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

Abstract

Disclosed herein are compounds of the formula (I), or pharmaceutically acceptable salts thereof wherein R1 and R2 represent a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, a —COOH group or a —OH group; R3′ and R3″ represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; R4 and R5 represent a hydrogen atom, a halogen atom, a —IMH2 group, a (C.sub.1-C.sub.3)alkyl group, a (C1-C3)alkoxy group, or a —OH group; or R4 and R5 together form an oxo group or R4 and R5 together form a ═NOCH.sub.3 group or a (C.sub.3-C.sub.5)cycloalkyl group; R7 represents a hydrogen atom, a methyl group, a —OH group or a fluorine atom; R6 represents a phenyl group, a fused phenyl group, a bicyclic group comprising 5 to 12 carbon atoms, a heteroaryl group comprising 2 to 9 carbon atoms and comprising from 1 to 3 heteroatoms, a cycloalkyl group comprising 3 to 7 carbon atoms, a (C3-C6) cycloalkyl (C1-C3) alkyl group, a 3 to 8 membered-heterocycloalkyl group, a (C1-C6)alkyl group or a phenyl (C.sub.1-C.sub.2) alkyl group; X represents —CH.sub.2—, —O— or —S—; Y represents —CH═, —N═ or —CR″═; R8 represents a (C.sub.1-C.sub.3) alkyl group, a halogen atom, a cyano group, or a (C.sub.1-C.sub.3) fluoroalkyl group; R9 represents a hydrogen atom or a fluorine atom; RIO and RIO′ represent a hydrogen atom or a fluorine atom; Rll represents a hydrogen atom a (C.sub.1-C.sub.3)alkyl group or a cyclopropyl group; n is 0, 1 or 2, and m is 0 or 1. Further disclosed are process for preparing the same, pharmaceutical compositions comprising them as well as said compounds of formula (I) for use as an inhibitor and degrader of estrogen receptors, in particular in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.

##STR00001##

Claims

1. A compound of the formula (I) or a pharmaceutically acceptable salt thereof: ##STR00701## wherein: R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, a —COOH group or a —OH group; R3′ and R3″ independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; R4 and R5 independently represent a hydrogen atom, a fluorine atom, a —NH.sub.2 group, a (C.sub.1-C.sub.3)alkyl group such as a methyl group, a (C.sub.1-C.sub.3)alkoxy group such as a methoxy group or an ethoxy group, or a —OH group; or R4 and R5 together form an oxo group or R4 and R5 together form a ═NOCH.sub.3 group or a (C.sub.3-C.sub.5)cycloalkyl group with the carbon atom to which they are attached; R7 represents a hydrogen atom, a methyl group, a —OH group or a fluorine atom; or alternatively R4 and R7 together form a cyclopropyl group together with the bond to which they are attached, that gives with the adjacent azetidine group an azaspiro[2.3]hexane; R6 represents a group selected from: a phenyl group, said phenyl group being optionally substituted by 1 to 3 substituents independently selected from a halogen atom; a (C.sub.1-C.sub.6)alkyl group optionally substituted with a cyano group or a —OH group; a (C.sub.1-C.sub.6)fluoroalkyl group; a (C.sub.3-C.sub.6)cycloalkyl group; a (C.sub.1-C.sub.6)alkoxy group; a (C.sub.1-C.sub.6)fluoroalkoxy group; a cyano group; a trifluoromethylsulfonyl group; a (C.sub.1-C.sub.4)alkylthio group; a (C.sub.1-C.sub.4)fluoroalkylthio group; a (C.sub.1-C.sub.4)alkylsulfonyl group; and a —OH group; a fused phenyl group, selected from phenyl groups fused with a (C.sub.3-C.sub.6)cycloalkyl, which (C.sub.3-C.sub.6)cycloalkyl ring optionally comprises an unsaturation and, wherein the fused phenyl is optionally substituted with 1 to 3 substituents independently selected from a (C.sub.1-C.sub.3)alkyl group, a hydroxy group, a halogen atom, a (C.sub.1-C.sub.6)fluoroalkyl group and a (C.sub.1-C.sub.3)alkoxy group; a bicyclic group comprising 5 to 12 carbon atoms, optionally comprising 1 to 2 unsaturations; optionally substituted with 1 to 4 substituents independently selected from: a fluorine atom, a —OH group, a (C.sub.1-C.sub.3)-alkyl group, a (C.sub.1-C.sub.3)fluoroalkyl group, a (C.sub.1-C.sub.3)alkoxy group, a (C.sub.1-C.sub.3)fluoroalkoxy group and an oxo group; a heteroaryl group comprising 2 to 9 carbon atoms and comprising from 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, and at least 5 atoms including carbon atoms and heteroatoms, such as a pyridyl group, a pyridone group or a pyrrolyl group, said heteroaryl group being optionally substituted with 1 to 3 substituents independently selected from a halogen atom, a (C.sub.1-C.sub.6)alkyl group, a (C.sub.1-C.sub.6)fluoroalkyl group, a (C.sub.1-C.sub.6)alkoxy group, a (C.sub.1-C.sub.6)fluoroalkoxy group, a cyano group, a carbamoyl group and a —OH group; a cycloalkyl group comprising 3 to 7 carbon atoms, said cycloalkyl group being saturated or partially saturated and being optionally substituted with 1 to 4 substituents independently selected from: a fluorine atom, a —OH group, a (C.sub.1-C.sub.3)alkyl group, a (C.sub.1-C.sub.3)fluoroalkyl group, a (C.sub.1-C.sub.3)alkoxy group, a (C.sub.1-C.sub.3)fluoroalkoxy group, an oxo group, a (C.sub.3-C.sub.6)cycloalkyl group, and a phenyl group, said (C.sub.3-C.sub.6)cycloalkyl or phenyl groups being optionally substituted with one or two halogen atom(s) or (C.sub.1-C.sub.3)alkyl group(s); a (C.sub.3-C.sub.6)cycloalkyl(C.sub.1-C.sub.3)alkyl group, optionally substituted on the cycloalkyl with 1 to 4 substituents independently selected from: a fluorine atom, a —OH group, a (C.sub.1-C.sub.4)alkyl group, a (C.sub.1-C.sub.3)fluoroalkyl group, a (C.sub.1-C.sub.3)fluoroalkoxy group and an oxo group; a 3 to 8 membered-heterocycloalkyl group comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, such as a tetrahydropyranyl or a tetrahydrofuranyl group, said heterocycloalkyl group being saturated or partially saturated and being optionally substituted with 1 to 3 substituents independently selected from: a fluorine atom, a (C.sub.1-C.sub.3)alkyl group, a (C.sub.1-C.sub.3)fluoroalkyl group, a (C.sub.1-C.sub.3)fluoroalkoxy group, an oxo group, a (C.sub.1-C.sub.3)alkoxy group and a —OH group; a (C.sub.1-C.sub.6)alkyl group, such as an isobutyl group or an ethylbutyl group, said alkyl group being optionally substituted with 1 to 4 substituents independently selected from: a fluorine atom, a (C.sub.1-C.sub.3)alkoxy group, a (C.sub.1-C.sub.3)fluoroalkoxy group and a —OH group; and a phenyl(C.sub.1-C.sub.2)alkyl group, said phenyl group being optionally substituted with 1 to 3 substituents independently selected from a halogen atom; a (C.sub.1-C.sub.3)alkyl group; a (C.sub.1-C.sub.3)fluoroalkyl group; a (C.sub.1-C.sub.3)alkoxy group; a (C.sub.1-C.sub.3) fluoroalkoxy group; a cyano group; and a —OH group; X represents —CH.sub.2—, —O— or —S—; Y represents —CH═, —N═ or —CR″═, wherein R″ represents a (C.sub.1-C.sub.3)alkyl group or a halogen atom, such as a fluorine or a chlorine atom, a cyano group, or a (C.sub.1-C.sub.3)fluoroalkyl group, such as a trifluoromethyl; R8 independently represents a (C.sub.1-C.sub.3)alkyl group, such as a methyl group, a halogen atom, such as a fluorine atom, a cyano group, or a (C.sub.1-C.sub.3)fluoroalkyl group, such as a trifluoromethyl; R9 represents a hydrogen atom or a fluorine atom; R10 and R10′ independently represent a hydrogen atom or a fluorine atom; R11 represents a hydrogen atom, or a (C.sub.1-C.sub.3)alkyl group or a cyclopropyl; n is 0, 1 or 2, and m is 0 or 1.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R1 and R2 are a hydrogen atom.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that R3 is —COOH.

4. The compound of formula (I) according to any one of claim 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that X represents —CH.sub.2—.

5. The compound of formula (I) according to any one of claim 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that R4 and R5 represent independently from each other a hydrogen atom, a fluorine atom, a methyl group, a methoxy group, an ethoxy group, a —NH.sub.2 group or a —OH group; or R4 and R5 together form an oxo group, a ═NOCH.sub.3 group or a cyclopropyl group with the carbon atom to which they are attached or alternatively R4 and R7 together form a cyclopropyl group together with the bond to which they are attached, in particular both of R4 and R5 represent hydrogen atoms or a fluorine atom, or one of R4 and R5 represents a hydrogen atom and the other a fluorine atom or a —OH group, or one of R4 and R5 represents a methyl group and the other a hydroxy group or a fluorine atom, more particularly R4 and R5 both represent a hydrogen atom.

6. The compound of formula (I) according to any one of claim 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that R7 represents a hydrogen atom, a —OH group, a methyl group or a fluorine atom, more particularly a hydrogen atom.

7. The compound of formula (I) according to any one of claim 1 to 6, characterized in that R6 represents a phenyl group, said phenyl group being optionally substituted with 1 to 3 substituents independently selected from a chlorine atom, a fluorine atom, a methyl group, an ethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a hydroxy methyl group, a 2-hydroxyethyl group, a fluoromethyl group, a difluoromethyl group, a 2,2-difluoroethyl group, a methoxy group, an ethoxy group, a cyano group, a cyanomethyl group, a trifluoromethylsulfonyl group, a methylsulfanyl group, a difluoromethylsulfanyl group, a methylsulfonyl group and a difluoromethoxy group.

8. The compound of formula (I) according to any one of claim 1 to 6, characterized in that R6 represents a fused phenyl group, selected from a bicyclo[4.2.0]octa-trienyl group and an indanyl group, said groups being optionally substituted with one or two fluorine atoms.

9. The compound of formula (I) according to any one of claim 1 to 6, characterized in that R6 represents a pyridyl group, said pyridyl group being optionally substituted with 1 to 3 substituents independently selected from a halogen atom, a (C.sub.1-C.sub.6)alkyl group, a (C.sub.1-C.sub.6)fluoroalkyl group, a (C.sub.1-C.sub.6)alkoxy group, a (C.sub.1-C.sub.6)fluoroalkoxy group, a carbamoyl and a —OH group, and more particularly selected from a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a trifluoromethyl group, a difluoromethyl group, a methoxy group and a carbamoyl group, a pyridone, optionally substituted with 1 to 3 substituents independently selected from a halogen atom, a (C.sub.1-C.sub.3)alkyl group, a (C.sub.1-C.sub.3)fluoroalkyl group, a (C.sub.1-C.sub.3)alkoxy group and a (C.sub.1-C.sub.3)fluoroalkoxy group, and more particularly selected from a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a trifluoromethyl group and a difluoromethyl group or a pyrrole group, optionally substituted with 1 or 2 substituents selected from a (C.sub.1-C.sub.6)alkyl group, such as a methyl group.

10. The compound of formula (I) according to any one of claim 1 to 6, characterized in that R6 represents a cycloalkyl group selected from a cyclohexyl group, a cyclopentyl group, a cycloheptyl group, a cycloheptenyl group and a cyclohexenyl group, said cycloalkyl group being optionally substituted with 1 to 4 substituents independently selected from: a fluorine atom, a —OH group, a (C.sub.1-C.sub.3)alkyl group, a (C.sub.1-C.sub.3)fluoroalkyl group, a (C.sub.1-C.sub.3)alkoxy group, a (C.sub.1-C.sub.3)fluoroalkoxy group, an oxo group, a (C.sub.3-C.sub.6)cycloalkyl group and a phenyl group, said (C.sub.3-C.sub.6)cycloalkyl or phenyl groups being optionally substituted with one or two halogen atom(s) or a (C.sub.1-C.sub.3)alkyl group, said cycloalkyl being advantageously substituted with 1 to 2 substituents independently selected from: a fluorine atom, a methyl group, and a cyclohexyl group substituted by two halogen atoms, in particular fluor atoms.

11. The compound of formula (I) according to any one of claim 1 to 6, characterized in that R6 represents a heterocycloalkyl group, and more particularly a tetrahydropyranyl group, said heterocycloalkyl group being optionally substituted with 1 to 3 substituents independently selected from: a (C.sub.1-C.sub.6)alkyl group, a fluorine atom and a —OH group.

12. The compound of formula (I) according to any one of claim 1 to 6, characterized in that R6 represents a bicyclic group selected from a spiro[3.3]hept-1-ene or a spiro[3.3]hept-2-ane group, said group being optionally substituted with 1 to 4 substituents independently selected from: a (C.sub.1-C.sub.3)alkyl group, a fluorine atom, a (C.sub.1-C.sub.3)alkoxy group, a (C.sub.1-C.sub.3)fluoroalkoxy group and a —OH group, and in particular optionally substituted with 1 or 2 fluorine atoms, a bicyclo[2.2.1]heptan-2-yl or a bicyclo[3.2.1]octan-3-yl group, said group being optionally substituted with 1 to 4 substituents independently selected from: a (C.sub.1-C.sub.3)alkyl group, a fluorine atom, a (C.sub.1-C.sub.3)alkoxy group, a (C.sub.1-C.sub.3)fluoroalkoxy group and a —OH group.

13. The compound of formula (I) according to any one of claim 1 to 6, characterized in that R6 represents a (C.sub.1-C.sub.6)alkyl group selected from an ethyl, an isobutyl group and an ethylbutyl, said alkyl group being optionally substituted with 1 to 4 substituents independently selected from: a fluorine atom, a (C.sub.1-C.sub.3)alkoxy group, a (C.sub.1-C.sub.3)fluoroalkoxy group and a —OH group, and in particular optionally substituted with 1 or 3 fluorine atoms.

14. The compound of formula (I) according to any one of claim 1 to 6, characterized in that R6 represents a cis-1,3a,4,5,6,6a-hexahydropentalenyl group or a octahydropentalenyl group.

15. The compound of formula (I) according to any one of claim 1 to 6, characterized in that R6 represents a cyclobutylmethyl group.

16. The compound of formula (I) according to any one of claim 1 to 6, characterized in that R6 represents a phenyl(C.sub.1-C.sub.2)alkyl group, in particular chosen from a phenylmethyl or a phenylethyl.

17. The compound of formula (I) according to any one of claim 1 to 6, characterized in that R3′ and R3″ represent a hydrogen atom.

18. The compound of formula (I) according to any one of claim 1 to 6, characterized in that R8 independently represents a methyl group or a fluorine atom and n is 0, 1 or 2.

19. The compound of formula (I) according to anyone of claims 1 to 18, wherein Y represents —CH═, —C(CH.sub.3)═, —CF═ or —N═, and in particular —CH═ or —N═.

20. The compound of formula (I) according to anyone of claims 1 to 19, wherein R9 represents a hydrogen atom.

21. The compound of formula (I) according to anyone of claims 1 to 20, wherein R10 and R10′ represent a hydrogen atom.

22. The compound of formula (I) according to anyone of claims 1 to 21, wherein R11 represents a hydrogen atom.

23. The compound of formula (I) according to anyone of claims 1 to 22, wherein m is 1.

24. The compound of formula (I) according to anyone of claims 1 to 23, or a pharmaceutically acceptable salt thereof, in particular hydrochloride salt thereof, characterized in that said compound is selected from the following compounds: 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (1) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (2) 8-(2-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (3) 8-(4,4-difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (4) 8-(4,4-difluorocyclohex-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (5) 8-cyclopentyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (6) 8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (7) 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (8) 8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (9) 8-(2,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (10) 8-(2-fluoro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (11) 8-(4-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (12) 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (13) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-((1s,4s)-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (14) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-((1r,4r)-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (15) 8-(2-fluoro-4-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (16) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (17) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(6-methoxypyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (18) 8-(2,3-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (19) 8-(4-(difluoromethoxy)-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (20) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxypyridin-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (21) 8-(2,3-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (22) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (23) 8-(2-chloro-4-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (24) 8-(4-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (25) 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (26) 8-(4-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (27) 8-(3-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (28) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-methoxy-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (29) 8-(2-chloro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (30) 8-(2-fluoro-6-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (31) 8-(3-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (32) 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (33) 8-(2-chloro-6-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (34) 8-(2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (35) 8-(4-fluoro-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (36) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (37) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (38) 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (39) 8-(2,4-dichlorophenyl)-9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (40) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (41) and (42) 8-(2,4-dichlorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (43) and (44) 8-(3,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (45) 8-(2,4-dichlorophenyl)-9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (46) 8-(2,4-dichlorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (47) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (48) 4-(2-chlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylic acid, (49) 8-(6,6-difluorospiro[3.3]hept-1-en-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (50) 8-(6,6-difluorospiro[3.3]heptan-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (51), and 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]thiepine-8-carboxylic acid, (52), 8-(bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (53), 8-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (54), 8-(7-fluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (55), 8-(5-fluoro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (56), 8-(2-(difluoromethyl)-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (57), 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (58), 8-(2-chloro-4-fluorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (59), 8-(3-chloro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (60), 8-(3,4-bis(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (61), 8-(4-fluoro-2-(fluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (62), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(cis-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (63), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(trans-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (64), 8-(3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (65), 8-(3-fluoro-2-(trifluoromethyl)phenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (66), 8-(3-(difluoromethyl)-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (67), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (68), 8-(4-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (69), 8-(5-fluoro-2-methoxypyridin-4-yl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (70), 8-(3-fluoro-2-methoxypyridin-4-yl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (71), 8-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (72), 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (73), 8-(4-chloro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (74), 8-(2-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (75), 8-(4-chloro-2-(difluoromethyl)phenyl)-4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (76), 8-(2,4-dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 1 (77), 8-(2,4-dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid isomer 2 (78), 8-(4-fluoro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (79), 8-(2-fluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (80), 8-(2,4-difluorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (81), 8-(5-chloro-3-(difluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (82), 8-(3-fluoro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (83), 8-(3-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (84), 8-(3,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (85), 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (86), 8-(2-chloro-3-fluorophenyl)-4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (87), 8-(3-chloro-4-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (88), 8-(5-chloro-4-(trifluoromethyl)pyridin-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (89), 8-(3-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (90), 8-(2-fluoro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (91), 8-(2,4-dichlorophenyl)-4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (92), 8-(6-(difluoromethyl)-2,3-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (93), 8-(3-chlorophenyl)-4-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (94), 8-(6-(difluoromethyl)-4-methylpyridin-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (95), 8-(3,3-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride Isomer 1 (96), 8-(3,3-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride Isomer 2 (97), 8-(5-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (98), 8-(4-(difluoromethyl)-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (99), 8-(2-cyano-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (100), 8-(4-chloro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (101), 8-(3-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (102), 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 (103), 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2 (104), 8-(2-carbamoylpyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (105), 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2 (106), 8-(2-chloro-4-methylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2 (107), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(trans-3-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (108), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(cis-3-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (109), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(1H-pyrrol-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (110), 8-(4-chloro-2-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (111), 8-(4-chloro-2-methylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2 (112), 8-(4-ethyl-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (113), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-((trifluoromethyl)sulfonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (114), 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (115), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-mesityl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (116), 8-(4-(difluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (117), 8-(3-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (118), 8-(4-cyano-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (119), 8-(2-fluoro-4-(methylthio)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (120), 8-(2,4-dichlorophenyl)-9-(2,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (121), 8-(2,4-dimethylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2 (122), 8-(2-chloro-3-methylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2 (123), 8-(2-chloro-4-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (124), 8-(2-chloro-4-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2 (125), 8-(2-chloro-3-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2 (126), 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2 (127), 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (128), 8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (129), 8-(2-fluoro-4-(methylsulfonyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (130), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(1-methyl-1H-pyrrol-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (131), 8-(2,6-dimethylpyridin-3-yl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (132), 8-(4-chloro-2-(2,2,2-trifluoroethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (133), 8-(2,5-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (134), 9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (135), 8-(4-fluoro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (136), 8-(3-cyano-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (137), 8-(4-((difluoromethyl)thio)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (138), 8-(4-fluoro-2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (139), 8-(4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (140), 8-(2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (141), 8-(2,4-dichlorophenyl)-9-(3,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (142), 8-(2,6-dimethylpyridin-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (144), 8-(4-chloro-2-(cyanomethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (144), 8-(2-chloro-4-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (145), 8-(2-(fluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (146), 8-(3-cyanophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (147), 8-(5-chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (148), 8-(2-ethyl-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (149), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (150), 8-(2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (151), 8-(2-ethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (152), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4,6-trifluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (153), 8-(4-chloro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (154), 8-(2-cyano-5-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (155), 8-(5-cyano-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (156), 8-(2-cyano-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (157), 8-(2-cyano-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (158), 8-(4,6-bis(trifluoromethyl)pyridin-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (159), 8-(2-chloro-4-fluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (160), 8-(2,3-difluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (161), 8-(cyclohept-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (162), 8-cycloheptyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (163), 8-(2-(difluoromethyl)-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (164), 8-(3-fluoro-2-(fluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (165), 8-(2-cyano-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (166), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)-3,5-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (167), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (168), 8-(2,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (169), 8-(4-chloro-2-cyanophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (170), 8-(4-chloro-2,3-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (171), 8-(3-fluoro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (172), 8-(2-chloro-3-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (173), 8-(4-fluoro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (174), 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride Isomer 1 (175), 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride Isomer 2 (176), 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 (177), 8-(4-chloro-2-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 (178), 8-(2-chloro-4-methylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 (179), 8-(2-(difluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (180), 8-(2,4-dimethylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 (181), 8-(2-chloro-3-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 (182), 8-(4-chloro-2-methylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 (183), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)-3-methylazetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (184), 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 (185), 9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 (186), 8-(2-chloro-4-fluorophenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 (187), 8-(2-chloro-3-methylphenyl)-9-(4-(fluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 (188), 8-(2-chloro-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (189), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (190), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (191), 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (192), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-methylpyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (193), 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 (194), 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2 (195), (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid (196), (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid (197), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (198), 8-(4-chloro-2-methylphenyl)-9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (199), 9-(4-(difluoro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (200), 8-(4-ethoxy-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (201), 8-(5-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (202), 8-(5-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (203), 8-(2-fluoro-5-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (204), 8-(2-chlorophenyl)-2-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (205), 8-(2,4-dichlorophenyl)-2-fluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (206), 8-(3,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (207), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl-1,1-d2)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (208), 8-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (209), 8-(2,3-difluoro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (210), 8-(2,4-dichloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (211), 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (212), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (213), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (214), 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)cyclopropyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (215), 8-(2-chloro-4-fluorophenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (216), 8-(2-chloro-4-methylphenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (217), 8-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (218), 8-(5-chloro-3-fluoropyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (219), 8-(2-chloro-6-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (220), 8-(4-chloro-2-(difluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (221), 8-(2,6-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (222), 8-(2,4-dichlorophenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (223), 8-(2-chlorophenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (224), 8-(2,4-dichlorophenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (225), 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (226), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 (227), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2 (228), 8-(2,4-dichlorophenyl)-9-(4-(ethoxy(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 (229), 8-(2,4-dichlorophenyl)-9-(4-(ethoxy(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2 (230), 8-(2-ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (231), 8-(3-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (232), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)-3-hydroxyazetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (233), 8-(3,5-dichloropyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (234), 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 (235), 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2 (236), 8-(4-chloro-2-(trifluoromethyl)phenyl)-9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (237), 9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (238), 8-(2,4-dichlorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (239), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (240), 9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (241), 8-(2-chloro-4-fluorophenyl)-9-(4-((3-fluoro-1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (242), 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 (243), 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2 (244), 2-cyano-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (245), 4-cyano-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, formic acid (246), 4-chloro-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (247), 2-chloro-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (248), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (249), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (250), sodium 8-(3-(difluoromethyl)-5-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (251), 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (252), 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (253), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (254), 8-(2-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (255), 8-(2-methyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (256), 8-(2-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (257), 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (258), 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (259), 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (260), 8-(2,4-dichlorophenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (261), 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride (262), 4-(4-chloro-2-methylphenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylic acid (263), sodium 4-(2-chloro-4-fluorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylate (264), 8-(2-chloro-4-methylphenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (265), 8-(3,5-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (266), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (267), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (268), 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (269), 8-(2,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (270), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (271), 8-(4-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (272), sodium 8-(5-(difluoromethyl)-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (273), sodium 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (274), 8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (275), 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (276), 8-(2-chloro-3-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (277), 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (278), 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (279), 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (280), 8-(2,4-difluorophenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (281), 8-(4-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (282), 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-4-methoxy-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (283), 8-(2-(difluoromethyl)-4,6-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (284), 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-fluoro-2,3-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (285), 8-(2-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (286), 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (287), 9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-fluoro-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (288), 8-(4-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (289), 8-(4-fluoro-3-(2,2,2-trifluoroethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (290), 8-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (291), 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (292), 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (293), 8-(cyclobutylmethyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (294), 8-(2-fluoro-5-(2,2,2-trifluoroethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (295), 8-(2-(difluoromethyl)-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (296), 8-(3-(2,2-difluoroethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (297), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(2,2,2-trifluoroethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (298), sodium 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(cis-1,3a,4,5,6,6a-hexahydropentalen-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (299), 8-(6-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (300), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2-(2,2,2-trifluoroethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (301), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1 (302), 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2 (303), 3-(4-(8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzyl)-1-(3-fluoropropyl)azetidine (304), 8-(2,4-dichlorophenyl)-2,4-difluoro-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (305), 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (306) 8-(bicyclo[2.2.1]heptan-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, mixture of isomers (307) 3-(2,4-dichlorophenyl)-4-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylic acid (308) 8-(4-fluoro-2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (309) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (310) 8-benzyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (311) 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (312) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (313) 3-(2,4-difluorophenyl)-4-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-2H-thiochromene-7-carboxylic acid (314) 8-(4-chlorophenyl)-7-ethyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (315) 8-(bicyclo[3.2.1]octan-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (316) 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (317) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (318) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(2-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (319) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(hydroxymethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (320) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 1 (321) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-isopropyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 2 (322) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (323) 8-(4-chlorophenyl)-7-cyclopropyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (324) 8-(4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (325) 8-(3,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (326) 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 1 (327) 18-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 2 (328) 8-(4-chlorophenyl)-7-ethyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 1 (329) 8-(4-chlorophenyl)-7-ethyl-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 2 (330) 8-((1R,2S)-2-(4,4-difluorocyclohexyl)cyclopropyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (331) 8-(5-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (332) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7-methyl-8-(3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Mixture of isomers (333) 8-(3-chloro-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (334) 8-(3-fluoro-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (335) 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(octahydropentalen-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 1 (336).

25. A process for preparing a compound of formula (I) as described in anyone of claims 1 to 24, wherein a compound of formula 1G ##STR00702## wherein R1, R2, R3′, R3″, R4, R5, R6, R7, Y, R8, R9, R10, R10′, R11, n, m, X are as described in any of claims 1 to 24 and R3a is carboxylic ester such as COOMe, COOEt, or protected OH with O-pivaloyl for example, is converted to compound of formula (I), in presence of a source of hydroxide ions, such as NaOH in solution in methanol, said step being optionally preceded by a step for obtaining compound 1G, wherein a compound of formula 1F ##STR00703## wherein, R1, R2, R3′, R3″, R4, R5, R7, Y, R8, R9, R10, R10′, R11, n, m, X are as described in any of claims 1 to 24 and R3a is as defined above, is subjected to a Suzuki coupling with a boronic reagent R6B(OR′).sub.2, wherein —B(OR′).sub.2 is a boronic acid or a pinacolate ester and R6 is as defined in any of claim 1 or 7 to 13.

26. A process for preparing a compound of formula (I) as described in anyone of claims 1 to 24, wherein a compound of formula 1Fa ##STR00704## wherein R1, R2, R3, R3′, R3″, R4, R5, R7, Y, R8, R9, R10, R10′, n, m, X are as described in any of claims 1 to 24, is submitted to a Suzuki coupling with a boronic reagent R6B(OR′).sub.2, wherein —B(OR′).sub.2 is a boronic acid or a pinacolate ester and R6 is defined as in any of claim 1 or 7 to 13, said step being optionally preceded by a step for obtaining compound 1Fa, wherein a compound of formula 1F ##STR00705## wherein R1, R2, R3′, R3″, R4, R5, R7, Y, R8, R9, R10, R10′, R11, n, m, X are as described in any of claims 1 to 24 and R3a is carboxylic ester such as COOMe, COOEt, or protected OH with O-pivaloyl, is converted to a compound 1Fa in the presence of a source of hydroxide ions, such as NaOH in solution in methanol.

27. Compounds selected from compounds of formula 1E, 1F, 1G and 1Fa, or any of its pharmaceutically acceptable salt, ##STR00706## ##STR00707## wherein R1, R2, R3, R3′, R3″, R4, R5, R7, Y, R8, R9, R10, R10′, R11, n, m, X are as described in any of claims 1 to 24 and R3a is carboxylic ester such as COOMe, COOEt, or protected OH with O-pivaloyl.

28. Compound of formula 1D or 1D′, or any of their pharmaceutically acceptable salt ##STR00708## wherein R1, R2, R4, R5, R7, R8, R9, R10, R10′, Y and n are as described in any of claims 1 to 24.

29. A medicament, characterized in that it comprises a compound of formula (I) according to any of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any of claims 1 to 24, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

31. A compound of formula (I) according to any of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use as an inhibitor and degrader of estrogen receptors.

32. A compound of formula (I) according to any of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.

33. A compound of formula (I) for use according to claim 32, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

Description

EXAMPLES

[1265] Method A:

Example 1. 9-(4-((1-(3-Fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Hydrochloride

[1266] ##STR00618##

Step 1: Methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1267] ##STR00619##

[1268] A mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) (103 mg, 212.45 μmol), phenyl-boronic acid (37.14 mg, 298.51 μmol), Cs.sub.2CO.sub.3 (224 mg, 673.75 μmol), and Pd(dppf)Cl.sub.2, complex with DCM (13.15 mg, 15.46 μmol) in dioxane (1 ml) and water (0.4 ml) was microwaved at 80° C. for 30 minutes. Water (2 ml) and DCM (5 ml) were added. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was treated on SCX column. The residue obtained was purified by flash chromatography eluting with a gradient of MeOH in DCM (100/0 to 95/05, v/v) to give 41 mg (40%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1269] LC/MS (m/z, MH+): 484

Step 2: 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Hydrochloride

[1270] ##STR00620##

[1271] To a solution of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (40.8 mg, 84.45 μmol) in MeOH (1.5 ml) was added a solution of NaOH (300 μl, 1 M) and the reaction mixture was heated to reflux for 50 minutes. After cooling, water (5 ml) and DCM (5 ml) were added and pH was adjusted to 2 with HCl 1N. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100/0 to 90/10, v/v) to give 30 mg (70.8%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride.

Example 2. 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid (2)

[1272] ##STR00621##

Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1273] ##STR00622##

[1274] Step 1 of Example 2 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) and 2,4-dichlorophenyl-boronic acid to give 100 mg (62%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1275] LC/MS (m/z, MH+): 552

Step 2: 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid

[1276] ##STR00623##

[1277] To a solution of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (100 mg, 181 μmol) in MeOH (3 ml) was added a solution of NaOH (250 μl, 1 M) and the reaction mixture was heated to reflux for 2.5 hours. After cooling, water (5 ml) and DCM (5 ml) were added and pH was adjusted to 5 with HCl 1N. After hydrophobic Column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100/0 to 90/10, v/v) to give 48 mg (49%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[1278] Method B:

Example 148. 8-(5-chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid

[1279] ##STR00624##

Step 1: Methyl 8-(5-chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1280] ##STR00625##

[1281] Step 1 of Example 148 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 8) and 2-bromo-5-chloro-3-methyl-pyridine to give 71 mg (47%) of methyl 8-(5-chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1282] LC/MS (m/z, MH+): 533

Step 2: 8-(5-Chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid

[1283] ##STR00626##

[1284] Step 2 of example 148 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 8-(5-chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 21 mg (30%) of 8-(5-chloro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[1285] Method C:

Example 4. 8-(4,4-Difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]Annulene-3-carboxylic Acid Hydrochloride

[1286] ##STR00627##

Step 1: Methyl 8-(4,4-difluorocyclohex-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]Annulene-3-carboxylate

[1287] ##STR00628##

[1288] Step 1 of Example 4 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) and (4,4-difluorocyclohex-1-en-1-yl)boronic acid to give 55 mg (347%) of methyl 8-(4,4-difluorocyclohex-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1289] LC/MS (m/z, MH+): 524.

Step 2: Methyl 8-(4,4-difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1290] ##STR00629##

[1291] A mixture of methyl 8-(4,4-difluorocyclohex-1-en-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (55 mg, 105 μmol), Pd/C 10% (18.67 mg, 175 μmol) in MeOH (3 ml) and EtOAc (2 ml) was hydrogenated at 50° C. and 5 bars of H.sub.2 for 15 hours. The reaction mixture was filtered, the filtrate was evaporated 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 55 mg (99%) of methyl 8-(4,4-difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1292] LC/MS (m/z, MH+): 526

Step 3: 8-(4,4-difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Hydrochloride

[1293] ##STR00630##

[1294] Step 3 of Example 4 was prepared following a similar procedure to that of step 2 of Example 1 from methyl 8-(4,4-difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 46 mg (80.6%) of 8-(4,4-difluorocyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride.

[1295] Method D:

Example 39. 8-(2,4-Dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid

[1296] ##STR00631##

Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1297] ##STR00632##

[1298] Step 1 of Example 39 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 5) and (4-bromobenzyl)(1-(3-fluoropropyl)azetidin-3yl)methanone (Intermediate 11) to give 111 mg (46%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as an orange viscous oil.

[1299] LC/MS (m/z, MH+): 566

Step 2: 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid

[1300] ##STR00633##

[1301] Step 2 of Example 39 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 69 mg (63%) of 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[1302] Method E:

Example 231. 8-(2-Ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid

[1303] ##STR00634##

Step 1: Methyl 8-(2-ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1304] ##STR00635##

[1305] To a mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) (50 mg, 103 μmol) in THF (1 ml) were added nickel(II) chloride ethylene glycol dimethyl ether complex (1 mg, 5 μmol), 4,4′-di-tert-butyl-2,2′-bipyridine (1.38 mg, 5.14 μmol), sodium carbonate (21.79 mg, 205.58 μmol), (Ir[dF(CF.sub.3)ppy]2(dtbpy))PF.sub.6 (1.15 mg, 1.03 μmol), 3-(bromomethyl)pentane (63 μl, 308 μmol) and tris(trimethylsilyl)silane (30 μl, 150 μmol). The degassed reaction mixture was irradiated under LED blue light (Photoreactor Penn OC ml) for 2 hours. Potassium fluoride 1 M (2 ml) and EtOAc were added. The organic layer was separated, washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of DCM/EtOAc/MeOH from 100/0/0 to 50/45/05 to give 21 mg (42%) of methyl 8-(2-ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1306] LC/MS (m/z, MH+): 492

Step 2: 8-(2-Ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid

[1307] ##STR00636##

[1308] Step 2 of Example 231 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 8-(2-ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 17 mg (87%) of 8-(2-ethylbutyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[1309] Method F

Example 115. 8-(2,4-Dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Hydrochloride

[1310] ##STR00637##

Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1311] ##STR00638##

[1312] Step 1 of Example 115 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 5) and 3-(4-bromo-2,3-difluorobenzylidene)-1-(3-fluoropropyl)azetidine (Intermediate 34) to give 215 mg (58%) of methyl 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as an orange oil.

[1313] LC/MS (m/z, MH+): 586

Step 2: Methyl 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1314] ##STR00639##

[1315] To a solution of methyl 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (165 mg, 0.281 mmol) in ethanol (30 mL) was added PtO.sub.2 (32 mg, 0.14 mmol). The suspension was hydrogenated in an autoclave at room temperature under 2 bars of hydrogen for 2 hours. The mixture was filtered with ethanol washes then the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with DCM/MeOH: 90/10 to give 140 mg (84%) of methyl 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

LC/MS (m/z, MH+): 588

Step 3: 8-(2,4-Dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Hydrochloride

[1316] ##STR00640##

[1317] To a solution of methyl 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (140 g, 0.238 mmol) in methanol (2 mL), THF (1 mL) and water (0.5 mL) was added LiOH (59 mg, 2.38 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, taken into water and acidified with 1N aqueous HCl to pH 3. The resulting precipitate was filtered and dried to give 44 mg (30%) of 8-(2,4-dichlorophenyl)-9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride as a white solid.

[1318] Method G:

Example 262. 6-(2,4-Dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic Acid Hydrochloride

[1319] ##STR00641##

Step 1: Methyl 6-(2,4-dichlorophenyl)-5-[4-[[1-(3-fluoropropyl)azetidin-3-yl]methyl]phenyl]-7,8-dihydronaphthalene-2-carboxylate

[1320] ##STR00642##

[1321] Step 1 of Example 262 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 6-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-7,8-dihydronaphthalene-2-carboxylate (Intermediate 52) and 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)azetidine (Intermediate 2), to give 48 mg (43%) of methyl 6-(2,4-dichlorophenyl)-5-[4-[[1-(3-fluoropropyl)azetidin-3-yl]methyl]phenyl]-7,8-dihydronaphthalene-2-carboxylate.

[1322] LC/MS (m/z, MH+): 538

Step 2: 6-(2,4-Dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic Acid Hydrochloride

[1323] ##STR00643##

[1324] Step 2 of Example 262 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 6-(2,4-dichlorophenyl)-5-[4-[[1-(3-fluoropropyl)azetidin-3-yl]methyl]phenyl]-7,8-dihydronaphthalene-2-carboxylate to give 22 mg (47%) of 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride.

[1325] Method H:

Example 77. 8-(2,4-dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid, Hydrochloride Isomer 1

[1326] ##STR00644##

Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1327] ##STR00645##

[1328] Step 1 of Example 77 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 5) and 3-(4-bromobenzylidene)-1-(3-fluoropropyl)azetidine (Intermediate 47) to give 101 mg (86%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1329] LC/MS (m/z, MH+): 550

Step 2: Methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1330] ##STR00646##

[1331] To a solution of diethylzinc (1.13 mL, 1.13 mmol, 1 M in hexanes) at 0° C. under Argon atmosphere was added a solution of diiodomethane (90 μL, 1.13 mmol) in DCM (1 mL). The mixture was stirred at 0° C. for 30 minutes then a solution of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (310 mg, 0.563 mmol) in DCM (6 mL) was dropwise added. The resulting mixture was stirred overnight allowing the temperature to warm up to room temperature then quenched with a 1N aqueous HCl solution (10 mL) and diluted with water. The aqueous layer was separated and extracted three times with DCM. The combined organic layers were washed with a saturated aqueous solution of NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of MeOH in DCM (100/0 to 80/20, v/v) to give 132 mg (33%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a mixture of two isomers.

[1332] LC/MS (m/z, MH+): 550

[1333] The mixture of two isomers of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate was separated by chiral HPLC (conditions: flash Chiralcel OD-H 250×30 mm, 5 μm; Heptane 95%/Isopropanol 5%/TEA 0.1%; 45 mL/min) to give 54 mg of isomer 1 and 43 mg of isomer 2.

Step 3: 8-(2,4-dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid, Hydrochloride Isomer 1

[1334] ##STR00647##

[1335] To a solution of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 (43 mg, 80 μmol) in methanol (9 mL)/THF (3 mL)/water (3 mL) was added LiOH (30.5 mg, 1.27 mmol). The reaction mixture was stirred at room temperature overnight then quenched with 1N aqueous HCl to pH 1 and extracted three times with DCM. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 31 mg (74%) of 8-(2,4-dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride Isomer 1 as a white solid.

Example 78. 8-(2,4-dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid, Hydrochloride Isomer 2

[1336] ##STR00648##

[1337] Example 78 was prepared following a similar procedure to that of step 3 of Example 77 from methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2 to give 41 mg (78%) of 8-(2,4-dichlorophenyl)-9-(4-(5-(3-fluoropropyl)-5-azaspiro[2.3]hexan-1-yl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride Isomer 2 as a white solid.

Example 105. 8-(2-carbamoylpyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Hydrochloride

[1338] ##STR00649##

Step 1: methyl 8-(2-cyanopyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1339] ##STR00650##

[1340] Step 1 of Example 105 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) and 2-cyanopyridine-4-boronic acid pinacol ester to give 227 mg (44%) of methyl 8-(2-cyanopyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1341] LC/MS (m/z, MH+): 510

Step 2: 8-(2-carbamoylpyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Hydrochloride

[1342] ##STR00651##

[1343] To a solution of methyl 8-(2-cyanopyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (227 mg, 445 μmol) in MeOH (10 ml) was added a 1 M solution of NaOH (2.8 ml, 2.8 mmol) and the reaction mixture was heated to reflux for 1 hour. After cooling, water (5 ml) and DCM (5 ml) were added and pH was adjusted to 2 with HCl 1N. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100/0 to 90/10, v/v) to give 94 mg (41%) of 8-(2-carbamoylpyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride.

Example 110. 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(1H-pyrrol-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Hydrochloride

[1344] ##STR00652##

Step 1: tert-butyl 2-(9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-8-yl)-1H-pyrrole-1-carboxylate

[1345] ##STR00653##

[1346] Step 1 of Example 110 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) and N-Boc-2-pyrroleboronic acid to give 223 mg (89%) of tert-butyl 2-(9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-8-yl)-1H-pyrrole-1-carboxylate.

[1347] LC/MS (m/z, MH+): 573

Step 2: 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(1H-pyrrol-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Hydrochloride

[1348] ##STR00654##

[1349] To a solution of tert-butyl 2-(9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-8-yl)-1H-pyrrole-1-carboxylate (93 mg, 162 μmol) in MeOH (10 ml) was added a solution of NaOH (1.02 ml, 1.02 mmol) and the reaction mixture was heated to reflux for 1 hour. After cooling, water (5 ml) and DCM (5 ml) were added, and pH was adjusted to 2 with HCl 1N. After hydrophobic column decantation, the organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a gradient of MeOH in DCM (100/0 to 90/10, v/v) to give 30 mg (32%) of 8-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride and 12 mg (16%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(1H-pyrrol-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride.

Example 175. 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Hydrochloride Isomer 1

[1350] ##STR00655##

Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1351] ##STR00656##

[1352] To a solution of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Step 1 of Example 235) (200 mg, 343 μmol) in DCM (5 mL) at −78° C. was added diethylaminosulfur trifluoride (90 μl, 0.69 mmol). The mixture was stirred for 1 hour at −78° C. then for 6 hours allowing the temperature to warm up to room temperature. Saturated aqueous solution of NaHCO.sub.3 and DCM were added. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of gradient of DCM/MeOH/NH.sub.4OH from 100/0/0 to 90/10/1 to give 153 mg (77%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as mixture of two isomers.

[1353] LC/MS (m/z, MH+): 584

[1354] The mixture of two isomers of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate was separated by chiral SFC (conditions: flash Chiralcel OD-H (250×30 mm, 5 μm); supercritical CO.sub.2 80%/[0.1% TEA/MeOH] 20%; 3 mL/min) to give 35 mg of isomer 1 and 37 mg of isomer 2.

Step 2: 8-(2,4-Dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Hydrochloride Isomer 1

[1355] ##STR00657##

[1356] Example 175 was prepared following a similar procedure to that of step 3 of Example 77 from methyl 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 to give 31 mg (82%) of 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride Isomer 1.

Example 176. 8-(2,4-Dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride Isomer 2

[1357] ##STR00658##

[1358] Example 176 was prepared following a similar procedure to that of step 3 of Example 77 from methyl 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2 to give 26 mg (75%) of 8-(2,4-dichlorophenyl)-9-(4-(1-fluoro-1-(1-(3-fluoropropyl)azetidin-3-yl)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride Isomer 2.

Example 235. 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Hydrochloride Isomer 1

[1359] ##STR00659##

Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1360] ##STR00660##

[1361] To a solution of 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (Step 1 of Example 39) (100 mg, 176 μmol) in THF (5 mL) at −10° C. was added a 3 M solution of methyl magnesium bromide in ether (180 μL, 530 μmol). The mixture was stirred at −10° C. for 45 minutes. The reaction mixture was slowly quenched by addition of a saturated aqueous solution of NH.sub.4Cl and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give 102 mg (99%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as mixture of two isomers.

[1362] LC/MS (m/z, MH+): 582

[1363] The mixture of two isomers of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate was separated by chiral HPLC (conditions: flash Chiralpak AY-H 250×4.6 mm, 5 μm; Heptane 89/EtOH 10/MeOH 1/TEA 0.2; 45 mL/min) to give 20 mg of isomer 1 and 19 mg of isomer 2.

Step 2: 8-(2,4-Dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid, Hydrochloride Isomer 1

[1364] ##STR00661##

[1365] Example 235 was prepared following a similar procedure to that of step 3 of Example 77 from methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 to give 4 mg (21%) of 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride Isomer 1.

Example 236. 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid, Hydrochloride Isomer 2

[1366] ##STR00662##

[1367] Example 236 was prepared following a similar procedure to that of step 3 of Example 77 from methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2 to give 7 mg (35%) of 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-yl)-1-hydroxyethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, hydrochloride Isomer 2.

Example 194. 8-(2,4-Dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Isomer 1

[1368] ##STR00663##

Step 12: Methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 and Isomer 2

[1369] ##STR00664##

[1370] Step 1 of Example 194 Isomer 1 and Isomer 2 were prepared following a similar procedure to that of step 1 of Example 1 from 3-(4-bromobenzyl)-1-(2,3-difluoropropyl)azetidine (Intermediate 50) and methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 5) to give 278 mg (66%) as a mixture of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 and Isomer 2.

[1371] The mixture of two isomers was separated by chiral chromatography (condition: flash Chiralpak IF 5 m (250×30 mm), eluent: Heptane 95 EtOH 5 TEA 0.1 to give 91 mg of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 and 94 mg of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2.

[1372] LC/MS (m/z, MH+): 570

Step 2: 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Isomer 1

[1373] ##STR00665##

[1374] Step 2 of Example 194 Isomer 1 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 to give 75 mg (84%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1.

Example 195. 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Isomer 2

[1375] ##STR00666##

[1376] Example 195 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate isomer 2 to give 90 mg (98%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2.

Example 196. (E)-8-(2,4-Dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid, Trifluoroacetic Acid

[1377] ##STR00667##

[1378] Step 1: Methyl(E)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and methyl (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

##STR00668##

[1379] A mixture of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate acid (Step 1 of Example 39) (500 mg, 882 μmol) and O-methylhydroxylamine hydrochloride (184 mg, 2.21 mmol) in pyridine (5 ml) was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. The 2 isomers were separated by SFC (condition: flash Chiralpak IG 5 μm (3×25 cm), eluent CO.sub.2/11% (MeOH+0.1% DEA) to give 111 mg (21%) of methyl(E)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and 34 mg (6%) of methyl (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1380] LC/MS (m/z, MH+): 595

Step 2: (E)-8-(2,4-Dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid, Trifluoroacetic Acid

[1381] ##STR00669##

[1382] Step 2 of Example 196 isomer 1 was prepared following a similar procedure to that of step 2 of Example 2 from methyl(E)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 86 mg (66%) of (E)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid.

Example 197. (Z)-8-(2,4-Dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid, Trifluoroacetic Acid

[1383] ##STR00670##

[1384] Example 197 was prepared following a similar procedure to that of step 2 of Example 2 from methyl (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 12 mg (30%) of (Z)-8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxyimino)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acetate.

Example 227. 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Isomer 1

[1385] ##STR00671##

Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1

[1386] ##STR00672##

[1387] Step 1 of Example 227 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 5) and (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol Isomer 1 (Intermediate 14) to give 191 mg (64%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1.

[1388] LC/MS (m/z, MH+): 568

Step 2: Methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1

[1389] ##STR00673##

Step 3: 8-(2,4-Dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Isomer 1

[1390] ##STR00674##

[1391] To a solution of methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 (100 mg, 170 μmol) in methanol (5 mL) and water (1 mL) was added LiOH (12 mg, 511 μmol). The reaction mixture was stirred at room temperature for 3 hours then quenched with 1N aqueous HCl to pH 6-7 and extracted three times with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/00 to 95/05 to give 28 mg (29%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1.

Example 228. 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Isomer 2

[1392] ##STR00675##

Step 1: Methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2

[1393] ##STR00676##

[1394] Step 1 of Example 228 was prepared following a similar procedure to that of step 1 of Example 1 from methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 5) and (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanol Isomer 2 (Intermediate 15) to give 186 mg (62%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2.

[1395] LC/MS (m/z, MH+): 568

Step 2: Methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2

[1396] ##STR00677##

[1397] Step 2 of Example 228 was prepared following a similar procedure to that of step 2 of Example 227 from methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(hydroxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2 to give 175 mg (91%) of methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2.

[1398] LC/MS (m/z, MH+): 586

Step 3: 8-(2,4-Dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Isomer 2

[1399] ##STR00678##

[1400] Step 3 of Example 228 was prepared following a similar procedure to that of step 3 of Example 227 from methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2 to give 25 mg (26%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2.

Example 229. 8-(2,4-dichlorophenyl)-9-(4-(ethoxy(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Isomer 1

[1401] ##STR00679##

[1402] Example 229 was prepared following a similar procedure to that of step 3 of Example 227 from methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 and EtOH to give 15 mg (30%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1.

Example 230. 8-(2,4-dichlorophenyl)-9-(4-(ethoxy(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Isomer 2

[1403] ##STR00680##

[1404] Example 230 was prepared following a similar procedure to that of step 3 of Example 227 from methyl 9-(4-(chloro(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2 and EtOH to give 34 mg (34%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)(methoxy)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2.

Example 243. 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Isomer 1

[1405] ##STR00681##

Step 1: Methyl 9-(4-(azido(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1

[1406] ##STR00682##

[1407] Step 1 of Example 243 was prepared following a similar procedure to that of step 1 of Example 1 from 3-(azido(4-bromophenyl)methyl)-1-(3-fluoropropyl)azetidine Isomer 1 (Intermediate 25) and methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 5) to give 500 mg (99%) of methyl 9-(4-(azido(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1.

[1408] LC/MS (m/z, MH+): 593

Step 2: Methyl 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1

[1409] ##STR00683##

[1410] A mixture of methyl 9-(4-(azido(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 (300 mg, 505 μmol) and triphenylphosphine (132 mg, 505 μmol) in THF (4 ml) was stirred at room temperature for 24 hours. DCM (100 ml) and water (100 ml) were added. After decantation, the organic layer was dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure and the residue obtained purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/00 to 80/20 to give 44 mg (15%) of methyl 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1.

[1411] LC/MS (m/z, MH+): 567

Step 3: 9-(4-(Amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Isomer 1

[1412] ##STR00684##

[1413] Step 3 of Example 243 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 1 to give 33 mg (79%) of 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 1.

Example 244. 9-(4-(Amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Isomer 2

[1414] ##STR00685##

Step 1: Methyl 9-(4-(azido(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2

[1415] ##STR00686##

[1416] Step 1 of Example 244 was prepared following a similar procedure to that of step 1 of Example 1 from 3-(azido(4-bromophenyl)methyl)-1-(3-fluoropropyl)azetidine isomer 2 (Intermediate 26) and methyl 8-(2,4-dichlorophenyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 5) to give 550 mg (97%) of methyl 9-(4-(azido(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2.

[1417] LC/MS (m/z, MH+): 593

Step 2: Methyl 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2

[1418] ##STR00687##

[1419] Step 2 of Example 244 was prepared following a similar procedure to that of step 2 of Example 243 from methyl 9-(4-(azido(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2 to give 140 mg (44%) of methyl 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2.

[1420] LC/MS (m/z, MH+): 567

Step 3: 9-(4-(Amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid Isomer 1

[1421] ##STR00688##

[1422] Step 3 of Example 244 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate Isomer 2 to give 22 mg (52%) of 9-(4-(amino(1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid Isomer 2.

Example 252. 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid

[1423] ##STR00689##

Step 1: tert-butyl 3-((6-(8-(2-chlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate

[1424] ##STR00690##

[1425] Step 1 of Example 252 was prepared following a similar procedure to that of step 1 of Example 1 from tert-butyl 3-((6-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate (Intermediate 48) and (2-chlorophenyl)boronic acid to give 87 mg (41%) of tert-butyl 3-((6-(8-(2-chlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate.

[1426] LC/MS (m/z, MH+): 559

Step 2: methyl 9-(5-(azetidin-3-ylmethyl)pyridin-2-yl)-8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Trifluoroacetic Acid

[1427] ##STR00691##

[1428] Step 2 of Example 252 was prepared following a similar procedure to that of step 2 of Intermediate 11 from tert-butyl 3-((6-(8-(2-chlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate to give methyl 9-(5-(azetidin-3-ylmethyl)pyridin-2-yl)-8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid which was used in the next step without further purification.

Step 3: methyl 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1429] ##STR00692##

[1430] Step 3 of Example 252 was prepared following a similar procedure to that of step 4 of Intermediate 28 from methyl 9-(5-(azetidin-3-ylmethyl)pyridin-2-yl)-8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid to give 35 mg (43%) of methyl 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1431] LC/MS (m/z, MH+): 519

Step 4: 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid

[1432] ##STR00693##

[1433] Step 4 of Example 252 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 32 mg (44%) of 8-(2-chlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

Example 253. 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid

[1434] ##STR00694##

Step 1: tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate

[1435] ##STR00695##

[1436] Step 1 of Example 253 was prepared following a similar procedure to that of step 1 of Example 1 from tert-butyl 3-((6-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate (Intermediate 48) and (2,4-dichlorophenyl)boronic acid to give 105 mg (47%) of tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate.

[1437] LC/MS (m/z, MH+): 593

Step 2: methyl 9-(5-(azetidin-3-ylmethyl)pyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, Trifluoroacetic Acid

[1438] ##STR00696##

[1439] Step 2 of Example 253 was prepared following a similar procedure to that of step 2 of Intermediate 11 from tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methyl)azetidine-1-carboxylate to give methyl 9-(5-(azetidin-3-ylmethyl)pyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid which was used in the next step without further purification.

Step 3: methyl 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[1440] ##STR00697##

[1441] Step 3 of Example 253 was prepared following a similar procedure to that of step 4 of Intermediate 28 from methyl 9-(5-(azetidin-3-ylmethyl)pyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid to give methyl 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1442] LC/MS (m/z, MH+): 553

Step 4: 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic Acid

[1443] ##STR00698##

[1444] Step 4 of Example 253 was prepared following a similar procedure to that of step 2 of Example 2 from methyl 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 17 mg (18% for two last steps) of 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-yl)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

Example 254. 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol

[1445] ##STR00699##

[1446] Example 254 was prepared following a similar procedure to that of step 1 of Example 1 from 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (Intermediate 49) and 2,4-dichlorophenyl-boronic acid to give 120 mg (52%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol as an off-white solid.

Example 255. 8-(2-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol

[1447] ##STR00700##

[1448] Example 255 was prepared following a similar procedure to that of step 1 of Example 1 from 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (Intermediate 49) and 2-chlorophenyl-boronic acid to give 130 mg (61%) of 8-(2-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-yl)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol as a brownish solid.

[1449] The compounds according to Table 1a above were subjected to pharmacological tests for determining their degradation effects on estrogen receptors.

[1450] Test: Estrogen Receptor Degradation Activity

[1451] Said test involves measuring the in vitro degradation activity of the compounds of the Table 1a.

[1452] The measurements of the degradation activities were made using a breast cancer cell ERα in cell western assay as described hereunder.

[1453] 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 2.5p L at final concentrations ranging from 0.3-0.0000018 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 μM 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.

[1454] 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.

[1455] The % of ERα levels decrease were determined as follows: % inhibition=100*(1−(sample−fulvestrant: DMSO−fulvestrant)).

[1456] The Table 2 below indicates the estrogen receptor degradation activity results for the compounds of Table 1a tested at 0.3 μM, and demonstrates that said compounds have a significant degradation activity on estrogen receptors.

TABLE-US-00003 TABLE 2 % Degradation Degradation Compound No. IC.sub.50 (nM) At 0.3 μM 1 0.4 83 2 0.3 91 3 0.3 89 4 0.9 85 5 0.5 86 6 0.8 82 7 0.5 90 8 0.4 92 9 0.3 92 10 0.3 92 11 0.4 91 12 0.4 93 13 0.3 85 14 0.8 80 15 4 86 16 0.4 94 17 0.3 90 18 1.6 95 19 0.3 91 20 0.3 91 21 2.1 89 22 0.3 92 23 0.2 91 24 0.4 92 25 0.3 91 26 0.3 92 27 0.5 94 28 0.4 93 29 0.6 98 30 0.4 94 31 0.3 89 32 0.6 94 33 0.2 89 34 0.2 79 35 0.4 91 36 0.6 89 37 0.4 87 38 7 83 39 1.2 92 40 0.4 91 41 1.6 95 42 3.3 94 43 0.4 90 44 0.5 90 45 0.3 86 46 0.6 88 47 0.4 93 48 0.5 86 49 3.4 82 50 10.5 88 51 0.7 89 52 255 54 53 0.4 91 54 0.6 94 55 0.5 93 565 0.7 90 206 0.4 86 207 1.1 92 208 0.2 95 209 88.7 100 210 0.3 88 211 0.1 96 212 0.1 87 213 0.2 94 214 2.8 86 215 0.3 67 216 13.2 83 217 6.2 86 218 0.5 92 219 6.5 92 220 0.3 87 221 0.2 91 222 2.4 88 223 0.2 92 224 43.0 82 225 6.6 82 226 0.1 90 227 0.6 75 228 0.6 76 229 0.6 77 230 0.7 78 231 0.3 83 232 0.1 88 233 0.5 85 234 1.3 84 235 4.5 62 236 0.4 100 237 5.8 88 238 1.2 81 239 0.4 93 240 0.5 85 241 3.7 92 242 1.7 78 243 15.6 78 244 13.6 86 245 269.0 100 246 31.6 73 247 1.8 97 248 2.2 90 249 0.4 90 250 0.6 90 251 0.7 87 252 48.6 67 253 4.0 89 254 1.4 85 255 0.6 74 256 1 82 257 0.7 83 258 0.8 87 259 0.4 87 260 0.6 86 261 0.8 89 262 1.6 91 263 0.8 90 264 1.1 95 265 0.4 83 266 0.3 90 267 0.8 89 268 0.5 89 269 180 100 270 225 100 271 16.2 83 272 0.6 90 273 0.6 89 274 6.5 84 275 0.4 89 276 0.4 85 277 0.3 82 278 0.2 84 279 0.2 84 280 0.3 86 281 0.4 84 282 0.4 86 283 93.3 90 284 0.3 96 285 0.4 89 286 0.3 88 287 0.4 86 288 0.5 81 289 0.3 86 290 0.8 84 291 0.8 84 292 0.4 93 293 0.6 86 294 0.2 92 295 0.7 86 296 0.7 91 297 0.7 81 298 0.5 82 299 0.7 90 300 11.2 88 301 0.5 89 302 0.6 90 303 0.4 90 304 17.4 89 305 1.2 85 306 25.8 82 307 0.4 84 308 1.4 94 309 0.4 88 310 0.4 85 311 9 73 312 0.3 91 313 0.3 90 314 3 87 315 1 87 316 1.2 81 317 1.6 87 318 0.6 94 319 48 73 320 110 80 321 0.5 88 322 0.6 87 323 0.6 84 324 0.8 86 325 0.5 89 326 0.7 91 327 4.7 86 328 0.4 88 329 1.3 89 330 7 91 331 10.7 77 332 0.4 85 333 0.4 87 334 0.4 91 335 0.6 93 336 0.9 86

[1457] It is therefore apparent that the tested compounds have degradation activities for estrogen receptors, with IC50 less than 1 μM and with degradation levels greater than 50%. The compounds of formula (I) can therefore be used for preparing medicaments, especially medicaments which are degraders of estrogen receptors.

[1458] Accordingly, also provided herein are medicaments which comprise a compound of the formula (I), or a pharmaceutically acceptable salt thereof.

[1459] Herein are also provided the compounds of formula (I) defined above, or pharmaceutically acceptable salts thereof, for use as medicines.

[1460] Herein are also provided the compounds of formula (I) defined above, or pharmaceutically acceptable salt thereof, for use in therapy, especially as inhibitors and degraders of estrogen receptors.

[1461] Herein are also provided the compounds of formula (I) defined above, or a pharmaceutically acceptable salts thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.

[1462] A particular aspect is a compound of formula (I) defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[1463] In an embodiment, the cancer is a hormone dependent cancer.

[1464] In another embodiment, the cancer is an estrogen receptor dependent cancer, particularly the cancer is an estrogen receptor a dependent cancer.

[1465] In another embodiment, the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancer, or a metastasis thereof.

[1466] In another embodiment, the metastasis is a cerebral metastasis.

[1467] In another embodiment, the cancer is breast cancer. Particularly, the breast cancer is an estrogen receptor positive breast cancer (ERα positive breast cancer).

[1468] In another embodiment, the cancer is resistant to anti-hormonal treatment.

[1469] 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, mTOR or PI3K inhibitors.

[1470] According to another aspect, herein is provided 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.

[1471] Herein is also provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful in treating any of the pathological conditions indicated above, more particularly useful in treating cancer.

[1472] Herein are also provided the pharmaceutical compositions comprising as active principle a compound of formula (I). These pharmaceutical compositions comprise an effective dose of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

[1473] 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.

[1474] In the pharmaceutical compositions 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.

[1475] 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 of formula (I) in creams, gels, ointments or lotions.

[1476] As an example, a unit administration form of a compound of formula (I) in tablet form may comprise the following components:

TABLE-US-00004 Compound of formula (I) 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

[1477] There may be particular cases in which higher or lower dosages are appropriate. 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.