 4 The crude product was purified by flash chromatography eluting with a gradient of EtOAc in heptane (5% EtOAc to 100% EtOAc, v / v) to give 54 mg (47%) of (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1-methylcyclopropane-1-carboxamide. EXAMPLES

[0219] (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2-hydroxycyclopent-2-en-1-one [ka]

[0220] Step 1: (S)-2-((tert-butyldimethylsilyl)oxy)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)cyclopent-2-en-1-one [ka] 3-Bromo-2-((tert-butyldimethylsilyl)oxy)cyclo-pent-2-en-1-one (91.53 mg, 314 μmol), (S)-3-(4-(8-(2,4-dichlorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)-pyrrolidine [Example 1] (200 mg, 314 μmol), Cs in 1,4-dioxane (2 ml), and water (2 ml). 2 CO 3 (256 mg, 785 μmol), and Pd(dppf)Cl 2 A solution of (13.8 mg, 18.9 μmol) was heated in a microwave at 90° C. for 30 min. The reaction mixture was poured into water, extracted with EtOAc, and the organic phase was washed with water and brine, and Na 2 SO 4Drying at 40° C., filtration and evaporation under reduced pressure afforded 225 mg of crude (S)-2-((tert-butyldimethylsilyl)oxy)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)cyclopent-2-en-1-one (85% LCMS purity), which was used in the next step without further purification.

[0221] Step 2: (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2-hydroxycyclopent-2-en-1-one [ka] To a solution of crude (S)-2-((tert-butyldimethylsilyl)oxy)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)cyclopent-2-en-1-one (225 mg, 314 μmol) in THF (2 ml) was added TBAF 1M in THF (625 μl, 625 μmol) at 0° C. The reaction mixture was stirred at room temperature for 40 min and diluted with EtOAc. The organic phase was washed with water and brine and diluted with Na 2 SO 4 The brownish oil was dried at 40° C., filtered and evaporated under reduced pressure. The brownish oil was purified by flash chromatography eluting with a mixture of DCM and MeOH (95 / 05, v / v) to give 134 mg (70%) of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)-pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2-hydroxycyclopent-2-en-1-one as a beige solid. EXAMPLES

[0222] (S,Z)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-N,3-dimethylthiazol-2(3H)-imine hydrochloride [ka] To a solution of (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-one [Example 39] (100 mg, 181 μmol) in DCM (4 ml) was added benzyltrimethylammonium dichloroiodate (200 mg, 557 μmol). The reaction mixture was stirred under reflux for 16 h. EtOH (10 ml) and N,N'-dimethylthiourea (19.9 mg, 181 μmol) were added and the mixture was heated to 80° C. under nitrogen to evaporate the DCM and then heated under reflux for 3 h. After the addition of water, the mixture was extracted with EtOAc and the organic phase was washed with water and brine and concentrated to 100° C. with 100% NaCl. 2 SO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (70 / 30, v / v) to give 12 mg (10%) of (S,Z)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-N,3-dimethylthiazol-2(3H)-imine as a beige solid. EXAMPLES

[0223] (S)-5-(8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2H-tetrazole, 2,2,2-trifluoroacetate [ka] Obtained in 35% yield from (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile [Example 64] by a method similar to Example 16. EXAMPLES

[0224] tert-Butyl (S)-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate [ka]

[0225] Step 1: (S)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [ka] To a solution of (S)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-ol [WO2017140669] (2 g, 4.37 mmol) in DCM (200 ml) and pyridine (536 μl, 6.6 mmol) was added trifluoromethanesulfonic anhydride (1.8 ml, 8.7 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 18 hours. Cold water (5 ml) and saturated NaHCO 3 (10 ml) was added. After decantation, the organic phase was diluted with MgSO 4Drying at 40° C., filtration and evaporation under reduced pressure gave 2.6 g (100%) of crude (S)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate.

[0226] LC / MS (m / z, M-H + ):590.

[0227] Step 2: tert-Butyl (S)-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate [ka] To a mixture of (S)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (170 mg, 288 μmol) in toluene (1 ml) was added tert-butyl carbamate (43 mg, 360 μmol), tris(dibenzylideneacetone)dipalladium(0) (41 mg, 43 μmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (18 mg, 43 μmol), and sodium tert-butoxide (50 mg, 519 μmol). The reaction mixture was microwaved at 100 °C for 1 h. The reaction mixture was partitioned between EtOAc and water, and the organic phase was washed with brine and MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (95 / 5, v / v) to give 36 mg (22%) of tert-butyl (S)-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate. EXAMPLES

[0228] (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid [ka] To a mixture of methyl (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate [Example 56] (180 mg, 279.24 μmol) in MeOH (20 ml) and THF (10 ml) was added a solution of NaOH 2M (1 ml, 1 mmol). The reaction mixture was stirred at 60° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added, followed by a solution of HCl 5N until pH 5 was reached. The mixture was extracted twice with EtOAc and the organic phase was washed with brine and MgSO 4 The extract was dried at 40° C., filtered, and evaporated under reduced pressure to give 120 mg (68%) of (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid. EXAMPLES

[0229] (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazol-5-amine [ka]

[0230] Step 1: (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopropanenitrile [ka] To a mixture of DMSO (3 ml) and MeCN (138.83 μl, 2.64 mmol), sodium hydride (70.35 mg, 1.76 mmol) was added and the reaction mixture was stirred at room temperature for 20 min, followed by the addition of methyl (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [WO2017140669] (500 mg, 879.49 μmol). The reaction mixture was stirred at room temperature for 2 h, water was added slowly and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with brine and diluted with MgSO 4 The mixture was dried at 70° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM in MeOH (95 / 5; v / v) to give (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopropanenitrile 430 mg (75%). LC / MS (m / z, MH + ):577.

[0231] Step 2: (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazol-5-amine [ka] To a solution of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopropanenitrile (150 mg, 259.73 μmol) in EtOH (1.5 ml) was added hydrazine hydrate (59.70 mg, 1.17 mmol). The reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was concentrated under reduced pressure and EtOAc was added. The organic layer was washed twice with water and once with brine. The organic layer was collected and diluted with MgSO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The residue was purified by flash chromatography using a gradient of MeOH in DCM (100 / 0 to 90 / 10, v / v) to give (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazol-5-amine 70 mg (46%). EXAMPLES

[0232] (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)(3-hydroxyazetidin-1-yl)methanone [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (100 mg, 180.35 μmol) in DCM (10 ml) was added DIPEA (94.39 μl, 541.04 μmol), HBTU (75.24 mg, 198.38 μmol) and 3-hydroxyazetidine hydrochloride (20.37 mg, 180.35 μmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and EtOAc was added. The organic layer was extracted with K 2 CO 3 The organic phase was washed twice with a saturated aqueous solution of MgSO 4 The residue was purified by flash chromatography eluting with a gradient of EtOAc in heptane (5% EtOAc to 100% EtOAc, v / v) to give 82 mg (75%) of (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)(3-hydroxyazetidin-1-yl)methanone. EXAMPLES

[0233] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-(oxetan-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (100 mg, 180.35 μmol) in DCM (10 ml) was added DIPEA (94.39 μl, 541.04 μmol), HBTU (75.24 mg, 198.38 μmol) and 3-oxetamine (13.59 mg, 180.35 μmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and EtOAc was added. The organic layer was extracted with K 2 CO 3 The organic phase was washed twice with a saturated aqueous solution of MgSO 4 The residue was purified by flash chromatography eluting with a gradient of EtOAc in heptane (5% EtOAc to 100% EtOAc, v / v) to give (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-(oxetan-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide 100 mg (91%). EXAMPLES

[0234] Ethyl (S)-2-((8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-2-oxoacetate [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (100 mg, 190.30 μmol) in DCM (10 ml) was added TEA (66.98 μl, 475.5 μmol) and ethyl oxalyl chloride (32.60 μl, 285.45 μmol) at 0° C. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. EtOAc was added and the organic phase was washed with K 2 CO 3 The organic phase was washed twice with a saturated aqueous solution of MgSO 4 The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 90 / 10, v / v) to give ethyl (S)-2-((8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-2-oxoacetate 50 mg (42%). EXAMPLES

[0235] (S)-N1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxalamide [ka] To a solution of ethyl (S)-2-((8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-2-oxoacetate [Example 76] (40 mg, 63.94 μmol) in MeOH (1 ml) was added ammonia 7M in MeOH (18.27 μl, 127.88 μmol). The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure and EtOAc was added. The organic layer was extracted with K2 CO 3 The organic layer was collected and washed twice with a saturated aqueous solution of MgSO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 90 / 10, v / v) to give 30 mg (79%) of ethyl (S)-N1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxalamide. EXAMPLES

[0236] (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [ka]

[0237] Step 1: Methyl (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [ka] To a solution of methyl (S)-8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide [WO2017140669] (6.3 g, 10.80 mmol) in 1,4-dioxane (50 ml), 2-chloro-4-methylphenylboronic acid (2.01 g, 11.45 mmol), Cs in water (20 ml) 2 CO 3(11.27 g, 34.56 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (499 mg, 648.00 μmol) were added. The reaction mixture was heated at 70° C. for 1 h, poured into water and extracted with DCM. The organic extracts were washed with water, filtered through hyflo and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (97 / 3, v / v) to give 2.92 g (49.3%) of methyl (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC / MS (m / z, MH + ):548.

[0238] Step 2: (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [ka] To a solution of methyl (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (1 g, 1.82 mmol) in MeOH (15 ml) was added NaOH solution (2 M, 3 ml, 6 mmol). The reaction mixture was refluxed for 1 h and hydrochloric acid 1N was added until a pH of 6-7 was reached. The aqueous phase was extracted with DCM and the organic extracts were washed with MgSO 4 The mixture was dried at 40° C. for 1 hour, filtered, and evaporated under reduced pressure to give crude (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, 963 mg (99%). LC / MS (m / z, MH + ):534.

[0239] Step 3: (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [ka] The synthesis was carried out as in Example 3, substituting (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid with (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (963 mg, 1.8 mmol) to give (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide 571 mg (59%). LC / MS (m / z, M-H + ):533.

[0240] Step 4: Methyl (S)-(8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate [ka] As in Example 25, (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide was converted to (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro The synthesis was carried out substituting hydro-5H-benzo[7]annulene-3-carboxamide (571 mg, 1.07 mmol) to give methyl (S)-(8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate 407 mg (67.5%). LC / MS (m / z, MH + ):563.

[0241] Step 5: (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [ka] As in Example 28, (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate was converted to (S)-(8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl) The synthesis was carried out substituting (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine (407 mg, 723 μmol) to give 247 mg (67.7%) of (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine. EXAMPLES

[0242] (S)-8-(6-ethoxy-2-fluoropyridin-3-yl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [ka] Obtained in 85% yield from methyl (S)-8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide [WO2017140669] by a method similar to Example 78, steps 1, 2, and 3. EXAMPLES

[0243] (S)-8-(6-ethoxy-2-fluoropyridin-3-yl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile 2,2,2-trifluoroacetate [ka] Obtained in 70% yield from (S)-8-(6-ethoxy-2-fluoropyridin-3-yl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 79] by a method similar to Example 22. EXAMPLES

[0244] (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzamide [ka] (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid [Example 72] (200 mg, 279.11 μmol), pyridine (57.40 mg, 725.68 μmol), di-tert-butyl dicarbonate (91.37 mg, 418.66 μmol) and NH 4 HCO 3 (33.10 mg, 418.66 μmol) was stirred at room temperature for 48 h. The reaction mixture was concentrated under reduced pressure and then EtOAc was added. The organic layer was washed twice with water and once with brine. The organic layer was collected and diluted with MgSO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100 / 0 to 90 / 10, v / v) to give 70 mg (40%) of (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzamide. EXAMPLES

[0245] (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanol [ka] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)-pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (200 mg, 361 μmol) in THF (4 ml) was added borane dimethylsulfide complex 2M in THF (1.08 ml, 2.16 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 hours and cooled again to 0° C. KH 2PO 4 A saturated aqueous solution of (4 ml) was thoroughly added and stirred at room temperature for 20 min. After addition of EtOAc, the organic phase was washed with water and brine, and then Na 2 SO 4 The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (90 / 10, v / v) to give 115 mg (21%) of a white solid. This compound was refluxed in THF for 6 h (decomposition of the boron complex) and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (95 / 5, v / v) to give 68 mg (33%) of (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanol as a white solid. EXAMPLES

[0246] Methyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate [ka] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (350 mg, 478.34 μmol), Pd(dppf) in 1,4-dioxane (13 ml), and water (3 ml). 2 Cl 2 (21 mg, 28.70 μmol), Cs 2 CO 3A mixture of 2-methoxycarbonylphenylboronic acid (389.63 mg, 1.20 mmol) and 2-methoxycarbonylphenylboronic acid (124.25 mg, 669.67 μmol) was heated in a microwave at 90 °C for 30 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted twice with EtOAc. The organic phase was washed with brine and diluted with MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of EtOAc in heptane (95 / 5 to 0 / 100, v / v) to give methyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate 70 mg (23%). EXAMPLES

[0247] (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1-hydroxycyclopropane-1-carboxamide formate [ka] To a solution of 1-hydroxycyclopropane-1-carboxylic acid (58.28 mg, 570.90 μmol) in dimethylformamide (5 ml) was added HATU (160.80 mg, 418.66 μmol) and TEA (161.28 μl, 1.14 mmol). The reaction mixture was stirred at room temperature for 10 min and (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (200 mg, 380.60 μmol) was added. The reaction mixture was stirred at 40° C. overnight. The reaction mixture was concentrated under reduced pressure and EtOAc was added. The organic layer was extracted with K 2 CO 3 The organic layer was collected and washed twice with a saturated aqueous solution of MgSO4 The residue was purified by flash chromatography eluting with a gradient of EtOAc in heptane (5% EtOAc to 100% EtOAc, v / v) to give (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1-hydroxycyclopropane-1-carboxamide formate 13 mg (5%). EXAMPLES

[0248] (S)-1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-4-hydroxypyrrolidin-2-one [ka] (S)-3-(4-(3-bromo-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [Example 11] (135 mg, 229 μmol), (S)-4-hydroxy-2-pyrrolidinone (28.36 mg, 275 μmol), (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (3.4 mg, 22.9 μmol), cuprous iodide (2.2 mg, 11.45 μmol), and K in 3 ml of toluene. 2 CO 3 A solution of (63 mg, 458 μmol) was placed in a 5 ml sealed microwave vessel. After 1 min of sonication, the mixture was heated in an oil bath at 110° C. for 16 h.

[0249] After adding water, the mixture was extracted with EtOAc, and the organic phase was washed with water and brine, and then added Na 2 SO 4The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (90 / 10, v / v) to give 30 mg (21%) of (S)-1-(8-(2,4-dichloro-phenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo-[7]annulen-3-yl)-4-hydroxypyrrolidin-2-one as a beige solid. EXAMPLES

[0250] (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid [ka] To a mixture of methyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate [Example 83] (240 mg, 372.32 μmol) in MeOH (15 ml) and THF (15 ml) was added a solution of NaOH 2M (2 ml, 4 mmol). The reaction mixture was stirred at 60° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added, followed by a solution of HCl 5N until pH 5 was reached. The mixture was extracted twice with EtOAc, the organic layer was collected and washed with brine. The organic phase was diluted with MgSO 4 The extract was dried at 40° C. for 1 hour, filtered, and evaporated under reduced pressure to give 170 mg (72%) of (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid. EXAMPLES

[0251] N-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2-difluorocyclopropane-1-carboxamide [ka] To a solution of 2,2-difluorocyclopropane-1-carboxylic acid (48.91 mg, 380.60 μmol) in DMF (5 ml) was added HATU (80.40 mg, 209.33 μmol) and TEA (80.64 μl, 570.90 μmol). The reaction mixture was stirred at room temperature for 10 min and (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (100 mg, 190.30 μmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and EtOAc was added. The organic layer was extracted with K 2 CO 3 The organic layer was collected and washed twice with a saturated aqueous solution of MgSO 4 The crude product was purified twice by flash chromatography, first eluting with a gradient of EtOAc in heptane (95 / 5 to 0 / 100, v / v) and then with a gradient of MeOH in DCM (100 / 0 to 90 / 10, v / v) to give 40 mg (33%) of N-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2-difluorocyclopropane-1-carboxamide. EXAMPLES

[0252] (S)-3-((8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-4-hydroxycyclobut-3-ene-1,2-dione [ka] As in Example 36, (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine was converted to (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine. The compound was prepared by substituting annulen-3-amine [Example 78] (233 mg, 461.32 μmol) to give (S)-3-((8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-4-hydroxycyclobut-3-ene-1,2-dione 100 mg. EXAMPLES

[0253] (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [ka] The compound was prepared as in Example 78, steps 3, 4, and 5, except starting from (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (1 g, 1.81 mmol), to obtain (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-amine 68 mg (34%). EXAMPLES

[0254] (S)-N-(8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanesulfonamide [ka] To a solution of (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine (58 mg, 114 μmol) [Example 89] in DCM (10 ml) was added methanesulfonyl chloride (10 μl, 126 μmol), and TEA (18 μl, 126 μmol). The reaction mixture was left at room temperature overnight, washed with water, brine, and diluted with MgSO. 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by preparative SFC to give 22 mg (63%) of (S)—N-(8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanesulfonamide. EXAMPLES

[0255] (S)-1-(3-fluoropropyl)-3-(4-(8-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine [ka] As in Example 1, steps 1 and 2, except that (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol is replaced with (S)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-ol The compound was prepared by substituting [7]annulen-3-ol [WO2017140669] (2 g, 4.37 mmol) to give (S)-1-(3-fluoropropyl)-3-(4-(8-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine 45 mg (31.3%). EXAMPLES

[0256] (S)-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-yl)boronic acid [ka] Obtained as a by-product in Example 91 to give 19 mg (16%) of (S)-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-yl)boronic acid. EXAMPLES

[0257] (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetic acid [ka]

[0258] Step 1: Methyl 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)acetate [ka] To a solution of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.2 g, 5.02 mmol) in DMF (10 ml) was added 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (2.1 g, 10.59 mmol), zinc chloride (342 mg, 2.51 mmol), bis(dibenzylideneacetone)palladium (149 mg, 251 μmol) and tri-tert-butylphosphine (63 mg, 301 μmol). The reaction mixture was heated at 130° C. for 3 h. After cooling to room temperature, the reaction mixture was evaporated under reduced pressure and the residue was purified by flash chromatography eluting with isopropyl ether to give 411 mg (35%) of methyl 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)acetate. (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate

[0259] Step 2: Methyl 2-(9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate [ka] To a solution of 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)acetate (650 mg, 2.8 mmol), DCM (20 ml) and pyridine (338 μl, 4.2 mmol) was added trifluoromethanesulfonic anhydride (0.94 ml, 5.6 mmol) dropwise. The reaction mixture was stirred at room temperature for 18 hours. Cold water (5 ml) and saturated NaHCO 3 (10 ml) was added. After decantation, the organic phase was diluted with MgSO 4 The mixture was dried at 40° C. for 1 hour, filtered, and evaporated under reduced pressure to give methyl 2-(9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate 1 g (98%). LC / MS (m / z, MH + ):365.

[0260] Step 3: Methyl (S)-2-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate [ka] To a solution of methyl 2-(9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate (1.05 g, 2.88 mmol) in 1,4-dioxane (25 ml), add (S)-1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine (1.11 g, 3.17 mmol) [WO2017140669], Cs 2 CO 3 (1.88g, 5.76mmol), Pd(dppf)Cl 2 (222 mg, 288 μmol) and water (5 ml) were added. The reaction mixture was heated at 60° C. for 45 min and partitioned between water (40 ml) and DCM (40 ml). The organic phase was washed with MgSO 4 The residue was concentrated in DCM / MeOH / NH 4Purification by column chromatography eluting with OH 28% (37 / 18 / 2; V / V / V) gave 1.2 g (95%) of methyl (S)-2-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate. LC / MS (m / z, MH + ):438.

[0261] Step 4: Methyl (S)-2-(8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate hydrobromide [ka] To a solution of methyl (S)-2-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate (900 mg, 2.06 mmol) in DCM (30 ml) was added pyridinium tribromide (888 mg, 2.78 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Water (30 ml) was added and NaHCO 3 The pH was adjusted to 7 with a concentrated solution of MgSO. After decantation, the organic phase was diluted with MgSO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (1–3%, V / V) to give methyl (S)-2-(8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate hydrobromide 1g (81%). LC / MS (m / z, MH + ):596.

[0262] Step 5: Methyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate [ka] To a solution of methyl (S)-2-(8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate hydrobromide (300 mg, 502 μmol) in 1,4-dioxane (5 ml), (2,4-dichlorophenyl)boronic acid (115 mg, 603 μmol), Pd(dppf)Cl 2 (23 mg, 30 μmol) and 1.5 M Cs 2 CO 3 (670 μl, 1 mmol) was added. The reaction mixture was heated at 70° C. for 45 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography eluting with isopropyl ether / MeOH (95 / 05; V / V / V) to give 110 mg (38%) of methyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate. LC / MS (m / z, MH + ):582.

[0263] Step 6: (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetic acid [ka] To a solution of methyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate (110 mg, 188 μmol) in MeOH (5 ml) was added NaOH 5N (151 μl, 755 μmol). The reaction mixture was heated at reflux for 2 h. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in water (10 ml) and aqueous HCl (5 M) was added until pH 5 was reached. The slurry was extracted with DCM and diluted with MgSO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The resulting residue was purified on a strong cation exchange (SCX) column to give (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetic acid 65 mg (60%). LC / MS (m / z, MH + ):568. EXAMPLES

[0264] (S)-2-(3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)propan-2-ol [ka] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (250 mg, 379.63 μmol), 1,4-dioxane (13 ml), Pd(dppf) 2 Cl 2A mixture of (16.67 mg, 22.78 μmol), water (3 ml), cesium carbonate (272.12 mg, 835.19 μmol) and (3-(2-hydroxypropan-2-yl)phenyl)boronic acid (100.71 mg, 531.49 μmol) was heated in a microwave at 90° C. for 30 minutes. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted twice with ethyl acetate. The organic layers were collected, washed with a saturated aqueous solution of NaCl, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting crude product was purified by flash chromatography eluting with a gradient of ethyl acetate in heptane (95 / 5 to 0 / 100, v / v) to give 220 mg (90%) of (S)-2-(3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)propan-2-ol. EXAMPLES

[0265] (S)-2-(4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)propan-2-ol [ka] (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (300 mg, 455.56 μmol), 1,4-dioxane (13 ml), Pd(dppf) 2 Cl 2A mixture of (20 mg, 27.33 μmol), water (3 ml), cesium carbonate (326.55 mg, 1 mmol) and (4-(2-hydroxypropan-2-yl)phenyl)boronic acid (118.36 mg, 637.78 μmol) was heated in a microwave at 90° C. for 30 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted twice with ethyl acetate. The organic layers were collected, washed with a saturated aqueous solution of NaCl, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting crude product was purified by flash chromatography eluting with a gradient of ethyl acetate in heptane (95 / 5 to 0 / 100, v / v) to give 60 mg (60%) of (S)-2-(4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)propan-2-ol. EXAMPLES

[0266] (S)-3-(4-(8-(2-chloro-3-fluorophenyl)-3-(3-nitrophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [ka] To a solution of (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 98, Step 1] (260 mg, 404.94 μmol) in 1,4-dioxane (13 ml), 3-nitrophenylboronic acid (68.97 mg, 404.94 μmol) as a solution in water (3 ml), Pd(dppf) 2 Cl 2 (17.78 mg, 24.30 μmol), and Cs 2 CO 3(290.26 mg, 890.86 μmol) was added. The reaction mixture was heated in a microwave at 90° C. for 30 minutes. The reaction mixture was diluted with EtOAc and saturated K 2 CO 3 The solution was washed with brine and MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with mixtures of heptane / EtOAc and EtOAc / MeOH (95 / 5; and 95 / 5; v / v) to give 175 mg (70.3%) of (S)-3-(4-(8-(2-chloro-3-fluorophenyl)-3-(3-nitrophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine. EXAMPLES

[0267] (S)-3-(8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)aniline [ka] To a solution of (S)-3-(4-(8-(2-chloro-3-fluorophenyl)-3-(3-nitrophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [Example 96] (150 mg, 243.86 μmol) in iPrOH (35 ml) was added zinc powder (95.66 mg, 1.46 mmol) as a solution in water (5 ml), and NH 4 Cl (104.35 mg, 1.95 mmol) was added. The reaction mixture was refluxed for 2 h, filtered, rinsed with iPrOH, and the filtrate was evaporated under reduced pressure. The residue was dissolved in EtOAc and saturated K 2 CO 3 The solution was washed with brine and MgSO 4The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with mixtures of heptane / EtOAc and EtOAc / MeOH (95 / 5; and 95 / 5; v / v) to give (S)-3-(8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)aniline 95 mg (67%). EXAMPLES

[0268] (S)-2-(4-(8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)propan-2-ol [ka]

[0269] Step 1: (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [ka] As in Example 1, step 1, except that (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol was replaced with (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol This compound was prepared by substituting benzo[7]annulen-3-ol [WO2017140669] (750 mg, 1.47 mmol) to give (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate 800 mg (85%). LC / MS (m / z, MH + ):642.

[0270] Step 2: (S)-2-(4-(8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)propan-2-ol [ka] (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (200 mg, 311.49 μmol), 1,4-dioxane (13 ml), Pd(dppf) 2 Cl 2A mixture of (13.68 mg, 18.69 μmol), water (3 ml), cesium carbonate (223.28 mg, 685.27 μmol) and (4-(2-hydroxypropan-2-yl)phenyl)boronic acid (80.93 mg, 436.08 μmol) was heated in a microwave at 60° C. for 30 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted twice with ethyl acetate. The organic layer was collected and purified by HPLC. 2 CO 3 The mixture was washed with a saturated aqueous solution of ethyl acetate, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with a mixture of ethyl acetate in heptane (95 / 5, v / v) and ethyl acetate in methanol (95 / 5; v / v) to give 60 mg (60%) of (S)-2-(4-(8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)propan-2-ol.

[0271] The compounds according to the invention were subjected to pharmacological tests to determine their disruptive effect on the estrogen receptor.

[0272] Test: Estrogen receptor degrading activity Said test involves measuring the in vitro decomposition activity of the compounds of the invention.

[0273] Degradation activity was measured using breast cancer cell ERα in a cell Western assay described below.

[0274] MCF7 cells (ATCC) were seeded in 384-well microplates (coated with collagen) 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 next day, nine-point serial 1:5 dilutions of each compound were added to the cells in 2.5 μL increments at final concentrations ranging from 3 to 0.000018 μM (column "% Degraded at 3 μM" in Table 2) or 0.3 to 0.0000018 μM (column "% Degraded at 0.3 μM" in Table 2), or 0.1 μM for fulvestrant (used as a positive control). Four hours after compound addition, cells were fixed by adding 25 μL of formalin (5% final concentration formalin containing 0.1% triton) for 10 min at room temperature, 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. The LI-COR blocking buffer was removed, and the cells were incubated overnight in a refrigerator 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 for 60 minutes at 37°C in LI-COR (0.1% tween-20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and DNA dye Syto-64 (final concentration 2 μM). The cells were then washed three times in PBS and scanned in an ACUMEN explorer (TTP-Labtech). The integrated intensity of green and red fluorescence was measured to determine the levels of ERα and DNA, respectively.

[0275] In this test, the degradation activity against estrogen receptors was measured using the concentration that degrades 50% of the estrogen receptor (or IC 50 ) in nM units.

[0276] The % reduction in ERα levels was determined as follows: % inhibition = 100 x (1 - (sample-fulvestrant:DMSO-fulvestrant)).

[0277] Table 2 below shows the estrogen receptor degrading activity results for compounds according to the invention tested at either 3 μM or 0.3 μM, demonstrating that said compounds have significant degrading activity against the estrogen receptor.

[0278] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0279] Thus, the compounds of the present invention have an IC of less than 1 μM for the estrogen receptor. 50 and has a degradation activity at a degradation level of more than 50%. Therefore, the compounds according to the present invention can be used for the manufacture of drugs, particularly drugs that are degraders of estrogen receptors.

[0280] Thus, in another of its aspects, the present invention provides a medicament comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof.

[0281] The present invention also relates to compounds of formula (I) as defined above, or a pharma- ceutically acceptable salt thereof, for use in therapy, especially as inhibitors and degraders of estrogen receptors.

[0282] The present invention also relates to a compound of formula (I) as defined above, or a pharma- ceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

[0283] In particular, the present invention relates to a compound of formula (I) as defined above, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer.

[0284] In one embodiment, the cancer is a hormone-dependent cancer.

[0285] In another embodiment, the cancer is an estrogen receptor dependent cancer, particularly, the cancer is an estrogen receptor alpha dependent cancer.

[0286] 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.

[0287] In another embodiment, the metastasis is a brain metastasis.

[0288] In another embodiment, the cancer is breast cancer. In particular, the breast cancer is estrogen receptor positive breast cancer (ERα positive breast cancer).

[0289] In another embodiment, the cancer is resistant to anti-hormonal treatment.

[0290] In a further embodiment, compounds of formula (I) are used as single agents or in combination with other agents, such as CDK4 / 6 or PI3K inhibitors.

[0291] According to another of its aspects, the present invention also relates to a method for treating the above indicated pathological conditions, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof. In one embodiment of this method of treatment, the subject is a human.

[0292] The present invention also relates to the use of a compound of formula (I) according to the invention, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament useful in the treatment of any of the above indicated pathological conditions, more particularly useful in the treatment of cancer.

[0293] According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active ingredient, a compound according to the invention, which contain an effective dose of at least one compound according to the invention, or a pharma- ceutical acceptable salt thereof, and furthermore at least one pharma- ceutical acceptable excipient.

[0294] Said excipients are chosen according to the desired pharmaceutical form and method of administration from the customary excipients known to those skilled in the art.

[0295] In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its base, acid, zwitterion or salt thereof, in unit dosage form, in admixture with conventional pharmaceutical excipients, can be administered to animals and humans for the treatment of the above disorders or diseases.

[0296] 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, ocular and intranasal dosage forms, forms for inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal dosage forms and implants. For topical application, the compounds according to the invention can be used as creams, gels, ointments or lotions.

[0297] As an example, a unit dosage form of a compound according to the invention in tablet form may contain the following components: Compound according to the present invention 50.0 mg Mannitol 223.75mg Croscarmellose sodium 6.0mg Corn starch 15.0mg Hydroxypropyl methylcellulose 2.25mg Magnesium stearate 3.0mg

[0298] In certain cases, higher or lower dosages may be appropriate; such dosages do not depart from the scope of the invention. According to the usual 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. Compounds of formula (I) 【Chemistry 1】 [In the formula, -Ar represents a phenyl or 6-membered heteroaryl group, and the phenyl or 6-membered heteroaryl group is not a halogen atom, an -OH group, (C 1 ~C 3 ) alkyl group, (C 1 ~C 3 ) alkoxy groups, such as trifluoromethoxy (C 1 ~C 3 ) optionally substituted with 1 to 3 groups selected from perfluoroalkoxy groups and oxooxazolidinyl groups, such as 2-oxooxazolidin-3-yl; - R1 and R2 independently represent a hydrogen atom or a deuterium atom; -R3 is -(1)-COR4 group, -(2)-BOR5OR6 group, -(3)-X-Z group, -(4) a fluorine atom, -OH group, or -COOH group, which is 1 to 8 groups selected from the group consisting of a -OH group and a -COOH group; (C 1 ~C 6 ) alkyl group or (C 1 ~C 6 ) an alkenyl group, -(5)-X-S(O) n (R7) p (R8) q base, -(6)-NH 2 group or a -CN group, -(7)-O-R11 group, -(8)-NH-COR9 group, -(9)-C(=NH)NHOH group, -(10)-NH-C(NH)-R9' group, -(11) -NHCOCOOR12 group or -NHCOCONR12'R12'' group represents R4 is (C 1 ~C 6 ) an alkyl group, an -NRR' group, an -NHNH 2 group, -NHNHCONH 2 group, -NHNHCS-1H-imidazolyl group or -NHSO 2 CH 3 R and R′ are each independently a hydrogen atom, an —OH group, 1 ~C 6 ) an alkoxy group or (C 1 ~C 6 ) represents an alkyl group; R5 and R6 are independently a hydrogen atom, (C 1 ~C 6 )alkyl groups, optionally together with the boron atom to which they are attached, forming a 4- or 5-membered ring, said ring comprising 1 to 4 (C 1 ~C 4 ) optionally substituted with alkyl groups; R7 and R8 are independently optionally partially or fully substituted with fluorine atoms (C 1 ~C 6 ) an alkyl group, —NH 2 represents a group or an ═NH group, R9 is a hydrogen atom, 1 ~C 6 ) an alkoxy group, (C 1 ~C 6 ) alkyl group or (C 3 ~C 6 ) represents a cycloalkyl group, 1 ~C 6 ) an alkoxy group, (C 1 ~C 6 ) alkyl group or (C 3 ~C 6 ) Cycloalkyl groups are those which contain 1 to 3 fluorine atoms, —OH groups or (C 1 ~C 4 ) optionally substituted with alkyl groups; R9′ is (C 1 ~C 6 ) alkyl group or (C 3 ~C 6 ) represents a cycloalkyl group; R11 is optionally substituted with 1 to 6 fluorine atoms (C 1 ~C 6 ) represents an alkyl group; R12 is (C 1 ~C 6 ) represents an alkyl group; R12' and R12'' are independently a hydrogen group or (C 1 ~C 6 ) an alkyl group, X represents a bond, an —NH— group, an —CONH— group, or a —CO— group; Z is, (i) 4- or 5-membered cycloalkyl, (ii) a 4- or 5-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur; (iii) a 4- or 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur; wherein the cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted by 1 to 3 groups selected from -OH, oxo, =NR12'R12'' and thiooxo groups; or (iv) Hydroxy group, COOR12′ group, —CONH 2 group, -NO 2 group, -NH 2 The group or itself is optionally substituted by a hydroxy group (C 1 ~C 6 ) a phenyl group optionally substituted with an alkyl group represents n is an integer and means 1 or 2; p+q is an integer and means 1 or 2, p and q are each an integer and means 0, 1, or 2, and when n is 1, p+q is 2, and when n is 2, p+q is 1, and the sulfur atom remains pentavalent; When n is 1 and p+q is 2, the two groups R7 and R8 on the sulfur atom, together with the sulfur atom to which they are attached, further comprise (C 1 ~C 6 ) forming a 5-membered ring optionally substituted with 1 to 3 groups selected from alkyl and oxo groups, or a pharma- ceutically acceptable salt thereof.

2. Compounds of formula (I) according to claim 1, characterized in that Ar represents a phenyl or pyridinyl group, said phenyl or pyridinyl group being optionally substituted by one or two radicals selected from among chlorine, fluorine, hydroxy, methyl, trifluoromethoxy, 2-oxooxazolidin-3-yl and ethoxy, or a pharma- ceutically acceptable salt thereof.

3. R3 represents a -COR4 group, where R4 is (C 1 ~C 6 ) an alkyl group, an -NRR' group, an -NHNH 2 group, -NHNHCONH 2 group, -NHNHCS-1H-imidazolyl group or -NHSO 2 CH 3 represents a group, R and R′ are independently a hydrogen atom, an —OH group, (C 1 ~C 6 ) an alkoxy group or (C 1 ~C 6 3. Compounds of formula (I) according to claim 1 or 2, characterized in that they represent an alkyl group, or a pharma- ceutically acceptable salt thereof.

4. R3 represents a -BOR5OR6 group, where R5 and R6 are independently a hydrogen atom or (C 1 ~C 6 3. Compounds of formula (I) according to claim 1 or 2, characterized in that: or a pharma- ceutically acceptable salt thereof.

5. R3 represents an -X-Z group, where X represents a bond, an -NH- group, an -CONH- group or an -CO- group; Z is, (i) 4- or 5-membered cycloalkyl, (ii) a 4- or 5-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur; (iii) a 4- or 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein the cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted by 1 to 3 groups selected from -OH, oxo, =NR12'R12'' and thiooxo groups; or (iv) Hydroxy group, COOR12′ group, —CONH 2 group, -NO 2 group, -NH 2 The group or itself is optionally substituted by a hydroxy group (C 1 ~C 6 ) a phenyl group optionally substituted with an alkyl group R12' and R12'' are independently a hydrogen group or (C 1 ~C 6 3. Compounds of formula (I) according to claim 1 or 2, characterized in that: or a pharma- ceutically acceptable salt thereof.

6. R3 is, (i) 4- or 5-membered cycloalkyl, (ii) a 4- or 5-membered heterocycloalkyl group containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur; (iii) a 4- or 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur; wherein the cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted by 1 to 3 groups selected from -OH, oxo, =NR12'R12'' and thiooxo groups; or (iv) Hydroxy group, COOR12′ group, —CONH 2 group, -NO 2 group, -NH 2 The group or itself is optionally substituted by a hydroxy group (C 1 ~C 6 ) a phenyl group optionally substituted with an alkyl group R12' and R12'' are independently a hydrogen group or (C 1 ~C 6 10. A compound of formula (I) according to claim 1, 2 or 5, characterized in that it is an alkyl group, or a pharma- ceutically acceptable salt thereof.

7. R3 is, (i) 4- or 5-membered cycloalkyl, (ii) a 4- or 5-membered heterocycloalkyl group containing from 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, or (iii) 4- or 5-membered heteroaryl groups containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur. Compounds of formula (I) according to claims 1, 2 or 5, characterized in that said cycloalkyl, heteroaryl or heterocycloalkyl radicals are optionally substituted by 1 to 3 radicals selected from -OH and oxo radicals, or a pharma- ceutically acceptable salt thereof.

8. R3 is substituted by 1 to 4 groups selected from a fluorine atom, a —OH group, and a —COOH group; 1 ~C 6 ) alkyl group or (C 1 ~C 6 3. Compounds of formula (I) according to claim 1 or 2, characterized in that they represent an alkenyl group, or a pharma- ceutically acceptable salt thereof.

9. R3 is -CONHSO 2 (CH 3 ) group, —SO 2 N.H. 2 Group, —SO(CH 3 )NH group, -SO 2 CH 3 group, -NHSO 2 (CH 3 ) group or -NHSO 2 (CF 3 3. Compounds of formula (I) according to claim 1 or 2, characterized in that they represent a group selected from the group or a pharma- ceutically acceptable salt thereof.

10. R3 is -NH 2 Compounds of formula (I) according to claim 1 or 2, characterized in that they represent a group, or a -CN group, or a pharma- ceutically acceptable salt thereof.

11. R3 represents a -O-R11 group, where R11 is optionally substituted with 1 to 6 fluorine atoms (C 1 ~C 6 3. Compounds of formula (I) according to claim 1 or 2, characterized in that they represent an alkyl group, or a pharma- ceutically acceptable salt thereof.

12. R3 represents a -NH-COR9 group, where R9 is (C 1 ~C 6 ) an alkoxy group, (C 1 ~C 6 ) alkyl group or (C 3 ~C 6 ) represents a cycloalkyl group, 1 ~C 6 ) alkyl group or (C 3 ~C 6 ) Cycloalkyl groups are those which contain 1 to 3 fluorine atoms, —OH groups or (C 1 ~C 4 3. Compounds of formula (I) according to claim 1 or 2, characterized in that they are optionally substituted by alkyl groups. or a pharma- ceutically acceptable salt thereof.

13. R3 represents a -NH-C(NH)-R9' group, where R9′ is (C 1 ~C 6 ) alkyl group or (C 3 ~C 6 3. Compounds of formula (I) according to claim 1 or 2, characterized in that they represent a cycloalkyl group, or a pharma- ceutically acceptable salt thereof.

14. R3 represents a -NHCOCOOR12 group or a -NHCOCONR12'R12'' group, where R12 is (C 1 ~C 6 ) represents an alkyl group; R12' and R12'' are independently a hydrogen group or (C 1 ~C 6 ) represents an alkyl group A compound of formula (I) according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof.

15. The following compound: -(S)-3-(4-(8-(2,4-dichlorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine (1) -(S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)boronic acid (2) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (3) -(S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)isoxazol-3-ol (4) -1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2-difluoroethan-1-ol (5) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide (6) -(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazole (7) -(S)-3-(4-(8-(2,4-dichlorophenyl)-3-(difluoromethyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine (8). -(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-thiadiazole (9) -1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroethan-1-ol (10) -(S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2-dihydro-3H-pyrazol-3-one (12) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)isoxazol-5(4H)-one (13) -(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl)hydrazine-1-carboxamide (14) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-(methylsulfonyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (15) -(S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluorophenyl) (16) 6,7-dihydro-5H-benzo[7]annulen-3-yl-oxyphenyl-2H-tetrazole (17) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-(2H-tetrazol-5-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (17) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (18) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (19) -(S,E)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acrylic acid (20). -(S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole (21) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile (22) -(S)-4-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole (23) -(S)-3-(4-(3-(difluoromethoxy)-8-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine (24). -Methyl (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate (25) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboximidamide (26). -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-oxadiazol-5(4H)-one (27) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine (28) -4-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3H-1,2,3,5-oxathiadiazole 2-oxide hydrochloride (29) —(S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanesulfonamide (30). -(S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazole-2(3H)-oxo N (31) -tert-butyl (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate (32) -(S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxathiazol-2-one (33) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-oxadiazole-5(4H)-thione (34). —(S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,1,1-trifluoromethanesulfonamide (35). -(S)-3-((8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-4-hydroxycyclobut-3-ene-1,2-dione (36). -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-thiadiazol-5(4H)-one (37). -(S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-methoxy-1,5-dihydro-2H-pyrrol-2-one (38). -(S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-one (39) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxazolidin-2-one (40). -(S)-3-(8-(2-chloro-4-(2-oxooxazolidin-3-yl)phenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxazolidin-2-one (41) -(S)-4-(3-amino-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-8-yl)-3-chlorophenol (42) -5-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)imidazolidine-2,4-dione (43) -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (44) -(S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazole-2(3H)-thiazole On (45) —(S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetimidamide (46). —(S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroacetamide (47) —(S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetamide (48). -1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-ol (49) -(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)propan-2-ol (50) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole (51) -(S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol (52). -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol (53). -(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol (54). -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid (55). -Methyl (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate (56) -Methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate (57) -(S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)pyrrolidin-2-one (58). -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N'-(1H-imidazole-1-carbonothioyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide (59) —(S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)cyclopropanecarboxamide (60). -(S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)thiazol-2-amine (61) —(S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)pivalamide (62) -(S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (63) -(S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile 2,2,2-trifluoroacetate (64) -1-(8-(2-chloro-3-fluorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroethan-1-ol (65) —(S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1-fluorocyclopropane-1-carboxamide (66) —(S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1-methylcyclopropane-1-carboxamide (67) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2-hydroxycyclopent-2-en-1-one (68) -(S,Z)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-N,3-dimethylthiazol-2(3H)-imine hydrochloride (69) -(S)-5-(8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2H-tetrazole 2,2,2-trifluoroacetate (70) -tert-Butyl (S)-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate (71) -(S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid (72) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazol-5-amine (73) -(S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)(3-hydroxyazetidin-1-yl)methanone (74). -(S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-(oxetan-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (75) -Ethyl(S)-2-((8-(2,4-dichlorophenyl)-9-(4-((1-( 3-Fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-2-oxoacetate (76) —(S)—N1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxalamide (77) -(S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine (78) -(S)-8-(6-ethoxy-2-fluoropyridin-3-yl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (79) -(S)-8-(6-ethoxy-2-fluoropyridin-3-yl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile 2,2,2-trifluoroacetate (80) -(S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzamide (81) -(S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanol (82) -Methyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate (83) —(S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1-hydroxycyclopropane-1-carboxamide formate (84). -(S)-1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-4-hydroxypyrrolidin-2-one (85). -(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid (86) -N-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2-difluorocyclopropane-1-carboxamide (87). -(S)-3-((8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-4-hydroxycyclobut-3-ene-1,2-dione (88) -(S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine (89) —(S)—N-(8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanesulfonamide (90). -(S)-1-(3-fluoropropyl)-3-(4-(8-phenyl-3-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine (91) -(S)-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-yl)boronic acid (92). -(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetic acid (93) -(S)-2-(3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)propan-2-ol (94) -(S)-2-(4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)propan-2-ol (95) -(S)-3-(4-(8-(2-chloro-3-fluorophenyl)-3-(3-nitrophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine (96) -(S)-3-(8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)aniline (97) and (S)-2-(4-(8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)propan-2-ol (98) 15. The compound of formula (I) according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, selected from:

16. A medicament comprising a compound of formula (I) according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient.

18. A compound of formula (I) as defined in any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, for use as an inhibitor and degrader of estrogen receptors.

19. 16. A compound of formula (I) as defined in any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hyperplasia or inflammation.

20. 20. A compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use according to claim 19, for use in the treatment of cancer.

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