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

Abstract

The present application relates to compounds of formula (I), or pharmaceutically acceptable salts thereof: wherein R1 and R2 represent hydrogen or deuterium; R3 represents hydrogen, COOH or OH; R3 and R3 represent hydrogen, methyl, methoxy, chlorine, fluorine or cyano; R4 and R41 represent hydrogen or fluorine; R5 represents hydrogen, fluorine or (C1-C3)alkyl; R6 represents phenyl, fused phenyl, bicyclic group comprising 5 to 12 carbon atoms, heteroaryl group comprising 2 to 9 carbon atoms and comprising from 1 to 3 heteroatoms, cycloalkyl group comprising 3 to 7 carbon atoms, (C.sub.3-C.sub.6)cycloalkyl(C1-C3)alkyl group, 3 to 8 membered-heterocycloalkyl group comprising 1 or 2 heteroatoms, (C1-C6)alkyl, and phenyl(C1-C2)alkyl group; X represents CH.sub.2, O or S; Y represents CH?, N? or CR?, wherein R represents (C1-C3)alkyl, halogen, cyano, or (C1-C3)fluoroalkyl; R7 represents (C1-C3)alkyl, halogen atom, cyano, or (C1-C3)fluoroalkyl; R8 represents hydrogen or fluorine; R9 represents hydrogen, (C1-C.sub.3)alkyl or a cyclopropyl; 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: ##STR00470## 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 R4 independently represent a hydrogen atom or a fluorine atom; R5 represents a hydrogen atom, a fluorine atom or a (C.sub.1-C.sub.3)alkyl group; 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, said (C.sub.3-C.sub.6)cycloalkyl optionally comprises an unsaturation, and wherein the fused phenyl group 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, 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)fluoro alkyl 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 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, a methyl group or an ethyl 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, 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 trifluoromethyl; R7 independently represents a (C.sub.1-C.sub.3)alkyl group such as methyl, a halogen atom such as a fluorine atom, a cyano group, or a (C.sub.1-C.sub.3)fluoroalkyl group such as trifluoromethyl; R8 represents a hydrogen atom or a fluorine atom; R9 represents a hydrogen atom, 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 claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized in that R3 and R3 represent a hydrogen atom.

5. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized in that R4 and R4 represent a hydrogen atom.

6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized in that X represents CH.sub.2.

7. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that R5 represents a hydrogen atom.

8. The compound of formula (I) according to any one of claims 1 to 7, 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 cyclopropyl group, a methoxy group and a cyano group.

9. The compound of formula (I) according to any one of claims 1 to 7, characterized in that R6 represents a fused phenyl group, selected from a bicyclo[4.2.0]octatrienyl group, a indanyl group or a tetrahydronaphthalenyl group, optionally substituted with one or two fluorine atom.

10. The compound of formula (I) according to any one of claims 1 to 7, characterized in that R6 represents a bicyclic group selected from a bicyclo[4.1.0]heptanyl, a bicyclo[3.1.0]hexanyl, a spiro[2.3]hexanyl and a bicyclo[3.2.1]octan-3-yl, 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; advantageously said bicyclic group is unsubstituted.

11. The compound of formula (I) according to any one of claims 1 to 7, 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 and a (C.sub.1-C.sub.6)alkoxy group, and more particularly selected from a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group and a methoxy group.

12. The compound of formula (I) according to any one of claims 1 to 7, characterized in that R6 represents a cycloalkyl chosen from a cyclohexyl or a cyclopropyl group, said cycloalkyl 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 group being optionally substituted with one or two halogen atom(s) or (C.sub.1-C.sub.3)alkyl group(s), said cycloalkyl being advantageously substituted with 1 to 2 substituents independently selected from: a methyl group, a phenyl group and a cyclohexyl group substituted by two halogen atoms, in particular fluor atoms.

13. The compound of formula (I) according to any one of claims 1 to 7, characterized in that R6 represents a cyclobutylmethyl, 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, said cyclobutylmethyl being advantageously unsubstituted.

14. The compound of formula (I) according to any one of claims 1 to 7, characterized in that R6 represents a tetrahydropyranyl group, said tetrahydropyranyl group being optionally substituted with 1 to 3 substituents independently selected from: a fluorine atom, a (C.sub.1-C.sub.3)alkoxy group, a (C.sub.1-C.sub.3)fluoroalkyl group, a (C.sub.1-C.sub.3)fluoroalkoxy group and a OH group, said tetrahydropyranyl group being advantageously unsubstituted.

15. The compound of formula (I) according to any one of claims 1 to 7, characterized in that R6 represents an isobutyl group, said isobutyl 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, said isobutyl group being advantageously unsubstituted.

16. The compound of formula (I) according to any one of claims 1 to 7, 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 claims 1 to 16, characterized in that R7 independently represents a methyl group, a cyano group, a trifluoromethyl group or a fluorine atom and n is 0, 1 or 2.

18. The compound of formula (I) according to anyone of claims 1 to 17, wherein Y represents CH?, N? or CR?, R representing a fluorine atom, a cyano group, or a trifluoromethyl group.

19. The compound of formula (I) according to anyone of claims 1 to 18, wherein m is 1.

20. The compound of formula (I) according to anyone of claims 1 to 19, or a pharmaceutically acceptable salt thereof, in particular hydrochloride salt thereof, characterized in that said compound is selected from the following compounds: 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (1) 8-(3-fluoro-2-methoxypyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (2) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (3) 8-(6-fluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (4) 8-(4-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (5) 8-(5-fluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (6) 8-(4-fluoro-2,3-dihydro-1H-inden-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (7) 8-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (8) 8-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (9) 8-(2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (10) 8-(4-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (11) 8-(7-fluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (12) 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (13) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (14) 8-(2,4-difluorophenyl)-9-(5-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (15) 8-(2,4-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (16) 8-(2,4-difluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (17) 8-(5-fluoro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (18) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (19) 8-(2,4-difluorophenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (20) 8-(2,6-difluoro-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (21) 8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (22) 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (23) 8-(3-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (24) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (25) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-fluoro-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (26) 8-(2,4-difluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-5-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (27) 8-(4-fluoro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-5-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (28) 8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (29) 8-(4-fluoro-2-methylphenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (30) 8-(2,4-difluorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-6-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (31) 8-(5-fluoro-3-methylpyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (32) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4,6-trifluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (33) 8-(4-cyclopropyl-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (34) 8-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (35) 9-(3,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (36) 8-(4-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (37) 8-(5-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (38) 8-(4-cyclopropyl-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (39) 8-(2-cyclopropyl-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (40) 8-(2-chloro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (41) 8-(2-chloro-6-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (42) 9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4-difluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (43) 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (44) 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2,5-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (45) 9-(3-cyano-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (46) 8-(3-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (47) 8-(2-fluoro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (48) 8-(2-fluoro-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (49) 8-(2-chloro-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (50) 8-(2,6-difluoro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (51) 9-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4-difluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (52) 8-(2,4-difluorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (53) 8-(2,4-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (54) 8-(2,3-difluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (55) 8-(2-fluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (56) 8-(2-fluoro-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (57) 8-(4-chloro-2-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (58) 9-(3,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4-difluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (59) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (60) 8-(4-fluoro-2-methylphenyl)-9-(5-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (61) 8-(4-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-6-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (62) 8-(2,4-dichlorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (63) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (64) 9-(2,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (65) 8-(2,4-dichlorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-6-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (66) 8-(4-fluoro-2-methylphenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (67) 9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (68) 9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-fluoro-4-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (69) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (70) 8-(2,4-dichlorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-5-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (71) 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (72) 8-(2,4-dichlorophenyl)-9-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (73) 8-(2,4-dichlorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (74) 8-(2-chloro-4-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (75) 8-(2-chloro-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (76) 8-(2,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (77) 8-(2-chloro-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (78) 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (79) 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-carboxylic acid hydrochloride (80) 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (81) 8-(4-chloro-2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (82) 8-(4-chloro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (83) 8-(4-cyano-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (84) 8-(3-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (85) 8-(2-ethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (86) 8-(4-fluoro-2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (87) 8-(2-cyano-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (88) 8-(4-chloro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (89) 8-(4-fluoro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (90) 8-(3-cyano-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (91) 8-(2,4-dichlorophenyl)-9-(2,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (92) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (93) 8-(2,3-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (94) 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (95) 8-(2-ethyl-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (96) 8-(2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (97) 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (98) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(o-tolyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (99) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-acid, (100) 8-(2,4-dichlorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (101) 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (102) 8-(2,4-dichlorophenyl)-9-(3-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (103) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3,5-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride, (104) 8-(2,4-dichlorophenyl)-9-(3,5-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (105) 6-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7,8-dihydronaphthalene-2-carboxylic acid hydrochloride, (106) 8-(3-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (107) 8-(4-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (108) 8-(2,4-dichlorophenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (109) 8-(3-methyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (110) 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (111) 8-(3,4-difluoro-2-methylphenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (112) 8-(2-methyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3,3,3-trifluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (113) 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylic acid hydrochloride (114) 4-(2,4-dichlorophenyl)-5-[4-[[1-(3-fluoropropyl)azetidin-3-ylidene]methyl]phenyl]-2,3-dihydro-1-benzothiepine-8-carboxylic acid;hydrochloride (115) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (116) 8-(2,4-dichlorophenyl)-9-(4-((1-(3,3-difluoropropyl-1,1-d2)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (117) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (118) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(5-methyl-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (119) 3-(4-(8-(2-chlorophenyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)-1-(3-fluoropropyl)azetidine (120) 8-(2-fluoro-5-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (121) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl-1,1-d2)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (122) 8-(2-chloro-5-fluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (123) 8-(2,4-difluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (124) 8-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (125) 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (126) 8-(4-chloro-3-fluoro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (127) 8-(4-chloro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (128) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-fluoro-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (129) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2,3-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (130) 8-(2-chloro-3-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (131) 8-(4-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (132) 8-(2-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (133) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (134) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (135) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (136) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (137) 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (138) 9-(2-cyano-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (139) 8-(2-chloro-5-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (140) 8-(4-cyclopropyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (141) Sodium 8-(2,4-difluorophenyl)-9-(2-fluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (142) 8-(3-chloro-5-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (143) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-methyl-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (144) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methyl-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (145) 8-(3,4-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (146) 8-(2-chloro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (147) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-methoxy-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (148) 8-(4-ethoxy-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (149) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methoxy-5-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (150) 8-(2,5-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (151) 9-(2,3-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (152) 8-(5-fluoro-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (153) 8-(4-fluoro-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (154) 8-(3-fluoro-5-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (155) 8-(5-fluoro-2-methoxypyridin-4-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (156) 8-(4-fluoro-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (157) 8-(2,4-dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (158) 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid, (159) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(5-fluoro-2,3-dihydro-1H-inden-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (160) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-fluoro-2,3-dihydro-1H-inden-5-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (161) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(6-fluoro-2,3-dihydro-1H-inden-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (162) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,3-dihydro-1H-inden-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (163) 8-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (164) 9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(7-fluoro-2,3-dihydro-1H-inden-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (165) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (166) 8-benzyl-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-acid (167) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-phenethyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (168) 8-(cyclobutylmethyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (169) 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (170) 8-(3,3-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 1 (171) 8-(3,3-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 2 (172) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-((trans)-2-phenylcyclopropyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (173) 84(1R,6S,70-bicyclo[4.1.0]heptan-7-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (174) 8-(bicyclo[3.1.0]hexan-1-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (175) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(spiro[2.3]hexan-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (176) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(5,6,7,8-tetrahydronaphthalen-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (177), 8-(bicyclo[3.2.1]octan-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (178) 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 1 (179) 8-(3-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (180) 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (181) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (182) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (183) 8-(4-chlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 2 (184) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid hydrochloride (185) 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (186) 8-(trans-2-(4,4-difluorocyclohexyl)cyclopropyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture (187) 9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-8-(4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, mixture of isomers (188).

21. A process for preparing a compound of formula (I) as defined in anyone of claims 1 to 20, wherein a compound of formula 1K ##STR00471## wherein R1, R2, R3, R3, R4, R4, R5, R6, R7, R8, R9, m, n, X and Y are as defined in any of claims 1 to 19 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 1K, wherein a compound of formula 1T ##STR00472## wherein, R1, R2, R3, R3, R4, R4, R5, R7, R8, R9, m, n, X and Y are as defined in any of claims 1 to 19 and R3a is as defined above, is subjected to a Suzuki coupling with a boronic reagent R6B(OR).sub.2 or R6BF.sub.3K, wherein B(OR).sub.2 is a boronic acid or a pinacolate ester and R6 is as defined in any of claims 1 or 8 to 16.

22. A process for preparing a compound of formula (I) as defined in anyone of claims 1 to 20, wherein a compound of formula 1Ta ##STR00473## wherein R1, R2, R3, R3, R4, R4, R5, R7, R8, R9, m, n, X and Y are as defined in any of claims 1 to 19 and R3a is as defined in the preceding claim, is submitted to a Suzuki coupling with a boronic reagent R6B(OR).sub.2 or R6BF.sub.3K, wherein B(OR).sub.2 is a boronic acid or a pinacolate ester and R6 is defined as in any of claims 1 or 8 to 16, said step being optionally preceded by a step for obtaining compound 1Ta, wherein a compound of formula 1T ##STR00474## wherein R1, R2, R3, R3, R4, R4, R5, R7, R8, R9, m, n, X and Y are as defined in any of claims 1 to 19 and R3a is as defined above, is converted to a compound 1Ta in the presence of a source of hydroxide ions, such as NaOH in solution in methanol.

23. Compounds selected from compounds of formula 1T, 1K and 1Ta, or any of their pharmaceutically acceptable salt, ##STR00475## wherein R1, R2, R3, R3, R3, R4, R4 R5, R7, R8, R9, m, n, X and Y are as defined in any of claims 1 to 19 and R3a is carboxylic ester such as COOMe, COOEt, or protected OH with O-pivaloyl.

24. Compound of formula 1F, or any of its pharmaceutically acceptable salt ##STR00476## wherein R1, R2, R4, R4, R5, R7, R8, Y and n are as defined in any of claims 1 to 19.

25. A medicament, characterized in that it comprises a compound of formula (I) according to any of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

27. A compound of formula (I) according to any of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use as an inhibitor and degrader of estrogen receptors.

28. A compound of formula (I) according to any of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.

29. A compound of formula (I) for use according to claim 28, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

Description

EXAMPLES

Method A

Example 1: 8-(2,4-Dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

[0945] ##STR00420##

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

[0946] ##STR00421##

[0947] A mixture of 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 4) (100 mg, 211 ?mol), 3-(4-bromobenzylidene)-1-(3-fluoropropyl)azetidine (Intermediate 1) (60 mg, 211 ?mol), Cs.sub.2CO.sub.3 (178 mg, 534.5 ?mol), and Pd(dppf)Cl.sub.2, complex with DCM (11 mg, 13 ?mol) in dioxane (1 mL) and water (0.4 mL) was heated to reflux 1 hour. 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 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.

[0948] LC/MS (m/z, MH+): 550

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

[0949] ##STR00422##

[0950] 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 (101 mg, 183.6 ?mol) in MeOH (0.50 mL) and THF (1 mL) was added a solution of NaOH 1N (0.55 mL) 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 SFC (Flash DCPAK B 5 ?m; 250?30 mm; supercritical CO.sub.2 70%/MeOH 30%/TEA 0.1% at 120 mL/min) to give 47.5 mg (45%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

Method B

Example 79: 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

[0951] ##STR00423##

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

[0952] ##STR00424##

[0953] A mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) (100 mg, 206 ?mol), (2-chloro-4-fluoro-phenyl)boronic acid (54 mg, 310 ?mol), Cs.sub.2CO.sub.3 (141 mg, 433 ?mol), and Pd(dppf)Cl.sub.2, complex with DCM (15 mg, 21 ?mol) in dioxane (4 mL) and water (1 mL) was heated to reflux for 30 minutes. After cooling to room temperature, addition of EtOAc (200 mL) and water (50 mL). After decantation, the organic phase was dried over MgSO.sub.4, filtered and concentrated under reduced pressure to give 65 mg (59%) of methyl 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0954] LC/MS (m/z, MH+): 534

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

[0955] ##STR00425##

[0956] To a solution of methyl 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (65 mg, 121.7 ?mol) in MeOH (5 mL) and water (1 mL) was added LiOH (15 mg, 608 ?mol) and the reaction mixture was heated to 50? C. for 2 hours. After cooling, water (50 mL), EtOAc (100 mL) and Et.sub.2O (100 mL) were added and pH was adjusted to 7 with HCl 0.1N. After decantation, the organic phase was dried over MgSO.sub.4, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of MeOH in DCM (100/0 to 90/10, v/v) to give 43 mg (68%) of 8-(2-chloro-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

Method C

Example 8: 8-(Bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

[0957] ##STR00426##

Step 1: Methyl 8-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate

[0958] ##STR00427##

[0959] A mixture of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)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) (200 mg, 376 ?mol), 3-bromobicyclo[4.2.0]octa-1(6),2,4-triene (137 mg, 752 ?mol), Cs.sub.2CO.sub.3 (245 mg, 752 ?mol), and Pd(dppf)Cl.sub.2, complex with DCM (14 mg, 19 ?mol) in dioxane (8 mL) and water (2 mL) was heated to 95? C. for 3 hours. After cooling to room temperature, addition of EtOAc (200 mL) and water (50 mL). After decantation, the organic phase was dried over MgSO.sub.4, filtered concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of cyclohexane/EtOAc (100/0 to 100/0, v/v) to give 55 mg (29%) of methyl 8-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0960] LC/MS (m/z, MH+): 508

Step 2: 8-(Bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

[0961] ##STR00428##

[0962] Step 2 of Example 8 was prepared following a similar procedure to that of step 2 of Example 79 from methyl 8-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 16 mg (30%) of 8-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

Method D

Example 114: 4-(2,4-Dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylic acid hydrochloride

[0963] ##STR00429##

Step 1: Methyl 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylate

[0964] ##STR00430##

[0965] A mixture of methyl 4-(2,4-dichlorophenyl)-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepine-8-carboxylate (Intermediate 30) (250 mg, 504 ?mol), 1-(3-fluoropropyl)-3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylene]azetidine (Intermediate 2) (158 mg, 478 ?mol), Cs.sub.2CO.sub.3 (447 mg, 1.37 mmol), and Pd(dppf)Cl.sub.2, complex with DCM (33 mg, 41 ?mol) in dioxane (2 mL) and water (0.8 mL) was heated to 85? C. for 2 hours. After cooling to room temperature, addition of DCM (4 mL) and water (2 mL). After decantation in hydrophobic column, the organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc to give 69 mg (26%) of methyl 4-(2,4-dichlorophenyl)-8-carboxylate.

[0966] LC/MS (m/z, MH+): 552

Step 2: 4-(2,4-Dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylic acid

[0967] ##STR00431##

[0968] Step 2 of Example 115 was prepared following a similar procedure to that of step 2 of Example 79 from methyl 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylate to give 46 mg (65%) of 4-(2,4-dichlorophenyl)-5-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-2,3-dihydrobenzo[b]oxepine-8-carboxylic acid hydrochloride.

Method E

Example 60: 9-(4-((1-(3-Fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

[0969] ##STR00432##

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

[0970] ##STR00433##

[0971] To a mixture of methyl 8-bromo-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) (100 mg, 206 ?mol), tri-o-tolylphosphine (10 mg, 33 ?mol), Pd.sub.2(dba).sub.3 (9.5 mg, 16.5 ?mol) in DMF (4 mL) degassed and purged with argon for 5 min, was added a 0.5M solution of tetrahydropyran-4-ylzinc iodide (0.6 mL, 309.7 ?mol). After 2 hours of stirring at room temperature, EtOAc (100 mL), Et.sub.2O (100 mL) and water (150 mL) were added. After decantation, the organic phase was dried over MgSO.sub.4, filtered concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of cyclohexane/EtOEt (100/0 to 00/100, v/v) to give 60 mg (59%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0972] LC/MS (m/z, MH+): 490

Step 2: 9-(4-((1-(3-Fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

[0973] ##STR00434##

[0974] Step 2 of Example 60 was prepared following a similar procedure to that of step 2 of Example 79 from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 10 mg (17%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

Method F

Example 100: 9-(4-((1-(3-Fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

[0975] ##STR00435##

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

[0976] ##STR00436##

[0977] Step 1 of Example 100 was prepared following a similar procedure to that of step 1 of Example 79 from methyl 8-bromo-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Step 5 (Method 2) Intermediate 7) and 4,4,5,5,-tetramethyl-2-(2-methylpropo-1-en-1-yl)-1,3,2-dioxaborolane to give 224 mg (62%) methyl 9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-8-(2-methylprop-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0978] LC/MS (m/z, MH+): 476

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

[0979] ##STR00437##

[0980] A mixture of methyl 9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-8-(2-methylprop-1-en-1-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (224 mg, 471 ?mol), Pd/C 10% (90 mg, 85 ?mol) in EtOH (30 mL) and EtOAc (15 mL) was hydrogenated at 50? C. and 5 bars of H.sub.2 for 20 hours. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/MeOH (100/0 to 95/05, v/v) to give 150 mg (66%) 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.

[0981] LC/MS (m/z, MH+): 478

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

[0982] ##STR00438##

[0983] Step 3 of Example 100 was prepared following a similar procedure to that of step 6 (Method 2) of Intermediate 7 from methyl 5-[4-[1-(3-fluoropropyl)azetidine-3-carbonyl]phenyl]-6-isobutyl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate to give 75 mg (50%) of methyl 5-[4-[[1-(3-fluoropropyl)azetidin-3-yl]-hydroxy-methyl]phenyl]-6-isobutyl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate.

[0984] LC/MS (m/z, MH+): 480

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

[0985] ##STR00439##

[0986] Step 4 of Example 100 was prepared following a similar procedure to that of step 7 (Method 2) of Intermediate 7 from methyl 5-[4-[[1-(3-fluoropropyl)azetidin-3-yl]-hydroxy-methyl]phenyl]-6-isobutyl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate to give 71 mg (66%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0987] LC/MS (m/z, MH+): 462

Step 5: 9-(4-((1-(3-Fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

[0988] ##STR00440##

[0989] Step 5 of Example 100 was prepared following a similar procedure to that of step 2 of Example 79 from methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 44 mg (40%) of 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-isobutyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

Method G

Example 102: 8-(2,4-Dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

[0990] ##STR00441##

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

[0991] ##STR00442##

[0992] Step 1 of Example 102 was prepared following a similar procedure to that of step 1 of Example 1 from (4-bromophenyl)(1-(3-fluoropropyl)azetidin-3-yl)methanone 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 to give 270 mg (34%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(3-fluoropropyl)azetidine-3-carbonyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0993] LC/MS (m/z, MH+): 566

Step 2: 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

[0994] ##STR00443##

[0995] To 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 (430 mg, 759 ?mol) in THF (20 mL) cooled at ?20? C. was added methylmagnesium bromide 3M in Et.sub.2O (759 ?L, 2.28 mmol). After 45 minutes of stirring at ?10? C., saturated NH.sub.4Cl aqueous solution (5 mL), EtOAc (50 mL) and water (20 mL) were added. After decantation, the organic phase was dried over MgSO.sub.4, filtered concentrated under reduced pressure to give 442 mg (100%) 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.

[0996] LC/MS (m/z, MH+): 582

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

[0997] ##STR00444##

[0998] A mixture 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 (50 mg, 85.83 ?mol) in water (0.5 mL) and sulfuric acid (1 mL, 18.76 mmol) was stirred at room temperature for 2 hours. Ice and EtOAc were added and the pH was adjusted to 9 by addition of saturated aqueous solution of NaHCO.sub.3 and Na.sub.2CO.sub.3. After decantation, the organic phase was dried over MgSO.sub.4, filtered concentrated under reduced pressure and the residue obtained was purified by flash chromatography eluting with a gradient of DCM/MeOH (100/0 to 95/05, v/v) to give 24 mg (49%) of methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0999] LC/MS (m/z, MH+): 564

Step 4: 8-(2,4-Dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

[1000] ##STR00445##

[1001] Step 4 of Example 102 was prepared following a similar procedure to that of step 2 of Example 79 from methyl 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 6 mg (26%) of 8-(2,4-dichlorophenyl)-9-(4-(1-(1-(3-fluoropropyl)azetidin-3-ylidene)ethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

Method H

Example 159: 8-(2,4-Dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

[1002] ##STR00446##

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

[1003] ##STR00447##

[1004] Step 1 of Example 159 was prepared following a similar procedure to that of step 1 (Method 1) of Intermediate 7 from methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and 5-bromo-2-iodopyridine to give 108 mg (10%) of methyl 9-(5-bromopyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1005] LC/MS (m/z, MH+): 502

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

[1006] ##STR00448##

[1007] Step 2 of Example 159 was prepared following a similar procedure to that of step 1 (Method 2) of Intermediate 1 from methyl 9-(5-bromopyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 87 mg (68%) of tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methylene)azetidine-1-carboxylate.

[1008] LC/MS (m/z, MH+): 590

Step 3: Methyl 9-(5-(azetidin-3-ylidenemethyl)pyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid

[1009] ##STR00449##

[1010] Step 3 of Example 159 was prepared following a similar procedure to that of step 2 of Intermediate 1 from tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)pyridin-3-yl)methylene)azetidine-1-carboxylate to give methyl 9-(5-(azetidin-3-ylidenemethyl)pyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-trifluoroacetic acid which was used without further purification.

[1011] LC/MS (m/z, MH+): 491

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

[1012] ##STR00450##

[1013] Step 4 of example 159 was prepared following a similar procedure to that of step 5 (Method 2) of Intermediate 7 from methyl 9-(5-(azetidin-3-ylidenemethyl)pyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid to give 40 mg (49% for steps 3 and 4) of methyl 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1014] LC/MS (m/z, MH+): 551

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

[1015] ##STR00451##

[1016] Step 4 of Example 159 was prepared following a similar procedure to that of step 2 of Example 79 from methyl 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 34 mg (72%) of 8-(2,4-dichlorophenyl)-9-(5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, trifluoroacetic acid.

Method I

Example 158: 8-(2,4-Dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

[1017] ##STR00452##

Step 1: Tert-butyl 3-[(6-bromo-5-fluoro-3-pyridyl)methylene]azetidine-1-carboxylate

[1018] ##STR00453##

[1019] Step 1 of Example 158 was prepared following a similar procedure to that of step 1 (Method 2) of Intermediate 1 from 2-bromo-3-fluoro-5-iodo-pyridine to give 587 mg (61%) of tert-butyl 3-[(6-bromo-5-fluoro-3-pyridyl)methylene]azetidine-1-carboxylate.

[1020] LC/MS (m/z, MH+): 343

Step 2: 9-(5-((1-(Tert-butoxycarbonyl)azetidin-3-ylidene)methyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

[1021] ##STR00454##

[1022] Step 2 of Example 158 was prepared following a similar procedure to that of step 1 of Example 1 (Method A) from methyl 9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate and tert-butyl 3-[(6-bromo-5-fluoro-3-pyridyl)methylene]azetidine-1-carboxylate to give 585 mg (81%) of 9-(5-((1-(tert-butoxycarbonyl)azetidin-3-ylidene)methyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

[1023] LC/MS (m/z, MH+): 595

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

[1024] ##STR00455##

[1025] A mixture of 9-(5-((1-(tert-butoxycarbonyl)azetidin-3-ylidene)methyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid (585 mg, mmol), K.sub.2CO.sub.3 (271 mg, 1.96 mmol) and methyl iodide (209 mg, 1.47 mmol, 0.09 mL) in DMF (10 mL) was stirred at room temperature for 20 minutes. The reaction mixture was quenched by addition of water (50 mL) and then extracted with a mixture of EtOAc (30 mL) and Et.sub.2O (70 mL). After decantation, the organic phase was washed twice with water (50 mL), dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash chromatography, eluting with a gradient of cyclohexane/EtOAc: from 100/00 to 75/25 to give 327 mg (55%) of tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate.

[1026] LC/MS (m/z, MH+): 609

Step 4: Methyl 9-(5-(azetidin-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid

[1027] ##STR00456##

[1028] Step 4 of Example 158 was prepared following a similar procedure to that of step 2 of Intermediate 1 from tert-butyl 3-((6-(8-(2,4-dichlorophenyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate to give 287 mg (98%) of methyl 9-(5-(azetidin-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid.

[1029] LC/MS (m/z, MH+): 509

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

[1030] ##STR00457##

[1031] Step 5 of Example 158 was prepared following a similar procedure to that of step 5 (Method 2) of Intermediate 7 from methyl 9-(5-(azetidin-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(2,4-dichlorophenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid to give 90 mg (41%) of methyl 8-(2,4-dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[1032] LC/MS (m/z, MH+): 569

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

[1033] ##STR00458##

[1034] Step 6 of Example 158 was prepared following a similar procedure to that of step 2 of Example 79 from methyl 8-(2,4-dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 7 mg (14%) of 8-(2,4-dichlorophenyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

Method J

Example 166: 8-(2,4-Dichlorophenyl)-9-(4-((1-(3-fluoropropyl) azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture

[1035] ##STR00459##

Step 1: 9-(4-((1-(Tert-butoxycarbonyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture

[1036] ##STR00460##

[1037] Step 1 of Example 166 was prepared following a similar procedure to that of step 1 of Example 79 from tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate (Intermediate 43) to give 217 mg (88%) of 9-(4-((1-(tert-butoxycarbonyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid as a racemic mixture.

[1038] LC/MS (m/z, MH+): 590

Step 2: Methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid (racemic mixture)

[1039] ##STR00461##

[1040] Step 2 of Example 166 was prepared following a similar procedure to that of step 2 of Intermediate 1 from 9-(4-((1-(tert-butoxycarbonyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid to give 252 mg (100%) of methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid as a racemic mixture.

[1041] LC/MS (m/z, MH+): 504

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

[1042] ##STR00462##

[1043] Step 3 of Example 166 was prepared following a similar procedure to that of step 6 (Method 1) of Intermediate 7 from methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid to give 70 mg (30%) of methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture.

[1044] LC/MS (m/z, MH+): 564

Step 4: 8-(2,4-Dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture

[1045] ##STR00463##

[1046] Step 4 of Example 166 was prepared following a similar procedure to that of step 2 of Example 79 from methyl 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 38 mg (55%) of 8-(2,4-dichlorophenyl)-9-(4-((1-(3-fluoropropyl) azetidin-3-ylidene)methyl)phenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid as a racemic mixture.

Method K

Example 186: 8-(3,3-Dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture

[1047] ##STR00464##

Step 1: Tert-butyl 3-((5-fluoro-6-(tributylstannyl)pyridin-3-yl)methylene)azetidine-1-carboxylate

[1048] ##STR00465##

[1049] A mixture of tert-butyl 3-[(6-bromo-5-fluoro-3-pyridyl)methylene]azetidine-1-carboxylate (4 g, 11.66 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (0.82 g, 1.17 mmol), 1,1,1,2,2,2-hexabutyldistannane (17.64 mL, 34.97 mmol) in toluene (50 mL) was degassed and purged with Ar for 5 min then heated to 110? C. for 17 hours in a sealed tube. After cooling to room temperature, the reaction mixture was filtered and purified by flash chromatography, eluting with a gradient of cyclohexane/EtOAc: from 100/00 to 50/50 to give 2 g (31%) of tert-butyl 3-((5-fluoro-6-(tributylstannyl)pyridin-3-yl)methylene)azetidine-1-carboxylate.

[1050] LC/MS (m/z, MH+): 555

Step 2: Tert-butyl 3-((6-(8-(3,3-dimethylcyclohexyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate, racemic mixture

[1051] ##STR00466##

[1052] A mixture of methyl 8-(3,3-dimethylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 39) (0.46 g, 1 mmol), Pd(PPh.sub.3).sub.4 (231 mg, 200 ?mol), tert-butyl 3-((5-fluoro-6-(tributylstannyl)pyridin-3-yl)methylene)azetidine-1-carboxylate (1.11 g, 2 mmol) in toluene (20 mL) was degassed and purged with Ar for 5 min then heated to 80? C. for 2.5 hours in a sealed tube. After cooling to room temperature, the reaction mixture was filtered and transferred in a new tube, then Pd(PPh.sub.3).sub.4 (50 mg, 47 ?mol) was added and the mixture degassed. The tube was sealed and heated to 80? C. for 3 hours. After cooling to room temperature, Et.sub.2O (50 mL), EtOAc (50 mL) and a 10% aqueous solution of KF (50 mL) were added and the mixture was filtered. After decantation, the organic phase was washed with dried over MgSO.sub.4, filtered, concentrated under reduced pressure and the residue obtained was purified by flash chromatography, eluting with a gradient of cyclohexane/EtOAc: from 100/00 to 00/100 to give 67 mg (10%) of tert-butyl 3-((6-(8-(3,3-dimethylcyclohexyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate as a racemic mixture.

[1053] LC/MS (m/z, MH+): 575

Step 3: Methyl 9-(5-(azetidin-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(3,3-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid (racemic mixture)

[1054] ##STR00467##

[1055] Step 3 of Example 186 was prepared following a similar procedure to that of step 2 of Intermediate 1 from 9-(4-((1-(tert-butoxycarbonyl)azetidin-3-ylidene)methyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid to give methyl 9-(5-(azetidin-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(3,3-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoroacetic acid as a racemic mixture.

[1056] LC/MS (m/z, MH+): 475

Step 4: Methyl 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, racemic mixture

[1057] ##STR00468##

[1058] Step 4 of Example 186 was prepared following a similar procedure to that of step 6 (Method 1) of Intermediate 7 from methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-(2,4-dichlorophenyl)-7-methyl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, trifluoro acetic acid to give 35 mg (33%) of methyl 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate as a racemic mixture.

[1059] LC/MS (m/z, MH+): 535

Step 5: 8-(3,3-Dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, racemic mixture

[1060] ##STR00469##

[1061] Step 5 of Example 186 was prepared following a similar procedure to that of step 2 of Example 79 from methyl 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 25 mg (73%) of 8-(3,3-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid as a racemic mixture.

[1062] The compounds according to Table 1a above were subjected to pharmacological tests for determining their degradation effects on estrogen receptors.

[1063] Test: Estrogen Receptor Degradation Activity

[1064] Said test involves measuring the in vitro degradation activity of the compounds of the Table 1a.

[1065] The measurements of the degradation activities were made using a breast cancer cell ER? in cell western assay as described hereunder.

[1066] MCF7 cells (ATCC) were seeded in 384 wells microplate (collagen coated) at a concentration of 10000 cells/30 ?L per well in red phenol free MEM alpha medium (invitrogen) containing 5% charcoal dextran striped FBS. The following day, 9 points serial 1:5 dilution of each compound was added to the cells in 2.5 ?L at final concentrations ranging from 0.3-0.0000018 ?M (in table 2), or 0.1 ?M for fulvestrant (using as positive control). At 4 hours post compound addition the cells were fixed by adding 25 ?L of formalin (final concentration 5% formalin containing 0.1% triton) for 10 minutes at room temperature and then washed twice with PBS. Then, 50 ?L 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 ?L 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 ?M 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 ER? and DNA respectively.

[1067] 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.

[1068] The % of ER? levels decrease were determined as follows: % inhibition=100*(1?(sample?fulvestrant: DMSO?fulvestrant)).

[1069] The Table 2 below indicates the estrogen receptor degradation activity results for the compounds of Table 1a tested at 0.3 ?M, and demonstrates that said compounds have a significant degradation activity on estrogen receptors.

TABLE-US-00004 TABLE 2 Compound Degradation % Degradation No. IC.sub.50 (nM) At 0.3 ?M 1 0.4 96 2 0.6 92 3 0.3 90 4 0.8 86 5 1 88 6 0.4 92 7 0.6 90 8 0.4 86 9 0.6 90 10 0.2 90 11 0.3 91 12 0.4 93 13 0.5 89 14 0.2 88 15 0.6 87 16 0.4 93 17 0.5 89 18 0.6 90 19 0.2 93 20 0.3 92 21 0.3 93 22 0.5 93 23 0.4 96 24 0.2 95 25 0.5 92 26 0.4 91 27 0.9 92 28 1.0 90 29 0.3 96 30 1.8 91 31 0.8 92 32 2.4 88 33 0.3 92 34 0.3 90 35 0.4 93 36 0.4 89 37 0.4 87 38 0.2 91 39 0.2 87 40 0.3 87 41 0.2 92 42 0.2 91 43 0.4 92 44 0.4 91 45 0.7 89 46 6.0 94 47 0.3 91 48 0.3 95 49 0.3 98 50 0.1 93 51 0.4 95 52 0.3 97 53 0.3 94 54 0.4 93 55 1.0 94 56 0.2 93 57 0.2 93 58 0.2 99 59 0.4 93 60 2.3 91 61 0.8 93 62 0.5 99 63 0.7 90 64 0.3 93 65 0.3 95 66 0.4 98 67 0.5 99 68 0.3 96 69 0.5 94 70 0.2 101 71 0.2 101 72 0.3 97 73 0.3 98 74 0.5 92 75 1.1 92 76 0.5 94 77 0.4 92 78 0.6 93 79 0.4 97 80 0.6 98 81 0.4 98 82 0.5 90 83 0.4 93 84 2.1 92 85 0.2 94 86 0.2 92 87 0.4 94 88 2.4 94 89 0.2 98 90 0.2 93 91 0.9 87 92 0.3 98 93 0.6 97 94 0.2 96 95 0.2 94 96 0.2 98 97 0.2 95 98 0.3 96 99 0.3 95 100 0.3 94 101 0.4 93 102 0.3 89 103 0.2 92 104 4.9 79 105 0.1 94 106 1 93 107 1.3 93 108 1.2 92 109 1.4 91 110 2.9 93 111 1 90 112 27.8 100 113 0.3 90 114 0.4 91 115 120 100 116 0.7 90 117 0.9 90 118 0.4 93 119 0.9 94 120 2.68 98 121 0.7 94 122 0.4 94 123 0.7 94 124 1.2 93 125 0.7 91 126 0.5 93 127 0.6 93 128 1.1 93 129 1.0 94 130 1.6 96 131 1.1 95 132 0.8 95 133 1.0 92 134 1.1 93 135 0.5 96 136 0.8 92 137 3.7 92 138 1.8 95 139 3.1 97 140 0.5 92 141 0.4 88 142 0.3 96 143 3.7 81 144 0.4 90 145 4.3 85 146 1.4 88 147 0.3 90 148 1.2 90 149 0.4 87 150 1.7 88 151 0.2 90 152 0.2 93 153 0.5 92 154 0.4 92 155 0.3 91 156 0.6 89 157 3.1 88 158 0.4 94 159 20.4 97 160 0.6 93 161 1.2 92 162 1.9 93 163 0.8 98 164 1.4 93 165 1.9 96 166 0.6 95 167 1.1 89 168 0.3 95 169 0.3 90 170 0.2 85 171 0.4 88 172 0.4 89 173 0.7 90 174 2.6 86 175 0.3 87 176 0.3 93 177 1 92 178 1.4 95 179 1.4 91 180 0.5 90 181 0.5 91 182 0.6 89 183 0.4 92 184 0.4 90 185 0.5 90 186 1 92 187 1.6 86 188 1.8 89

[1070] It is therefore apparent that the tested compounds have degradation activities for estrogen receptors, with IC50 less than 1 ?M 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.

[1071] Accordingly, also provided herein are medicaments which comprise a compound of the formula (I), or a pharmaceutically acceptable salt thereof.

[1072] Herein are also provided the compounds of formula (I) defined above, or pharmaceutically acceptable salts thereof, for use as medicines.

[1073] 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.

[1074] 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.

[1075] A particular aspect is a compound of formula (I) defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[1076] In an embodiment, the cancer is a hormone dependent cancer.

[1077] In another embodiment, the cancer is an estrogen receptor dependent cancer, particularly the cancer is an estrogen receptor a dependent cancer.

[1078] In another embodiment, the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancer, or a metastasis thereof.

[1079] In another embodiment, the metastasis is a cerebral metastasis.

[1080] In another embodiment, the cancer is breast cancer. Particularly, the breast cancer is an estrogen receptor positive breast cancer (ER? positive breast cancer).

[1081] In another embodiment, the cancer is resistant to anti-hormonal treatment.

[1082] 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.

[1083] 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.

[1084] 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.

[1085] 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.

[1086] 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.

[1087] 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.

[1088] 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.

[1089] As an example, a unit administration form of a compound of formula (I) in tablet form may comprise the following components:

TABLE-US-00005 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

[1090] 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.