Novel Substituted 6,7-Dihydro-5H-Benzo[7]Annulene Compounds, Processes for Their Preparation and Therapeutic Uses Thereof

Abstract

The present invention relates to a compound of the formula (i) wherein Ar represents a phenyl or a 6-membered heteroaryl group, R1 and R2 represent independently a hydrogen atom or a deuterium atom, R3 represents (1) a —COR4 group, (2) a —BOR5OR6 group, (3) a —X—Z group, (4) a (C.sub.1-C.sub.6)alkyl group or a (C.sub.1-C.sub.6)alkenyl group, (5) a —X—S(O).sub.n(R7).sub.p(R8).sub.q group, (6) a halogen atom, a —NH.sub.2 group or a -CN group, (7) a —O—R11 group, (8) a —NH—COR9 group, (9) a —C(═NH)NHOH group, (10) a —NH—C(NH)—R9′ group, or (11) a —NHCOCOOR12 group or a —NHCOCONR12′R12″ group, X represents abond, a —NH— group, a —CONH— group or a —CO— group, Z represents a 4 or 5-membered cycloalkyl, a 4 or 5-membered heterocylcloalkyl group, a 4 or 5-membered heteroaryl group or a phenyl group or a pharmaceutically acceptable salt thereof. The present invention further relates to a medicament comprising said compound of formula (I) and to said compound of formula (I) for use as an inhibitor and degrader of estrogen receptors.

##STR00001##

Claims

1. A compound of the formula (I) ##STR00277## 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 (C.sub.1-C.sub.3)alkyl group, a (C.sub.1-C.sub.3)alkoxy group, a (C.sub.1-C.sub.3)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 —BOR5OR6 group, (3) a —X—Z group, (4) a (C.sub.1-C.sub.6)alkyl group or a (C.sub.1-C.sub.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(O).sub.n(R7).sub.p(R8).sub.q group, (6) a halogen atom, a —NH.sub.2 group or a —CN group, (7) a —O—R11 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 (C.sub.1-C.sub.6)alkyl group, a —NRR′ group, a —NHNH.sub.2 group, a —NHNHCONH.sub.2 group, a —NHNHCS-1H-imidazolyl group or a —NHSO.sub.2CH.sub.3 group, wherein R and R′ independently represent a hydrogen atom, a —OH group, a (C.sub.1-C.sub.6)alkoxy group or a (C.sub.1-C.sub.6)alkyl group, R5 and R6 independently represent a hydrogen atom, a (C.sub.1-C.sub.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 (C.sub.1-C.sub.4)alkyl groups, R7 and R8 independently represents a (C.sub.1-C.sub.6)alkyl group optionally partially or fully substituted by fluorine atoms, a —NH.sub.2 group or a ═NH group, R9 represents a hydrogen atom, a (C.sub.1-C.sub.6)alkoxy group, a (C.sub.1-C.sub.6)alkyl group or a (C.sub.3-C.sub.6)cycloalkyl group, each (C.sub.1-C.sub.6)alkoxy group, (C.sub.1-C.sub.6)alkyl group or (C.sub.3-C.sub.6)cycloalkyl group being optionally substituted by one to three fluorine atom(s), a —OH group or a (C.sub.1-C.sub.4)alkyl group, R9′ represents a (C.sub.1-C.sub.6)alkyl group or a (C.sub.3-C.sub.6)cycloalkyl group, R11 represents a (C.sub.1-C.sub.6)alkyl group, optionally substituted by one to six fluorine atoms, R12 represents a (C.sub.1-C.sub.6)alkyl group, R12′ and R12″ independently represent a hydrogen group or a (C.sub.1-C.sub.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 —CONH.sub.2 group, by a —NO.sub.2 group, by a —NH.sub.2 group or by a (C.sub.1-C.sub.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 (C.sub.1-C.sub.6)alkyl group and an oxo group, or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) according to claim 1, characterized in that 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.

3. The compound of formula (I) according to claim 1 or 2, characterized in that R3 represents a —COR4 group, wherein R4 represent a (C.sub.1-C.sub.6)alkyl group, a —NRR′ group, a —NHNH.sub.2 group, a —NHNHCONH.sub.2 group, a −NHNHCS-1H-imidazolyl group or a —NHSO.sub.2CH.sub.3 group, and R and R′ independently represent a hydrogen atom, a —OH group, a (C.sub.1-C.sub.6)alkoxy group or a (C.sub.1-C.sub.6)alkyl group, or a pharmaceutically acceptable salt thereof.

4. The compound of formula (I) according to claim 1 or 2, characterized in that R3 represents a —BOR5OR6 group, wherein R5 and R6 independently represent a hydrogen atom or a (C.sub.1-C.sub.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.

5. The compound of formula (I) according to claim 1 or 2, characterized in that 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 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 —CONH.sub.2 group, by a —NO.sub.2 group, by a —NH.sub.2 group or by a (C.sub.1-C.sub.6)alkyl group, itself optionally substituted by a hydroxy group, with R12′ and R12″ independently being a hydrogen group or a (C.sub.1-C.sub.6)alkyl group, or a pharmaceutically acceptable salt thereof.

6. The compound of formula (I) according to claim 1, 2 or 5, characterized in that 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-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 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 —CONH.sub.2 group, by a —NO.sub.2 group, by a —NH.sub.2 group or by a (C.sub.1-C.sub.6)alkyl group, itself optionally substituted by a hydroxy group, with R12′ and R12″ independently being a hydrogen group or a (C.sub.1-C.sub.6)alkyl group, or a pharmaceutically acceptable salt thereof.

7. The compound of formula (I) according to claim 1, 2 or 5, characterized in that 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 heterocycloalkyl 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.

8. The compound of formula (I) according to claim 1 or 2, characterized in that R3 represents a (C.sub.1-C.sub.6)alkyl group or a (C.sub.1-C.sub.6)alkenyl 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.

9. The compound of formula (I) according to claim 1 or 2, characterized in that R3 represents a group selected from a —SO.sub.2NHCO(CH.sub.3) group, a —CONHSO.sub.2(CH.sub.3) group, a —SO.sub.2NH.sub.2 group, a —SO(CH.sub.3)NH group, a —SO.sub.2CH.sub.3 group, a —NHSO.sub.2(CH.sub.3) group or a —NHSO.sub.2(CF.sub.3) group, or a pharmaceutically acceptable salt thereof.

10. The compound of formula (I) according to claim 1 or 2, characterized in that R3 represents a halogen atom, in particular a bromine atom, a —NH.sub.2 group, or a —CN group, or a pharmaceutically acceptable salt thereof.

11. The compound of formula (I) according to claim 1 or 2, characterized in that R3 represents a —O—R11 group, wherein R11 represents a (C.sub.1-C.sub.6)alkyl group optionally substituted by one to six fluorine atoms, preferably by one to three fluorine atoms, or a pharmaceutically acceptable salt thereof.

12. The compound of formula (I) according to claim 1 or 2, characterized in that R3 represents a —NH—COR9 group, wherein R9 represents a (C.sub.1-C.sub.6)alkoxy group, a (C.sub.1-C.sub.6)alkyl group or a (C.sub.3-C.sub.6)cycloalkyl group, each (C.sub.1-C.sub.6)alkyl group or (C.sub.3-C.sub.6)cycloalkyl group being optionally substituted by one to three fluorine atom(s), a —OH group or (C.sub.1-C.sub.4)alkyl or a pharmaceutically acceptable salt thereof.

13. The compound of formula (I) according to claim 1 or 2, characterized in that R3 represents a —NH—C(NH)—R9′ group, wherein R9′ represents a (C.sub.1-C.sub.6)alkyl group or a (C.sub.3-C.sub.6)cycloalkyl group, or a pharmaceutically acceptable salt thereof.

14. The compound of formula (I) according to claim 1 or 2, characterized in that R3 represents a —NHCOCOOR12 group or a —NHCOCONR12′R12″ group, wherein R12 represents a (C.sub.1-C.sub.6)alkyl group, and R12′ and R12″ independently represent a hydrogen group or a (C.sub.1-C.sub.6)alkyl group, or a pharmaceutically acceptable salt thereof.

15. A medicament, characterized in that it comprises a compound of formula (I) according to any of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any of claims 1 to 14, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

17. A compound of formula (I) according to any of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use as an inhibitor and degrader of estrogen receptors.

18. A compound of formula (I) according to any of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.

19. A compound of formula (I) for use according to claim 18, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

Description

EXAMPLES

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

[0343] ##STR00135##

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

[0344] ##STR00136##

[0345] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol [WO2017140669] (141 mg, 267.82 μmol), in DCM (2 ml) and pyridine (35 μl, 429 μmol) was added trifluoromethanesulfonic anhydride (96 μl, 568 μmol). The reaction mixture was stirred at room temperature for 15 minutes. Cold water (5 ml) and DCM (10 ml) was added. After decantation, the organic phase was dried over MgSO.sub.4, filtered and evaporated under reduced pressure to give 203 mg of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-1)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yltrifluoromethanesulfonate.

[0346] LC/MS (m/z, MH+): 558

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

[0347] ##STR00137##

[0348] A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-1)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (89 mg, 81 μmol), 1,4-dioxane (0.9 ml), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (55 mg, 216.59 μmol), bis(triphenylphosphine)palladium(II)chloride (7 mg, 10 μmol) and sodium acetate (45 mg, 543 μmol) was 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-1,3 ,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine.

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

[0349] ##STR00138##

[0350] A mixture of tert-butyl (S)-3-(4-(8-(2,4-dichlorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [Example 1] (159 mg, 250 μmol), in THF (1.6 ml), water (0.4 ml) and NaIO.sub.4 (160 mg, 749 μmol) was stirred at room temperature for 35 minutes. Hydrochloric acid 1M (0.17 ml, 170 μmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Water (10 ml) and DCM (10 ml) 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)boronic acid.

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

[0351] ##STR00139##

[0352] A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (511 mg, 921.58 μmol), pyridine (0.05 ml, 594.68 μmol), di-tert-butyl dicarbonate (105 mg, 460.79 μmol) and NH.sub.4HCO.sub.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-((1-(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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)isoxazol-3-ol

[0353] ##STR00140##

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

[0354] ##STR00141##

[0355] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (300 mg, 541.04 μmol), in THF (10 ml), was added CDI (164.50 mg, 811.57 μmol), and the reaction mixture was heated at reflux for 3 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 MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM, EtOAc, and MeOH (50/45/5, v/v/v) to give 0.56 g (85%) methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopropanoate.

[0356] LC/MS (m/z, MH+): 610

Step 2: 3-(8-(2,4-Dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxo-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide

[0357] ##STR00142##

[0358] A mixture of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopropanoate (100 mg, 163.79 μmol), o-(tetrahydro-2h-pyran-2-yl)hydroxylamine (60.59 mg, 491.36 μmol) and 4-dimethylaminopyridine (54 mg, 442.23 μmol) in 1-methyl-2-pyrrolidinone (2 ml) was microwaved at 120° C. for 2 hours. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over MgSO.sub.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)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxo-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide.

[0359] LC/MS (m/z, MH+): 695

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

[0360] ##STR00143##

[0361] To a solution of 3-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxo-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide (42 mg, 60.37 μmol) in MeOH (2 ml), was added conc. HCl (0.5 ml, 6.25 mmol), and the reaction mixture was stirred at room temperature for 40 minutes. Saturated NaHCO.sub.3 solution and EtOAc was added and the organic phase washed with water, dried over MgSO.sub.4, 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)isoxazol-3-ol.

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

[0362] ##STR00144##

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

[0363] ##STR00145##

[0364] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 44] (3.3g, 5.52 mmol) in THF (150 ml) cooled at −40° C., was added dropwise LiAlH.sub.4 (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 MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography, eluting with a gradient of MeOH in DCM (100/0 to 95/05, v/v) to give 2.7 g (91%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde

[0365] LC/MS (m/z, MH.sup.+): 538.

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

[0366] ##STR00146##

[0367] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde (100 mg, 185.71 μmol) in DMF (3 ml), was added (difluoromethyl)trimethylsilane (34.60 mg, 278.56 μmol) and phosphazene base P4-t-Bu 0.8M in hexane (46.43 μl, 37.14 μmol). The reaction mixture was stirred for 1 hour at room temperature. Then, water (2 ml) was added followed by a solution of HCl 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 K.sub.2CO.sub.3 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 MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography, eluting with a gradient of MeOH in DCM (100/0 to 95/05, v/v) to give 20 mg (18%) of 1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo [7]annulen-3-yl)-2,2-difluoroethan-1-ol.

Example 6. (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide

[0368] ##STR00147##

[0369] To a solution of methyl (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl]oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [WO2017140669] (849 mg, 1.49 mmol) in EtOH (15 ml), was added hydrazine hydrate (724.94 μl, 14.93 mmol). The reaction mixture was heated at reflux for 16 hours, and partitioned between EtOAc and water. The organic phase was washed with water and brine, dried over MgSO.sub.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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide.

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

[0370] ##STR00148##

[0371] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide [Example 6] (160 mg, 281.44 μmol) in acetic acid (1 ml), was added triethyl orthoformate (1 ml, 5.83 mmol). The reaction mixture was 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-((1-(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-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine

[0372] ##STR00149##

[0373] To a mixture of ((S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde [Example 5, Step 1] (300 mg, 557.12 μmol) in DCM (5 ml), was added bis(2-methoxyethyl)aminosulfur trifluoride 2.7M in toluene (2.06 ml, 5.57 mmol). The reaction mixture was stirred 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 MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography, eluting with a gradient of MeOH in DCM (100/0 to 95/05, v/v) to give 80 mg (26%) of S)-3-(4-(8-(2,4-dichlorophenyl)-3-difluoromethyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine

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

[0374] ##STR00150##

Step 1: Tert-butyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl)hydrazine-1-carboxylate

[0375] ##STR00151##

[0376] To a suspension of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (400 mg, 721.39 μmol) in MeCN (10 ml) was added DIPEA (377,99 μl, 2.16 mmol), tert-butyl carbazate (129 mg, 937.81 μmol), and TBTU (354.53 mg, 1.08 mmol). The reaction mixture was stirred at room temperature for 3 hours, partitioned between water and EtOAc, and the organic phase washed with water, dried over MgSO.sub.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 450 mg (93%) of tert-butyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl)hydrazine-1-carboxylate.

[0377] LC/MS (m/z, MH+): 668

Step 2: Tert-butyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonothioyl)hydrazine-1-carboxylate

[0378] ##STR00152##

[0379] To a solution of tert-butyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl)hydrazine-1-carboxylate (100 mg, 149.56 μmol) in 1,4-dioxane (1.5 ml), was added lawesson's reagent (62 mg, 149.56 μmol), and the reaction mixture was microwaved at 100° C. for 10 minutes. The reaction mixture was partitioned between water and EtOAc, and the organic phase washed with water, brine, dried over MgSO.sub.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 40 mg (39%) of tert-butyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonothioyl)hydrazine-1-carboxylate

[0380] LC/MS (m/z, MH+): 684

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

[0381] ##STR00153##

[0382] A mixture of tert-butyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonothioyl)hydrazine carboxylate (225 mg, 328.61 μmol), and HCl 4N in 1,4-dioxane (1 ml, 4.00 mmol), was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure to give 150 mg (78%) of crude (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene carbothiohydrazide.

[0383] LC/MS (m/z, MH+): 584

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

[0384] ##STR00154##

[0385] A suspension of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbothiohydrazide (150 mg, 256.59 μmol) in triethyl orthoformate (1.5 ml), was 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 MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM, EtOAc, and MeOH (50/45/5; v/v/v) to give 43.7 mg (33%) of (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazole.

Example 10. 1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroethan-1-ol

[0386] ##STR00155##

[0387] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde [Example 5, Step 1] (160 mg, 297.13 μmol) in THF (5 ml), was added (trifluoromethyl)trimethylsilane (58 μl, 0.392 mmol) and cesium fluoride (22 mg, 0.145 mmol). The reaction mixture was stirred for 1 hour at room temperature. Then, water (2 ml) was added followed by a solution of HCl 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 K.sub.2CO.sub.3 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 MgSO.sub.4, 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 1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroethan-1-ol.

Example 11. (S)-3-(4-(3-bromo-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine

[0388] ##STR00156##

Step 1: (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl chloride

[0389] ##STR00157##

[0390] To (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (300 mg, 541 μmol) was added thionyl chloride (3 mL) at 0° C. under an inert atmosphere, the reaction mixture was stirred at room temperature for 3 h. The thionyl chloride was evaporated under reduced pressure to afford 308 mg (99.4%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl chloride 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

[0391] ##STR00158##

[0392] To a suspension of 2-mercaptopyridine N-oxide sodium salt (136 mg, 876 μmol) in refluxing bromotrichloromethane (5 mL) at 105° C., was added dropwise (5 min) a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl chloride (308 mg, 537 μmol) and AIBN (22.5 mg, 134 μmol) in bromotrichloromethane (8 mL) 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)-1-(3-fluoropropyl)pyrrolidine.

Example 12. (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2-dihydro-3H-pyrazol-3-one

[0393] ##STR00159##

[0394] A solution of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopropanoate [Example 4, Step 1] (117 mg, 191.63 μmol), in EtOH (10 ml), THF (1 ml), and hydrazine hydrate (12 mg, 191.63 μmol) was 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 MgSO.sub.4, 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2-dihydro-3H-pyrazol-3-one.

Example 13. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)isoxazol-5(4H)-one

[0395] ##STR00160##

[0396] A mixture of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopropanoate oxopropanoate [Example 4, step 1] (80 mg, 131.03 μmol), in EtOH (4 ml), hydroxylamine hydrochloride (23.47 mg, 327.57 μmol) and NaHCO3 (22 mg, 262.06 μmol), 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 MgSO.sub.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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)isoxazol-5(4H)-one.

Example 14. (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl)hydrazine-1-carboxamide

[0397] ##STR00161##

[0398] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide [Example 6] (200 mg, 351.79 μmol) in chloroform (10 ml), was added acetic acid (20.74 μl, 351.79 μmol), and sodium cyanate (35.36 mg, 529.69 μmol). The reaction mixture was heated at 50° C. for 24 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 MgSO.sub.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 47.5 mg (22.1%) of (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonyl)hydrazine-1-carboxamide.

Example 15. (S)-8-(2,4-dichlorophe nyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-(methylsulfonyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide

[0399] ##STR00162##

[0400] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl]oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (150 mg, 270 μmol) in DCM (10 ml), was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (108 mg, 541 μmol), 4-dimethylaminopyridine (68.85 mg, 541 μmol), and methanesulfonamide (53 mg, 541 μmol). The reaction mixture was stirred at room temperature for 16 hours, and partitioned between DCM and water. The organic phase was washed with water and brine, dried over MgSO.sub.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 17.6 mg (10.3%) of (S)-8-(2,4-dichlorophe nyl)-9-(4-((1-(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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2H-tetrazole

[0401] ##STR00163##

[0402] A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile [Example 22] (43 mg, 66 μmol), dibutyltin oxide (5 mg, 20.47 μmol) and azidotrimethylsilane (36 μl, 260 μmol) in 1,4-dioxane (0.6 ml) was microwaved at 100° C. for 6 hours. After cooling and LCMS control, addition of dibutyltin oxide (5 mg, 20.47 μmol) and azidotrimethylsilane (36 μl, 260 μmol) 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), 5 μm, 250×30 mm; eluent: CO2 65%/MeOH (+0.1% TEA) 35% during 3 min, then CO2 60%/MeOH (+0.1% TEA) 40%; flow: 120 ml/min; Pinlet: 160 bars; Poutlet:100 bars; Temp oven: 40° C.; λ=254 nm to give 20 mg (53%) of (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2H-tetrazole.

Example 17. (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-(2H-tetrazol-5-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide

[0403] ##STR00164##

[0404] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl]oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (150 mg, 270 μmol) in DMF (15 ml), was added (1-[bis(dimethylamino) methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 114.29 mg, 5297.57 μmol), 4-dimethylaminopyridine (1.72 mg, 13.53 μmol), TEA (112.1 μl, 811.57 μmol), and amino tetrazole (23 mg, 270.52 μmol). 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 MgSO.sub.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 22.5 mg (13.4%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-(2H-tetrazol-5-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide.

Example 18. (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide

[0405] ##STR00165##

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

[0406] ##STR00166##

[0407] To a solution of (R)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (277 mg, 500 μmol) in DMF (6 ml) was added O-benzylhydroxylamine (96 mg, 90.94 μmol), HATU (333 mg, 850 μmol) and DIPEA (464 μl, 2.5 mmol). The reaction mixture was stirred at room temperature for 4 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 MgSO.sub.4, 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide.

[0408] LC/MS (m/z, MH+): 659

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

[0409] ##STR00167##

[0410] In an autoclave, a mixture of (S)—N-(benzyloxy)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (150 mg, 227 μmol) and Pd/C 10% (15 mg) in MeOH (6 ml) was hydrogenated (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-((1-(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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide

[0411] ##STR00168##

[0412] To a solution of (R)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (110 mg, 198 μmol) in DMF (2.5 ml) was added O-methylhydroxylamine hydrochloride (25 mg, 297 μmol), HATU (132 mg, 337 μmol) and DIPEA (184 μl, 992 μmol). The reaction mixture was stirred at room temperature for 4 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 MgSO.sub.4, 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-((1-(3-fluoropropyl)pyrrolidin-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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acrylic acid

[0413] ##STR00169##

Step 1: Tert-butyl (S,E)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acrylate

[0414] ##STR00170##

[0415] A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-1)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, step 1] (203 mg, 308 μmol), DMF (3 ml), ter-butyl acrylate (305 μl, 308 μmol), bis(triphenylphosphine)palladium(II)chloride (48 mg, 68 μmol) and TEA (382 μl, 308 μmol) was microwaved at 120° C. for 1 hour. Water (5 ml) and EtOAc (10 ml) was added. After decantation, the organic phase was dried over MgSO.sub.4, 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-((1-(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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acrylic acid

[0416] ##STR00171##

[0417] A mixture of tert-butyl (S,E)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acrylate (83 mg, 130 μmol) and hydrochloric acid (2.2 ml, 4N in 1,4-dioxane) was stirred at room temperature for 6 hours. The reaction mixture was evaporated under reduced pressure and the residue was treated on SCX (strong cation exchange) column to give 39 mg (52%) of (S,E)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acrylic acid.

Example 21. (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole

[0418] ##STR00172##

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

[0419] ##STR00173##

[0420] A mixture of (S)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [WO2017140669] (500 mg, 973 μmol), 1,4-dioxane (12 ml), water (2 ml), Cs.sub.2CO.sub.3 (666 mg, 2.04 mmol) and (1-(ter-butoxycarbonyl)-1H-pyrazol-4-yl)boronic acid (207 mg, 974 μmol), and Pd(dppf)Cl.sub.2 (43 mg, 58.42 μmol), 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 MgSO.sub.4, 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole.

[0421] LC/MS (m/z, MH+): 432

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

[0422] ##STR00174##

[0423] A mixture of (S)-4-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole (170 mg, 394 μmol), THF (15 ml) and pyridinium bromide perbromide (133 mg, 414 μmol) was stirred at room temperature for 2 hours. Water (20 ml) and DCM (100 ml) was added, followed by a saturated solution of NaHCO.sub.3 to reach pH 7. After decantation, the organic phase was dried over MgSO.sub.4, filtered and evaporated under reduced pressure to give 160 mg (80%) of (S)-4-(8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-1)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole.

[0424] LC/MS (m/z, MH+): 510

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

[0425] ##STR00175##

[0426] A mixture of (S)-4-(8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole (90 mg, 176 μmol), 1,4-dioxane (8 ml), Pd(dppf)Cl2 (9 mg, 11 μmol), water (1.5 ml), Cs.sub.2CO.sub.3 (121 mg, 370 μmol) and (2,4-dichlorophenyl)boronic acid (37 mg, 194 μmol) 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 MgSO.sub.4, 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole.

Example 22. (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile

[0427] ##STR00176##

[0428] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 3] (100 mg, 180.67 μmol) in THF (1 ml) cooled at 0° C., was added TEA (33 μl, 235 μmol) and TFAA (28 μl, 199 μmol). The reaction mixture was stirred for 15 minutes at 0° C. and 45 minutes at room temperature. NH4C1 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile as trifluoroacetate salt.

Example 23. (S)-4-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole

[0429] ##STR00177##

[0430] A mixture of tert-butyl (S)-4-(8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole [Example 21, step 2] (160 mg, 285 μmol) 1,4-dioxane (8 ml), Pd(dppf)Cl2 (14 mg, 17 μmol), water (1.5 ml), Cs.sub.2CO.sub.3 (195 mg, 599 μmol) and (4-trifluoromethoxy)phenyl)boronic acid (65 mg, 314 μmol) 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 MgSO.sub.4, 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole.

Example 24. (S)-3-(4-(3-(difluoromethoxy)-8-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine

[0431] ##STR00178##

[0432] To a solution of (S)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol [WO2017140669] (100 mg, 184.64 μmol) in MeCN (1.5 ml) cooled at 0° C., was added, KOH (122 mg, 1.85 mmol) in solution in water (0.5 ml) and diethyl (bromodifluoromethyl)phosphonate (54 μl, 295 μmol). 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-yl)phenoxy) -1-(3-fluoropropyl)pyrrolidine.

Example 25. Methyl (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate

[0433] ##STR00179##

[0434] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 3] (200 mg, 361.34 μmol) in DCM (5 ml), and MeOH (5 ml), at −78° C., was added 1,8-diazabicycloundec-7-ene (170.65 μl, 1.08 mmol), and N-bromosuccinimide (65.63 mg, 361.34 μmol). 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 MgSO.sub.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 47.5 mg (22.1%) of (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate.

Example 26. (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboximidamide

[0435] ##STR00180##

[0436] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile [Example 22] (526 mg, 809.84 μmol) in EtOH (10 ml), was added hydroxylamine hydrochloride (84.41 mg, 1.21 mmol), and DIPEA (418.68 mg, 3.24 mmol). The reaction mixture was heated at 80° C. for 4 hours, and the solvent removed under reduced pressure to give 344 mg (74.7%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboximidamide.

Example 27. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-oxadiazol-5(4H)-one

[0437] ##STR00181##

[0438] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboximidamide [Example 26] (175 mg, 307.82 μmol) in 1,4-dioxane (5 ml), was added 1,8-diazabicycloundec-7-ene (53.30 μl, 338.60 μmol), and CDI (76.40 mg, 461.73 μmol). The reaction mixture was heated at reflux for 1 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 MgSO.sub.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 102.5 mg (56%) of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-oxadiazol-5(4H)-one.

Example 28. (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine

[0439] ##STR00182##

[0440] To a solution of (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate [Example 25] (70 mg, 119.96 μmol) in MeOH (5 ml), was added potassium hydroxide solution 7N in MeOH (2 ml, 14 mmol). The reaction mixture was heated at reflux overnight, and diluted with EtOAc.

[0441] The organic phase was washed with water and brine, dried over MgSO.sub.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 14 mg (22.2%) of ((S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine.

Example 29. 4-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3H-1,2,3,5-oxathiadiazole 2-oxide hydrochloride.

[0442] ##STR00183##

[0443] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboximidamide [Example 26] (1.2 g, 2.11 mmol) in THF (5 ml), was added at 0° C., pyridine (343.49 μl, 4.22 mmol), and thionyl chloride (230 μl, 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 MgSO.sub.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 173.8 mg (13%) of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-oxadiazol-5(4H)-one hydrochloride.

Example 30. (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl) pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methane sulfonamide

[0444] ##STR00184##

[0445] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (200 mg, 380.60 μmol) in DCM (10 ml), was added methanesulfonyl chloride (33 μl, 418.66 μmol), and TEA (59 μl, 418.66 μmol). The reaction mixture was stirred at room temperature overnight, and washed with water and brine, dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (98/02; v/v) to give 67.3 mg (22.2%) of (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl) pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methane sulfonamide.

Example 31. (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl) pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazol-2(3H)-one

[0446] ##STR00185##

[0447] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide [Example 6] (141 mg, 248.01 μmol) in 1,4-dioxane (5 ml), was added 1,8-diazabicycloundec-7-ene (43.72 mg, 272.82 μmol), and CDI (61.56 mg, 372.02 μmol). The reaction mixture was microwaved at 160° C. for 20 minutes, and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (98/02, v/v) to give 27 mg (18.3%) of (S)-5-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl) pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazol-2(3H)-one.

Example 32. Tert-butyl (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate

[0448] ##STR00186##

[0449] Triethylamine (5.59 ml, 39.68 mmol), was added to solid (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (10 g, 18.03 mmol) and the mixture was stirred at room temperature for 1 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 Büchner, rinsed with water and dried. The crude compound was purified by flash chromatography eluting with EtOAc to give 5.8 g (51%) of tert-butyl (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate.

[0450] Alternative Method:

[0451] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (500 mg, 0.85 mmol), tert-butyl carbamate (127 mg, 1.06 mmol), and sodium tert-butoxide (147 mg, 1.51 mmol), in anhydrous toluene (5 ml), under argon, was added tBuXPhos (2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl, 151 mg, 0.31mmol), and Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0), 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.sub.2SO.sub.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-((1-(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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxathiazol-2-one

[0452] ##STR00187##

[0453] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 3] (200 mg, 361.34 μmol) in toluene (5 ml), was added chlorocarbonylsulfenyl chloride (57 mg, 433.60 μmol). The reaction mixture was refluxed for 1 hour, diluted with EtOAc and washed successively with water, brine, dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified first by flash chromatography eluting with a mixture of DCM and MeOH (99/01; v/v) and then by reverse phase HPLC to give 121.5 mg (55%) of (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazole.

Example 34. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-oxadiazole-5(4H)-thione

[0454] ##STR00188##

[0455] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboximidamide [Example 26] (218 mg, 383.46 μmol) in 1,4-dioxane (5 ml), was added 1,8-diazabicycloundec-7-ene (482 μl, 3 mmol), and TCDI (108 mg, 575.18 μmol). The reaction mixture was heated at reflux for 2 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 MgSO.sub.4, 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-oxadiazole-5(4H)-thione.

Example 35. (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,1,1-trifluoromethanesulfonamide

[0456] ##STR00189##

[0457] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (200 mg, 380.60 μmol) in DCM (10 ml), was added trifluoromethane sulfonic anhydride (70 μl, 418.66 μmol), and TEA (59 μl, 418.66 μmol). The reaction mixture was stirred at room temperature for 2 hours, and washed with water and brine, dried over MgSO.sub.4, 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-((1-(3-fluoropropyl)pyrrolidin-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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-4-hydroxycyclobut-3-ene-1,2-dione

[0458] ##STR00190##

[0459] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (200 mg, 380.60 μmol) in DMF (10 ml), was added 3,4-dihydrocyclobuty-3-ene-1,2-dione (48 mg, 418.66 μmol). 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 MgSO.sub.4, 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-4-hydroxycyclobut-3-ene-1,2-dione.

Example 37. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,2,4-thiadiazol-5(4H)-one

[0460] ##STR00191##

[0461] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-hydroxy-6,7-dihydro-5H-benzo[7]annulene-3-carboximidamide [Example 26] (324 mg, 569.91 μmol) in THF (10 ml), was added TCDI (128 mg, 683.89 μmol). The reaction mixture was stirred at room temperature for 1 hour, and partitioned between EtOAc and water, the organic phase was washed with water and brine, dried over MgSO.sub.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 MgSO.sub.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-((1-(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)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-methoxy-1,5-dihydro-2H-pyrrol-2-one

[0462] ##STR00192##

[0463] To a solution of (S)-3-(4-(3-bromo-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [Example 11] (50 mg, 0.084 mmol), in 1,4-dioxane (1.5 ml) and DMF (0.25 ml), was added 4-methoxy-3-pyrrolin-2-one (30 mg, 0.25 mmol), potassium phosphate (22 mg, 0.11 mmol), cuprous iodide (25 mg, 0.14 mmol), and N,N′-dimethylethylenediamine (0.02 ml, 0.17 mmol), under argon. The reaction mixture was microwaved at 100° C. for 5 hours, diluted with EtOAc, washed with water, and brine, dried over MgSO.sub.4, 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)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-methoxy-1,5-dihydro-2H-pyrrol-2-one.

Example 39. (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-one

[0464] ##STR00193##

[0465] To a solution of methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopropanoate [Example 4, Step 1] (300 mg, 491.36 μmol) in THF (10 ml) was added NaOH solution (1N, 3 ml). The reaction mixture was stirred at 50° C. for 16 hours, poured into water and extracted with EtOAc, dried over MgSO.sub.4, filtered and evaporated under pressure to give 229 mg (84%) of (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-one.

[0466] Alternative Method:

[0467] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 44] (500 mg, 836.75 μmol) in THF (10 ml), was added 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 NH4Cl was added, and the mixture was extracted with EtOAc, and the organic phase washed with water, brine, dried over MgSO.sub.4, filtered and evaporated under reduced pressure to give 350 mg (76%) of (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-one.

Example 40. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxazolidin-2-one

[0468] ##STR00194##

[0469] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (100 mg, 0.151 mmol), 2-oxazolidone (27.3 mg, 0.30 mmol), and sodium tert-butoxide (30 mg, 0.304 mmol) in anhydrous toluene (2 ml), 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(0), (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 MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of EtOAc, heptane, and MeOH (75/20/5, v/v/v) to give 45 mg (50%) of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxazolidin-2-one.

Example 41. (S)-3-(8-(2-chloro-4-(2-oxooxazolidin-3-yl)phenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxazolidin-2-one

[0470] ##STR00195##

[0471] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (100 mg, 0.151 mmol), 2-oxazolidone (19 mg, 0.212 mmol), and sodium tert-butoxide (43 mg, 0.432 mmol) in anhydrous toluene (2 ml), 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(0), (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 MgSO.sub.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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxazolidin-2-one.

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

[0472] ##STR00196##

Step 1: Tert-butyl (S)-(8-(2-chloro-4-hydroxyphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate

[0473] ##STR00197##

[0474] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (500 mg, 0.85 mmol), tert-butyl carbamate (127 mg, 1.06 mmol), and sodium tert-butoxide (147 mg, 1.51 mmol), in anhydrous toluene (5 ml), under argon, was added tBuXPhos (2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl, 151 mg, 0.31mmol), and Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0), 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 Na.sub.2SO.sub.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 400 mg (86.8%) of tert-butyl (S)-(8-(2-chloro-4-hydroxyphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate. LC/MS (m/z, MH+): 607

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

[0475] ##STR00198##

[0476] To a solution of tert-butyl(S)-(8-(2-chloro-4-hydroxyphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate (100 mg, 0.16 mmol) in anhydrous DCM (2 ml) was added TFA (trifluoroacetic acid, 0.2 ml). The reaction mixture was stirred for 16 hours, diluted with EtOAc, washed with saturated sodium bicarbonate solution, dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to give 70 mg (86.4%) of (S)-4-(3-amino-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-8-yl)-3-chlorophenol.

Example 43. 5-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)imidazolidine-2,4-dione

[0477] ##STR00199##

[0478] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde [Example 5, step 1] (200 mg, 371.41 μmol) in MeOH (2 ml), was added NH.sub.4CO.sub.3 (107.06 mg, 1.11 mmol), potassium cyanide (26.60 mg, 408.55 μmol), 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 Na2SO4, 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)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)imidazolidine-2,4-dione.

Example 44. (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide

[0479] ##STR00200##

[0480] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (3 g, 5.41 mmol) in DMF (100 ml) was added DIPEA (2.83 ml, 16.23 mmol), HBTU (3 g, 7.75 mmol) and N,O-dimethylhydroxylamine hydrochloride (604.71 mg, 5.95 mmol). The reaction mixture was stirred at room temperature for 4 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 MgSO.sub.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-((1-(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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazole-2(3H)-thione

[0481] ##STR00201##

[0482] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide [Example 6] (386 mg, 678.96 μmol) in 1,4-dioxane (10 ml), was added DBU (120 mg, 746.86 mol), and TCDI (191 mg, 178.03 mol). 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 MgSO.sub.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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazole-2(3H)-thione.

Example 46. (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetimidamide

[0483] ##STR00202##

[0484] To a mixture of methyl acetimidate hydrochloride (375.26 mg, 3.43 mmol) in MeCN (10 ml), was added TEA (480.94 μl, 3.43 mmol). The reaction mixture was stirred for 15 minutes at room temperature. Then, (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (600 mg, 1.14 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solid was filtered off, and washed with EtOAc (200 ml). The organic phase was washed twice with water, once with brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The crude product obtained was purified by flash chromatography eluting in a first 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetimidamide.

Example 47. (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroacetamide

[0485] ##STR00203##

[0486] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (180 mg, 342.54 μmol) in THF (5 ml), was added TEA (57.71 μl, 411.05 μmol) and TFAA (57.75 μl, 411.05 μmol). The reaction mixture was stirred 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 MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100/0 to 90/10, v/v) to give 200 mg (79%) of (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroacetamide.

Example 48. (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetamide

[0487] ##STR00204##

[0488] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (100 mg, 190.30 μmol) in DCM (5 ml), was added at 0° C. TEA (58.94 μl, 418.66 μmol) and acetyl chloride (33.26 μl, 456.72 μmol). 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 MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100/0 to 90/10, v/v) to give 86 mg (80%) of (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetamide.

Example 49. 1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-ol

[0489] ##STR00205##

[0490] To a mixture of (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-one [Example 39] (200 mg, 361.98 μmol) in EtOH (20 ml), was added at 0° C. NaBH4 (27.39 mg, 723.97 μmol). 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 MgSO.sub.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 140 mg (70%) of 1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-ol.

Example 50. (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)propan-2-ol

[0491] ##STR00206##

[0492] To a mixture of (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-one [Example 39] (200 mg, 361.98 μmol) in anhydrous THF (10 ml), was added at 0° C. methyl magnesium bromide (361.98 μl, 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 MgSO.sub.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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)propan-2-ol.

Example 51. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole

[0493] ##STR00207##

[0494] A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, step 1] (350 mg, 478.34 μmol), 1,4-dioxane (13 ml), Pd(dppf)2C12 (21 mg, 28.70 μmol), water (3 ml), Cs.sub.2CO.sub.3 (389.63 mg, 1.20 mmol) and 1H-Pyrazole-3-boronic acid pinacol ester (136.78 mg, 669.67 μmol) 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 MgSO.sub.4, 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazole.

Example 52. (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol

[0495] ##STR00208##

[0496] A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, step 1] (300 mg, 410 mol), 1,4-dioxane (13 ml), Pd(dppf).sub.2Cl.sub.2 (18 mg, 24.60 mol), water (3 ml), Cs.sub.2CO.sub.3 (333.97 mg, 1.03 mmol) and (4-hydroxyphenyl)boronic acid (71.43 mg, 492.01 μmol) 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 MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of EtOAc in heptane (95/5 to 0/100, v/v) to give 140 mg (57%) of (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol.

Example 53. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol

[0497] ##STR00209##

[0498] A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, step 1] (300 mg, 410 mol), 1,4-dioxane (13 ml), Pd(dppf).sub.2Cl.sub.2 (18 mg, 24.60 μmol), water (3 ml), Cs.sub.2CO.sub.3 (333.97 mg, 1.03 mmol) and (3-hydroxyphenyl)boronic acid (79.17 mg, 574.01 μmol) 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 MgSO.sub.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 150 mg (61%) of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol.

Example 54. (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol

[0499] ##STR00210##

[0500] A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, step 1] (300 mg, 410 mol), 1,4-dioxane (13 ml), Pd(dppf).sub.2Cl.sub.2 (18 mg, 24.60 mol), water (3 ml), Cs.sub.2CO.sub.3 (333.97 mg, 1.03 mmol) and (2-hydroxyphenyl)boronic acid (67.86 mg, 492.01 μmol) 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 MgSO.sub.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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenol

Example 55. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid

[0501] ##STR00211##

[0502] To a mixture of methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate [Example 57] (280 mg, 434.37 μmol) in MeOH (20 ml) and THF (10 ml), was added a solution of NaOH 2M (10 ml, 434.37 μmol). The reaction mixture was stirred 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 HCl 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 MgSO.sub.4, filtered and evaporated under reduced pressure to give 175 mg (64%) of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid.

Example 56. Methyl (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate

[0503] ##STR00212##

[0504] A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, step 1] (400 mg, 546.67 μmol), 1,4-dioxane (13 ml), Pd(dppf).sub.2Cl.sub.2 (24 mg, 32.80 μmol), water (3 ml), Cs.sub.2CO.sub.3 (445.29.63 mg, 1.37 mmol) and 4-methoxycarbonylphenyl boronic acid (142 mg, 765.34 μmol) 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 MgSO.sub.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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate.

Example 57. Methyl (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate

[0505] ##STR00213##

[0506] A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, step 1] (400 mg, 546.67 μmol), 1,4-dioxane (13 ml), Pd(dppf).sub.2Cl.sub.2 (24 mg, 32.80 μmol), water (3 ml), Cs.sub.2CO.sub.3 (445.29 mg, 1.37 mmol) and 3-methoxycarbonylphenyl boronic acid (118 mg, 656.01 μmol) 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 MgSO.sub.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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate.

Example 58. (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)pyrrolidin-2-one

[0507] ##STR00214##

[0508] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoro-methanesulfonate [Example 1, step 1] (100 mg, 0.216mmo1), 2-oxazolidone (27 mg, 0.302 mmol), and sodium tert-butoxide (43 mg, 0.432 mmol), in anhydrous toluene (2 ml) in a microwave-vessel, under argon, was added t-Bu-XPhos (28 mg, 0.065 mmol), and Pd.sub.2(dba).sub.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 Na.sub.2SO.sub.4, 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 50×250 mm, 5 μm column applying the following gradient with A: H2O/0.1% formic acid and B: CH3CN/0.1% formic acid: 30% of B at t=0 min, 30% of B at t=5 min, 50% of B at t=25 min and subsequent lyophilization provided 5 mg (4%) of a white solid of (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)pyrrolidin-2-one.

Example 59. (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N′-(1H-imidazole-1-carbonothioyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbohydrazide

[0509] ##STR00215##

[0510] The procedure followed is described in Example 45, The residue was further purified by flash chromatography eluting with a mixture of DCM and MeOH (90/10, v/v) to give 238 mg (51.7%) of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N′-(1H-imidazole-1-carbonothioyl)-6,7-dihydro-5H-benzo[7]annulene carbohydrazide.

Example 60. (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)cyclopropanecarboxamide

[0511] ##STR00216##

[0512] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (600 mg, 1.14 mmol) in DCM (60 ml) was added TEA (138.65 mg, 1.37 mmol) and cyclopropanecarbonyl chloride (127.09 μl, 1.37 mmol). The reaction mixture was stirred 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 K.sub.2CO.sub.3 and once with brine. The organic layers were collected, dried over MgSO.sub.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 480 mg (71%) of (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)cyclopropanecarboxamide.

Example 61. (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)thiazol-2-amine

[0513] ##STR00217##

[0514] To a mixture of (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-one [Example 39] (150 mg, 271.49 μmol) in anhydrous THF (20 ml), was added phenyltrimethylammonium tribromide (244.94 mg, 651.58 μmol), and the reaction mixture was stirred 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 μmol) 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 MgSO.sub.4, filtered and evaporated under reduced pressure. The crude product obtained was purified by flash chromatography eluting in a first 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)thiazol-2-amine.

Example 62. (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)pivalamide

[0515] ##STR00218##

[0516] To a mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (600 mg, 1.14 mmol) in DCM (60 ml), was added 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 MgSO.sub.4, 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)pivalamide.

Example 63. (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide

[0517] ##STR00219##

[0518] Obtained from (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] in 81% yield by an analogous method to Example 3.

Example 64. (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile, 2,2,2-trifluoroacetate

[0519] ##STR00220##

[0520] Obtained from (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 63] in 44% yield by an analogous method to Example 22.

Example 65. 1-(8-(2-chloro-3-fluorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroethan-1-ol

[0521] ##STR00221##

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

[0522] ##STR00222##

[0523] This compound has been prepared as described in Example 44 starting from (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (440 mg, 818 μmol) to give 300 mg (63%) of (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide.

[0524] LC/MS (m/z, MH.sup.+): 581

Step 2: (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde

[0525] ##STR00223##

[0526] This compound has been prepared as described in Example 5, Step 1, starting from (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-methoxy-N-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide (300 mg, 516 μmol) to give 240 mg (89%) of (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde.

[0527] LC/MS (m/z, MH.sup.+): 522

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

[0528] ##STR00224##

[0529] This compound has been prepared as described in Example 10 starting from (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbaldehyde (240 mg, 459.74 μmol) to give 120 mg (44%) of 1-(8-(2-chloro-3-fluorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2,2-trifluoroethan-1-ol.

Example 66. (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1-fluorocyclopropane-1-carboxamide

[0530] ##STR00225##

[0531] To a solution of 1-fluorocyclopropane-1-carboxylic acid (10.01 mg, 91.34 μmol) in DCM (5 ml) was added 1(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (17.87 mg, 91.34 μmol) and 4-dimethylaminopyridine (11.27 mg, 91.34 μmol). The reaction mixture was stirred 10 minutes at room temperature and (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (40 mg, 76.12 μmol) was added. The reaction mixture was stirred 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.sub.2CO.sub.3 and once with brine. The organic layers were collected, dried over MgSO.sub.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 42 mg (90%) of (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl) fluorocyclopropane-1-carboxamide.

Example 67. (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1-methylcyclopropane-1-carboxamide

[0532] ##STR00226##

[0533] To a solution of 1-methylcyclopropane-1-carboxylic acid (58.32 mg, 570.90 μmol) in DCM (5 ml) was added 1(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (111.68 mg, 570.90 μmol) and 4-dimethylaminopyridine (70.45 mg, 570.90 μmol). The reaction mixture was stirred 10 minutes at room temperature and (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (100 mg, 190.30 μmol) was added. The reaction mixture was stirred 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 K.sub.2CO.sub.3 and once with brine. The organic phase was dried over MgSO.sub.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 54 mg (47%) of (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1-methylcyclopropane carboxamide.

Example 68. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2-hydroxycyclopent-2-en-1-one

[0534] ##STR00227##

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

[0535] ##STR00228##

[0536] A solution of 3-bromo-2-((tert-butyldimethylsilyl)oxy)cyclo-pent-2-en-1-one (91.53 mg, 314 μmol), (S)-3-(4-(8-(2,4-dichlorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)-pyrrolidine [Example 1] (200 mg, 314 μmol), Cs.sub.2CO.sub.3 (256 mg, 785 μmol), and Pd(dppf)Cl.sub.2 (13.8 mg, 18.9 μmol) 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 Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to give 225 mg of crude (S)-2-((tert-butyldimethylsilyl)oxy)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)cyclopent-2-en-1-one (85% LCMS purity) which was used without further purification in the next step.

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

[0537] ##STR00229##

[0538] To a solution of crude (S)-2-((tert-butyldimethylsilyl)oxy)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)cyclopent-2-en-1-one (225 mg, 314 μmol) in THF (2 ml) was added at 0° C. TBAF 1M in THF (625 μl, 625 μmol). 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 Na.sub.2SO.sub.4, 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-((1-(3-fluoropropyl)-pyrro-lidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2-hydroxycyclopent-2-en-1-one.

Example 69. (S,Z)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-N,3-dimethylthiazol-2(3H)-imine hydrochloride

[0539] ##STR00230##

[0540] To a solution of (S)-1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)ethan-1-one [Example 39] (100 mg, 181 μmol) in DCM (4 ml) was added benzyltrimethylammonium dichloroiodate (200 mg, 557 μmol). The reaction mixture was stirred under reflux for 16 hours. EtOH (10 ml) and N,N′-dimethylthiourea (19.9 mg, 181 μmol) 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 3 h. After addition of water the mixture was extracted with EtOAc, the organic phase was washed with water and brine, dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a mixture of DCM and MeOH (70/30, v/v) to give 12 mg (10%) of (S,Z)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-N,3-dimethylthiazol-2(3H)-imine as a beige-colored solid.

Example 70. (S)-5-(8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2H-tetrazole, 2,2,2-trifluoroacetate

[0541] ##STR00231##

[0542] Obtained from (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile [Example 64] in 35% yield by an analogous method to Example 16.

Example 71. tert-butyl (S)-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate

[0543] ##STR00232##

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

[0544] ##STR00233##

[0545] To a solution of (S)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-ol [WO2017140669] (2 g, 4.37 mmol), in DCM (200 ml) and pyridine (536 μl, 6.6 mmol) was added 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 NaHCO3 (10 ml) was added. After decantation, the organic phase was dried over MgSO.sub.4, filtered and evaporated under reduced pressure to give 2.6 g (100%) of crude (S)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-yltrifluoromethanesulfonate.

[0546] LC/MS (m/z, MH.sup.+): 590.

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

[0547] ##STR00234##

[0548] To a mixture of (S)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-be nzo[7]annulen-3-yl trifluoromethanesulfonate (170 mg, 288 μmol), in toluene (1 ml), was added tert-butyl-carbamate (43 mg, 360 μmol), tri(dibenzilideneacetone)dipalladium(0) (41 mg, 43 μmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (18 mg, 43 μmol), and sodium tert-butoxide (50 mg, 519 μmol). The reaction mixture was microwaved at 100° C. for 1 hour. The reaction mixture was partitioned between EtOAc and water, the organic phase was washed with brine, dried over MgSO.sub.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 36 mg (22%) of tert-butyl (S)-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate.

Example 72. (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid

[0549] ##STR00235##

[0550] To a mixture of methyl (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate [Example 56] (180 mg, 279.24 μmol) in MeOH (20 ml) and THF (10 ml), was added a solution of NaOH 2M (1 ml, 1 mmol). The reaction mixture was stirred 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 HCl 5N to reach pH 5. The mixture was extracted twice with EtOAc and the organic phase was washed with brine, dried over MgSO.sub.4, filtered and evaporated under reduced pressure to give 120 mg (68%) of (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid.

Example 73. (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazol-5-amine

[0551] ##STR00236##

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

[0552] ##STR00237##

[0553] To a mixture of DMSO (3 ml) and MeCN (138.83 μl, 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate [WO2017140669] (500 mg, 879,49 μmol). The reaction mixture was stirred 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 MgSO.sub.4, 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 430 m (75%) of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-1)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopropanenitrile. LC/MS (m/z, MH.sup.+): 577.

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

[0554] ##STR00238##

[0555] To a solution of (S)-3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-3-oxopropanenitrile (150 mg, 259.73 μmol) in EtOH (1.5 ml) was added hydrazine hydrate (59.70 mg, 1.17 mmol). The reaction mixture was stirred at 100° C. for 3 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 MgSO.sub.4 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1H-pyrazol-5-amine.

Example 74. (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)(3-hydroxyazetidin-1-yl)methanone

[0556] ##STR00239##

[0557] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (100 mg, 180.35 μmol) in DCM (10 ml) was added DIPEA (94.39 μl, 541.04 μmol), HBTU (75.24 mg, 198.38 μmol) and 3-hydroxyazetidine hydrochloride (20.37 mg, 180.35 μmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and EtOAc was added. The organic layer was washed twice with a saturated aqueous solution of K.sub.2CO.sub.3 and once with brine. The organic phase was dried over MgSO.sub.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 82 mg (75%) of (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)(3-hydroxyazetidin-1-yl)methanone.

Example 75. (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-N-(oxetan-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide

[0558] ##STR00240##

[0559] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (100 mg, 180.35 μmol) in DCM (10 ml) was added DIPEA (94.39 μl, 541.04 μmol), HBTU (75.24 mg, 198.38 μmol) and 3-oxetamine (13.59 mg, 180.35 μmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and EtOAc was added. The organic layer was washed twice with a saturated aqueous solution of K.sub.2CO.sub.3 and once with brine. The organic phase was dried over MgSO.sub.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-((1-(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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-2-oxoacetate

[0560] ##STR00241##

[0561] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (100 mg, 190.30 μmol) in DCM (10 ml) was added at 0° C., TEA (66.98 μl, 475.5 μmol) and ethyloxalyl chloride (32.60 μl, 285.45 μmol). 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 K.sub.2CO.sub.3 and once with brine.

[0562] The organic phase was dried over MgSO4 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-2-oxoacetate.

Example 77. (S)—N1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxalamide

[0563] ##STR00242##

[0564] To a solution of ethyl (S)-2-((8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino)-2-oxoacetate [example 76] (40 mg, 63.94 μmol) in MeOH (1 ml) was added ammonia 7M in MeOH (18.27 μl, 127.88 μmol).The reaction mixture was stirred 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.sub.2CO.sub.3 and once with brine. The organic layers were collected, dried over MgSO.sub.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)—N1-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)oxalamide.

Example 78. (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine

[0565] ##STR00243##

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

[0566] ##STR00244##

[0567] To a solution of methyl (S)-8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide [WO2017140669] (6.3 g, 10.80 mmol), in 1,4-dioxane (50 ml), was added 2-chloro-4-methylphenylboronic acid (2.01 g, 11.45 mmol), Cs.sub.2CO.sub.3 (11.27 g, 34.56 mmol) in water (20 ml) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (499 mg, 648.00 μmol). 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate. LC/MS (m/z, MH.sup.+): 548.

Step 2: (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

[0568] ##STR00245##

[0569] To a solution of methyl (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (1 g, 1.82 mmol), in MeOH (15 ml), was added NaOH solution (2M, 3 ml, 6 mmol). The reaction mixture was refluxed for 1 hour, and hydrochloric acid 1N was added to reach pH 6-7. The aqueous phase was extracted with DCM, and the organic extracts dried over MgSO.sub.4, filtered and evaporated under reduced pressure to give 963 mg (99%) of crude (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid. LC/MS (m/z, MH.sup.±): 534.

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

[0570] ##STR00246##

[0571] The synthesis was performed as in Example 3, replacing (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid with (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (963 mg, 1.8 mmol) to give 571 mg (59%) of (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide. LC/MS (m/z, MH.sup.+): 533.

Step 4: methyl (S)-(8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate

[0572] ##STR00247##

[0573] The synthesis was performed as in Example 25, replacing (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(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-((1-(3-fluoropropyl)pyrrolidin-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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate. LC/MS (m/z, MH.sup.+): 563.

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

[0574] ##STR00248##

[0575] The synthesis was performed as in Example 28, replacing (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate with (S)-(8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)carbamate (407 mg, 723 μmol) to give 247 mg (67.7%) of (S)-8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine.

Example 79. (S)-8-(6-ethoxy-2-fluoropyridin-3-yl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide

[0576] ##STR00249##

[0577] Obtained from methyl (S)-8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide [WO2017140669] 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carbonitrile 2,2,2-trifluoroacetate

[0578] ##STR00250##

[0579] Obtained from (S)-8-(6-ethoxy-2-fluoropyridin-3-yl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxamide [Example 79] in 70% yield by an analogous method to Example 22.

Example 81. (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzamide

[0580] ##STR00251##

[0581] A mixture of (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid [Example 72] (200 mg, 279.11 μmol), pyridine (57.40 mg, 725.68 μmol), di-tert-butyl dicarbonate (91.37 mg, 418.66 μmol) and NH.sub.4HCO.sub.3 (33.10 mg, 418.66 μmol) 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 MgSO.sub.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 70 mg (40%) of (S)-4-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzamide.

Example 82. (S)-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanol

[0582] ##STR00252##

[0583] To a solution of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)-pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (200 mg, 361 μmol) in THF (4 ml) was added at 0° C. borane dimethyl sulfide complex 2M in THF (1.08 ml, 2.16 mmol). The reaction mixture was stirred 16 h at room temperature and cooled again to 0° C. A saturated aqueous solution of KH.sub.2PO.sub.4 (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 Na.sub.2SO.sub.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 115 mg (21%) of a white solid. This compound was refluxed for 6 h 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanol as a white solid.

Example 83. methyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate

[0584] ##STR00253##

[0585] A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (350 mg, 478.34 μmol), Pd(dppf).sub.2Cl.sub.2 (21 mg, 28.70 μmol), Cs.sub.2CO.sub.3 (389.63 mg, 1.20 mmol), and 2-methoxycarbonylphenyl boronic acid (124.25 mg, 669.67 μmol) 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 MgSO.sub.4, 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate.

Example 84. (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1-hydroxycyclopropane-1-carboxamide formate

[0586] ##STR00254##

[0587] To a solution of 1-hydroxycyclopropane-1-carboxylic acid (58.28 mg, 570.90 μmol) in dimethylformamide (5 ml) was added HATU (160.80 mg, 418.66 μmol) and TEA (161.28 μl, 1.14 mmol). The reaction mixture was stirred at room temperature for 10 minutes and, (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (200 mg, 380.60 μmol) 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 K.sub.2CO.sub.3 and once with brine. The organic layers were collected, dried over MgSO.sub.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 13 mg (5%) of (S)—N-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-1-hydroxycyclopropane-1-carboxamide formate.

Example 85. (S)-1-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-4-hydroxypyrrolidin-2-one

[0588] ##STR00255##

[0589] A solution of (S)-3-(4-(3-bromo-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [Example 11], (135 mg, 229 μmol), (S)-4-hydroxy-2-pyrrolidi-none (28.36 mg, 275 μmol), (1R,2R)—N,N′-dimethyl-1,2-cyclohexanedi-amine, (3.4 mg, 22.9 μmol), cuprous iodide (2.2 mg, 11.45 μmol), and K.sub.2CO.sub.3 (63 mg, 458 μmol) 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 16 h. After addition of water the mixture was extracted with EtOAc, the organic phase was washed with water and brine, dried over Na.sub.2SO.sub.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 30 mg (21%) of a beige solid of (S)-1-(8-(2,4-dichloro-phenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo-[7]annulen-3-yl)-4-hydroxypyrrolidin-2-one.

Example 86. (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid

[0590] ##STR00256##

[0591] To a mixture of methyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoate [Example 83] (240 mg, 372.32 μmol) in MeOH (15 ml) and THF (15 ml), was added a solution of NaOH 2M (2 ml, 4 mmol). The reaction mixture was stirred at 60° C. for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Water was added, followed by a solution of HCl 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 MgSO.sub.4, filtered and evaporated under reduced pressure to give 170 mg (72%) of (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)benzoic acid

Example 87. N-(8-(2,4-dichlorophenyl)-9-(4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2-difluorocyclopropane-1-carboxamide

[0592] ##STR00257##

[0593] To a solution of 2,2-difluorocyclopropane-1-carboxylic acid (48.91 mg, 380.60 μmol) in DMF (5 ml) was added HATU (80.40 mg, 209.33 μmol) and TEA (80.64 μl, 570.90 μmol). The reaction mixture was stirred at room temperature 10 minutes and, (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 28] (100 mg, 190.30 μmol) was added. The reaction mixture was stirred 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.sub.2CO.sub.3 and once with brine. The organic layers were collected, dried over MgSO.sub.4 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)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)-2,2-difluorocyclopropane-1-carboxamide.

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

[0594] ##STR00258##

[0595] The compounds was prepared as in Example 36, replacing (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine [Example 78] (233 mg, 461.32 μmol) to give 100 mg of (S)-3-((8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)amino) hydroxycyclobut-3-ene-1,2-dione.

Example 89. (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine

[0596] ##STR00259##

[0597] The compound was prepared as in Example 78, Steps 3,4 5, but starting from (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid [WO2017140669] (1 g, 1.81 mmol), to give 68 mg (34%) of (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine.

Example 90. (S)—N-(8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)methanesulfonamide

[0598] ##STR00260##

[0599] To a solution of (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-amine (58 mg, 114 μmol) [Example 89] in DCM (10 ml), was added methanesulfonyl chloride (10 μl, 126 μmol), and TEA (18 μl, 126 μmol). The reaction mixture was left at room temperature overnight and washed with water, brine, dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The residue was purified by preparative SFC to give 22 mg (63%) of (S)—N-(8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl) -6,7-dihydro-5H-benzo[7]annulen-3-yl)methanesulfonamide.

Example 91. (S)-1-(3-fluoropropyl)-3-(4-(8-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine

[0600] ##STR00261##

[0601] The compound was prepared as in Example 1, Steps 1 and 2 but replacing (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol with (S)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-ol [WO2017140669] (2 g, 4.37 mmol) to give 45 mg (31.3%) of (S)-1-(3-fluoropropyl)-3-(4-(8-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)pyrrolidine.

Example 92. (S)-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-yl)boronic acid

[0602] ##STR00262##

[0603] Obtained in Example 91 as a by product to give 19 mg (16%) of (S)-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-yl)boronic acid.

Example 93. (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetic acid

[0604] ##STR00263##

Step 1: Methyl 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)acetate

[0605] ##STR00264##

[0606] To a solution of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]-annulen-5-one (1.2 g, 5.02 mmol) in DMF (10 ml), was added 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (2.1 g, 10.59 mmol), zinc chloride (342 mg, 2.51 mmol), bis(dibenzylideneacetone)palladium (149 mg, 251 μmol) and tri-tert-butylphosphine (63 mg, 301 μmol). The reaction mixture was heated at 130° C. for 3 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate

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

[0607] ##STR00265##

[0608] To a solution of 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)acetate (650 mg, 2.8 mmol), DCM (20 ml) and pyridine (338 μl, 4.2 mmol) was added 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 NaHCO.sub.3 (10 ml) was added. After decantation, the organic phase was dried over MgSO.sub.4, 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.sup.+): 365.

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

[0609] ##STR00266##

[0610] 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)-1-(3-fluoropropyl)-3-(4-(4,4,5 ,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)phenoxy)pyrrolidine (1.11 g, 3.17 mmol) [WO2017140669], Cs.sub.2CO.sub.3 (1.88 g, 5.76 mmol), Pd(dppf)Cl.sub.2 (222 mg, 288 μmol) 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 MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with DCM/MeOH/NH4OH 28% (37/18/2; V/V/V) to give 1.2 g (95%) of methyl methyl (S)-2-(9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-enzo [7]annulen-3-yl)acetate. LC/MS (m/z, MH.sup.+): 438.

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

[0611] ##STR00267##

[0612] To a solution of methyl (S)-2-(9-(4-((1-(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 NaHCO.sub.3. After decantation, the organic phase was dried over MgSO.sub.4, 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate hydrobromide. LC/MS (m/z, MH.sup.+): 596.

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

[0613] ##STR00268##

[0614] To a solution of methyl (S)-2-(8-bromo-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate hydrobromide (300 mg, 502 μmol) in 1,4-dioxane (5 ml), was added (2,4-dichlorophenyl)boronic acid (115 mg, 603 μmol), Pd(dppf)Cl.sub.2 (23 mg, 30 μmol) and a solution of 1.5M of Cs.sub.2CO.sub.3 (670 μl, 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate. LC/MS (m/z, MH.sup.+): 582.

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

[0615] ##STR00269##

[0616] To a solution of methyl (S)-2-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetate (110 mg, 188 μmol) in MeOH (5 ml), was added NaOH 5N (151 μl, 755 μmol). The reaction mixture was heated at reflux for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was taken up in water (10 ml) and aqueous HCl (5 M) added to reach pH 5. The slurry was extracted with DCM, dried over MgSO.sub.4 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)acetic acid. LC/MS (m/z, MH.sup.+): 568.

Example 94. (S)-2-(3-(8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)propan-2-ol

[0617] ##STR00270##

[0618] A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (250 mg, 379.63 μmol), 1,4-dioxane (13 ml), Pd(dppf).sub.2Cl.sub.2 (16.67 mg, 22.78 μmol), water (3 ml), Cesium carbonate (272.12 mg, 835.19 μmol) and (3-(2-hydroxypropan-2-yl)phenyl)boronic acid (100.71 mg, 531.49 μmol) was 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-((1-(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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)propan-2-ol

[0619] ##STR00271##

[0620] A mixture of (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 1, Step 1] (300 mg, 455.56 μmol), 1,4-dioxane (13 ml), Pd(dppf).sub.2Cl.sub.2 (20 mg, 27.33 μmol), water (3 ml), Cesium carbonate (326.55 mg, 1 mmol) and (4-(2-hydroxypropan-2-yl)phenyl)boronic acid (118.36 mg, 637.78 μmol) was 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-((1-(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)-1-(3-fluoropropyl)pyrrolidine

[0621] ##STR00272##

[0622] To a solution of (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate [Example 98, Step 1] (260 mg, 404.94 μmol), in 1,4-dioxane (13 ml), was added 3-nitrophenylboronic acid (68.97 mg, 404.94 μmol), Pd(dppf).sub.2Cl.sub.2 (17.78 mg, 24.30 μmol), and Cs.sub.2CO.sub.3 (290.26 mg, 890.86 μmol) 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 K.sub.2CO.sub.3 solution, brine, dried over MgSO.sub.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 175 mg (70.3%) of (S)-3-(4-(8-(2-chloro-3-fluorophenyl)-3-(3-nitrophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine.

Example 97. (S)-3-(8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)aniline

[0623] ##STR00273##

[0624] To a solution of (S)-3-(4-(8-(2-chloro-3-fluorophenyl)-3-(3-nitrophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)phenoxy)-1-(3-fluoropropyl)pyrrolidine [Example 96] (150 mg, 243.86 μmol), in iPrOH (35 ml), was added zinc powder (95.66 mg, 1.46 mmol), and NH.sub.4Cl (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.sub.2CO.sub.3 solution, brine, dried over MgSO.sub.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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)aniline.

Example 98. (S)-2-(4-(8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)propan-2-ol

[0625] ##STR00274##

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

[0626] ##STR00275##

[0627] This compound was prepared as in Example 1, Step 1, but replacing (S)-8-(2,4-dichlorophenyl)-9-(4-((1-(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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol [WO2017140669] (750 mg, 1.47 mmol) to give 800 mg (85%) of (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate. LC/MS (m/z, MH.sup.+): 642.

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

[0628] ##STR00276##

[0629] A mixture of (S)-8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (200 mg, 311.49 μmol), 1,4-dioxane (13 ml), Pd(dppf).sub.2Cl.sub.2 (13.68 mg, 18.69 μmol), water (3 ml), Cesium carbonate (223.28 mg, 685.27 μmol) and (4-(2-hydroxypropan-2-yl)phenyl)boronic acid (80.93 mg, 436.08 μmol) was 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 K.sub.2CO.sub.3, 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-((1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl) -6,7-dihydro-5H-benzo[7]annulen-3-yl)phenyl)propan-2-ol.

[0630] The compounds according to the invention were subjected to pharmacological tests for determining their degradation effects on estrogen receptors.

[0631] Test: Estrogen Receptor Degradation Activity

[0632] Said test involves measuring the in vitro degradation activity of the compounds of the invention.

[0633] The measurements of the degradation activities were made using a breast cancer cell ERα in cell western assay as described hereunder.

[0634] MCF7 cells (ATCC) were seeded in 384 wells microplate (collagen coated) at a concentration of 10000 cells/30 μL, 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 2.5 μL at final concentrations ranging either from 3-0.000018 μM (column « % Degradation at 3 μM in table 2) or from 0.3-0.0000018 μM (column « % Degradation at 0.3 μM in table 2), or 0.1 μM for fulvestrant (using as positive control). At 4 hours post compound addition the cells were fixed by adding 25 μL of formalin (final concentration 5% formalin containing 0.1% triton) for 10 minutes at room temperature and then washed twice with PBS. Then, 50 μL of LI-COR blocking buffer containing 0.1% Triton was added to plate for 30 minutes at room temperature. LI-COR blocking buffer was removed and cells were incubated overnight at cold room with 50 μL anti-ER rabbit monoclonal antibody (Thermo scientific MA1-39540) 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 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 ERα and DNA respectively.

[0635] The degradation activity with respect to estrogen receptors in this test is given by the concentration which degrades 50% of the estrogen receptor (or IC.sub.50) in nM.

[0636] The % of ERα levels decrease were determined as follows: % inhibition=100*(1−(sample-fulvestrant: DMSO-fulvestrant)).

[0637] The Table 2 below indicates the estrogen receptor degradation activity results for the compounds according to the invention tested either at 3 μM or at 0.3 and demonstrates that said compounds have a significant degradation activity on estrogen receptors.

TABLE-US-00002 TABLE 2 Degradation % Degradation % Degradation Compound No. IC.sub.50 (nM) At 3 μM At 0.3 μM 1 2 86 / 2 3 92 / 3 5 95 / 4 7 87 / 5 8 93 / 6 9 88 / 7 11 86 / 8 11 95 / 9 12 79 / 10 22 92 / 11 23 94 / 12 24 83 / 13 40 76 / 14 50 90 / 15 93 90 / 16 123 86 / 17 166 84 / 18 0.2 85 / 19 10 86 / 20 6 85 / 21 0.7 78 / 22 27 82 / 23 6 74 / 24 77 74 / 25 115 65 / 26 9 90 / 27 299 71 / 28 0.8 94 / 29 24 91 / 30 103 70 / 31 1.8 95 / 32 310 73 / 33 20 95 / 34 753 66 / 35 320 52 / 36 277 93 / 37 194 98 / 38 281 69 / 39 4 94 / 40 104 66 / 41 392 74 / 42 0.2 90 / 43 13 95 / 44 23 50 / 45 22 96 / 46 153 95 / 47 61 78 / 48 111 70 / 49 3.8 90 / 50 50 / 73 51 10 81 / 52 11 87 / 53 11 91 / 54 21 90 / 55 23 84 / 56 45 89 / 57 71 87 / 58 63 77 / 59 24 91 / 60 75 74 / 61 6 76 / 62 89 / 68 63 1 97 / 64 21 102  / 65 5 / 90 66 111 / 74 67 26 / 79 68 63 / 67 69 134 / 69 70 40 / 74 71 17 / 91 72 51 / 74 73 13 / 89 74 240 / 59 75 158 / 71 76 120 / 75 77 57 / 55 78 1 / 90 79 5 / 91 80 55 / 90 81 47 / 67 82 1 / 93 83 158 / 63 84 112 / 71 85 125 / 69 86 19 / 88 87 110 / 73 88 232 / 51 89 1 / 95 90 61 / 77 91 2 / 90 92 1 / 85 93 99 84 / 94 40 / 64 95 72 / 66 96 4 / 76 97 7 / 90 98 50 59

[0638] It is therefore apparent that the compounds of the invention have degradation activities for estrogen receptors, with IC50 less than 1 μM 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.

[0639] Accordingly, in another of its aspects, the invention provides medicaments which comprise a compound of the formula (I), or a pharmaceutically acceptable salt thereof.

[0640] 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.

[0641] 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.

[0642] 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.

[0643] In an embodiment, the cancer is a hormone dependent cancer.

[0644] In another embodiment, the cancer is an estrogen receptor dependent cancer, particularly the cancer is an estrogen receptor α dependent cancer.

[0645] In another embodiment, the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancer, or a metastasis thereof.

[0646] 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 (ERα positive breast cancer).

[0647] In another embodiment, the cancer is resistant to anti-hormonal treatment.

[0648] 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.

[0649] 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.

[0650] 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.

[0651] 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.

[0652] 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.

[0653] 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.

[0654] 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.

[0655] As an example, a unit administration form of a compound according to the invention in tablet form may comprise the following components:

TABLE-US-00003 Compound according to the invention 50.0 mg Mannitol 223.75 mg Sodium croscarmellose 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg

[0656] 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.