Novel Substituted 6,7-Dihydro-5H-Benzo[7]Annulene Compounds, Processes for their Preparation and Therapeutic Uses Thereof
Compounds of formula (I): wherein R1 and R2 represent hydrogen or deuterium atoms; R3 represents a hydrogen atom or a —COOH, a —OH or a —OPO(OH) 2 group; R4 represents a hydrogen atom or a fluorine atom; R5 represents a hydrogen atom or a —OH group; wherein at least one of R3 or R5 is different from a hydrogen atom; when R3 represents a —COOH, —OH or —OPO(OH) 2 group, then R5 represents a hydrogen atom; when R5 represents a —OH group, then R3 and R4 represent hydrogen atoms; and R6 is selected from an optionally substituted phenyl, heteroaryl, cycloalkyl and heterocycloalkyl group; and the preparation and the therapeutic uses of the compounds of formula (I) as inhibitors and degraders of estrogen receptors, useful especially in the treatment of cancer.
1 . A compound of formula (I):
wherein:
R1 and R2 represent independently a hydrogen atom or a deuterium atom;
R3 represents a hydrogen atom, a —COOH group, a —OH group, or a —OPO(OH) 2 group;
R4 represents a hydrogen atom or a fluorine atom;
R5 represents a hydrogen atom or a —OH group;
wherein:
at least one of R3 or R5 is different from a hydrogen atom;
when R3 represents a —COOH group, a —OH group or a —OPO(OH) 2 group, then R5 represents a hydrogen atom; and
when R5 represents a —OH group, then R3 and R4 represent hydrogen atoms;
R6 is selected from:
a phenyl group or a heteroaryl group comprising 3 to 9 carbon atoms and comprising from 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, said phenyl and heteroaryl groups being unsubstituted or substituted with 1 to 3 substituents independently selected from: a (C 1 -C 6 )-alkyl group unsubstituted or substituted with one or more fluorine atoms; a halogen atom; a —OH group; a (C 1 -C 6 )-alkoxy group unsubstituted or substituted with one or more fluorine atoms; a cyano group; a sulphur group substituted with 5 fluorine atoms or (C 1 -C 6 )-alkyl groups substituted with two or more fluorine atoms; a sulfonyl-(C 1 -C 6 )-alkyl group wherein said (C 1 -C 6 )-alkyl group is unsubstituted or substituted with two or more fluorine atoms; a silane group substituted with 3 (C 1 -C 6 )-alkyl groups; an amine group unsubstituted or substituted with one or more (C 1 -C 6 )-alkyl groups; an amide group unsubstituted or substituted with one or more (C 1 -C 6 )-alkyl groups; a heterocycloalkyl group saturated or partially saturated, comprising 3 to 5 carbon atoms and comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulphur; and a heteroaryl group comprising 2 to 4 carbon atoms and comprising 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur and being unsubstituted or substituted with an oxo group; and
a cycloalkyl group or a heterocycloalkyl group comprising 4 to 9 carbon atoms and comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulphur, said cycloalkyl or heterocycloalkyl groups being saturated or partially saturated and being unsubstituted or substituted with 1 to 4 substituents independently selected from: a fluorine atom; a —OH group; a (C 1 -C 6 )-alkyl group; a —COOR7 group wherein R7 is an (C 1 -C 6 )-alkyl group; and an oxo group;
or a pharmaceutically acceptable salt thereof.
2 . The compound of formula (I) according to claim 1 , wherein R6 is a phenyl group unsubstituted or substituted with 1 to 3 substituents independently selected from: a (C 1 -C 6 )-alkyl group unsubstituted or substituted with one or more fluorine atoms; a halogen atom; a —OH group; a (C 1 -C 6 )-alkoxy group unsubstituted or substituted with one or more fluorine atoms; a cyano group; a sulphur group substituted with 5 fluorine atoms or (C 1 -C 6 )-alkyl groups substituted with two or more fluorine atoms; a sulfonyl-(C 1 -C 6 )-alkyl group wherein said (C 1 -C 6 )-alkyl group is unsubstituted or substituted with two or more fluorine atoms; a silane group substituted with 3 (C 1 -C 6 )-alkyl groups; an amine group unsubstituted or substituted with one or more (C 1 -C 6 )-alkyl groups; an amide group unsubstituted or substituted with one or more (C 1 -C 6 )-alkyl groups; a heterocycloalkyl group saturated or partially saturated, comprising 3 to 5 carbon atoms and comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulphur; and a heteroaryl group comprising 2 to 4 carbon atoms and comprising 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur and being unsubstituted or substituted with an oxo group;
or a pharmaceutically acceptable salt thereof.
3 . The compound of formula (I) according to claim 1 , wherein R6 is a phenyl group unsubstituted or substituted with 1 to 3 substituents independently selected from: a methyl group; an ethyl group; an isopropyl group; a tert-butyl group; a —CHF 2 group; a —CF 3 group; a —CF 2 CH 3 group; a chlorine atom; a fluorine atom; a —OH group; a —OCH 3 group; a —OCH 2 CH 3 group; a —OCH 2 CH 2 F group; a —OCHF 2 group; a —OCH 2 CF 2 group; a —OCF 3 group; a —OCH 2 CF 3 group; a cyano group; a —SCHF2 group; a —SCF 3 group; a —SF 5 group; a —SO 2 CH 3 group; a —SO 2 CF 3 group; a —Si(CH 3 ) 3 group; an oxetane group; a piperidine group; a morpholine group; a pyrrolidine group; and a triazolone group;
or a pharmaceutically acceptable salt thereof.
4 . The compound of formula (I) according to claim 1 , wherein R3 is a —COOH group or a —OH group;
or a pharmaceutically acceptable salt thereof.
5 . The compound of formula (I) according to claim 1 , which is 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-3-ol; or a pharmaceutically acceptable salt thereof.
6 . The compound of formula (I) according to claim 1 , which is 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid; or a pharmaceutically acceptable salt thereof.
7 . The compound of formula (I) according to claim 1 , which is 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol; or a pharmaceutically acceptable salt thereof.
8 . The compound of formula (I) according to claim 1 , which is 6-(6-ethoxy-2-fluoro-3-pyridyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol; or a pharmaceutically acceptable salt thereof.
9 . The compound of formula (I) according to claim 1 , which is 6-(2-ethoxypyrimidin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol; or a pharmaceutically acceptable salt thereof.
10 . The compound of formula (I) according to claim 1 , which is [5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-yl] dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
11 . A process for preparing a compound of formula (I) according to claim 1 , comprising submitting a compound of formula (D) below
wherein R1, R2, R3, R4 and R5 are as defined in claim 1 ,
to a Suzuki coupling with a boronic reagent of Formula R6B(OR′) 2 wherein (—B(OR′) 2 ) is a boronic acid or a pinacolate ester and wherein R6 is as defined in claim 1 .
12 . A compound selected from the group consisting of the following formulae:
wherein R1, R2, R3, R4, R5 and R6 are as defined in formula (I) according to claim 1 .
13 . A pharmaceutical composition comprising a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
14 . The pharmaceutical composition according to claim 13 , wherein the compound of formula (I) is 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-(1H-indol-5-yl)-8,9-dihydro-7H-benzo[7]annulen-3-ol; or a pharmaceutically acceptable salt thereof.
15 . The pharmaceutical composition according to claim 13 , wherein the compound of formula (I) is 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid; or a pharmaceutically acceptable salt thereof.
16 . The pharmaceutical composition according to claim 13 , wherein the compound of formula (I) is 5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol; or a pharmaceutically acceptable salt thereof.
17 . The pharmaceutical composition according to claim 13 , wherein the compound of formula (I) is 6-(6-ethoxy-2-fluoro-3-pyridyl)-1-fluoro-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol; or a pharmaceutically acceptable salt thereof.
18 . The pharmaceutical composition according to claim 13 , wherein the compound of formula (I) is 6-(2-ethoxypyrimidin-5-yl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulen-2-ol; or a pharmaceutically acceptable salt thereof.
19 . The pharmaceutical composition according to claim 13 , wherein the compound of formula (I) is [5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-6-[4-(trifluoromethoxy)phenyl]-8,9-dihydro-7H-benzo[7]annulen-2-yl] dihydrogen phosphate; or a pharmaceutically acceptable salt thereof.
20 . A method of treating a disease involving inhibition and degradation of estrogen receptors, comprising 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.
21 . A method of treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation, comprising 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.
22 . A method of treating cancer, comprising 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.
23 . The method according to claim 22 , wherein the cancer is an estrogen receptor dependent cancer.
24 . The method according to claim 22 , wherein the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancer, or a metastasis thereof.
25 . The method according to claim 23 , wherein the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancer, or a metastasis thereof.
26 . The method according to claim 24 , wherein the metastasis is a cerebral metastasis.
27 . The method according to claim 22 , wherein the cancer is resistant to anti-hormonal treatment.