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

Abstract

The present invention relates to compounds of formula (I), or pharmaceutically acceptable salts thereof: (I), 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 R4 represent hydrogen or fluorine; R5 represents hydrogen, fluorine or (C.sub.1-C.sub.3)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(C.sub.1-C.sub.3)alkyl group, 4 to 7 membered-heterocycloalkyl group comprising 1 or 2 heteroatoms, (C.sub.1-C.sub.6)alkyl, and phenyl(C.sub.1-C.sub.2)alkyl group; X represents CH.sub.2, O or S; Y represents CH, N or CR, wherein R represents (C.sub.1-C.sub.3)alkyl, halogen, cyano, or (C.sub.1-C.sub.3)fluoroalkyl; R7 represents (C.sub.1-C.sub.3)alkyl, halogen atom, cyano, or (C.sub.1-C.sub.3)fluoroalkyl; R8 represents hydrogen or fluorine; R9 represents hydrogen, (C.sub.1-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: ##STR00194## 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 phenyl group fused with a hetero(C.sub.4-C.sub.6)cycloalkyl, which hetero(C.sub.4-C.sub.6)cycloalkyl ring 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, 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 4 to 7 membered-heterocycloalkyl group comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, 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, 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, a cyano group, or a (C.sub.1-C.sub.3)fluoroalkyl group; R7 independently 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; 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 a pharmaceutically acceptable salt thereof, characterized in that R3 is COOH.

4. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R3 and R3 represent a hydrogen atom.

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

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

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

8. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, 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, a trifluoromethoxy group, a 1,1-difluoroethyl group, a difluoromethyl group, a difluoromethoxy group, a fluoromethyl group and a cyano group.

9. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R6 represents a fused phenyl group, selected from a bicyclo[4.2.0]octatrienyl group, an indanyl group or a tetrahydronaphthalenyl group, optionally substituted with one or two fluorine atom or R6 represents a chromanyl group.

10. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, 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.

11. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, 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).

12. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, 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.

13. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y represents CH, N or CR, and R represents a fluorine atom, a cyano group, or a trifluoromethyl group.

14. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1.

15. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R6 represents a phenyl group fused with a hetero(C.sub.4-C.sub.6)cycloalkyl, which hetero(C.sub.4-C.sub.6)cycloalkyl ring 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.

16. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R6 represents 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; wherein said phenyl is substituted by at least one trifluoromethoxy group, by at least one 1,1-difluoroethyl group, by at least one difluoromethyl group, by at least one difluoromethoxy group or by at least one fluoromethyl group.

17. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that said compound is selected from the following compounds: 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-6-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (1) 8-(3,4-difluoro-2-(trifluoromethyl)phenyl)-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-methoxy-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (3) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-6-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (4) 8-(2-ethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (5) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-6-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (6) 8-(3-fluoro-2-methoxy-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (7) 8-(3-ethyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (8) 8-(2-fluoro-6-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (9) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-mesityl-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (10) 8-(2-chloro-4,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (11) 8-(3-fluoro-2,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (12) 8-(3-chloro-2,4-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)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-(2-methoxy-4,6-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (14) 8-(2-(1,1-difluoroethyl)-4-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (15) 8-(2-chloro-6-(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-chloro-6-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (17) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-methoxy-2,6-dimethylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (18) 8-(4-ethyl-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (19) 8-(2-fluoro-6-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (20) 8-(2-chloro-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (21) 8-(2-fluoro-6-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (22) 8-(2-chloro-6-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (23) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-3-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (24) 8-(2-ethyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (25) 8-(2-fluoro-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (26) 8-(4-fluoro-2,5-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (27) 8-(4-(difluoromethyl)-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (28) 8-(4-(difluoromethyl)-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (29) 8-(2-(difluoromethyl)-3-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (30) 8-(4-(difluoromethyl)-3-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (31) 8-(2-(fluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (32) 8-(2-(difluoromethoxy)-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (33) 8-(3-chloro-2-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (34) 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, Isomer 1, (35) 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, Isomer 2, (36) 8-(2-(difluoromethyl)-4-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (37) 8-(3-fluoro-2-(fluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (38) 8-(2-ethyl-3-fluorophenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (39) 8-(3-fluoro-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (40) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methoxy-2-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (41) 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol, (42) 8-(2-(difluoromethyl)-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (43) 8-(4-(difluoromethyl)-2-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (44) 8-(2-(difluoromethyl)-5-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (45) 8-(3-chloro-2-ethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (46) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(5-methoxy-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (47) 8-(2-cyclopropyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (48) 8-(3-chloro-2-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (49) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (50) 8-(4-(difluoromethyl)-2-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (51) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methoxy-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (52) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(3-methyl-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (53) 8-(4-(difluoromethyl)-2-(trifluoromethoxy)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (54) 8-(4-(difluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (55) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(trans-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (56) 8-(2-(difluoromethyl)-5-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (57) 8-(2-(difluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (58) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (59) 8-(2-(difluoromethyl)-3-methoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (60) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(cis-4-methylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (61) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(4-methoxy-2-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (62) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-3-(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (63) 8-(chroman-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (64) 8-(4,4-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, (65) 9-(5-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (66) 8-(chroman-8-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (67) 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (68) 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 1, (69) 8-(2,4-dichlorophenyl)-9-(4-((1-(2,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, Isomer 2, (70) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-4,6-bis(trifluoromethyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (71) 8-(2,4-dimethyl-6-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (72) 8-(3-fluoro-2-methyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (73) 8-(2,6-diethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (74) 8-(3-fluoro-2,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (75) 8-(2-fluoro-4,6-dimethylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (76) 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methyl-6-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (77) 8-(2,5-dimethyl-4-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (78) 8-(2,3-bis(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (79) 8-(2,6-diethyl-4-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (80) 8-(2,3-dimethoxyphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (81) 8-(3,4-dimethoxyphenyl)-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-methoxy-6-methylphenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (83) or 8-(2,6-dimethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid, (84).

18. A process for preparing a compound of formula (I) as defined in claim 1, wherein a compound of formula 1K; ##STR00195## wherein R1, R2, R3, R3, R4, R4, R5, R6, R7, R8, R9, m, n, X and Y are as defined in claim 1 and R3a is a carboxylic ester or protected OH, is converted to compound of formula (I), in presence of a source of hydroxide ions, said step being optionally preceded by a step for obtaining compound 1K, wherein a compound of formula 1T ##STR00196## wherein, R1, R2, R3, R3, R4, R4, R5, R7, R8, R9, m, n, X and Y are as defined in claim 1 and R3a is a carboxylic ester or protected OH, 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 claim 1.

19. A process for preparing a compound of formula (I) as defined in claim 1, wherein a compound of formula 1Ta: ##STR00197## wherein R1, R2, R3, R3, R4, R4, R5, R7, R8, R9, m, n, X, and Y are as defined in claim 1 and R3a is a carboxylic ester or protected OH, 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 claim 1, said step being optionally preceded by a step for obtaining compound 1Ta, wherein a compound of formula 1T: ##STR00198## wherein R1, R2, R3, R3, R4, R4, R5, R7, R8, R9, m, n, X and Y are as defined in claim 1 and R3a is a carboxylic ester or protected OH, is converted to a compound 1Ta in the presence of a source of hydroxide ions.

20. A compound of formula 1K or pharmaceutically acceptable salt thereof, ##STR00199## 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; R7 independently 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; 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; m is 0 or 1; n is 0, 1 or 2; 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, a cyano group, or a (C.sub.1-C.sub.3)fluoroalkyl group; R3a is carboxylic ester or protected OH and R6 represents a phenyl group fused with a hetero(C.sub.4-C.sub.6)cycloalkyl, which hetero(C.sub.4-C.sub.6)cycloalkyl ring 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.

21. (canceled)

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

23. A method for inhibiting and degrading estrogen receptors, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

24. A method of treating ovulatory dysfunction, cancer, endometriosis, benign prostatic hypertrophy or inflammation, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

25. The method of claim 24, which method comprises the treatment of cancer.

Description

EXAMPLES: COMPOUNDS OF FORMULA (I)

Method A

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

##STR00164##

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

##STR00165##

[0334] 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 4) (200 mg, 413 mol), (2-methoxy-3-methyl-phenyl)boronic acid (137 mg, 826 mol), Cs.sub.2CO.sub.3 (283 mg, 867 mol), and Pd(dppf)Cl.sub.2, complex with DCM (30 mg, 41 mol) in dioxane (8 mL) and water (2 mL) was heated to 90 C. 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 and the residue obtained was purified by flash chromatography eluting with a gradient of cyclohexane/EtOAc (100/0 to 0/100, v/v) to give 153 mg (70%) of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0335] LC/MS (m/z, MH+): 526

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

##STR00166##

[0336] To a solution of methyl 9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-8-(2-methoxy-3-methylphenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (153 mg, 291.1 mol) in MeOH (40 mL) and water (8 mL) was added LiOH (28 mg, 1.16 mmol) and the reaction mixture was stirred at RT overnight. 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 80/20, v/v) to give 148 mg (99%) 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 as a white solid.

Method B

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

##STR00167##

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

##STR00168##

[0337] 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 5) (200 mg, 338 mol), 1-bromo-2-ethyl-3-(trifluoromethyl)benzene (129 mg, 508 mol), Cs.sub.2CO.sub.3 (232 mg, 711 mol), and Pd(dppf)Cl.sub.2, complex with DCM (25 mg, 34 mol) in dioxane (8 mL) and water (2 mL) was heated to 90 C. for 1 hour. 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 0/100, v/v) to give 113 mg (58%) of methyl 8-(2-ethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0338] LC/MS (m/z, MH+): 578

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

##STR00169##

[0339] Step 2 of Example 5 was prepared following a similar procedure to that of step 2 of Example 3 from methyl 8-(2-ethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 71 mg (64%) of 8-(2-ethyl-3-(trifluoromethyl)phenyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

Method C

Examples 35 and 36: 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, Isomer 1 and Isomer 2

##STR00170##

Step 1: Methyl 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-carboxylate, Isomer 1 and Isomer 2

##STR00171##

[0340] 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 4) (250 mg, 516 mol), potassium trifluoro(spiro[2.3]hexan-1-yl)borate (194 mg, 1032 mol), Cs.sub.2CO.sub.3 (336 mg, 1032 mol), and Pd(dppf)Cl.sub.2, complex with DCM (37 mg, 52 mol) in toluene (6 mL) and water (2 mL) was heated to 90 C. for 4 hours in a sealed tube. 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 and the residue obtained was purified by flash chromatography eluting with a gradient of cyclohexane/EtOAc (100/0 to 0/100, v/v) and reverse phase preparative HPLC on a RP-18 column with a gradient of ACN in water (30/70 to 100/0, v/v) to give 76 mg (30%) of methyl 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-carboxylate as a racemic mixture of Isomer 1 and Isomer 2.

[0341] LC/MS (m/z, MH+): 486

[0342] The racemic mixture of methyl 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-carboxylate was separated by chiral SFC (column CHIRALPAK IJ, supercritical CO.sub.2 80%/MeOH 20%/TEA 0.1%) to give 28 mg of Isomer 1 and 29 mg of Isomer 2.

Step 2 of Example 35: 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, Isomer 1

##STR00172##

[0343] Step 2 of Example 35 was prepared following a similar procedure to that of step 2 of Example 3 from methyl 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-carboxylate, Isomer 1 to give 12 mg (44%) of 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, Isomer 1.

Step 2 of Example 36: 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, Isomer 2

##STR00173##

[0344] Step 2 of Example 36 was prepared following a similar procedure to that of step 2 of Example 3 from methyl 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-carboxylate, Isomer 2 to give 16 mg (57%) of 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 acids, Isomer 2.

Method D

Example 68: 8-(4,4-Dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

##STR00174##

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

##STR00175##

[0345] A mixture of methyl 8-(4,4-dimethylcyclohexyl)-9-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 7) (162 mg, 350 mol), 1-(3-fluoropropyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)azetidine (Intermediate 2) (140 mg, 420 mol), Pd(dppf)Cl.sub.2 complex with DCM (26 mg, 40 mol), Cs.sub.2CO.sub.3 (229 mg, 0.7 mmol) in dioxane (6 ml) and water (1.5 ml) was heated to 95 C. for 1 hour. After cooling to room temperature, water (50 mL), EtOAc (100 mL) and Et.sub.2O (100 mL) were added. After decantation, the organic phase was dried over MgSO.sub.4, filtered, concentrated under reduced pressure. The residue obtained was purified by flash chromatography eluting with a gradient of cyclohexane/EtOAc (100/0 to 0/100, v/v) to give 120 mg (66%) of methyl 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0346] LC/MS (m/z, MH+): 516

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

##STR00176##

[0347] Step 2 of Example 68 was prepared following a similar procedure to that of step 2 of Example 3 from methyl 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 110 mg (94%) of 8-(4,4-dimethylcyclohexyl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

Method E

Example 64: 8-(Chroman-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

##STR00177##

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

##STR00178##

[0348] Step 1 of Example 64 was prepared following a similar procedure to that of Intermediate 5 from tert-butyl 3-(4-(8-bromo-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate (Intermediate 4, Method 1, Step 4) to give 1.37 g (63%) of tert-butyl 3-(4-(3-(methoxycarbonyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate.

[0349] LC/MS (m/z, MH+): 516

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

##STR00179##

[0350] Step 2 of Example 64 was prepared following a similar procedure to that of step 1 of Example 5 from tert-butyl 3-(4-(3-(methoxycarbonyl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate and 5-bromochromane to give 120 mg (59%) of tert-butyl 3-(4-(8-(chroman-5-yl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate.

[0351] LC/MS (m/z, MH+): 578

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

##STR00180##

[0352] Step 3 of Example 64 was prepared following a similar procedure to that of step 2 of Intermediate 1 from tert-butyl 3-(4-(8-(chroman-5-yl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)benzylidene)azetidine-1-carboxylate including additional quenching with saturated aqueous NaHCO.sub.3 solution to give 100 mg (100%) of methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-(chroman-5-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0353] LC/MS (m/z, MH+): 478

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

##STR00181##

[0354] Step 4 of Example 64 was prepared following a similar procedure to that of step 5 of Intermediate 4 (Method 2) from methyl 9-(4-(azetidin-3-ylidenemethyl)phenyl)-8-(chroman-5-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 35 mg (31%) of methyl 8-(chroman-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0355] LC/MS (m/z, MH+): 538

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

##STR00182##

[0356] Step 5 of Example 64 was prepared following a similar procedure to that of step 2 of Example 3 from methyl 8-(chroman-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 31 mg (91%) of 8-(chroman-5-yl)-9-(4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

Method F

Example 65: 8-(4,4-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

##STR00183##

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

##STR00184##

[0357] A mixture of tert-butyl 3-((6-chloro-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate (Intermediate 9) (715 mg, 2.4 mmol), methyl 8-(4,4-dimethylcyclohexyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (Intermediate 10) (700 mg, 1.6 mmol), Cs.sub.2CO.sub.3 (1.56 g, 4.79 mmol) in 40 ml of toluene and 10 ml of water in a sealed tube was degazed with argon for 5 min. CataCXium A Pd G3 ((di(1-adamantyl)-n-butylphosphine)-2-(2-amino-1,1-biphenyl)palladium(II) methanesulfonate, CAS number 1651823-59-4) (116 mg, 0.16 mmol) was added. The tube was sealed and the reacting mixture was stirred at 90 C. for 18 h. Water (10 ml) and Et.sub.2O (30 ml) were added and the organic layer was washed with 10 ml of water, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of EtOAc in cyclohexane (100/0 to 50/50, v/v) to give 560 mg (60%) of tert-butyl 3-((6-(8-(4,4-dimethylcyclohexyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate.

[0358] LC/MS (m/z, MH+): 575

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

##STR00185##

[0359] A mixture of tert-butyl 3-((6-(8-(4,4-dimethylcyclohexyl)-3-(methoxycarbonyl)-6,7-dihydro-5H-benzo[7]annulen-9-yl)-5-fluoropyridin-3-yl)methylene)azetidine-1-carboxylate (640 mg, 1.11 mmol) in DCM (4 ml) and trifluoroacetic acid (4 ml) was stirred at RT for 1 h then concentrated under reduced pressure to give 1.3 g of crude methyl 9-(5-(azetidin-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid which was used as such in the next step.

[0360] LC/MS (m/z, MH+): 475.

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

##STR00186##

[0361] A mixture of crude methyl 9-(5-(azetidin-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid (370 mg, 0.47 mmole), 1-fluoro-3-iodopropane (97 mg, 0.52 mmole) and DIEA (244 mg, 1.89 mmol) in acetonitrile (10 ml) was stirred at RT for 20 h then half concentrated under reduced pressure and directly purified by flash chromatography eluting with a gradient of a mixture AcOEt/MeOH:80/20 in cyclohexane (100/0 to 0/100, v/v) to give 100 mg (40%) of methyl 8-(4,4-dimethylcyclohexyl)-9-(3-fluoro-5-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)pyridin-2-yl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0362] LC/MS (m/z, MH+): 535

Step 4: 8-(4,4-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

##STR00187##

[0363] Step 5 of Example 65 was prepared following a similar procedure to that of step 2 of Example 3 from methyl 8-(4,4-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 51 mg (35%) of 8-(4,4-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.

Example 66: 9-(5-((1-(3,3-Difluoropropyl)azetidin-3-ylidene)methyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid

##STR00188##

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

##STR00189##

[0364] Step 1 of Example 66 was prepared following a similar procedure to that of step 3 of Example 65 from methyl 9-(5-(azetidin-3-ylidenemethyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate, 2,2,2-trifluoroacetic acid and 3,3-difluoropropyl trifluoromethanesulfonate (Intermediate 11) to give 174 mg (46%) of methyl 9-(5-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate.

[0365] LC/MS (m/z, MH+): 555

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

##STR00190##

[0366] Step 2 of Example 66 was prepared following a similar procedure to that of step 2 of Example 3 from methyl 9-(5-((1-(3,3-difluoropropyl)azetidin-3-yl)methyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate to give 32 mg (16%) of 9-(5-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)-3-fluoropyridin-2-yl)-8-(4,4-dimethylcyclohexyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylic acid.

Method G

Example 42: 8-(3-Chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol

##STR00191##

Step 1: 8-(3-Chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate

##STR00192##

[0367] Step 1 of Example 42 was prepared following a similar procedure to that of step 1 of Example 3 from 8-bromo-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate (Intermediate 6) and (3-chloro-2-methyl-phenyl)boronic acid to give 21 mg (61%) of 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate.

[0368] LC/MS (m/z, MH+): 590

Step 2: 8-(3-Chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol

##STR00193##

[0369] Step 2 of Example 42 was prepared following a similar procedure to that of step 2 of Example 3 from 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl pivalate to give 12.5 mg (69%) of 8-(3-chloro-2-methylphenyl)-9-(4-((1-(3,3-difluoropropyl)azetidin-3-ylidene)methyl)phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol.

[0370] The compounds according to Table 1a above were subjected to pharmacological tests for determining their degradation effects on estrogen receptors.

Test: Estrogen Receptor Degradation Activity

[0371] Said test involves measuring the in vitro degradation activity of the compounds of the Table 1a.

[0372] The measurements of the degradation activities were made using a breast cancer cell ER in cell western assay as described hereunder.

[0373] 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.

[0374] 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.

[0375] The % of ER levels decrease were determined as follows: % inhibition=100*(1(samplefulvestrant:DMSOfulvestrant)).

[0376] 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 0.3 92 2 1 90 3 0.7 90 4 1.1 90 5 0.3 93 6 0.3 91 7 0.5 94 8 0.8 93 9 0.6 96 10 0.5 93 11 0.4 92 12 0.7 92 13 0.4 91 14 0.6 91 15 0.4 91 16 0.3 92 17 0.5 91 18 0.6 91 19 0.2 92 20 0.6 94 21 0.5 93 22 0.5 94 23 0.4 91 24 0.5 91 25 0.4 91 26 0.2 91 27 0.5 93 28 0.5 94 29 0.6 93 30 0.4 91 31 37.8 95 32 0.3 91 33 0.3 91 34 0.7 94 35 0.3 91 36 0.2 92 37 0.6 91 38 0.4 90 39 0.3 92 40 0.5 91 41 0.7 91 42 6.4 53 43 0.5 91 44 0.5 93 45 0.6 93 46 0.5 91 47 0.5 93 48 0.9 94 49 0.5 93 50 8.5 92 51 0.5 92 52 0.4 94 53 1.2 91 54 0.5 95 55 0.6 94 56 0.7 92 57 0.7 93 58 0.2 93 59 0.9 92 60 0.6 93 61 0.9 91 62 0.5 93 63 1.0 94 64 3.1 96 65 0.8 91 66 1.7 86 67 1.0 90 68 0.7 86 69 1.3 74 70 1.8 81 71 0.5 95 72 0.3 100 73 0.3 85 74 0.8 90 75 0.2 95 76 0.2 95 77 0.7 95 78 0.4 94 79 0.4 100 80 1.2 105 81 0.7 92 82 1.4 95 83 0.4 94 84 0.6 91

[0377] 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.

[0378] Accordingly, also provided herein are medicaments which comprise a compound of the formula (I), or a pharmaceutically acceptable salt thereof.

[0379] Herein are also provided the compounds of formula (I) defined above, or pharmaceutically acceptable salts thereof, for use as medicines.

[0380] 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.

[0381] 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.

[0382] A particular aspect is a compound of formula (I) defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0383] In an embodiment, the cancer is a hormone dependent cancer.

[0384] In another embodiment, the cancer is an estrogen receptor dependent cancer, particularly the cancer is an estrogen receptor a dependent cancer.

[0385] In another embodiment, the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancer, or a metastasis thereof.

[0386] In another embodiment, the metastasis is a cerebral metastasis.

[0387] In another embodiment, the cancer is breast cancer. Particularly, the breast cancer is an estrogen receptor positive breast cancer (ER positive breast cancer).

[0388] In another embodiment, the cancer is resistant to anti-hormonal treatment.

[0389] 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.

[0390] 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.

[0391] 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.

[0392] 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.

[0393] 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.

[0394] 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.

[0395] 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.

[0396] 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

[0397] 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.