NOVEL SUBSTITUTED 6,7-DIHYDRO-5H-BENZO[7]ANNULENE COMPOUNDS, PROCESSES FOR THEIR PREPARATION AND THERAPEUTIC USES THEREOF

The present invention relates to novel substituted 6,7-dihydro-5H- benzo[7]annulene compounds, the processes for their preparation, as well as the therapeutic uses thereof, in particular as anticancer agents via selective antagonism and degradation of estrogen receptors.

The Estrogen Receptors (ER) belong to the steroid/nuclear receptor superfamily involved in the regulation of eukaryotic gene expression, cellular proliferation and differentiation in target tissues. ERs are in two forms: the estrogen receptor alpha (ERa) and the estrogen receptor beta (ERP) respectively encoded by the ESR1 and the ESR2 genes. ERa and ERP are ligand-activated transcription factors which are activated by the hormone estrogen (the most potent estrogen produced in the body is 17P-estradiol). In the absence of hormone, ERs are largely located in the cytosol of the cell. When the hormone estrogen binds to ERs, ERs migrate from the cytosol to the nucleus of the cell, form dimers and then bind to specific genomic sequences called Estrogen Response Elements (ERE). The DNA/ER complex interacts with co-regulators to modulate the transcription of target genes.

ERa is mainly expressed in reproductive tissues such as uterus, ovary, breast, bone and white adipose tissue. Abnormal ERa signaling leads to development of a variety of diseases, such as cancers, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammation diseases and osteoporosis.

ERa is expressed in not more than 10% of normal breast epithelium but approximately 50-80% of breast tumors. Such breast tumors with high level of ERa are classified as ERa-positive breast tumors. The etiological role of estrogen in breast cancer is well established and modulation of ERa signaling remains the mainstay of breast cancer treatment for the majority ERa-positive breast tumors. Currently, several strategies for inhibiting the estrogen axis in breast cancer exist, including: 1- blocking estrogen synthesis by aromatase inhibitors that are used to treat early and advanced ERa-positive breast cancer patients; 2- antagonizing estrogen ligand binding to ERa by tamoxifen which is used to treat ERa-positive breast cancer patients in both pre- and post- menopausal setting; 3- antagonizing and downregulating ERa levels by fulvestrant, which is used to treat breast cancer in patients that have progressed despite endocrine therapies such as tamoxifen or aromatase inhibitors.

Although these endocrine therapies have contributed enormously to reduction in breast cancer development, about more than one-third of ERa-positive patients display de- novo resistance or develop resistance over time to such existing therapies. Several mechanisms have been described to explain resistance to such hormone therapies. For example, hypersensitivity of ERa to low estrogen level in treatment with aromatase inhibitors, the switch of tamoxifen effects from antagonist to agonist effects in tamoxifen treatments or multiple growth factor receptor signaling pathways. More recently, acquired mutations in ERa occurring after initiation of hormone therapies may play a role in treatment failure and cancer progression. Certain mutations in ERa, particularly those identified in the Ligand Binding Domain (LBD), result in the ability to bind to DNA in the absence of ligand and confer hormone independence in cells harboring such mutant receptors.

Most of the endocrine therapy resistance mechanisms identified rely on ERa- dependent activity. One of the new strategies to counterforce such resistance is to shut down the ERa signaling by removing ERa from the tumor cells using Selective Estrogen Receptors degraders (SERDs). Clinical and preclinical data showed that a significant number of the resistance pathways can be circumvented by the use of SERDs.

There is still a need to provide SERDs with good degradation efficacy.

Document WO2017/140669 discloses some substituted 6,7-dihydro-5H- benzo[7]annulene compounds useful as SERDs.

The objective of the present invention is to provide novel compounds able to selectively antagonize and degrade the estrogen receptors (SERDs compounds), for use in cancer treatment.

The present invention relates to the compounds of the formula (I):

wherein:

- Ar represents a phenyl or a 6-membered heteroaryl group, said phenyl or 6-membered heteroaryl group being optionally substituted with one to three groups selected from halogen atoms, a -OH group, a (Ci-C3)alkyl group, a (Ci-C3)alkoxy group, a (Ci-C3)perfluoroalkoxy group, such as a trifluoromethoxy and an oxooxazolidinyl group, such as a 2-oxooxazolidine-3-yl,

- R1 and R2 represent independently a hydrogen atom or a deuterium atom;

- R3 represents

- (1) a -COR4 group,

- (2) a -B0R50R6 group,

- (3) a -X-Z group,

- (4) a (Ci-C ₆ )alkyl group or a (Ci-C ₆ )alkenyl group, optionally substituted by 1 to 8 groups selected from a fluorine atom, a -OH group and a -COOH group,

- (5) a -X-S(0)„(R7)p(R8)q group,

- (6) a halogen atom, a -NH2 group or a -CN group,

- (7) a -O-Rll group,

- (8) a -NH-COR9 group,

- (9) a -C(=NH)NHOH group,

- (10) a -NH-C(NH)-R9’ group,

- (11) a -NHCOCOOR12 group or a -NHCOCONR12’R12” group, R4 represent a (Ci-C ₆ )alkyl group, a -NRR’ group, a -NHNEh group, a -NHNHCONH2 group, a -NHNHCS-lH-imidazolyl group or a -NHSO2CH3 group, wherein R and R’ independently represent a hydrogen atom, a -OH group, a (Ci-C ₆ )alkoxy group or a (Ci-C ₆ )alkyl group,

R5 and R6 independently represent a hydrogen atom, a (Ci-C ₆ )alkyl group, optionally forming with the bore atom to which they are attached a 4 or 5-membered ring, said ring being optionally substituted by 1 to 4 (Ci-COalkyl groups,

R7 and R8 independently represents a (Ci-C ₆ )alkyl group optionally partially or fully substituted by fluorine atoms, a -NH2 group or a =NH group,

R9 represents a hydrogen atom, a (Ci-C ₆ )alkoxy group, a (Ci-C ₆ )alkyl group or a (C3-C6)cycloalkyl group, each (Ci-C ₆ )alkoxy group, (Ci-C ₆ )alkyl group or (C3-C6)cycloalkyl group being optionally substituted by one to three fluorine atom(s), a -OH group or a (Ci-COalkyl group,

R9’ represents a (Ci-C ₆ )alkyl group or a (C3-C6)cycloalkyl group,

Rll represents a (Ci-C ₆ )alkyl group, optionally substituted by one to six fluorine atoms,

R12 represents a (Ci-C ₆ )alkyl group,

R12’ and R12” independently represent a hydrogen group or a (Ci-C ₆ )alkyl group,

X represents a bond, a -NH- group, a -CONH- group or a -CO- group,

Z represents

(i) a 4 or 5-membered cycloalkyl,

(ii) a 4 or 5-membered heterocylcloalkyl group comprising 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur,

(iii) a 4 or 5-membered heteroaryl group comprising 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, said cycloalkyl, heteroaryl or heterocycloalkyl group being optionally substituted by 1 to 3 groups selected from a -OH group, an oxo group, a =NR12’R12” group and a thiooxo group, or

(iv) a phenyl group optionally substituted by a hydroxy group, by a COOR12’ group, by a -CONH2 group, by a -NO2 group, by a -NH2 group or by a (Ci-C ₆ )alkyl group itself optionally substituted by a hydroxy group, n is an integer and means 1 or 2, p+q is an integer and means 1 or 2, with each of p and q being an integer and meaning 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 stays pentavalent, and when n is 1 and p+q is 2, the two groups R7 and R8 on the sulfur atom may further form with the sulfur atom to which they are attached a 5-membered ring, optionally substituted by 1 to 3 groups selected from a (Ci-C ₆ )alkyl group and an oxo group. or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) contain one or more asymmetric carbon atoms, more particularly one asymmetric carbon atom on the pyrrolydinyl group. They may therefore exist in the form of enantiomers. These enantiomers form part of the invention.

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

The compounds of formula (I) may be present as well under tautomer forms and are part of the invention. This is for example true for the compounds comprising heteroaryl groups.

The compounds of formula (I) may exist in the form of bases, acids, zwitterion or of addition salts with acids or bases. Such addition salts, bases, acids and zwitterion form part of the invention. Hence, the invention relates, inter alia, to the compounds of formula (I) or to pharmaceutically acceptable salts thereof.

These salts may be prepared with pharmaceutically acceptable acids or bases, although the salts of other acids or bases useful, for example, for purifying or isolating the compounds of formula (I) also form part of the invention.

Among suitable salts which form part of the invention, the following may be cited: trifluoroacetate, hydrochloride and formate, In the context of the present invention, the terms below have the following definitions unless otherwise mentioned throughout the instant specification:

- a halogen atom: a fluorine, a chlorine, a bromine or an iodine atom, and in particular a fluorine and a chlorine atom;

- an oxo : a “=0” group;

- a thiooxo: a “=S” group;

- a cyano group: a “-CºN” group;

- an amine group: a nitrogen atom unsubstituted or substituted with one or more (Ci-C ₆ )alkyl groups; - an alkyl group: a linear or branched saturated hydrocarbon-based aliphatic group comprising, unless otherwise mentioned, from 1 to 6 carbon atoms (noted “(Ci-C ₆ )alkyl”). By way of examples, mention may be made of, but not limited to: methyl, ethyl, propyl, n- propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl groups, and the like;

- a (Ci-C ₆ )alkyl group optionally partially or fully substituted by fluorine atoms respectively means a (Ci-C ₆ )alkyl being substituted by at least one fluorine atom or wherein each hydrogen atom is replaced by a fluorine atom. In this last case, said groups may be designated as perfluoro alkyl groups. Examples of perfluoroalkyl groups are trifluoromethyl group or perfluoroprolyl group;

- a alkenyl group: a linear or branched hydrocarbon-based aliphatic group comprising at least one unsaturation and comprising, unless otherwise mentioned, from 1 to 6 carbon atoms (noted “(Ci-C6)-alkenyl”);

- an alkoxy group: an -O-alkyl group where the alkyl group is as previously defined. By way of examples, mention may be made of, but not limited to: methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, isobutoxy, pentoxy or hexoxy groups, and the like;

- a perfluoro alkoxy group: an alkoxy group of which all the hydrogen atoms have been substituted with a fluorine atom. By way of example, mention may be made of trifluoromethoxy group and the like;

- a cycloalkyl group: a cyclic alkyl group comprising, unless otherwise mentioned, from 4 to 5 carbon atoms (noted “4 or 5-membered cycloalkyl group”), saturated or partially unsaturated and unsubstituted or substituted. By way of examples, mention may be made of, but not limited to: cyclobutyl, cyclopentyl, cyclobutenyl, cyclopentenyl groups and the like;

- a heterocycloalkyl group: a monocyclic alkyl group comprising, unless otherwise mentioned, from 4 to 5 carbon atoms (noted “4 or 5-membered heterocycloalkyl group”) and containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur. Such heterocycloalkyl group may be saturated or partially saturated and unsubstituted or substituted. By way of examples of heterocyclo alkyl groups, mention may be made of, but not limited to: azetidine, oxetane, thietane, 2H-pyrrole, 1H-, 2H- or 3H-pyrroline, pyrrolidine, THF , tetrahydrothiophene, oxadiazole and more particularly 1,3,4-oxadiazole or 1,3,5-oxadioazole, thiadiazole and more particularly 1,3,4-thiadiazole, isoxazoline, 2- or 3-pyrazoline and more particularly 3-pyrazoline, pyrroline, pyrazolidine, imidazoline, imidazolidine, thiazolidine, isooxazoline, isoxazolidine, dioxalane, oxathiazole, oxathiadiazole, dioxazole groups and the like.- a 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. By way of examples of 4 or 5-membered heteroaryl groups, mention may be made of, but not limited to: pyrrole, furan, thiophene, oxazole, isoxazole, triazole, tetrazole, oxadiazole, furazan, thiazole, isothiazole, thiadiazole, pyrazole, imidazole groups and the like;

- a 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. By way of examples of 6-membered heteroaryl group, mention may be made of, but not limited to: pyridine, pyrimidine, pyridazine, triazine groups and the like.

- A zwitterion means: a globally neutral molecule with a positive and a negative electrical charge and having an acid group and a basic group.

In an embodiment, in the compound of formula (I), R1 and R2 represent hydrogen atoms.

In another embodiment, in the compounds of formula (I), R1 and R2 represent deuterium atoms.

In another embodiment, in the compounds of formula (I), Ar represents a phenyl or a pyridinyl group, in particular a 3-pyridinyl group, said phenyl or pyridinyl group being optionally substituted with one or two groups selected among chlorine, fluorine, hydroxy, methyl, trifluoromethoxy, 2-oxooxazolidine-3-yl and ethoxy, or a pharmaceutically acceptable salt thereof. In another embodiment, in the compound of formula (I), the phenyl or on the 6- membered heteroaryl group may be substituted by one or two groups selected from halogen atoms, a hydroxy, a methyl or ethyl group, a methoxy or ethoxy group, a trifluoromethoxy and an oxooxazolidinyl group, such as a 2-oxooxazolidine-3-yl. In another embodiment in the compounds of formula (I), Ar represents a group selected from:

In another embodiment, in the compounds of formula (I), R3 represents a -COR4 group, wherein R4 represent a (Ci-C ₆ )alkyl group, a -NRR’ group, a -NHNth group, a -NHNHCONHi group, a -NHNHCS-lH-imidazolyl group or a -NHSO2CH3 group, and

R and R’ independently represent a hydrogen atom, a -OH group, a (Ci-C ₆ )alkoxy group or a (Ci-C ₆ )alkyl group, or a pharmaceutically acceptable salt thereof.

In another embodiment, in the compounds of formula (I), R3 represents a -B0R50R6 group, wherein R5 and R6 independently represent a hydrogen atom or a (Ci-C ₆ )alkyl group, optionally forming with the bore atom to which they are attached a 5-membered ring, said ring being optionally substituted by 1 to 4 methyl groups, or a pharmaceutically acceptable salt thereof.

In another embodiment, in the compounds of formula (I), R3 represents a -B(OH)2 group group, wherein Ra, Rb, Rc and Rd independently represent a (Ci-C4)alkyl, and in particular a methyl group.

In another embodiment, in the compounds of formula (I), R3 represents a -X-Z group, wherein

X represents a bond, a -NH- group, a -CONH- group or a -CO- group,

Z represents a

(i) 4 or 5-membered cycloalkyl, more particularly chosen from a cyclobutenyl and a cyclopentenyl,

(ii) a 4 or 5-membered heterocylcloalkyl group comprising 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, more particularly chosen from an azetidinyl, an oxetanyl, a dihydropyrazolyl, a dihydroisoxazolyl, a dihydropyrrolyl and more particularly a 1,5 — dihydro-2H-pyrrolyl, an oxazolidinyl, an imidazolidinyl, a dioxazolyl, and even more particularly a 1,2,4-dioxazolyl, an oxathiazolyl, and even more particularly a

1.3.4-oxathiazolyl, an oxathiadiazolyl and a pyrrolidinyl,

(iii) a 4 or 5-membered heteroaryl group comprising 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, more particularly chosen from a triazolyl, even more particularly a 1,2,4-triazolyl, an isoxazolyl, a thiazolyl, an oxadiazolyl, even more particularly a 1,3,5-oxadiazolyl, a 1,3,4-oxadiazolyl, a 1,2,4-oxadiazolyl or a

1.2.5-oxadiazolyl, a thiadiazolyl, and even more particularly a 1,3,5-thiadiazolyl, a 1,2,4-thiadiazolyl, a 1,2,5-thiadiazolyl or a 1,3,4-thiadiazolyl, a tetrazolyl and a pyrazolyl, said cycloalkyl, heteroaryl or heterocyclo alkyl group being optionally substituted by 1 to 3 groups selected from a -OH group, an oxo group, a =NR12’R12” group and a thiooxo group, or

(iv) a phenyl group optionally substituted by a hydroxy group, by a COOR12’ group, by a -CONH2 group, by a -NO2 group, by a -NH2 group or by a (Ci-C ₆ )alkyl group, itself optionally substituted by a hydroxy group, with R12’ and R12” independently being a hydrogen group or a (Cl-C6)alkyl group, or a pharmaceutically acceptable salt thereof.

In another embodiment in the compounds of formula (I), R3 represents a group selected from In another embodiment, in the compounds of formula (I), R3 represents a

(i) 4 or 5-membered cycloalkyl, more particularly chosen from a cyclopentenyl,

(ii) a 4 or 5-membered heterocylcloalkyl group comprising 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, more particularly chosen from a dihydropyrazolyl, a dihydroisoxazolyl, a dihydropyrrolyl and more particularly a 1,5 — d i h yd o - 2 //- p y ro 1 y 1 , an oxazolidinyl, an imidazolidinyl, a dioxazolyl, and even more particularly a 1,2,4-dioxazolyl, an oxathiazolyl, and even more particularly a 1,3,4-oxathiazolyl, an oxathiadiazolyl and a pyrrolidinyl,

(iii) a 4 or 5-membered heteroaryl group comprising 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, more particularly chosen from a triazolyl, even more particularly a 1,2,4-triazolyl, an isoxazolyl, a thiazolyl, an oxadiazolyl, even more particularly a 1,3,5- oxadiazolyl, a 1,3,4-oxadiazolyl, a 1,2,4-oxadiazolyl or a 1,2,5- oxadiazolyl, a thiadiazolyl, and even more particularly a 1,3,5- thiadiazolyl, a 1,2,4-thiadiazolyl, a 1,2,5-thiadiazolyl or a 1,3,4- thiadiazolyl, a tetrazolyl, and a pyrazolyl, said cycloalkyl, heteroaryl or heterocycloalkyl group being optionally substituted by 1 to 3 groups selected from a -OH group, an oxo group, a

=NR12’R12” group and a thiooxo group, or

(iv) a phenyl group optionally substituted by a hydroxy group, by a COOR12’ group, by a -CONH2 group, by a -NO2 group, by a -NH2 group or by a (Ci-C ₆ )alkyl group, itself optionally substituted by a hydroxy group, with R12’ and R12” independently being a hydrogen group or a (Ci-C ₆ )alkyl group, or a pharmaceutically acceptable salt thereof.

In another embodiment, in the compounds of formula (I), R3 represents a (i) 4 or 5-membered cycloalkyl, more particularly chosen from a cyclobutenyl, (ii) a 4 or 5-membered heterocylcloalkyl group comprising 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, more particularly chosen from an azetidinyl and an oxetanyl, or

(iii) a 4 or 5-membered heteroaryl group comprising 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, more particularly chosen from a tetrazolyl said cycloalkyl, heteroaryl or heterocyclo alkyl group being optionally substituted by 1 to 3 groups selected from a -OH group and an oxo group, or or a pharmaceutically acceptable salt thereof.

In another embodiment, in the compounds of formula (I), R3 represents a (Ci-C ₆ )alkyl group or a (Ci-Cejalkcnyl group, optionally substituted by 1 to 4 groups selected from a fluorine atom, a -OH group and a -COOH group, or a pharmaceutically acceptable salt thereof.

In another embodiment, in the compounds of formula (I), R3 represents a group selected from a -S0 ₂ NHC0(CH ₃ ) group, a -C0NHS0 ₂ (CH ₃ ) group, a -SO2NH2 group, a -SO(CH3)NH group, a -SO2CH3 group, a -NHS0 ₂ (CH ₃ ) group or a -NHS0 ₂ (CF ₃ ) group, or a pharmaceutically acceptable salt thereof.

In another embodiment, in the compounds of formula (I), R3 represents a halogen atom, in particular a bromine atom, a -NH2 group, or a -CN group, or a pharmaceutically acceptable salt thereof.

In another embodiment, in the compounds of formula (I), R3 represents a -O-Rll group, wherein

Rll represents a (Ci-C ₆ )alkyl group optionally substituted by one to six fluorine atoms, preferably by one to three fluorine atoms, or a pharmaceutically acceptable salt thereof.

In another embodiment, in the compounds of formula (I), R3 represents a -NH-COR9 group, wherein R9 represents a (Ci-C ₆ )alkoxy group, a (Ci-C ₆ )alkyl group or a (C3-C6)cycloalkyl group, each (Ci-C ₆ )alkyl group or (C3-C6)cycloalkyl group being optionally substituted by one to three fluorine atom(s), a -OH group or (Ci-COalkyl group, or a pharmaceutically acceptable salt thereof.

In another embodiment, in the compounds of formula (I), R3 represents a -NH-C(NH)-R9’ group, wherein

R9’ represents a (Ci-C ₆ )alkyl group or a (C3-C6)cycloalkyl group, or a pharmaceutically acceptable salt thereof.

In another embodiment, in the compounds of formula (I), R3 represents a -NHCOCOOR12 group or a -NHCOCONR12’R12” group, wherein R12 represents a (Ci-C ₆ )alkyl group, and

R12’ and R12” independently represent a hydrogen group or a (Ci-C ₆ )alkyl group, or a pharmaceutically acceptable salt thereof.

In another embodiment, in the compounds of formula (I),

Ar represents a phenyl or a pyridinyl group, in particular a 3-pyridinyl group, said phenyl or pyridinyl group being optionally substituted with one or two groups selected among chlorine, fluorine, hydroxy, methyl, trifluoromethoxy, 2-oxooxazolidine-3-yl and ethoxy,

R1 and R2 represent independently a hydrogen atom,

R3 represents

- (1) a -COR4 group, wherein R4 represent a (Ci-C ₆ )alkyl group, a -NRR’ group, a -NHNH2 group, a-NHNHCONH2 group, a -NHNHCS-imidazol-l-yl group or a -NHSO2CH3 group, and R and R’ independently represent a hydrogen atom, a -OH group, a (Ci-C ₆ )alkoxy group and a (Ci-C ₆ )alkyl group,

(2) a 4,4,5,5-tetramethyl-l,3,2-dioxaborolane-2-yl or a -B(OH)2 group,

- (3) a cyclopentenyl, • a -NH-Z group, wherein Z is a cyclobutenyl,

• a -CO-Z group, wherein Z is an azetidinyl,

• a 4 or 5-membered heterocylcloalkyl group comprising 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, more particularly chosen from an azetidinyl, a dihydropyrazolyl, a dihydroisoxazolyl, a dihydropyrrolyl and more particularly a 1,5 — d i h y d ro - 2 //- p y ro 1 y 1 , an oxazolidinyl, an imidazolidinyl, a dioxazolyl, and even more particularly a 1,2,4-dioxazolyl, an oxathiazolyl, and even more particularly a 1,3,4-oxathiazolyl, an oxathiadiazolyl and a pyrrolidinyl,

• a -CO-NH-Z group, wherein Z is an oxetanyl,

• a 4 or 5-membered heteroaryl group comprising 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, more particularly chosen from a triazolyl, even more particularly a

1.2.4-triazolyl, an isoxazolyl, a thiazolyl, an oxadiazolyl, even more particularly a 1,3,5-oxadiazolyl, a 1,3,4-oxadiazolyl, a

1.2.4-oxadiazolyl or a 1,2,5-oxadiazolyl, a thiadiazolyl, and even more particularly a 1,3,5-thiadiazolyl, a

1.2.4-thiadiazolyl, a 1,2,5-thiadiazolyl or a 1,3,4-thiadiazolyl, a tetrazolyl, and a pyrazolyl,

• a -CO-NH-Z group, wherein Z is a tetrazolyl, said cycloalkyl, heteroaryl or heterocyclo alkyl group being optionally substituted by 1 to 3 groups selected from a -OH group, an oxo group, a =NR12R12’ group and a thiooxo group, or

• a phenyl group optionally substituted by a hydroxy group, by a COOR12’ group, by a -CONH2 group, by a -NO2 group, by a -NH2 group or by a (Ci-C ₆ )alkyl group, itself optionally substituted by a hydroxy group, with R12’ and R12” independently being a hydrogen group or a (Ci-C ₆ )alkyl group, (4) a (Ci-C ₆ )alkyl group or a (Ci-C ₆ )alkenyl group, optionally substituted by 1 to 8 groups selected from a fluorine atom, a -OH group and a -COOH group,

- (5) a -CONHSO2CH3 group, a -NH-SO2CH3 group, a -NHSO2-CF3 group or a -NHSO2CH3 group,

(6) a halogen atom, a -NH2 group or a -CN group,

(7) a OCF2H group,

(8) a -NH-COR9 group, wherein R9 represents a (Ci-C ₆ )alkoxy group, a (Ci-C ₆ )alkyl group or a (C3-C6)cycloalkyl group, each (Ci-C ₆ )alkyl group or (C3-C6)cycloalkyl group being optionally substituted by one to three fluorine atom(s), a -OH group or (Ci-COalkyl group,

- (9) a -C(=NH)NHOH group,

(10) a -NH-C(NH)-R9’ group, wherein R9’ represents a (Ci-C3)alkyl group,

- (11) a -NHCOCOOR12 group or a -NHCOCONR12’R12” group, wherein

R12 represents a (Ci-C ₆ )alkyl group,

R12 and R12’ independently represent a hydrogen group or a (Ci-C ₆ )alkyl group, or a pharmaceutically acceptable salt thereof.

Among the compounds of formula (I) that are subject matter of the invention, mention may be made in particular of the following compounds:

- (S)-3-(4-(8-(2,4-dichlorophenyl)-3-(4,4,5,5-tetramethyl-l,3, 2-dioxaborolan-2- yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-l-(3-fluoro propyl)pyrrolidine (1) -(S)-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrol idin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)boronic acid (2)

-(S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (3)

-(S)-5-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)isoxazol- 3-ol (4) -l-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2-difl uoroethan-l-ol (5) -(S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydraz ide (6)

-(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- y l)oxy)phcnyl)-6,7-di hydro-5 H-bcnzo[7Jannulcn-3-yl)-l ,3, 4-oxadiazolc (7)

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

-(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- y l)oxy)phcnyl)-6,7-di hydro-5 H-bcnzo[7Jannulcn-3-yl)-l ,3, 4-thiadiazolc (9)

-l-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-tr ifluoroethan-l-ol (10)

-(S)-3-(4-(3-bromo-8-(2,4-dichlorophenyl)-6,7-drhydro-5H- benzo[7]annulen- 9-yl)phenoxy)-l-(3-fluoropropyl)pyrrolidine (11)

-(S)-5-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,2-dihy dro-3H-pyrazol-3-one (12) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-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-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl)hy drazine-l-carboxamide (14)

-(S)-8-(2,4-dichlorophe nyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3- yl)oxy)phenyl)-(methylsulfonyl)-6,7-dihydro-5H-benzo[7]annul ene-3-carboxamide (15) -(S)-5-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2H-tetra zole (16)

-(S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-N-(2H-tetrazol-5-yl)-6,7-drhydro-5H-benzo[7]a nnulene-3-carboxamide

(17)

-(S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-c arboxamide (18) -(S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- yl)oxy)phenyl)-N-methoxy-6,7-drhydro-5H-benzo[7]annulene-3-c arboxamide (19) -(S,E)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)py rrolidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y 1) acrylic acid (20)

-(S)-4-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y 1) - 1 H-pyrazole (21)

-(S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitril e (22)

-(S)-4-(9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phen yl)-8-(4- (trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-y l)-lH-pyrazole (23) -(S)-3-(4-(3-(difluoromethoxy)-8-(4-(trifluoromethoxy)phenyl )-6,7-dihydro-5H- benzo[7]annulen-9-yl)phenoxy)-l-(3-fluoropropyl)pyrrolidine (24)

-Methyl (S)-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate (25)

-(S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-c arboximidamide (26) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,2,4-ox adiazol-5(4H)-one (27) -(S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine (28)

-4-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3H-l,2,3 ,5-oxathiadiazole 2-oxide hydrochloride (29)

-(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl) pyrrolidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y l)methane sulfonamide (30)

-(S)-5-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl) pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,3,4-ox adiazol-2(3H)-one (31)

-Tert-butyl (S)-(8-(2,4-dichlorophenyl)-9-(4-((l-(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-((l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,3,4-ox athiazol-2-one (33) -(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,2,4-ox adiazole-5(4H)-thione (34) -(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-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-((l-(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-((l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,2,4-th iadiazol-5(4H)-one (37) -(S)-l-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-methox y-l,5-dihydro-2H-pyrrol- 2-one (38)

-(S)-l-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-l-o ne (39)

-(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxazolidi n-2-one (40) -(S)-3-(8-(2-chloro-4-(2-oxooxazolidin-3-yl)phenyl)-9-(4-((l -(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3- yl)oxazolidin-2-one (41)

-(S)-4-(3-amino-9-(4-((l-(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)-l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)imidazoli dine-2,4-dione (43) -(S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]ann ulene-3-carboxamide (44)

-(S)-5-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- y l)oxy)phcnyl)-6,7-di hydro-5 H-bcnzo[7Jannulcn-3-yl)-l ,3, 4-oxadiazolc-2(3H)-thionc (45) -(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetimida mide (46)

-(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-tr ifluoroacetamide (47) -(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y 1) acetamide (48)

-l-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-l-o l (49)

-(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-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-((l-(3-fluoropropyl)p yrrolidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y 1) - 1 H-pyrazole (51)

-(S)-4-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol (52)

-(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y l)phenol (53)

-(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol (54)

-(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-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-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy )phenyl)-6,7 -dihydro-5H-benzo [7 ] annulen- 3 -yl)benzoate (56)

-methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y l)benzoate (57 )

-(S)-l-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- yl)oxy )phenyl)-6,7 -dihydro-5H-benzo [7 ] annulen- 3 -yl)pyrrolidin-2-one (58) -(S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- yl)oxy)phenyl)-N'-(lH-imidazole-l-carbonothioyl)-6,7-dihydro -5H-benzo[7]annulene-3- carbohydrazide (59)

-(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)cycloprop anecarboxamide (60) -(S)-4-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-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-((l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)pivalamid e (62) -(S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl)py rrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (63)

-(S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl )pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitril e 2,2,2-trifluoroacetate (64) -l-(8-(2-chloro-3-fluorophenyl)-9-(4-(((S)-l-(3-fluoropropyl )pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-tr ifluoroethan-l-ol (65) -(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l-fluoro cyclopropane-l- carboxamide (66)

-(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l-methyl cyclopropane-l- carboxamide (67)

-(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2-hydrox ycyclopent-2-en-l-one

(68)

-(S,Z)-4-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl )pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-N,3-dime thylthiazol-2(3H)-imine hydrochloride (69)

-(S)-5-(8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropro pyl)pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2H-tetra zole 2,2,2-trifluoroacetate (70)

-tert-butyl (S)-(9-(4-((l-(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-((l-(3-fluoropropyl)p yrrolidin-3- yl)oxy )phenyl)-6,7 -dihydro-5H-benzo [7 ] annulen- 3 -yl)benzoic acid (72)

-(S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-lH-pyraz ol-5-amine (73) -(S)-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrol idin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)(3-hydrox yazetidin-l-yl)methanone (74)

-(S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-N-(oxetan-3-yl)-6,7-dihydro-5H-benzo[7]annule ne-3-carboxamide (75) -ethyl (S)-2-((8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-2- oxoacetate (76)

-(S)-Nl-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl) pyrrolidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y l)oxalamide (77 )

-(S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(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-((l-(3-fluoro propyl)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-((l-(3-fluoro propyl)pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitril e 2,2,2-trifluoroacetate (80) -(S)-4-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzamide (81)

-(S)-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanol (82)

-methyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate (83)

-(S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l-hydrox ycyclopropane-l- carboxamide formate (84)

-(S)-l-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l-(3-fluoroprop yl)pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-4-hydrox ypyrrolidin-2-one (85) -(S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid (86)

-N-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2-difl uorocyclopropane-l- carboxamide (87)

-(S)-3-((8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropr opyl)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-((l-(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-((l-(3-fluoropropyl )pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanesu lfonamide (90) -(S)-l-(3-fluoropropyl)-3-(4-(8-phenyl-3-(4,4,5,5-tetramethy l- 1,3,2- dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pheno xy)pyrrolidine (91) -(S)-(9-(4-((l-(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-((l-(3-fluoropropyl)p yrrolidin-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-((l-(3-fluoropropy l)pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)pr opan-2-ol (94)

-(S)-2-(4-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropy l)pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)pr opan-2-ol (95)

-(S)-3-(4-(8-(2-chloro-3-fluorophenyl)-3-(3-nitrophenyl)- 6,7-dihydro-5H- benzo[7]annulen-9-yl)phenoxy)- l-(3-fluoropropyl)pyrrolidine (96)

-(S)-3-(8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3-fluoropro pyl)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-((l-(3-fluorop ropyl)pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)pr opan-2-ol (98) or a pharmaceutically acceptable salt thereof.

Among the preceding listed compounds, the following compounds may particularly be cited: (2), (3), (5), (8), (10), (21), (28), (31), (42), (43), (45), (46), (49), (63), (64), (78), (80), (82), (89) and (92).

Another subject-matter of the instant invention is a compound selected from the above list, or a pharmaceutically acceptable salt thereof, for use in therapy, especially as an inhibitor and degrader of estrogen receptors.

Another subject-matter of the instant invention is a compound selected from the above list, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, especially breast cancer. Another subject-matter of the instant invention is a method of treating cancer, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof.

Another subject-matter of the instant invention is a pharmaceutical composition comprising as active principle an effective dose of a compound selected from the above list, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

In accordance with the invention, the compounds of the formula (I) can be prepared by the following processes.

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

General below methods for the preparation of compounds of the invention are optionally modified by the use of appropriate reagents and conditions for the introduction of the various moieties found in the formula (I) as described below.

The following abbreviations and empirical formulae are used:

AIBN 2,2'-azobisisobutyronitrile

CDI 1,1’ -carbonyldiimidazole

Cs ₂ C0 cesium carbonate

DBU l,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 l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

EtOH ethanol EtOAc ethyl acetate

HBTU 2-( 1 H-benzotriazol- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluoropho sphate

HC1 hydrochloric acid iPrOH isopropyl alcohol

K2CO3 potassium carbonate

L1AIH4 lithium aluminium hydride

MeCN acetonitrile

MeOH methanol

MgCh magnesium chloride

MgS0 ₄ magnesium sulfate

NaBH ₄ sodium borohydride

NaHCOs sodium bicarbonate

Na ₂ C0 ₃ sodium carbonate

NaI0 ₄ sodium periodate

NaOAc sodium acetate

NaOH sodium hydroxide

Na ₂ S0 ₄ sodium sulfate

NBS N-bromo succinimide

NH ₄ C0 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) pho sphorany lidene] pho sphorimidic triamide

Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

Pd(dppf)Cl2 1 , 1 '-Bis(diphenylphosphino)ferrocene

Pd(PPh ₃ ) ₂ Cl2 bis (triphenylphosphine) palladium(II) chloride

PIDA phenyliodine diaceteate

PTAB Phenyltrimethylammonium Perbromide

TBAF tetrabutylammonium fluoride tBuXPhos 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl TBTU 2-( lH-benzotri azole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethylaminium tetrafluorob orate

TCDI 1 , -thiocarbonyldiimidazole TEA triethylamine TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran

THPO-NH2 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine SCHEME la: Preparation of compounds of the formula (I) - General process

According to SCHEME la, in which Ar is defined as described above, compound 1A (prepared according to WO2017140669), can be converted in STEP 1 to the corresponding compound IB, by treatment with triflic anhydride, in presence of a base such as pyridine, in aprotic solvent such as DCM. This intermediate can be converted in STEP 2 to compound 1C by treatment for example with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane), and with a palladium catalyst, for example bis (triphenylphosphine) palladium(II) chloride Pd(PPh3)2Cl2, in solution in 1,4-dioxane at refluxing temperature or above in a sealed tube in a microwave apparatus, in presence of a base such as NaOAc. This compound 1C may be subjected in STEP 3 to a hydrolysis using NalCri in solution in THF and water at room temperature for example for 35 minutes to give compound ID.

Said route further allows to prepare for example the following compound:

SCHEME lb: Preparation of compounds of the formula (I) - General process

According to SCHEME lb, in which Ar is defined as described above, compound IB can be converted in STEP 1 to compound IE, by treatment in HECK conditions with tert-butyl acrylate, in the presence of a catalyst such as bis (triphenylphosphine) palladium(II) chloride, with TEA as base, in DMF, at a temperature around 120°C, for 1 hour. This compound IE can be converted in STEP 2 to compound IF in presence of an acid such as hydrochloric acid in solution in 1,4-dioxane.

SCHEME lc: Preparation of compounds of the formula (I) - General process

According to SCHEME lc, in which Ar is defined as described above, compound 1A (prepared according to WO2017140669), can be converted in STEP 1 to compound 1G, by treatment with diethyl (bromodifluoromethyl)phosphonate, in presence of potassium hydroxide, for example in a mixture of MeCN and water, at a temperature around 0°C for 1 hour. SCHEME id: Preparation of compounds of the formula (I) - General process

According to SCHEME Id, in which Ar is defined as described above, compound IB can be converted in STEP 1 to compound 1H, with 2-oxazolidone or pyrrolidinone, tBuXphos, Pd2(dba)3, sodium terbutylate, in toluene at room temperature.

SCHEME le: Preparation of compounds of the formula (I) - General process

According to SCHEME le, in which Ar is defined as described above, compound IB, can be converted in STEP 1 to compound II, with 2-oxazolidone, tBuXphos, Pd ₂ (dba) ₃ , sodium terbutylate, in toluene at 110°C.

SCHEME If: Preparation of compounds of the formula (I) - General process p

Compound 1L According to SCHEME If, in which Ar is defined as described above, compound 1J (prepared according to WO2017140669), can be converted in STEP 1 to compound IK, for example with (l-(ter-butoxycarbonyl)-lH-pyrazol-4-yl)boronic acid, Pd(dppf)Ch _, CS2CO3, for example in a mixture of 1,4-dioxane and water at 100°C in a microwave apparatus. Compound IK can be brominated in STEP 2 to compound 1L with pyridinium tribromide in THF, at room temperature. Compound 1L can be converted in STEP 3 to compound 1M in Suzuki conditions, with boronic acid derivatives, Pd(dppf)Ch _, CS2CO3, in a mixture of 1,4-dioxane and water at 100°C in a microwave apparatus.

Said procedure may be used for obtaining further compounds of formula (I) wherein R3 is a -X-Z group, wherein X is a bond, by using alternative starting materials in STEP 1, i.e. alternative boronic acid derivatives, the corresponding adaptations falling within the skills of to the man skilled in the art.

SCHEME lg: Preparation of compounds of the formula (I) - General process

STEP 1 STEP 2

OH OH 60 C, 2h ^ iTT

CC¾Me UP ¹ Compound IQ r Cornoound lR

Compound 1P COOH CONH ₂

According to SCHEME lg, in which Ar is defined as described above, compound IB (prepared according to WO2017140669), can be converted in STEP 1 to compound IN, with 3- pyrazole boronic acid in Suzuki conditions. Compound IB, can be converted in STEP 2 to compound 10, with hydroxyphenyl boronic acid in Suzuki conditions. Compound IB, can be converted in STEP 3 to compound IP, with methoxycarbonylphenyl boronic acid in Suzuki conditions. Compound IP can be converted to compound IQ in STEP 4 with NaOH in a mixture of MeOH and THF, at 60°C. Compound IQ can be converted in STEP 5 to compound 1R by treatment for example with NH4HCO3 and di-tert-butyl dicarbonate, in presence of a base such as pyridine, in solution in 1,4-dioxane at room temperature or above.

Compounds IB can be converted in STEP 6 to compound 1 S, with the corresponding boronic acid in Suzuki conditions.

SCHEME lh: Preparation of compounds of the formula (I) - General process

According to SCHEME lh, in which Ar is defined as described above, compound 1C (Scheme la), can be converted in STEP 1 to the corresponding compound IT, by treatment with 3-bromo-2-((tert-butyldimethylsilyl)oxy)cyclopent-2-en-l-one , in Suzuki conditions. This intermediate can be converted in STEP 2 to compound 1U by treatment with TB AF, in THF at room temperature.

SCHEME li: Preparation of compounds of the formula (I) - General process

STEP 1 STEP 2

According to SCHEME li, in which Ar is defined as described above, compound IB (prepared according to WO2017140669), can be converted in STEP 1 to compound IV, for example with nitro boronic acid in Suzuki conditions. Compound IV, can be converted in STEP 2 to compound 1W, for example with zinc powder and NHiCl in iPrOH at reflux.

SCHEME 2a: Preparation of compounds of the formula (I) - General process

Chiral Chiral Chiral Chsrs!

NHRa b HS Divi

Wherein -CO-NRaRb encompasses both meanings of (1) a -COR4 group, wherein R4 is as defined above and (3) a X-Z group, wherein X represents a -CO- group and Z is as defined above.

According to SCHEME 2a, in which Ar is defined as described above, compound 2 A (prepared according to WO2017140669), can be converted in STEP 1 to compound 2B, for example by treatment for example with NH4HCO3 and di-tert-butyl dicarbonate, in presence of a base such as pyridine, in solution in 1,4-dioxane at room temperature or above compound 2A can also be converted to compound 2B’ with the corresponding NHRaRb amine, in which Ra and Rb are defined as indicated above, in the presence of a coupling agent such as HBTU. Compound 2B can be converted as in STEP 2 to compound 2C, with TFA, and TEA, in DCM at room temperature for 16 hours. Compound 2C can be converted as in STEP 3 to compound 2D, with azidotrimethylsilane, in 1,4- dioxane, at 100°C for 11 hours, in a microwave apparatus.

SCHEME 2b: Preparation of compounds of the formula (I) - General process

According to SCHEME 2b, in which Ar is defined as described above, compound 2 A (prepared according to WO2017140669), can be converted in STEP 1 to compound 2E, for example by treatment with CDI, methyl potassium malonate, and MgCh in THF under reflux for 24 hours. Compound 2E can be converted in STEP 2 to compound 2F with THPO-NH2 (0-(tetrahydro-2H-pyran-2-yl)hydroxylamine), in NMP, at 120°C, for 2.5 hours in a microwave apparatus. Compounds 2F can be converted in STEP 3 to compound 2G, with concentrated HCI, in MeOH at room temperature. Compound 2E can also be converted in STEP 4 to compound 2H, with NaOH IN, in THF at 50°C. Compound 2E can likewise be converted in STEP 5 to compound 21, for example with hydrazine hydrate, in THF, at 80°C, in microwave apparatus. Compound 2E can furthermore be converted in STEP 6 to compound 2J, for example with hydroxylamine hydrochloride, in refluxing EtOH.

SCHEME 2c: Preparation of compounds of the formula (I) - General process

According to SCHEME 2c, in which Ar is defined as described above, compound 2A (prepared according to WO2017140669), can be converted in STEP 1 to the corresponding compound 2K, for example with N, O-dimethyl hydroxylamine hydrochloride, DIPEA, HBTU, in DMF, at room temperature for 4 hours. Compound 2K can be converted in STEP 2 to compound 2L, with LiAlHi, in THF at -30°C for 45 minutes. This compound 2L may be converted in STEP 3 to compound 2M, for example with (difluoromethyl)trimethylsilane, and P4-T-BU, in DMF at room temperature for 45 minutes. Compound 2K can be converted in STEP 4 to compound 2H, for example with a Grignard reagent, such as methylmagnesium bromide, in THF at 0°C. Compound 2L can also be converted in STEP 5 to compound 2N, for example with NH4CO3 and potassium cyanide in THF and water at 70°C. Compound 2L can likewise be converted in STEP 6 to compound 20, for example with deoxofluor (bis(2-methoxyethyl)aminosulfur trifluoride), in DCM, at room temperature for 24 hours. Compound 2L can furthermore be converted in STEP 7 to compound 2P, for example with trifluoromethyl trimethylsilane, and cesium fluoride in THF at room temperature.

SCHEME 2d: Preparation of compounds of the formula (I) - General process

According to SCHEME 2d, in which Ar is defined as described above, compound 2Q can be obtained in STEP 1 from compound 2A (prepared according to WO20 17140669), for example with DPA, in refluxing tert-butanol, for 16 hours. Compound 2Q can also be obtained from compound IB in STEP 2, for example with tert-butyl carbamate, potassium tert-butoxide, tBuXPhos, Pd2(dba)3, in refluxing toluene. Compound 2Q can be converted in STEP 3 to compound 2R, for example in acidic conditions such as TFA, in DCM at room temperature. Compound 2R can also be obtained from compound 2B in STEP 4, reacting first with PIDA, 2-(trimethylsilyl)ethanol, in DCM at 35°C, then with TBAF, and potassium fluoride in MeCN, at 55°C. Compound 2B can also be converted in STEP 5 to compound 2S, for example with DBU, NBS, in a mixture of solvents such as MeOH, and DCM at room temperature. Compound 2S can be converted in STEP 6 to compound 2R, for example with potassium hydroxide in refluxing MeOH.

SCHEME 2e: Preparation of compounds of the formula (I) - General process

Wherein the -NH-COY group encompasses both meanings of (3) a X-Z group, wherein X represents a -NHCO and Z is as defined above and (8) a -NH-COR9 group, wherein R9 is as defined above.

According to SCHEME 2e, in which Ar is defined as described above, compound 2R can be converted in STEP 1 to compound 2T, for example with trifluoromethane sulfonic anhydride, in the presence of TEA, in DCM at room temperature. Compound 2R can be converted in STEP 2 to compound 2U, for example with sulfonic chloride, in the presence of TEA, in DCM at room temperature. Compound 2R can be converted in STEP 3 to compound 2V, for example with squaric acid, in DMF, at 130°C in microwave apparatus. Compound 2R can be converted in STEP 4 to compound 2W, for example with methyl acetimidate hydrochloride, in the presence of TEA, in MeCN at room temperature. Compound 2R can be converted in STEP 5 to compound 2X, with for example an alcoyl chloride where Z and R9 are defined as described above, in the presence of TEA, in DCM at room temperature, or with a carboxylic acid where Z and R9 are defined as described above in presence of a coupling agent such as HATU, or ED AC in presence of a tertiary amine in DMF. Compound 2R can be converted in STEP 6 to compound 2Y, for example with trifluoracetic anhydride, in the presence of TEA, in THF at room temperature.

SCHEME 2f: Preparation of compounds of the formula (I) - General process

According to SCHEME 2f, in which Ar is defined as described above, compound 2C can be converted in STEP 1 to compound 2Z, with hydroxylamine hydrochloride, in EtOH at 80°C. Compound 2Z can be converted in STEP 2 to compound 2AA, with DBU, and CDI, at refluxing 1,4-dioxane. Compound 2Z can be converted in STEP 3 to compound 2AB, treating first with DBU, and TCDI , in THF at room temperature, then adding boron trifluoride-diethyl etherate. Compound 2Z can be converted in STEP 4 to compound 2AC, treating with DBU, and TCDI , in refluxing MeCN. Compound 2Z can be converted in STEP 5 to compound 2AD, treating with thionyl chloride, in presence of pyridine, in THF at room temperature. SCHEME 2g: Preparation of compounds of the formula (I) - General process

According to SCHEME 2g, in which Ar is defined as described above, compound 2A (prepared according to WO2017140669), can be converted in STEP 1 to compound 2AE, with tert-Butyl carbazate, TBTU, and DIPEA in MeCN at room temperature. Compound 2AE can be converted in STEP 2 to compound 2AF, with Lawesson’ reagent in 1,4-dioxane, at 110°C, in a microwave apparatus. Compound 2AF can be converted in STEP 3 to compound 2AG, with hydrochloric acid 4N in 1,4-dioxane, at room temperature. Compound 2AG can be converted in STEP 4 to compound 2AH, with triethyl orthoformate, at 100°C, in a microwave apparatus.

SCHEME 2h: Preparation of compounds of the formula (I) - General process

According to SCHEME 2h, in which Ar is defined as described above, compound 2A (prepared according to WO2017140669), can be converted in STEP 1 to compound 2AI, reacting first 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 in STEP 2 to compound 2AJ, with O-methylhydroxylamine hydrochloride, HATU, and DIPEA in DMF, at room temperature. Compound 2A can be converted in STEP 3 to compound 2AK, with DMAP and EDCI in DCM, at room temperature. Compound 2A can be converted in STEP 4 to compound 2AL, with amino tetrazole, HATU, and DMAP in DMF, at room temperature.

SCHEME 2i: Preparation of compounds of the formula (I) - General process Reflux, 3H

Compound 2A Compound 2AM —0 Compound 2A

According to SCHEME 2i, in which Ar is defined as described above, compound 2A (prepared according to WO2017140669), can be converted in STEP 1 to compound 2AM, using Barton’s conditions, reacting first with thionyl chloride at room temperature for 3 hours, followed by 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 in STEP 2 to compound 2AN, in Ullmann’s condition with 4-methoxy-3-pyrrolin-2-one, potassium phosphate, copper iodide, N,N’ -dimethyl ethylene diamine, in a mixture of 1,4-dioxane, and DMF, at 110°C in a microwave apparatus.

SCHEME 2i : Preparation of compounds of the formula (I) - General process

According to SCHEME 2j, in which Ar is defined as described above, compound 2B can be converted in STEP 1 to compound 2AO with chlorocarbonylsulfenyl chloride, in refluxing toluene.

SCHEME 2k: Preparation of compounds of the formula (I) - General process a ΐ CHsMgBr Ar pfT·.. /y

Ethanol

OH RT, 2 h 0 THF

Compound 2H RT. 16 h +LA4

Compound 2AP OH Compound 2AQ

2} Thiourea MeOH Rei!ux, 4 h

Y'N-

F /

1 Ar

H ₂ ^i

S C ^W ompound 2AR

According to SCHEME 2k, in which Ar is defined as described above, compound 2H (Scheme 2c), can be converted in STEP 1 to the corresponding compound 2AP with NaBH4, in EtOH, at room temperature. Compound 2H (Scheme 2c), can be converted in STEP 2 to the corresponding compound 2AQ with MeMgBr, in THF, at room temperature. Compound 2H (Scheme 2c), can be converted in STEP 3 to the corresponding compound 2AR treating first with PTAB, in THF, at room temperature, and followed by reacting with thiourea in refluxing MeOH.

SCHEME 21: Preparation of compounds of the formula (I) - General process

Compound 2R RT, 16 h O H Compound 2AS 0 H Comoound 2AT

According to SCHEME 21, in which Ar is defined as described above, compound 2R (Scheme 2d), can be converted in STEP 1 to the corresponding compound 2AS with ethyloxalyl chloride, and TEA in DCM, at room temperature compound 2AS, can be converted in STEP 2 to the corresponding compound 2AT with ammonia, in MeOH, at room temperature.

SCHEME 2m: Preparation of compounds of the formula (I) - General process

According to SCHEME 2m, in which Ar is defined as described above, compound 2H (Scheme 2c), can be converted in STEP 1 to the corresponding compound 2AEG treating first with benzyltrimethylammonium dichloroiodate, in refluxing DCM for 16 hours, then with N,N'- dimethylthiourea in refluxing EtOH for 3 hours.

SCHEME 2n: Preparation of compounds of the formula (I) - General process

Reflux, 16 h

According to SCHEME 2n, in which Ar is defined as described above, compound 2AM (Scheme 2i), can be converted in STEP 1 to compound 2AV, using (S)-4- hydroxy-2-pyrrolidinone, (lR,2R)-N,N'-dimethyl-l,2-cyclohexanediamine, cuprous iodide, potassium carbonate in refluxing toluene for 16 hours.

SCHEME 3a: Preparation of compounds of the formula (I) - General process

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

SCHEME 3b: Preparation of compounds of the formula (I) - General process

According to SCHEME 3b, in which Ar is defined as described above, compound 3 A can be converted in STEP 1 to compound 3G with MeCN and sodium hydride, in DMSO at room temperature. Compound 3G can be converted to compound 3H with hydrazine hydrate in EtOH at reflux.

SCHEME 4: Preparation of compounds of the formula (I) - General process According to SCHEME 4, in which Ar is defined as described above, compound

4A can be converted in STEP 1 to the corresponding compound 4B with l-(tert- butyldimethylsilyloxy)-l-methoxyethene in presence of zinc chloride and Pd(dib)2/P(t- Bu)3, in DMF at 135°C for 3 hours in a microwave apparatus. Compound 4B can be converted to compound 4C with triflic anahydride and pyridiine in DCM at room temperature. Compound 4C can be converted to compound 4E with compound 4D (prepared according to WO2017140669), in Suzuki conditions. Compound 4E can be converted to compound 4F with pyridinium tribromide in DCM at room temperature. Compound 4F can be converted to compound 4G with an arylboronic acid in Suzuki conditions. Compound 4G can be converted to compound 4H with NaOH in MeOH under reflux.

The examples with numbers indicated in bold in Table 1 are further detailed hereafter.

The

Spectra at 400 and 500 MHz were performed on a Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometer, respectively, with the chemical shifts (d in ppm) in the solvent dimethyl sulfoxide-d6 (d6-DMSO) referenced at 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.

The liquid chromatography /mass spectra (LC/MS) were obtained on a UPLC Acquity Waters instrument, light scattering detector Sedere and SQD Waters mass spectrometer using UV detection DAD 210<1<400 nm and column Acquity UPLC CSH C18 1.7 pm, dimension 2.1x30 mm, mobile phase H ₂ O + 0,1% HCO ₂ H/CH ₃ CN + 0,1% HCO ₂ H.

Table 1:

The examples which follow describe the preparation of some compounds in accordance with the invention. The numbers of the compounds exemplified below match those given in the Table 1 above. All reactions are performed under inert atmosphere, unless otherwise stated.

In the following examples, when the source of the starting products is not specified, it should be understood that said products are known compounds.

Examples:

Example 1. (S)-3-(4-(8-(2,4-dichlorophenyl)-3-(4,4,5,5-tetramethyl-l,3, 2-dioxaborolan-2- yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-l-(3-fluoro propyl)pyrrolidine

Step 1: (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3-l)oxy)phen yl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate.

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol [WO2017140669] (141 mg, 267.82 pmol), in DCM (2 ml) and pyridine (35 pi, 429 pmol) was added trifluoromethanesulfonic anhydride ( 96 mΐ, 568 mhioΐ). The reaction mixture was stirred at room temperature for 15 minutes. Cold water (5 ml) and DCM (10 ml) was added. After decantation, the organic phase was dried over MgSCri, filtered and evaporated under reduced pressure to give 203 mg of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3-l)oxy)phenyl)-6,7- dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate.

LC/MS (m/z, MH+): 558 Step 2: (S)-3-(4-(8-(2,4-dichlorophenyl)-3-(4,4,5,5-tetramethyl-l,3, 2-dioxaborolan-2-yl)- 6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-l-(3-fluoroprop yl)pyrrolidine

A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- l)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (89 mg, 81 mg, 216.59 pmol), bis(triphenylphosphine)palladium(II)chloride (7 mg, 10 pmol) and sodium acetate (45 mg, 543 pmol) was microwaved at 130°C for 5 hours. Water (5 ml) and DCM (10 ml) was added. After hydrophobe 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-l,3, 2-dioxaborolan-2-yl)-6,7- dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-l-(3-fluoropropyl)p yrrolidine.

Example 2. (S)-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)boronic acid

A mixture of tert-butyl (S)-3-(4-(8-(2,4-dichlorophenyl)-3-(4,4,5,5-tetramethyl-l,3, 2- dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pheno xy)-l-(3- fluoropropyl)pyrrolidine [Example 1] (159 mg, 250 pmol), in THF (1.6 ml), water (0.4 ml) and NaI0 ₄ ( 160 mg, 749 mihoΐ) was stirred at room temperature for 35 minutes. Hydrochloric acid 1M (0.17 ml, 170 m mol) was added. The reaction mixture was stirred at room temperature for 3 hours. Water (10 ml) and DCM (10 ml) was added. After hydrophobe 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-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H- benzo [7 ] annulen- 3 -y l)boronic acid .

Example 3. (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide

A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (511 mg, 921.58 pmol), pyridine (0.05 ml, 594.68 pmol), di-tert-butyl dicarbonate (105 mg, 460.79 pmol) and NH ₄ HC0 ₃ (112 mg, 1.38 mmol) in 1,4-dioxane (2.5 ml) was stirred at

40°C for 5 hours and room temperature for 18 hours. Water (10 ml) and DCM (10 ml) was added. After hydrophobe 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 236 mg (46%) of (S)-8-(2,4- dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H- benzo[7]annulene-3-carboxamide.

Example 4. (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)isoxazol- 3-ol

Step 1: Methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopro panoate To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (300 mg, 541.04 pmol), in THF (10 ml), was added CDI (164.50 mg, 811.57 pmol), and the reaction mixture was heated at reflux for 3 hours. 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 hours. The solvent was evaporated under reduced pressure and the residue partitioned between EtOAc and water, the organic phase was washed with water, dried over MgSC , 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 0.56g (85%) methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopro panoate.

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

Step 2: 3-(8-(2,4-Dichlorophenyl)-9-(4-(((S)-l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxo-N- ((tetrahydro-2H-pyran-2- yl)oxy )propanamide .

A mixture of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopro panoate (100 mg, 163.79 pmol), o-(tetrahydro-2h-pyran-2-yl)hydroxylamine (60.59 mg, 491.36 pmol) and 4- dimethylaminopyridine (54 mg, 442.23 pmol) in l-methyl-2-pyrrolidinone (2 ml) was microwaved at 120°C for 2 hours. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over MgS0 ₄ , filtered and evaporate 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 42 mg (37%) of 3-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)-3-oxo-N- ((tetrahydro-2H-pyran-2-yl)oxy)propan amide.

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

Step 3: (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)isoxazol- 3-ol

To a solution of 3-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l-(3-fluoropropyl)pyrro lidin-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 pmol) in MeOH (2 ml), was added cone. HC1 (0.5 ml, 6.25 mmol), and the reaction mixture was stirred at room temperature for 40 minutes.

Saturated NaHCC solution and EtOAc was added and the organic phase washed with water, dried over MgSCE, 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 21 mg (59%) of (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)isoxazol-

3-ol.

Example 5. l-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2-difl uoroethan-l-ol

Step 1: (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3-yl)oxy)phenyl)- 6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde

To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]ann ulene-3-carboxamide [Example 44] (3.3g, 5.52 mmol) in THF (150 ml) cooled at -40°C, was added dropwise L1AIH4 (4.14 ml, 8.28 mmol). The reaction mixture was stirred for 30 minutes at -30°C, and quenched with water (4 ml), NaOH 5N (4 ml) and again water (12 ml). The precipitate formed was filtered, washed with EtOAc and then, the organic layer was washed with brine. The organic phase was dried over MgSCU, 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-((l-(3- fluoropropy l)pyrrolidin- 3 -y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulene- 3 - carbaldehyde LC/MS (m/z, MH ⁺ ): 538.

Step 2: l-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2-difl uoroethan-l-ol

To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyd e (100 mg, 185.71 pmol) in DMF (3 ml), was added (difluoromethyl)trimethylsilane (34.60 mg, 278.56 pmol) and phosphazene base P4-t-Bu 0.8M in hexane (46.43 pi, 37.14 pmol). The reaction mixture was stirred for 1 hour at room temperature. Then, water (2 ml) was added followed by a solution of HC15N to reach pH 2. The reaction mixture was stirred for 1 hour at room temperature. Water (5 ml) was added followed by a saturated aqueous solution of K2CO3 to reach pH 10. The mixture was extracted twice with EtOAc and the organic layers were gathered and washed with brine. The organic phase was dried over MgSCF, 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 l-(8-(2,4-dichlorophen yl)-9-(4-(((S)-l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl) -6,7-dihydro-5H-benzo [7]annulen-3-yl)-2,2-difluoroethan-l-ol.

Example 6. (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydraz ide

To a solution of methyl (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-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 pi, 14.93 mmol). The reaction mixture was heated at reflux for 16 hours, and partitioned between EtOAc and water. The organic phase was washed with water and brine, dried over MgS0 ₄ , 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-((l-(3-fluoropropyl)pyrrolidin-3-y l)oxy)phenyl)-6, 7-dihydro- 5H-benzo [7] annulene-3 -carbohydrazide .

Example 7. (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,3,4-ox adiazole

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydraz ide [Example 6] (160 mg, 281.44 pmol) in acetic acid (1 ml), was added triethyl orthoformate (1 ml, 5.83 mmol). 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 127 mg (78%) of (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)- 1,3,4- oxadiazole.

Example 8. (S)-3-(4-(8-(2,4-dichlorophenyl)-3-(difluoromethyl)-6,7-dihy dro-5H- benzo[7]annulen-9-yl)phenoxy)-l-(3-fluoropropyl)pyrrolidine

To a mixture of ((S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyd e [Example 5, Step 1] (300 mg, 557.12 pmol) 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 for 72 hours at room temperature. Water was added and the mixture was extracted with DCM. The organic layer was washed with brine. The organic phase was dried over MgSC , 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]ann ulen-9-yl)phenoxy)-l-(3- fluoropropyl)pyrrolidine

Example 9. (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,3,4-th iadiazole

Step 1: Tert-butyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl)hy drazine-l-carboxylate To a suspension of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (400 mg, 721.39 pmol) in MeCN (10 ml) was added DIPEA (377,99 pi, 2.16 mmol), tert- butyl carbazate (129 mg, 937.81 pmol), and TBTU (354.53 mg, 1.08 mmol). The reaction mixture was stirred at room temperature for 3 hours, partitioned between water and EtOAc, and the organic phase washed with water, dried over MgSCC, 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-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H- benzo[7]annulene-3-carbonyl)hydrazine-l-carboxylate. LC/MS (m/z, MH+): 668

Step 2: Tert-butyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonothio yl)hydrazine-l- carboxylate

To a solution of tert-butyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulene-3- carbonyl)hydrazine-l-carboxylate (100 mg, 149.56 pmol) in 1,4-dioxane (1.5 ml), was added lawesson's reagent (62 mg, 149.56 pmol), and the reaction mixture was microwaved at 100°C for 10 minutes. The reaction mixture was partitioned between water and EtOAc, and the organic phase washed with water, brine, dried over MgSCL, 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-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H- benzo [7] annulene-3 -carbonothioyl)hydrazine- 1 -carboxylate LC/MS (m/z, MH+): 684

Step 3: (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3-yl)oxy)phenyl)- 6,7-dihydro-5H-benzo[7]annulene-3-carbothiohydrazide

A mixture of tert-butyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin- 3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonoth ioyl)hydrazine-l- carboxylate (225 mg, 328.61 pmol), and HC1 4N in 1,4-dioxane (lml, 4.00 mmol), was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure to give 150 mg (78%) of crude (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3- fluoropropy l)pyrrolidin- 3 -y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulene- 3 - carbothiohydrazide.

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

Step 4: (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,3,4-ox adiazole

A suspension of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbothiohy drazide (150 mg, 256.59 pmol) in triethyl orthoformate (1.5 ml), was microwaved at 100°C for 10 minutes. The reaction mixture was partitioned between water and EtOAc, and the organic phase washed with water, brine, dried over MgSCE, 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)- 1,3,4- oxadiazole.

Example 10. l-(8-(2,4-dichlorophenyl)-9-(4-(((S)- l-(3-fluoropropyl)pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-tr ifluoroethan-l-ol

To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyd e [Example 5, Step 1] (160 mg, 297.13 pmol) in THF (5 ml), was added (trifluoromethyl)trimethylsilane (58pl, 0.392 mmol) and cesium fluoride (22 mg, 0.145 mmol). The reaction mixture was stirred for 1 hour at room temperature. Then, water (2 ml) was added followed by a solution of HC1 5N to reach pH 2. The reaction mixture was stirred for 1 hour at room temperature. Water (5 ml) was added followed by a saturated aqueous solution of K2CO3 to reach pH 10. The mixture was extracted twice with EtOAc and the organic layers were collected and washed with brine. The organic phase was dried over MgSCU, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography with a gradient of MeOH in DCM (100/0 to 95/05, v/v) to give 44 mg (25%) of l-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l- (3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-b enzo [7]annulen-3-yl)-2,2,2- trifluoroethan-l-ol.

Example 11. (S)-3-(4-(3-bromo-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benz o[7]annulen- 9-yl)phenoxy)-l-(3-fluoropropyl)pyrrolidine Step 1: (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3-yl)oxy)phenyl)- 6,7-dihydro-5H-benzo[7]annulene-3-carbonyl chloride

To (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3-yl)oxy)phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (300 mg, 541 pmol) was added thionyl chloride (3mL) at 0°C under an inert atmosphere, the reaction mixture was stirred at room temperature for 3h. The thionyl chloride was evaporated under reduced pressure to afford 308 mg (99.4%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3- fluoropropy l)pyrrolidin- 3 -y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulene- 3 -c arbony 1 chloride which was engaged in the next step without further purification. Step 2: (S)-3-(4-bromo-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7 ]annulen-9- yl)phenoxy)- 1 -(3-fluoropropyl)pyrrolidine

To a suspension of 2-mercaptopyridine N-oxide sodium salt (136 mg, 876 mhioΐ) in refluxing bromotrichloromethane (5 mL) at 105°C, was added dropwise (5 min) a solution of (S)-8- (2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-y l)oxy)phenyl)-6, 7-dihydro-

5H-benzo[7]annulene-3-carbonyl chloride (308 mg, 537 mhioΐ) and AIBN (22.5 mg, 134 mhioΐ) in bromotrichloromethane (8 mL) under an inert atmosphere. After heating for 3 hours 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)-l-(3- fluoropropy l)pyrrolidine .

Example 12. (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,2-dihy dro-3H-pyrazol-3-one

A solution of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopro panoate [ Example 4, Step 1] (117 mg, 191.63 mihoΐ), in EtOH (10 ml), THF (1 ml), and hydrazine hydrate (12 mg, 191.63 mhioΐ) was microwaved at 80°C for 20 minutes. The reaction mixture was partitioned between water and EtOAc, and the organic phase washed with water, brine, dried over MgSCE, 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 19 mg (16%) of (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,2-dihy dro-3H-pyrazol-3-one.

Example 13. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)isoxazol- 5(4H)-one

A mixture of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopro panoate oxopropanoate [Example 4, stepl] (80 mg, 131.03 pmol), in EtOH (4 ml), hydroxylamine hydrochloride (23.47 mg, 327.57 pmol) and NaHC03 (22 mg, 262.06 pmol), was heated under reflux for

3 hours. The reaction mixture was partitioned between water and EtOAc, and the organic phase was washed with water, brine, dried over MgS0 ₄ , 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-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihyd ro-5H-benzo[7]annulen-3- yl)isoxazol-5(4H)-one.

Example 14. (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl)hy drazine-l-carboxamide

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydraz ide [Example 6] (200 mg, 351.79 pmol) in chloroform (10 ml), was added acetic acid (20.74 pi, 351.79 pmol), and sodium cyanate (35.36 mg, 529.69 pmol). The reaction mixture was heated at 50°C for 24 hours, and the solvent removed under reduced pressure. The residue was partitioned between DCM and water, the organic phase was washed with water and brine, dried over MgSCC, 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-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl)hy drazine-l-carboxamide.

Example 15. (S)-8-(2,4-dichlorophe nyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3- yl)oxy)phenyl)-(methylsulfonyl)-6,7-dihydro-5H-benzo[7]annul ene-3-carboxamide.

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl]oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (150 mg, 270 pmol) in DCM (10 ml), was added l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (108 mg, 541 pmol), 4-dimethylaminopyridine (68.85 mg, 541 pmol), and methanesulfonamide (53 mg, 541 pmol). The reaction mixture was stirred at room temperature for 16 hours, and partitioned between DCM and water. The organic phase was washed with water and brine, dried over MgSCC, 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-dichlorophe nyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-(methylsulfonyl)-6, 7-dihydro-5H- benzo[7]annulene-3-carboxamide.

Example 16. (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2H-tetra zole

A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitril e [Example 22] (43 mg, 66 pmol), dibutyltin oxide (5 mg, 20.47 pmol) and azidotrimethylsilane (36 pi, 260 pmol) in 1,4-dioxane (0.6 ml) was microwaved at 100°C for 6 hours. After cooling and LCMS control, addition of dibutyltin oxide (5 mg, 20.47 pmol) and azidotrimethylsilane (36 pi, 260 pmol) and the mixture was microwaved for additional 5 hours at 100°C. After cooling, water (5 ml) and DCM (10 ml) was added. After hydrophobe column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by Supercritical fluid chromatography (SFC) method, phase: 2-Ethylpyridine (Princeton), 5pm, 250x30 mm; eluent : C0265% / MeOH (+0.1% TEA) 35% during 3 min, then C0260% / MeOH (+0.1% TEA) 40%; flow : 120 ml/min; Pinlet : 160 bars; Poutlet : 100 bars ; Temp oven : 40°C ; l=254 nm to give 20 mg (53%) of (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)-2H- tetrazole.

Example 17. (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-N-(2H-tetrazol-5-yl)-6,7-dihydro-5H-benzo[7]a nnulene-3-carboxamide.

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl]oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (150 mg, 270 pmol) in DMF (15 ml), was added (l-[bis(dimethylamino) methylene] -1H- l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 114.29 mg, 5297.57 pmol), 4-dimethylaminopyridine (1.72 mg, 13.53 pmol), TEA (112.1 pi, 811.57 pmol), and amino tetrazole (23 mg, 270.52 pmol). The reaction mixture was stirred at room temperature for 16 hours, and partitioned between DCM and water. The organic phase was washed with water and brine, dried over MgSCC, 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-(2H-tetrazol-5-yl )-6,7-dihydro-5H- benzo[7]annulene-3-carboxamide. Example 18. (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-c arboxamide

Step 1: (S)-N-(benzyloxy)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluorop ropyl)pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide

To a solution of (R)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (277 mg, 500 pmol) in DMF (6 ml) was added O-benzylhydroxylamine ( 96 mg, 90.94 pmol), HATU (333 mg, 850 pmol) and DIPEA (464 pi, 2.5 mmol). The reaction mixture was stirred at room temperature for 4 hours. Cold water (25 ml) and a mixture of DCM / MeOH 80/20 (30 ml) was added. After decantation, the organic phase was dried over MgSCC, filtered and 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-((l-(3-fluorop ropyl)pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide .

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

Step 2: (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3-yl)oxy)phenyl)- N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide

In an autoclave, a mixture of (S)-N-(benzyloxy)-8-(2,4-dichlorophenyl)-9-(4-((l-(3- fluoropropy l)pyrrolidin- 3 -y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulene- 3 - carboxamide (150 mg, 227 pmol) and Pd/C 10% (15 mg) in MeOH (6 ml) was hydrogenated (H2, 2 bars) for 2,5 hours at 20°C. 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-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-N-hydroxy-6,7- dihydro-5H-benzo[7]annulene-3-carboxamide.

Example 19. (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-N-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-c arboxamide

To a solution of (R)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (110 mg, 198 pmol) in DMF (2.5 ml) was added O-methylhydroxylamine hydrochloride ( 25 mg, 297 pmol), HATU (132 mg, 337 pmol) and DIPEA (184 pi, 992 pmol). The reaction mixture was stirred at room temperature for 4 hours. Cold water (25 ml) and a mixture of DCM / MeOH 80/20 (30 ml) was added. After decantation, the organic phase was dried over MgSCri, filtered and 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 63 mg (54%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3-yl)oxy)phenyl)-N- methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide.

Example 20. (S,E)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y 1) acrylic acid

Step 1: Tert-butyl (S,E)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y 1) acrylate

A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- l)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, stepl] (203 mg, 308 pmol), DMF (3 ml), ter-butyl acrylate (305 pi, 308 pmol), bis(triphenylphosphine)palladium(II)chloride (48 mg, 68 pmol) and TEA (382 pi, 308 pmol) was microwaved at 120°C for 1 hour. Water (5 ml) and EtOAc (10 ml) was added. After decantation, the organic phase was dried over MgSCE, filtered and 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- ((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro- 5H-benzo[7]annulen-3- yl)acrylate .

Step 2. (S,E)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y 1) acrylic acid

A mixture of tert-butyl (S,E)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)acrylate (83 mg, 130 pmol) 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 treated on SCX (strong cation exchange) column to give 39 mg (52%) of (S,E)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3-yl)oxy)phenyl)-6,7- dihy dro- 5H-benzo [7 ] annulen- 3 -yl) acrylic acid . Example 21. (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y 1) - 1 H-pyrazole

Step 1: (S)-4-(9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)- 6, 7-dihydro -5H-benzo [7 ] annulen- 3 -y 1) - 1 H-pyrazole

A mixture of (S)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7 -dihydro-5H- benzo[7]annulen-3-yl trifluoromethanesulfonate [WO2017140669] (500 mg, 973 pmol), 1,4-dioxane (12 ml), water (2 ml), CS2CO3 (666 mg, 2.04 mmol) and (l-(ter- butoxycarbonyl)-lH-pyrazol-4-yl)boronic acid (207 mg, 974 pmol), and Pd(dppf)Cl2 (43 mg, 58.42 pmol), was microwaved at 100°C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue, addition of DCM (50 ml) and water (50 ml). After decantation, the organic phase was dried over MgSC , filtered and 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-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)- 6,7-dihydro-5H- benzo [7 ] annulen- 3 -y 1)- 1 H-pyrazole .

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

Step 2: (S)-4-(8-bromo-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy) phenyl)-6, 7-dihydro- 5H-benzo [7] annulen-3 -yl)- 1 H-pyrazole

A mixture of (S)-4-(9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)- 6,7-dihydro-5H- benzo[7]annulen-3-yl)-lH-pyrazole (170 mg, 394 pmol), THF (15 ml) and pyridinium bromide perbromide (133 mg, 414 pmol) was stirred at room temperature for 2 hours. Water (20 ml) and DCM (100 ml) was added, followed by a saturated solution of NaHCC to reach pH 7. After decantation, the organic phase was dried over MgSCC, filtered and evaporated under reduced pressure to give 160 mg (80%) of (S)-4-(8-bromo-9-(4-((l-(3- fluoropropy l)pyrrolidin- 3 -l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y 1) - 1 H- pyrazole. LC/MS (m/z, MH+): 510

Step 3: (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y 1) - 1 H-pyrazole A mixture of (S)-4-(8-bromo-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy) phenyl)-6,7- dihydro-5H-benzo[7]annulen-3-yl)-lH-pyrazole (90 mg, 176 pmol), 1,4-dioxane (8 ml), Pd(dppf)C12 (9 mg, 11 pmol), water (1.5 ml), CS2CO3 (121 mg, 370 pmol) and (2,4- dichlorophenyl)boronic acid (37 mg, 194 pmol) was microwaved at 100°C for 50 minutes. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue partitioned between DCM (50 ml) and water (50 ml). After decantation, the organic phase was dried over MgSCU, filtered and 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)-lH- pyrazole.

Example 22. (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitril e

To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 3] (100 mg, 180.67 pmol) in THF (1 ml) cooled at 0°C, was added TEA (33 pi, 235 pmol) and TFAA (28 mΐ, 199 mmol). The reaction mixture was stirred for 15 minutes at 0°C and 45 minutes at room temperature. NH4CI solution (5 ml) and DCM (10 ml) was added. After hydrophobe 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulene-3-carbonitrile as trifluoroacetate salt.

Example 23. (S)-4-(9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)- 8-(4- (trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-y l)-lH-pyrazole

A mixture of tert-butyl (S)-4-(8-bromo-9-(4-((l-(3-fluoropropyl)pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-lH-pyraz ole [Example 21, step 2] (160 mg, 285 pmol) 1,4-dioxane (8 ml), Pd(dppf)C12 (14 mg, 17 pmol), water (1.5 ml), CS2CO3 (195 mg, 599 pmol) and (4-trifluoromethoxy)phenyl)boronic acid (65 mg, 314 mihoΐ) was microwaved at 100°C for 50 minutes. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue, addition of DCM (50 ml) and water (50 ml). After decantation, the organic phase was dried over MgSC , filtered and 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-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)- 8-(4- (trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-y l)-lH-pyrazole.

Example 24. (S)-3-(4-(3-(difluoromethoxy)-8-(4-(trifluoromethoxy)phenyl) -6, 7-dihydro- 5H-benzo[7]annulen-9-yl)phenoxy)-l-(3-fluoropropyl)pyrrolidi ne

To a solution of (S)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-( 4- (trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-o l [WO2017140669] (100 mg, 184.64 pmol) in MeCN (1.5 ml) cooled at 0°C, was added, KOH (122 mg, 1.85 mmol) in solution in water (0,5 ml) and diethyl (bromodifluoromethyl)phosphonate (54 mΐ, 295 mhioΐ). The reaction mixture was stirred at 0°C for 2 hours. Addition of water (10 ml) and DCM (25 ml). After hydrophobe 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-y l)phenoxy)-l-(3- fluoropropy l)pyrrolidine .

Example 25. Methyl (S)-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 3] (200 mg, 361.34 pmol) in DCM (5 ml), and MeOH (5 ml), at -78°C, was added 1,8- diazabicycloundec-7-ene (170.65 pi, 1.08 mmol), and N-bromosuccinimide (65.63 mg, 361.34 pmol). The reaction mixture was allowed to reach room temperature overnight, and the solvent removed under reduced pressure. The residue was partitioned between DCM and water, the organic phase was washed with water and brine, dried over MgSCU, 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-((l-(3-fluoropropyl)pyrrolidin-3-y l)oxy)phenyl)-6, 7-dihydro- 5H-benzo[7]annulen-3-yl)carbamate.

Example 26. (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-c arboximidamide

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitril e [Example 22] (526 mg, 809.84 pmol) 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 hours, and the solvent removed under reduced pressure to give 344 mg (74.7%) of (S)-8- (2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-y l)oxy)phenyl)-N-hydroxy-6,7- dihydro-5H-benzo[7]annulene-3-carboximidamide. Example 27. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,2,4-ox adiazol-5(4H)-one. To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-c arboximidamide [Example 26] (175 mg, 307.82 pmol) in 1,4-dioxane (5 ml), was added 1,8- diazabicycloundec-7-ene (53.30 pi, 338.60 pmol), and CDI (76.40 mg, 461.73 pmol). The reaction mixture was heated at reflux for 1 hour, and the solvent removed under reduced pressure. The residue was partitioned between DCM and water, the organic phase was washed with water and brine, dried over MgSCU, 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-((l- (3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-b enzo[7]annulen-3-yl)- 1,2,4- oxadiazol-5(4H)-one.

Example 28. (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -amine To a solution of (S)-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate [Example 25] (70 mg, 119.96 pmol) in MeOH (5 ml), was added potassium hydroxide solution 7N 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, dried over MgSC , 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-((l-(3-fluoropropyl)pyrrolidin-3-y l)oxy)phenyl)-6, 7-dihydro- 5H-benzo[7]annulen-3-amine.

Example 29. 4-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3H-l,2,3 ,5-oxathiadiazole 2-oxide hydrochloride.

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-c arboximidamide [Example 26] (1.2 g, 2.11 mmol) in THF (5 ml), was added at 0°C, pyridine (343.49 pi, 4.22 mmol), and thionyl chloride (230 mΐ, 3.17 mmol) in solution in DCM (1 ml). The reaction mixture was stirred at room temperature overnight, and the solvent removed under reduced pressure. The residue was partitioned between DCM and water, the organic phase was washed with water and brine, dried over MgSCC, 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-((l- (3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-b enzo[7]annulen-3-yl)- 1,2,4- oxadiazol-5(4H)-one hydrochloride.

Example 30. (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl) pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methane sulfonamide.

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (200 mg, 380.60 pmol) in DCM (10 ml), was added methanesulfonyl chloride (33 pi, 418.66 pmol), and TEA (59 mΐ, 418.66 mhioΐ). The reaction mixture was stirred at room temperature overnight, and washed with water and brine, dried over MgSCU, 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-((l- (3-fluoropropyl) pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3 - yl)methane sulfonamide.

Example 31. (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl) pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,3,4-ox adiazol-2(3H)-one To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydraz ide [Example 6] (141 mg, 248.01 pmol) in 1,4-dioxane (5 ml), was added l,8-diazabicycloundec-7-ene (43.72 mg, 272.82 pmol), and CDI (61.56 mg, 372.02 pmol). 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-((l-(3-fluoropropyl) pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,3,4-ox adiazol-2(3H)-one. Example 32. Tert-butyl (S)-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate .

Triethylamine (5.59 ml, 39.68 mmol), was added to solid (S)-8-(2,4-dichlorophenyl)-9-(4- ((l-(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 hour. Diphenyl phosphoryl 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 hours. The reaction mixture was poured onto ice (250 g), and stirred at room temperature overnight. White fine solid formed which was filtered on Biichner, 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3- yl)carbamate.

Alternative method:

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-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), under argon, was added tBuXPhos (2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, 151 mg, 0.31mmol), and Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(O), 108 mg, 0.13 mmol). The reaction mixture was heated in a sealed tube at 110°C for 3 hours, diluted with EtOAc , washed with water, and brine, dried over Na ₂ S0 ₄ , 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-((l-(3- fluoropropyl) pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3 - yl)carbamate. Example 33. (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,3,4-ox athiazol-2-one To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 3] (200 mg, 361.34 pmol) in toluene (5 ml), was added chlorocarbonylsulfenyl chloride (57 mg, 433.60 pmol). The reaction mixture was refluxed for 1 hour, diluted with EtOAc and washed successively with water, brine, dried over MgSCri, 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-((l-(3-fluoropropyl)pyrro lidin-3-yl)oxy)phenyl)-6,7- dihydro-5H-benzo[7]annulen-3-yl)-l,3,4-oxadiazole. Example 34. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,2,4-ox adiazole-5(4H)-thione

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-c arboximidamide [Example 26] (218 mg, 383.46 pmol) in 1,4-dioxane (5 ml), was added 1,8- diazabicycloundec-7-ene (482 pi, 3 mmol), and TCDI (108 mg, 575.18 pmol). The reaction mixture was heated at reflux for 2 hours, and the solvent removed under reduced pressure. The residue was partitioned between DCM and water, the organic phase was washed with water and brine, dried over MgSC , filtered and evaporated under reduced pressure. The residue was first purified 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-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H- benzo[7]annulen-3-yl)-l,2,4-oxadiazole-5(4H)-thione.

Example 35. (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7 -dihydro-5H-benzo[7]annulen-3-yl)- 1 , 1 , 1-trifluoromethanesulfonamide To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (200 mg, 380.60 pmol) in DCM (KLml), was added trifluoromethane sulfonic anhydride (70 pi, 418.66 pmol), and TEA (59 mΐ, 418.66 mhioΐ). The reaction mixture was stirred at room temperature for 2 hours, and washed with water and brine, dried over MgSCU, filtered and evaporated under reduced pressure. The residue was first purified by flash chromatography eluting with a mixture of DCM and MeOH (98/02; v/v) and by reverse phase HPLC to give 52 mg (20.8%) of (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy )phenyl)-6, 7 -dihydro-5H-benzo[7]annulen-3-yl)- 1 , 1 , 1-trifluoromethanesulfonamide. Example 36. (S)-3-((8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-4- hydroxycyclobut-3-ene- 1,2-dione To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (200 mg, 380.60 pmol) in DMF (10 ml), was added 3,4-dihydrocyclobuty-3-ene-l,2-dione (48 mg, 418.66 pmol). The reaction mixture was stirred at room temperature for 1 hour, and microwaved at 130°C for 7 hours. The residue was diluted with EtOAc, washed with water and brine, dried over MgSCU, filtered and evaporated under reduced pressure. The residue was first purified by flash chromatography eluting with a mixture of DCM and MeOH (98/02, v/v) and by reverse phase HPLC to give 52 mg (20.8%) of (S)-3-((8-(2,4-dichlorophenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)amino)-4- hydroxycyclobut-3-ene-l,2-dione.

Example 37. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,2,4-th iadiazol-5(4H)-one

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-c arboximidamide [Example 26] (324 mg, 569.91 pmol) in THF (10 ml), was added TCDI (128 mg, 683.89 pmol). The reaction mixture was stirred at room temperature for 1 hour, and partitioned between EtOAc and water, the organic phase was washed with water and brine, dried over MgS0 ₄ , 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 hour, and partitioned between EtOAc and water, the organic phase was washed with water and brine, dried over MgS0 ₄ , filtered and evaporated under reduced pressure. The residue was first purified 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)- 1,2,4- thiadiazol-5 (4H) -one . Example 38. (S)-l-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-methox y-l,5-dihydro-2H-pyrrol-

2-one

To a solution of (S)-3-(4-(3-bromo-8-(2,4-dichlorophenyl)-6,7-dihydro-5H- benzo[7]annulen-9-yl)phenoxy)-l-(3-fluoropropyl)pyrrolidine [Example 11] (50mg,

0.084mmol), in 1,4-dioxane (1.5 ml) and DMF (0.25 ml), was added 4-methoxy-3-pyrrolin- 2-one (30mg, 0.25mmol), potassium phosphate (22mg, O.llmmol), cuprous iodide (25 mg, 0.14 mmol), and N,N'-dimethylethylenediamine (0.02ml, 0.17mmol), under argon. The reaction mixture was microwaved at 100°C for 5 hours, diluted with EtOAc, washed with water, and brine, dried over MgSCU, filtered and evaporated under reduced pressure. The residue was first purified by flash chromatography eluting with EtOAc, and then by reverse phase HPLC to give 6 mg (6%) of (S)-l-(8-(2,4-dichlorophenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)-3- methoxy- 1 ,5-dihydro-2H-pyrrol-2-one.

Example 39. (S)-l-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-l-o ne

To a solution of methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin- 3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxop ropanoate [Example 4, Step 1] (300 mg, 491.36 pmol) in THF (10 ml) was added NaOH solution (IN, 3ml). The reaction mixture was stirred at 50°C for 16 hours, poured into water and extracted with EtOAc, dried over MgSC , filtered and evaporated under pressure to give 229 mg (84%) of (S)-l-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3-yl)oxy)phenyl)-6,7- dihydro-5H-benzo[7]annulen-3-yl)ethan-l-one.

Alternative method:

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]ann ulene-3-carboxamide [Example 44] (500 mg, 836.75 pmol) in THF (10 ml), was added methylmagnesium bromide 2.5M solution in THF (1.7 ml , 5 mmol) at 0°C. The reaction mixture was stirred at room temperature for 4 hours. A saturated solution of NH4C1 was added, and the mixture was extracted with EtOAc, and the organic phase washed with water, brine, dried over MgS0 ₄ , filtered and evaporated under reduced pressure to give 350 mg (76%) of (S)-l-(8- (2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-y l)oxy)phenyl)-6, 7-dihydro- 5H-benzo[7]annulen-3-yl)ethan-l-one.

Example 40. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxazolidi n-2-one

To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7 -dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (100 mg, 0.151mmol), 2-oxazolidone (27.3 mg, 0.30 mmol), and sodium tert- butoxide (30 mg, 0.304 mmol) in anhydrous toluene (2 ml), under argon, was added tBuXPhos (2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, 20 mg, 0.050 mmol), and Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(O), (29 mg, 0.030 mmol). The reaction mixture was stirred at room temperature for 48 hours in a sealed tube, diluted with EtOAc, washed with water, dried over MgSCE, 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-((l- (3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-b enzo[7]annulen-3- yl)oxazolidin-2-one.

Example 41. (S)-3-(8-(2-chloro-4-(2-oxooxazolidin-3-yl)phenyl)-9-(4-((l- (3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3- yl)oxazolidin-2-one

To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-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), under argon, was added tBuXPhos (2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (20 mg, 0.050 mmol), and Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(O), (29 mg, 0.030 mmol). The reaction mixture was stirred at 110°C for 48 hours in a sealed tube, diluted with EtOAc, washed with water, dried over MgS0 ₄ , filtered and evaporated under reduced pressure. The residue was purified first by flash chromatography eluting 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-((l-(3-fluoropropyl)pyrrolid in-3-yl)oxy)phenyl)-6,7- dihydro-5H-benzo[7]annulen-3-yl)oxazolidin-2-one.

Example 42. (S)-4-(3-amino-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy) phenyl)-6,7- dihydro- 5H-benzo [7 ] annulen- 8 -y 1) - 3 -chlorophenol

Step 1: Tert-butyl (S)-(8-(2-chloro-4-hydroxyphenyl)-9-(4-((l-(3-fluoropropyl)p yrrolidin- 3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbama te To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-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), under argon, was added tBuXPhos (2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, 151 mg, 0.31mmol), and Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(O), 108 mg, 0.13 mmol). The reaction mixture was heated in a sealed tube at 110°C for 16 hours, diluted with EtOAc, washed with water, and brine, dried over NaiSCU, 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- ((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro- 5H-benzo[7]annulen-3- yl)carbamate.

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

Step 2: (S)-4-(3-amino-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy) phenyl)-6, 7-dihydro- 5H-benzo [7 ] annulen- 8 -y 1)- 3 -chlorophenol

To a solution of tert-butyl(S)-(8-(2-chloro-4-hydroxyphenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[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 hours, diluted with EtOAc, washed with saturated sodium bicarbonate solution, dried over NaiSC , filtered and evaporated under reduced pressure to give 70 mg (86.4%) of (S)-4-(3-amino-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-8-yl)-3- chlorophenol.

Example 43. 5-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)imidazoli dine-2,4-dione

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyd e [Example 5, step 1] (200 mg, 371.41 pmol) in MeOH (2 ml), was added NH4CO3 (107,06 mg, 1.11 mmol), potassium cyanide (26.60 mg, 408.55 pmol), water (2 ml), and THF (1 ml). The reaction mixture was heated in a sealed tube at 70°C for 20 hours, poured into water and extracted with EtOAc. The organic phase was washed with water, brine, dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by reverse phase HPLC to give 16 mg (7%) of 5-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)imidazoli dine-2,4-dione.

Example 44. (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]ann ulene-3-carboxamide

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-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 hours. 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 layers were collected, dried over MgS0 ₄ and concentrated under reduced pressure. The crude product obtained 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-N-methyl- 6,7-dihydro-5H- benzo[7]annulene-3-carboxamide. Example 45. (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l,3,4-ox adiazole-2(3H)-thione To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydraz ide [Example 6] (386 mg, 678.96 pmol) in 1,4-dioxane (10 ml), was added DBU (120 mg, 746.86 pmol), and TCDI (191 mg, 178.03 pmol). The reaction mixture was refluxed for 1 hour, and evaporated under reduced pressure. The residue was partitioned between DCM and water, and the organic phase washed with brine, dried over MgS0 ₄ , 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)- 1,3,4- oxadiazole-2 (3 H) - throne .

Example 46. (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetimida mide

To a mixture of methyl acetimidate hydrochloride (375.26 mg, 3.43 mmol) in MeCN (10 ml), was added TEA (480.94 mΐ, 3.43 mmol). The reaction mixture was stirred for 15 minutes at room temperature. Then, (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in- 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, dried over MgSCE and concentrated under reduced pressure. The crude product obtained was purified by flash chromatography eluting in a fist time with a gradient of MeOH in DCM (100/0 to 90/10, v/v) and in second time with a gradient of (MeOH/ 10% NH3-MeOH 2N) in DCM (90/10 to 75/25, v/v) to give 200 mg (31%) of (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetimida mide. Example 47. (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-tr ifluoroacetamide

To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (180 mg, 342.54 pmol) in THF (5 ml), was added TEA (57.71 pi, 411.05 pmol) and TFAA (57.75 pi, 411.05 pmol). The reaction mixture was stirred for 2 hours at room temperature. Water was added and the mixture was extracted twice with EtOAc. The organic layers were collected, washed with brine, dried over MgSCC, 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)-2,2,2- trifluoroacetamide . Example 48. (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y 1) acetamide

To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (100 mg, 190.30 pmol) in DCM (5 ml), was added at 0°C TEA (58.94 pi, 418.66 pmol) and acetyl chloride (33.26 pi, 456.72 mhioΐ). The reaction mixture was stirred for 48 hours at room temperature. Water was added and the mixture was extracted twice with DCM. The organic layers were collected, washed with brine, dried over MgSCC, 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- ((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro- 5H-benzo[7]annulen-3- yl)acetamide.

Example 49. l-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-l-o l

To a mixture of (S)-l-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-l-o ne [Example 39] (200 mg, 361.98 pmol) in EtOH (20 ml), was added at 0°C NaBfE (27.39 mg, 723.97 pmol). The reaction mixture was stirred 2 hours at room temperature. Then, water was added and the mixture was extracted twice with EtOAc. The organic layers were collected, washed with brine, dried over MgSCE, filtered and evaporated under reduced pressure. The residue was purified twice by flash chromatography eluting first with a gradient of EtOAc in heptane (95/5 to 0/100, v/v) and with a solution of EtOAc in MeOH (95/5, v/v) to give 140 mg (70%) of l-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l-(3-fluoropropyl)pyrro lidin-3-yl)oxy)phenyl)-6,7- dihydro-5H-benzo[7]annulen-3-yl)ethan-l-ol.

Example 50. (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)propan-2- ol

To a mixture of (S)-l-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-l-o ne [Example 39] (200 mg, 361.98 pmol) in anhydrous THF (10 ml), was added at 0°C methyl magnesium bromide (361.98 pi, 1.09 mmol). The reaction mixture was stirred 2 hours at room temperature. Then, water was added and the mixture was extracted twice with EtOAc. The organic layers were collected, washed with brine, dried over MgS0 ₄ , filtered and evaporated under reduced pressure. The residue was purified twice by flash chromatography eluting first with a gradient of EtOAc in heptane (95/5 to 0/100, v/v) and 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)propan-2- ol.

Example 51. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y 1) - 1 H-pyrazole

A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7 -dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, step 1] (350 mg, 478.34 pmol), 1,4-dioxane (13 ml), Pd(dppf)2Cl2 (21 mg, 28.70 pmol), water (3 ml), CS2CO3 (389.63 mg, 1.20 mmol) and lH-Pyrazole-3-boronic acid pinacol ester (136.78 mg, 669.67 pmol) was microwaved 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 EtOAc. The organic layers were collected, washed with brine, dried over MgSCE, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography with a gradient of MeOH in DCM (100/0 to 90/10, v/v) to give 140 mg (51%) of (S)-3-(8-(2,4-dichloirophenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)-lH- pyrazole.

Example 52. (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol

A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7 -dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, step 1] (300 mg, 410 pmol), 1,4-dioxane (13 ml), Pd(dppf)2Cl2 (18 mg, 24.60 pmol), water (3 ml), CS2CO3 (333.97 mg, 1.03 mmol) and (4-hydroxyphenyl)boronic acid (71.43 mg,

492.01pmol) was microwaved at 90°C for 45 minutes. 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 layers were collected, washed with brine, dried over MgSCE, 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)phenol.

Example 53. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol

A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7 -dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, step 1] (300 mg, 410 pmol), 1,4-dioxane (13 ml), Pd(dppfhCl2 (18 mg, 24.60 pmol), water (3 ml), CS2CO3 (333.97 mg, 1.03 mmol) and (3-hydroxyphenyl)boronic acid (79.17 mg,

574.01 pmol) was microwaved at 90°C for 45 minutes. 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 layers were collected, washed with brine, dried over MgSCri, filtered and evaporated under reduced pressure. The crude product obtained 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)phenol.

Example 54. (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y l)phenol

A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, step 1] (300 mg, 410 pmol), 1,4-dioxane (13 ml), Pd(dppfhCl2 (18 mg, 24.60 pmol), water (3 ml), CS2CO3 (333.97 mg, 1.03 mmol) and (2-hydroxyphenyl)boronic acid (67.86 mg, 492.01 pmol) was microwaved at 90°C for 45 minutes. 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 layers were collected, washed with brine, dried over MgS0 ₄ , filtered and evaporated under reduced pressure. The crude product obtained was purified twice by flash chromatography eluting first with a gradient of EtOAc in heptane (95/5 to 0/100, v/v) and 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-((l-(3-fluoropropyl)pyrro lidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y l)phenol

Example 55. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y l)benzoic acid

To a mixture of methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin- 3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoat e [Example 57] (280 mg, 434.37 pmol) in MeOH (20 ml) and THF (10 ml), was added a solution of NaOH 2M (10 ml, 434.37 pmol). The reaction mixture was stirred for 2 hours at 60°C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added, followed by a solution of HC1 5N until pH 5. The mixture was extracted twice with EtOAc and the organic layers were collected and washed with brine. The organic phase was dried over MgSCU, filtered and evaporated under reduced pressure to give 175 mg (64%) of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3-yl)oxy)phenyl)-6,7- dihy dro- 5H-benzo [7 ] annulen- 3 -y l)benzoic acid .

Example 56. Methyl (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate

A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7 -dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, step 1] (400 mg, 546.67 pmol), 1,4-dioxane (13 ml), Pd(dppf)2Cl2 (24 mg, 32.80 pmol), water (3 ml), CS2CO3 (445.29.63 mg, 1.37 mmol) and 4-methoxycarbonylphenyl boronic acid (142 mg, 765.34 pmol) was microwaved 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 EtOAc. The organic layers were collected, washed with brine, dried over MgS0 ₄ , filtered and evaporated under reduced pressure. The crude product obtained 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-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H- benzo [7 ] annulen- 3 -y l)benzoate .

Example 57. Methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate

A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, step 1] (400 mg, 546.67 pmol), 1,4-dioxane (13 ml), Pd(dppf)2Cl2 (24 mg, 32.80 pmol), water (3 ml), CS2CO3 (445.29 mg, 1.37 mmol) and 3-methoxycarbonylphenyl boronic acid (118 mg, 656.01 pmol) was microwaved 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 EtOAc. The organic layers were collected, washed with brine, dried over MgS0 ₄ , filtered and evaporated under reduced pressure. The crude product obtained 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-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H- benzo [7 ] annulen- 3 -y l)benzoate .

Example 58. (S)-l-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)pyrrolidi n-2-one To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7 -dihydro-5H-benzo[7]annulen-3-yl trifluoro-methanesulfonate [Example 1, step 1] (100 mg, 0.216mmol), 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 Pd2(dba)3 (41 mg, 0.043 mmol). After degassing 5 minutes with argon the tube was sealed and stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc, the organic phase was washed with water and brine, dried over NaiSCU, 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 a crude product. Further purification by preparative reverse phase high performance liquid chromatography at 20°C by using a CSH 50X250mm, 5pm column applying the following gradient with A: H2O/0.1% formic acid and B: CH3CN/0.1% formic acid: 30% of B at t=0min, 30% of B at t=5min, 50% of B at t=25min and subsequent lyophilization provided 5 mg (4%) of a white solid of (S)-l-(8-(2,4- dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H- benzo[7]annulen-3-yl)pyrrolidin-2-one.

Example 59. (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-N'-(lH-imidazole-l-carbonothioyl)-6,7-dihydro -5H-benzo[7]annulene-3- carbohydrazide

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-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-N'-(lH-imidazole-l-carbonothioyl)-6,7-dihydro -5H-benzo[7]annulene-3- carbohydrazide.

Example 60. (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)cycloprop anecarboxamide

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-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 pi, 1.37 mmol). The reaction mixture was stirred 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure and then, EtOAc was added. The organic layer was washed twice with a saturated aqueous solution of K2CO3 and once with brine. The organic layers were collected, dried over MgSCE and concentrated under reduced pressure. The crude product obtained 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-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)cycloprop anecarboxamide. Example 61. (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)thiazol-2 -amine

To a mixture of (S)-l-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-l-o ne [Example 39] (150 mg, 271.49 pmol) in anhydrous THF (20 ml), was added phenyltrimethylammonium tribromide (244.94 mg, 651.58 pmol), and the reaction mixture was stirred 7 hours at room temperature. The precipitate formed was filtered and washed three times with THF, and the organic phase was collected and evaporated under reduced pressure. The crude residue was taken up in MeOH (30 ml) and thiourea (22.73 mg, 298.64 pmol) was added. The reaction mixture was stirred at reflux during 4 hours. The reaction mixture was evaporated under reduce pressure and the crude residue was diluted in EtOAc. The organic layer was washed twice with brine, dried over MgS0 ₄ , filtered and evaporated under reduced pressure. The crude product obtained was purified by flash chromatography eluting in a fist time with a gradient of EtOAc in heptane (95/5 to 0/100, v/v) and in 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)thiazol-2- amine.

Example 62. (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)pivalamid e

To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-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 at 0°C TEA (138.65 mg, 1.37 mmol) and pivaloyl chloride (165.21 mg, 1.37 mmol). The reaction mixture was stirred for 4 hours at room temperature. Water was added and the mixture was extracted twice with DCM. The organic layers were collected, washed with brine, dried over MgSCU, filtered and evaporated under reduced pressure. The residue was purified by with 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3- yl)pivalamide. Example 63. (S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide

Obtained from (S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] in 81% yield by an analogous method to Example 3.

Example 64. (S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitril e, 2,2,2-trifluoroacetate

Obtained from (S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 63] in 44% yield by an analogous method to Example 22. Example 65. l-(8-(2-chloro-3-fluorophenyl)-9-(4-(((S)-l-(3-fluoropropyl) pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-tr ifluoroethan-l-ol

Step 1: (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]ann ulene-3-carboxamide

This compound has been prepared as described in Example 44 starting from (S)-8-(2-chloro- 3-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H- benzo[7]annulene-3-carboxylic acid [WO2017140669] (440 mg, 818 pmol) to give 300 mg (63%) of (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]ann ulene-3-carboxamide. LC/MS (m/z, MH ⁺ ): 581

Step 2: (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyd e

This compound has been prepared as described in Example 5, Step 1, starting from (S)-8- (2-chloro-3-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidi n-3-yl)oxy)phenyl)-N- methoxy-N-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxami de (300 mg, 516 pmol) to give 240 mg (89%) of (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3- fluoropropy l)pyrrolidin- 3 -y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulene- 3 - carbaldehyde.

LC/MS (m/z, MH ⁺ ): 522 Step 3: l-(8-(2-chloro-3-fluorophenyl)-9-(4-(((S)-l-(3-fluoropropyl) pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-tr ifluoroethan-l-ol

This compound has been prepared as described in Example 10 starting from (S)-8-(2-chloro- 3-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H- benzo[7]annulene-3-carbaldehyde (240 mg, 459.74 pmol) to give 120 mg (44%) of l-(8-(2- chloro-3-fluorophenyl)-9-(4-(((S)-l-(3-fluoropropyl)pyrrolid in-3-yl)oxy)phenyl)-6,7- dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroethan-l-ol.

Example 66. (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l-fluoro cyclopropane-l- carboxamide

To a solution of 1-fluorocyclopropane-l -carboxylic acid (10.01 mg, 91.34 pmol) in DCM (5 ml) was added l(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.87 mg, 91.34 pmol) and 4-dimethylaminopyridine (11.27 mg, 91.34 pmol).The reaction mixture was stirred 10 minutes at room temperature and (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-amine [Example 28] (40 mg, 76.12 pmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and EtOAc was added. The organic layer was washed twice with a saturated aqueous solution of K2CO3 and once with brine. The organic layers were collected, dried over MgSCU and concentrated under reduced pressure. The crude product obtained 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)-l- fluorocyclopropane- 1 -carboxamide.

Example 67. (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l-methyl cyclopropane-l- carboxamide

To a solution of 1-methylcyclopropane-l -carboxylic acid (58.32 mg, 570.90 pmol) in DCM (5 ml) was added l(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (111.68 mg, 570.90 pmol) and 4-dimethylaminopyridine (70.45 mg, 570.90 pmol). The reaction mixture was stirred 10 minutes at room temperature and (S)-8-(2,4-dichlorophenyl)-9-(4- ((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro- 5H-benzo[7]annulen-3-amine [Example 28] (100 mg, 190.30 pmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and EtOAc was added. The organic phase was washed twice with a saturated aqueous solution of K2CO3 and once with brine. The organic phase was dried over MgSCU and concentrated under reduced pressure. The crude product obtained 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-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6, 7 -dihydro-5H-benzo[7]annulen-3-yl)- 1-methylcyclopropane-l- carboxamide.

Example 68. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2-hydrox ycyclopent-2-en-l-one

Step 1: (S)-2-((tert-butyldimethylsilyl)oxy)-3-(8-(2,4-dichloropheny l)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3- yl)cyclopent-2-en-l-one

A solution of 3-bromo-2-((tert-butyldimethylsilyl)oxy)cyclo-pent-2-en-l-on e (91.53 mg, 314 pmol), (S)-3-(4-(8-(2,4-dichlorophenyl)-3-(4,4,5,5-tetramethyl-l,3, 2-dioxaborolan-2- yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-l-(3-fluoro propyl)-pyrrolidine [Example 1] (200 mg, 314 pmol), CS2CO3 (256 mg, 785 pmol), and Pd(dppf)Cl2 (13.8 mg, 18.9 pmol) in 1,4-dioxane (2 ml), and water (2 ml) was microwaved 30 minutes at 90°. The reaction mixture was poured into water, extracted with EtOAc, the organic phase was washed with water and brine, dried over Na2S04, filtered and evaporated under reduced pressure to give 225 mg of crude (S)-2-((tert-butyldimethylsilyl)oxy)-3-(8-(2,4- dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H- benzo[7]annulen-3-yl)cyclopent-2-en-l-one (85% LCMS purity) which was used without further purification in the next step.

Step 2: (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2-hydrox ycyclopent-2-en-l-one

To a solution of crude (S)-2-((tert-butyldimethylsilyl)oxy)-3-(8-(2,4-dichloropheny l)-9-(4- ((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro- 5H-benzo[7]annulen-3- yl)cyclopent-2-en-l-one (225 mg, 314 pmol) in THF (2 ml) was added at 0°C TBAF 1M in THF (625 pi, 625 pmol). The reaction mixture was stirred at room temperature for 40 minutes, and diluted with EtOAc. The organic phase was washed with water and brine, dried over NaiSC , 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 a beige solid of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)-pyrr o- lidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)- 2-hydroxycyclopent-2-en-l- one.

Example 69. (S,Z)-4-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-N,3-dime thylthiazol-2(3H)-imine hydrochloride

To a solution of (S)-l-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-l-o ne [Example 39] (100 mg, 181 pmol) in DCM (4 ml) was added benzyltrimethylammonium dichloroiodate (200 mg, 557 pmol). The reaction mixture was stirred under reflux for 16 hours. EtOH (10 ml) and

N,N'-dimethylthiourea (19.9 mg, 181 pmol) was added, the mixture was heated to 80°C under a stream of nitrogen in order to evaporate the DCM and then heated under reflux for 3h. After addition of water the mixture was extracted with EtOAc, the organic phase was washed with water and brine, dried over NaiSC , 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-((l- (3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-b enzo[7]annulen-3-yl)-N,3- dimethylthiazol-2(3H)-imine as a beige-colored solid.

Example 70. (S)-5-(8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl) pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2H-tetra zole, 2,2,2-trifluoroacetate Obtained from (S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitril e [Example 64] in 35% yield by an analogous method to Example 16.

Example 71. tert-butyl (S)-(9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8- phenyl-6, 7-dihydro-5H-benzo[7]annulen-3-yl)carbamate

Step 1: (S)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl )oxy)phenyl)-8-phenyl-6,7-dihydro- 5H-benzo[7]annulen-3-yl trifluoromethanesulfonate

To a solution of (S)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-p henyl-6, 7- dihydro-5H-benzo[7]annulen-3-ol [WO2017140669] (2 g, 4.37 mmol), in DCM (200 ml) and pyridine (536 pi, 6.6 mmol) was added dropwise at 0°C, trifluoromethanesulfonic anhydride (1.8 ml, 8.7 mmol) dropwise. The reaction mixture was stirred at room temperature for 18 hours. Cold water (5 ml) and saturated NaHCCE (10 ml) was added. After decantation, the organic phase was dried over MgSCC, filtered and evaporated under reduced pressure to give 2.6 g (100%) of crude (S)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3- yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-ylt rifluoromethanesulfonate. LC/MS (m/z, MH ⁺ ): 590.

Step 2: Tert-butyl (S)-(9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8- phenyl-6,7- dihydro-5H-benzo[7]annulen-3-yl)carbamate To a mixture of (S)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl )oxy)phenyl)-8-phenyl-6,7- dihydro-5H-be nzo[7]annulen-3-yl trifluoromethanesulfonate (170 mg, 288 pmol), in toluene (1 ml), was added tert-butyl-carbamate (43 mg, 360 pmol), tri( dibenzilideneacetone)dipalladium(O) (41 mg, 43 pmol), 2-di-tert-butylphosphino-2’,4’,6’- triisopropylbiphenyl (18 mg, 43 pmol), and sodium tert-butoxide (50 mg, 519 pmol). The reaction mixture was microwaved at 100 °C for 1 hour. The reaction mixture was partitioned between EtOAc and water, the organic phase was washed with brine, dried over MgSCC, 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-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8- phenyl- 6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate. Example 72. (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y l)benzoic acid

To a mixture of methyl (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin- 3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoat e [Example 56] (180 mg, 279.24 pmol) in MeOH (20 ml) and THF (10 ml), was added a solution of NaOH 2M (1 ml,

1 mmol). The reaction mixture was stirred for 2 hours at 60°C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added, followed by a solution of HC1 5N to reach pH 5. The mixture was extracted twice with EtOAc and the organic phase was washed with brine, dried over MgSCU, filtered and evaporated under reduced pressure to give 120 mg (68%) of (S)-4-(8-(2,4-dichlorophenyl)- 9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dih ydro-5H-benzo[7]annulen-3- yl)benzoic acid.

Example 73. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-lH-pyraz ol-5-amine

Step 1: (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3-l)oxy)phenyl)- 6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopropanenitrile

To a mixture of DMSO (3 ml) and MeCN (138,83 mΐ, 2,64 mmol), was added sodium hydride (70,35 mg, 1,76 mmol), and the reaction mixture was stirred at room temperature for 20 minutes, before adding methyl (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3- fluoropropy l)pyrrolidin- 3 -y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulene- 3 -c arboxy late

[WO2017140669] (500 mg, 879,49 pmol). The reaction mixture was stirred for 2 hours at room temperature, and water was slowly added, and the aqueous phase extracted with ethylacetate. The organic phase was washed with brine, dried over MgSCE, 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 430m (75%) of (S)-3-(8-(2,4- dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-l)oxy) phenyl)-6,7-dihydro-5H- benzo[7]annulen-3-yl)-3-oxopropanenitrile. LC/MS (m/z, MH ⁺ ): 577.

Step 2: (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-lH-pyraz ol-5-amine

To a solution of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopro panenitrile (150 mg, 259.73 pmol) 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 hours. 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 layers were collected, dried over MgSCU and concentrated under reduced pressure. The residue was purified by flash chromatography with a gradient of MeOH in DCM (100/0 to 90/10, v/v) to give 70 mg (46%) of (S)-3-(8- (2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-y l)oxy)phenyl)-6, 7-dihydro- 5H-benzo [7 ] annulen- 3 -y 1)- 1 H-pyrazol- 5 - amine .

Example 74. (S)-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y 1) (3 -hydroxy azetidin- 1 -y l)methanone

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (100 mg, 180.35 pmol) in DCM (10 ml) was added DIPEA (94.39 pi, 541.04 pmol), HBTU (75.24 mg, 198.38 pmol) and 3 -hydroxy azetidine hydrochloride (20.37 mg, 180.35 pmol). 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 washed twice with a saturated aqueous solution of K2CO3 and once with brine. The organic phase was dried over MgSCU and concentrated under reduced pressure. 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)(3- hydroxyazetidin- 1 -yl)methanone.

Example 75. (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-N-(oxetan-3-yl)-6,7-dihydro-5H-benzo[7]annule ne-3-carboxamide

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (100 mg, 180.35 pmol) in DCM (10 ml) was added DIPEA (94.39 pi, 54E04 pmol), HBTU (75.24 mg, 198.38 pmol) and 3-oxetamine (13.59 mg, 180.35 pmol). 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 washed twice with a saturated aqueous solution of K ₂ CO ₃ and once with brine. The organic phase was dried over MgS0 ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of EtOAc in heptane (5% EtOAc to 100% EtOAc, v/v) to give 100 mg (91%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-(oxetan-3-yl)-6,7 -dihydro-5H- benzo[7]annulene-3-carboxamide. Example 76. ethyl (S)-2-((8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-2- oxoacetate

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (100 mg, 190.30 pmol) in DCM (10 ml) was added at 0°C, TEA (66.98 pi, 475.5 pmol) and ethyloxalyl chloride (32.60 mΐ, 285.45 mmol). The reaction mixture was stirred at room temperature overnight, and concentrated under reduced pressure. EtOAc was added, and the organic phase was washed twice with a saturated aqueous solution of K2CO3 and once with brine. The organic phase was dried over MgSC 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 50 mg (42%) of ethyl (S)-2-((8-(2,4-dichlorophenyl)-9-(4-((l- (3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-b enzo[7]annulen-3- yl)amino)-2-oxoacetate.

Example 77. (S)-Nl-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxalamide To a solution of ethyl (S)-2-((8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrr olidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-2- oxoacetate [example 76] (40 mg, 63.94 pmol) in MeOH (1 ml) was added ammonia 7M in MeOH (18.27 pi, 127.88 pmol).The reaction mixture was stirred 5 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and EtOAc was added. The organic layer was washed twice with a saturated aqueous solution of K ₂ CO ₃ and once with brine. The organic layers were collected, dried over MgS0 ₄ 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)-Nl-(8-(2,4-dichlorophenyl)-9-(4-((l- (3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-b enzo[7]annulen-3- yl)oxalamide.

Example 78. (S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy )phenyl)-6,7 -dihydro-5H-benzo [7 ] annulen- 3 -amine

Step 1: Methyl (S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

To a solution of methyl (S)-8-bromo-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phe nyl)- 6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide [WO2017140669] (6.3 g, 10.80 mmol), in 1,4-dioxane (50 ml), was added 2-chloro-4-methylphenylboronic acid (2.01 g, 11.45 mmol), CS2CO3 (11.27 g, 34.56 mmol) in water (20 ml) and [I,G- bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (499 mg, 648.00 pmol). The reaction mixture was heated at 70°C for 1 hour, poured onto water, and extracted with DCM. The organic extracts were washed with water, filtered on 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-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)p henyl)-6,7-dihydro-5H- benzo[7]annulene-3-carboxylate. LC/MS (m/z, MH ⁺ ): 548.

Step 2: (S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

To a solution of methyl (S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(3- fluoropropy l)pyrrolidin- 3 -y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulene- 3 -c arboxy late (1 g, 1.82 mmol), in MeOH (15 ml), was added NaOH solution (2M, 3 ml, 6 mmol). The reaction mixture was refluxed for 1 hour, and hydrochloric acid IN was added to reach pH 6-7. The aqueous phase was extracted with DCM, and the organic extracts dried over MgS0 ₄ , filtered and evaporated under reduced pressure to give 963 mg (99%) of crude (S)- 8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3-yl)oxy)phenyl)-6,7- dihydro-5H-benzo[7]annulene-3-carboxylic acid. LC/MS (m/z, MH ⁺ ): 534.

Step 3: (S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide

The synthesis was performed as in Example 3, replacing (S)-8-(2,4-dichlorophenyl)-9-(4- ((l-(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-((l-(3-fluoropropyl)pyr rolidin- 3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxyli c acid (963 mg, 1.8 mmol) to give 571 mg (59%) of (S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulene-3- carboxamide. LC/MS (m/z, MH ⁺ ): 533.

Step 4: methyl (S)-(8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl)py rrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate

The synthesis was performed as in Example 25, replacing (S)-8-(2,4-dichlorophenyl)-9-(4- ((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro- 5H-benzo[7]annulene-3- carboxamide with (S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (571 mg, 1.07 mmol) to give 407 mg (67.5%) of methyl (S)-(8-(2-chloro-4-methylphenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3- yl)carbamate. LC/MS (m/z, MH ⁺ ): 563. Step 5: (S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -amine

The synthesis was performed as in Example 28, replacing (S)-(8-(2,4-dichlorophenyl)-9-(4- ((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro- 5H-benzo[7]annulen-3- yl)carbamate with (S)-(8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl)py rrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate (407 mg, 723 pmol) to give 247 mg (67.7%) of (S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-amine. Example 79. (S)-8-(6-ethoxy-2-fluoropyridin-3-yl)-9-(4-((l-(3-fluoroprop yl)pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide

Obtained from methyl (S)-8-bromo-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phe nyl)- 6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide [WO2017140669] in 85% yield by an analogous method to Example 78, Steps 1,2,3.

Example 80. (S)-8-(6-ethoxy-2-fluoropyridin-3-yl)-9-(4-((l-(3-fluoroprop yl)pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitril e 2,2,2-trifluoroacetate

Obtained from (S)-8-(6-ethoxy-2-fluoropyridin-3-yl)-9-(4-((l-(3-fluoroprop yl)pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 79] in 70% yield by an analogous method to Example 22.

Example 81. (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzamide

A mixture of (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid [Example 72] (200 mg, 279.11 pmol), pyridine (57.40 mg, 725.68 pmol), di-tert-butyl dicarbonate (91.37 mg, 418.66 pmol) and NH4HCO3 (33.10 mg, 418.66 pmol) in 1,4-dioxane (40 ml) was stirred at room temperature for 48 hours. 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 layers were collected, dried over MgSCE 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-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H- benzo [7 ] annulen- 3 -y l)benzamide .

Example 82. (S)-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrroli din-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanol

To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)-pyrroli din-3- yl)oxy )phenyl)-6,7 -dihydro-5H-benzo [7 ] annulene-3 -carboxylic acid [W 02017140669] (200 mg, 361 pmol) in THF (4 ml) was added at 0°C borane dimethyl sulfide complex 2M in THF (1.08 ml, 2.16 mmol). The reaction mixture was stirred 16h at room temperature and cooled again to 0°C. A saturated aqueous solution of KH2PO4 (4 ml) was added thoroughly and stirred for 20 min at room temperature. After addition of EtOAc the organic phase was washed with water and brine, dried over Na2S04, 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 115 mg (21%) of a white solid. This compound was refluxed for 6h in THF (decomposition of 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)methanol as a white solid.

Example 83. methyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate

A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7 -dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (350 mg, 478.34 pmol), Pd(dppf)2Cl2 (21 mg, 28.70 pmol), CS2CO3 (389.63 mg, 1.20 mmol), and 2-methoxycarbonylphenyl boronic acid (124.25 mg, 669.67 pmol) in 1,4- dioxane (13 ml), and water (3 ml), was microwaved 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 EtOAc. The organic phase was washed with brine, dried over MgSCE, 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 70 mg (23%) of methyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)benzoate.

Example 84. (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-l-hydrox ycyclopropane-l- carboxamide formate

To a solution of 1-hydroxy cyclopropane- 1 -carboxylic acid (58.28 mg, 570.90 pmol) in dimethylformamide (5 ml) was added HATU (160.80 mg, 418.66 pmol) and TEA (161.28 pi, 1.14 mmol). The reaction mixture was stirred at room temperature for 10 minutes and, (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3-yl)oxy)phenyl)-6,7- dihydro-5H-benzo[7]annulen-3-amine [Example 28] (200 mg, 380.60 pmol) was added. The reaction mixture was stirred overnight at 40°C. The reaction mixture was concentrated under reduced pressure, and EtOAc was added. The organic layer was washed twice with a saturated aqueous solution of K2CO3 and once with brine. The organic layers were collected, dried over MgSCE and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of EtOAc in heptane (5% EtOAc to 100% EtOAc, v/v) to give 13 mg (5%) of (S)-N-(8-(2,4-dichlorophenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)-l- hydroxy cyclopropane- 1 -carboxamide formate.

Example 85. (S)-l-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l-(3-fluoropropyl)p yrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-4-hydrox ypyrrolidin-2-one

A solution of (S)-3-(4-(3-bromo-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benz o[7]annulen- 9-yl)phenoxy)-l-(3-fluoropropyl)pyrrolidine [Example 11], (135 mg, 229pmol), (S)-4- hydroxy-2-pyrrolidi-none (28.36 mg, 275 pmol), (lR,2R)-N,N'-dimethyl-l,2- cyclohexanedi-amine, (3.4 mg, 22.9 pmol), cuprous iodide (2.2 mg, 11.45 pmol), and K2CO3 (63 mg, 458 pmol) in 3 ml toluene was placed in a sealed 5 ml micro-wave vessel. After 1 minute of ultrasonication the mixture was heated in an oil bath at 110°C for 16h. After addition of water the mixture was extracted with EtOAc, the organic phase was washed with water and brine, dried over Na2S04, 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 a beige solid of (S)-l-(8-(2,4-dichloro-phenyl)- 9-(4-(((S)-l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7 -dihydro-5H-benzo- [7 ] annulen- 3 -y 1) -4 -hy droxypyrrolidin-2-one .

Example 86. (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y l)benzoic acid

To a mixture of methyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin- 3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoat e [Example 83] (240 mg, 372.32 pmol) 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 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added, followed by a solution of HC1 5N to reach pH 5. The mixture was extracted twice with EtOAc and the organic layers were collected and washed with brine. The organic phase was dried over MgSCE, filtered and evaporated under reduced pressure to give 170 mg (72%) of (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3-yl)oxy)phenyl)-6,7- dihydro-5H-benzo[7]annulen-3-yl)benzoic acid

Example 87. N-(8-(2,4-dichlorophenyl)-9-(4-(((S)-l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2-difl uorocyclopropane-l- carboxamide

To a solution of 2,2-difluorocyclopropane-l -carboxylic acid (48.91 mg, 380.60 pmol) in DMF (5 ml) was added HATU (80.40 mg, 209.33 pmol) and TEA (80.64 pi, 570.90 pmol). The reaction mixture was stirred at room temperature 10 minutes and, (S)-8-(2,4- dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H- benzo[7]annulen-3-amine [Example 28] (100 mg, 190.30 pmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and EtOAc was added. The organic layer was washed twice with a saturated aqueous solution of K ₂ CO ₃ and once with brine. The organic layers were collected, dried over MgSCE and concentrated under reduced pressure. The crude product obtained was purified twice by flash chromatography eluting first with a gradient of EtOAc in heptane (95/5 to 0/100, v/v) and 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)-l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2-difl uorocyclopropane-l- carboxamide.

Example 88. (S)-3-((8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl )pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-4- hydroxycyclobut-3-ene- 1,2-dione

The compounds was prepared as in Example 36, replacing (S)-8-(2,4-dichlorophenyl)-9-(4- ((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro- 5H-benzo[7]annulen-3-amine with (S)-8-(2-chloro-4-methylphenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 78] (233 mg, 461.32 pmol) to give 100 mg of (S)-3-((8-(2-chloro-4-methylphenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)amino)-4- hydroxycyclobut-3-ene-l,2-dione.

Example 89. (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy )phenyl)-6,7 -dihydro-5H-benzo [7 ] annulen- 3 -amine

The compound was prepared as in Example 78, Steps 3,45, but starting from (S)-8-(2- chloro-3-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3 -yl)oxy)phenyl)-6, 7-dihydro- 5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (1 g, 1.81 mmol), to give 68 mg (34%) of (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -amine .

Example 90. (S)-N-(8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3-fluoropropyl) pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanesu lfonamide

To a solution of (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine (58 mg, 114 pmol) [Example 89] in DCM (10 ml), was added methanesulfonyl chloride (10 pi, 126 pmol), and TEA (18 pi, 126 pmol). The reaction mixture was left at room temperature overnight and washed with water, brine, dried over MgSCE, 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-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)p henyl)-6,7-dihydro-5H- benzo [7] annulen-3 -yl)methanesulfonamide .

Example 91. (S)-l-(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)pheno xy)pyrrolidine

The compound was prepared as in Example 1, Steps 1 and 2 but replacing (S)-8-(2,4- dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H- benzo[7]annulen-3-ol with (S)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8- phenyl-6, 7-dihydro-5H-benzo[7]annulen-3-ol [WO2017140669] (2 g, 4.37 mmol) to give

45 mg (31.3%) of (S)-l-(3-fluoropropyl)-3-(4-(8-phenyl-3-(4,4,5,5-tetramethyl -l,3,2- dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pheno xy)pyrrolidine.

Example 92. (S)-(9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8- phenyl-6,7- dihydro-5H-benzo[7]annulen-3-yl)boronic acid

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

Example 93. (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y 1) acetic acid Step 1: Methyl 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)acetate

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 l-(tert-butyldimethylsilyloxy)-l-methoxyethene (2.1 g, 10.59 mmol), zinc chloride (342 mg, 2.51 mmol), bis(dibenzylideneacetone)palladium (149 mg, 251 pmol) and tri-tert-butylphosphine (63 mg, 301 pmol). The reaction mixture was heated at 130°C for 3 hours. After cooling to room temperature, the reaction mixture was evaporated under reduced pressure and the residue was purified by flash chromatography eluting with isopropylether 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-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl trifluoromethanesulfonate

Step 2: Methyl 2-(9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7 ]annulen-3- yl)acetate

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 mΐ, 4.2 mmol) was added dropwise trifluoromethanesulfonic anhydride ( 0.94 ml, 5.6 mmol). The reaction mixture was stirred at room temperature for 18 hours. Cold water (5 ml) and saturated NaHC0 ₃ (10 ml) was added. After decantation, the organic phase was dried over MgSCC, filtered and evaporated under reduced pressure to give 1 g (98%) of methyl 2-(9-(((trifluoromethyl)sulfonyl)oxy)- 6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate. LC/MS (m/z, MH ⁺ ): 365.

Step 3: Methyl (S)-2-(9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)- 6, 7-dihydro- 5H-benzo[7]annulen-3-yl)acetate

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), was added (S)-l- (3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborola n-2-yl)phenoxy)pyrrolidine (1.11 g, 3.17 mmol) [WO2017140669], Cs ₂ C0 ₃ (1.88 g, 5.76 mmol), Pd(dppf)Cl ₂ (222 mg, 288 pmol) and water (5 ml). The reaction mixture was heated at 60°C for 45 minutes, and partitioned between water (40 ml) and DCM (40 ml). The organic phase was dried over MgS0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with DCM/MeOH/NH40H 28% (37/18/2; V/V/V) to give 1,2 g (95%) of methyl methyl (S)-2-(9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)- 6,7-dihydro-5H-enzo[7]annulen-3-yl)acetate. LC/MS (m/z, MH ⁺ ): 438.

Step 4: Methyl (S)-2-(8-bromo-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy) phenyl)-6,7- dihydro-5H-benzo[7]annulen-3-yl)acetate hydrobromide

To a solution of methyl (S)-2-(9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)- 6,7- dihydro-5H-enzo[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 pH was adjusted to 7 with concentrated solution of NaHCOi. After decantation, the organic phase was dried over MgSCL, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (1 to 3%, V/V) to give 1 g (81%) of methyl (S)-2-(8-bromo-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy) phenyl)- 6, 7-dihydro-5H-benzo[7]annulen-3-yl)acetate hydrobromide. LC/MS (m/z, MH ⁺ ): 596. Step 5: Methyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y 1) acetate

To a solution of methyl (S)-2-(8-bromo-9-(4-((l-(3-fluoropropyl)pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate hydrobromide (300 mg, 502 pmol) in 1,4-dioxane (5 ml), was added (2,4-dichlorophenyl)boronic acid (115 mg, 603 pmol), Pd(dppf)Cl2 (23 mg, 30 pmol) and a solution of 1,5M of CS2CO3 (670 pi, 1 mmol). The reaction mixture was heated at 70°C for 45 minutes. 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-((l-(3-fluoropropyl)pyrro lidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate. LC/MS (m/z, MH ⁺ ): 582.

Step 6: (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin-3- y l)oxy )pheny 1) -6,7 -dihydro- 5H-benzo [7 ] annulen- 3 -y 1) acetic acid

To a solution of methyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrro lidin- 3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate (110 mg, 188 pmol) in MeOH (5 ml), was added NaOH 5N (151 pi, 755 pmol). The reaction mixture was heated at reflux for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was taken up in water (10 ml) and aqueous HC1 (5 M) added to reach pH 5. The slurry was extracted with DCM, dried over MgSC and concentrated under reduced pressure. The residue obtained was purified on strong cation exchange (SCX) column to give 65 mg (60%) of (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)acetic acid. LC/MS (m/z, MH ⁺ ): 568.

Example 94. (S)-2-(3-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)py rrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)pr opan-2-ol

A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7 -dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (250 mg, 379.63 pmol), 1,4-dioxane (13 ml), Pd(dppf)2Cl2 (16.67 mg, 22.78 pmol), water (3 ml), Cesium carbonate (272.12 mg, 835.19 pmol) and (3-(2-hydroxypropan- 2-yl)phenyl)boronic acid (100.71 mg, 531.49 pmol) was mirowaved 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 saturated aqueous solution of NaCl, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product obtained 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- ((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro- 5H-benzo[7]annulen-3- yl)phenyl)propan-2-ol

Example 95. (S)-2-(4-(8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)py rrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)pr opan-2-ol

A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolid in-3- yl)oxy)phenyl)-6,7 -dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (300 mg, 455.56 pmol), 1,4-dioxane (13 ml), Pd(dppf)2Cl2 (20 mg, 27.33 pmol), water (3 ml), Cesium carbonate (326.55 mg, 1 mmol) and (4-(2-hydroxypropan-2- yl)phenyl)boronic acid (118.36 mg, 637.78 pmol) was mirowaved 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 saturated aqueous solution of NaCl, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product obtained 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- ((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro- 5H-benzo[7]annulen-3- yl)phenyl)propan-2-ol

Example 96. (S)-3-(4-(8-(2-chloro-3-fluorophenyl)-3-(3-nitrophenyl)-6,7- dihydro-5H- benzo[7]annulen-9-yl)phenoxy)-l-(3-fluoropropyl)pyrrolidine

To a solution of (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 98, Step 1] (260 mg, 404,94 pmol), in 1,4-dioxane (13 ml), was added 3-nitrophenylboronic acid (68,97 mg, 404,94 pmol), Pd(dppf)2C12 (17,78 mg, 24,30 pmol), and Cs2C03 (290,26 mg, 890,86 pmol) in solution in water (3 ml). The reaction mixture was microwaved at 90°C for 30 minutes. The reaction mixture was diluted with EtOAc, washed with a saturated K2CO3 solution, brine, dried over MgSC , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture 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)-l-(3-fluoropropyl)pyrrolidine.

Example 97. (S)-3-(8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3-fluoropropyl) pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)aniline

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)-l-(3-fluoropropyl)pyrrolidine [Example 96] (150 mg, 243,86 pmol), in iPrOH (35 ml), was added zinc powder (95,66 mg, 1,46 mmol), and NH4CI (104,35 mg, 1,95 mmol) in solution in water (5 ml). The reaction mixture was refluxed for 2 hours, filtered, rinsed with iPrOH and the filtrate was evaporated under reduced pressure.

The residue was taken up in EtOAc, washed with a saturated K ₂ CO ₃ solution, brine, dried over MgS0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of heptane/EtOAc and EtOAc/MeOH (95/5; and 95/5; v/v) to give 95 mg (67%) of (S)-3-(8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-yl)aniline.

Example 98. (S)-2-(4-(8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3-fluoroprop yl)pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)pr opan-2-ol

Step 1: (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate This compound was prepared as in Example 1, Step 1, but replacing (S)-8-(2,4- dichlorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy )phenyl)-6,7-dihydro-5H- benzo[7]annulen-3-ol by (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3- fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benz o[7]annulen-3-ol [WO2017140669] (750 mg, 1.47 mmol) to give 800 mg (85%) of (S)-8-(2-chloro-3- fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)p henyl)-6,7-dihydro-5H- benzo[7]annulen-3-yl trifluoromethanesulfonate. LC/MS (m/z, MH ⁺ ): 642.

Step 2: (S)-2-(4-(8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3-fluoroprop yl)pyrrolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)pr opan-2-ol

A mixture of (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((l-(3-fluoropropyl)pyr rolidin-3- yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (200 mg, 311.49 pmol), 1,4-dioxane (13 ml), Pd(dppf)2Cl2 (13.68 mg, 18.69 pmol), water (3 ml), Cesium carbonate (223.28 mg, 685.27 mihoΐ) and (4-(2-hydroxypropan-2-yl)phenyl)boronic acid (80.93 mg, 436.08 pmol) was mirowaved at 60°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 saturated aqueous solution of K2CO3, dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude product obtained 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-((l-(3-fluoropropyl)pyrrolidin-3-yl)oxy)p henyl)-6,7-dihydro-5H- benzo [7 ] annulen- 3 -y l)pheny l)propan-2 -ol .

The compounds according to the invention were subjected to pharmacological tests for determining their degradation effects on estrogen receptors.

Test: Estrogen receptor degradation activity

Said test involves measuring the in vitro degradation activity of the compounds of the invention.

The measurements of the degradation activities were made using a breast cancer cell ERa in cell western assay as described hereunder.

MCF7 cells (ATCC) were seeded in 384 wells microplate (collagen coated) at a concentration of 10000 cells/ 30 pL per well in red phenol free MEM alpha medium (invitrogen) containing 5% charcoal dextran striped FBS. The following day, 9 points serial 1:5 dilution of each compound was added to the cells in 2.5pL at final concentrations ranging either from 3-0.000018 mM (column « % Degradation at 3 pM in table 2) or from 0.3- 0.0000018 pM (column « % Degradation at 0.3 pM in table 2), or 0.1 pM for fulvestrant (using as positive control). At 4 hours post compound addition the cells were fixed by adding 25 pL of formalin (final concentration 5% formalin containing 0.1% triton) for 10 minutes at room temperature and then washed twice with PBS. Then, 50 pL of LI-COR blocking buffer containing 0.1% Triton was added to plate for 30 minutes at room temperature. LI- COR blocking buffer was removed and cells were incubated overnight at cold room with 50 pL anti-ER rabbit monoclonal antibody (Thermo scientific MAI-39540) diluted at 1:1000 in LI-COR blocking buffer containing 0.1% tween-20. Wells which were treated with blocking buffer but no antibody were used as background control. Wells were washed twice with PBS (0.1% tween-20) and incubated at 37 °C for 60 minutes in LI-COR (0.1% tween- 20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and Syto-64 a DNA dye (2 mM final concentration). Cells were then washed 3 times in PBS and scanned in ACUMEN explorer (TTP-Labtech). Integrated intensities in the green fluorescence and red fluorescence were measured to determine the levels of ERa and DNA respectively.

The degradation activity with respect to estrogen receptors in this test is given by the concentration which degrades 50% of the estrogen receptor (or IC50) in nM.

The% of ERa levels decrease were determined as follows: % inhibition = 100 * (1- (sample - fulvestrant: DMSO - fulvestrant)).

The Table 2 below indicates the estrogen receptor degradation activity results for the compounds according to the invention tested either at 3 mM or at 0.3 mM, and demonstrates that said compounds have a significant degradation activity on estrogen receptors.

Table 2:

It is therefore apparent that the compounds of the invention have degradation activities for estrogen receptors, with IC50 less than 1 mM and with degradation levels greater than 50%. The compounds according to the invention can therefore be used for preparing medicaments, especially medicaments which are degraders of estrogen receptors.

Accordingly, in another of its aspects, the invention provides medicaments which comprise a compound of the formula (I), or a pharmaceutically acceptable salt thereof. The invention also relates to the compounds of formula (I) defined above, or a pharmaceutically acceptable salt thereof, for use in therapy, especially as inhibitors and degraders of estrogen receptors.

The invention also relates to the compounds of formula (I) defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.

In particular, the invention relates to the compounds of formula (I) defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

In an embodiment, the cancer is a hormone dependent cancer.

In another embodiment, the cancer is an estrogen receptor dependent cancer, particularly the cancer is an estrogen receptor a dependent cancer.

In another embodiment, the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancer, or a metastasis thereof.

In another embodiment, the metastasis is a cerebral metastasis.

In another embodiment, the cancer is breast cancer. Particularly, the breast cancer is an estrogen receptor positive breast cancer (ERa positive breast cancer).

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

In a further embodiment, the compound of formula (I) is as used as single agent or in combination with other agents such as CDK4/6 or PI3K inhibitors.

The present invention, according to another of its aspects, also relates to a method of treating the pathological conditions indicated above, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In an embodiment of this method of treatment, the subject is a human.

The present invention also relates to the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to the present invention, for the manufacture of a medicament useful in treating any of the pathological conditions indicated above, more particularly useful in treating cancer. According to another of its aspects, the present invention relates to pharmaceutical compositions comprising as active principle a compound according to the invention. These pharmaceutical compositions comprise an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

The said excipients are selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intra-tracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, or its base, acid, zwitterion or salt thereof, may be administered in a unit administration form, in a mixture with conventional pharmaceutical excipients, to animals and to human beings for the treatment of the above disorders or diseases.

The unit administration forms appropriate include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intra-tracheal, intra-ocular and intra-nasal administration forms, forms for inhalative, topical, transdermal, subcutaneous, intra-muscular or intravenous administration, rectal administration forms and implants. For topical application it is possible to use the compounds according to the invention in creams, gels, ointments or lotions.

As an example, a unit administration form of a compound according to the invention in tablet form may comprise the following components:

Compound according to the invention 50.0 mg

Mannitol 223.75 mg

Sodium croscarmellose 6.0 mg

Com starch 15.0 mg Hy droxypropy lmethy lcellulo se 2.25 mg Magnesium stearate 3.0 mg

There may be particular cases in which higher or lower dosages are appropriate; such dosages do not depart from the scope of the invention. According to usual practice, the dosage that is appropriate for each patient is determined by the doctor according to the mode of administration and the weight and response of the said patient.