Substituted 6,7-dihydro-5H-benzo[7]annulene compounds, processes for their preparation and therapeutic uses thereof

1. A process for preparing 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;

the process comprising submitting a compound of formula (D) below

wherein R1, R2, R3, R4 and R5 are as defined above for the compound of formula I, and

wherein R3 and R5 are optionally in protected form,

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 above for the compound of formula I;

and optionally deprotecting a protected R3 and/or R5 group.

2. A compound selected from the group consisting of the following formulae:

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;

and when R3 represents a —COOH or a —OH group or when R5 represents a —OH group, said R3 or R5 group is optionally protected:

and salts thereof.

3. The process according to claim 1 , wherein when R3 represents a protected —COOH group, said group is protected as a methyl ester and when R3 or R5 represents a protected —OH group, said R3 or R5 group is protected as a pivaloyl ester.

4. The process according to claim 1 , wherein the process further comprises a step of brominating a compound for Formula (C):

to obtain a compound of Formula D, wherein R1, R2, R3, R4 and R5 are as defined in claim 1 for the compound of Formula D.

5. The process according to claim 2 , wherein when R3 represents a protected —COOH group, said group is protected as a methyl ester and when R3 or R5 represents a protected —OH group, said R3 or R5 group is protected as a pivaloyl ester.

6. The process according to claim 4 , wherein the process further comprises a Suzuki coupling of a compound of formula (B):

with a reagent of formula (1):

to give the compound of formula (C), wherein

R1 and R2 represent independently a hydrogen atom or a deuterium atom;

R3 represents a hydrogen atom, a protected —COOH group, a protected —OH group, or a —OPO(OH) 2 group;

R4 represents a hydrogen atom or a fluorine atom;

R5 represents a hydrogen atom or a protected —OH group;

wherein:

at least one of R3 or R5 is different from a hydrogen atom;

when R3 represents a protected —COOH group, a protected —OH group or a —OPO(OH) 2 group, then R5 represents a hydrogen atom; and

when R5 represents a protected —OH group, then R3 and R4 represent hydrogen atoms.

7. The process according to claim 4 , wherein when R3 represents a protected —COOH group, said group is protected as a methyl ester and when R3 or R5 represents a protected —OH group, said R3 or R5 group is protected as a pivaloyl ester.

8. The process according to claim 1 for preparing a compound of Formula 51 below or a pharmaceutically acceptable salt thereof,

wherein the compound of Formula (D) is the compound of Formula (D5):

9. The process according to claim 8 , wherein the process further comprises brominating a compound of Formula (C3) below:

to obtain the compound of formula (D5) as defined in claim 8 .

10. The process according to claim 1 , the process comprising deprotecting a compound of Formula (Ib):

wherein R1, R2, R4 and R6 are as defined in claim 1 for a compound of Formula (I).

11. The process according to claim 10 , wherein the compound of Formula (Ib) 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 methyl ester.

12. The process according to claim 1 , the process comprising deprotecting a compound of formula:

to obtain 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid.

13. A process for preparing a compound of formula 51 as defined in claim 8 , wherein the process further comprises deprotecting 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid methyl ester.

14. The compound according to claim 2 , selected from the following formulae:

wherein

R1 and R2 represent independently a hydrogen atom or a deuterium atom;

R3 represents a hydrogen atom, a protected —COOH group, a protected —OH group, or a —OPO(OH) 2 group;

R4 represents a hydrogen atom or a fluorine atom;

R5 represents a hydrogen atom or a protected —OH group;

wherein:

at least one of R3 or R5 is different from a hydrogen atom;

when R3 represents a protected —COOH group, a protected —OH group or a —OPO(OH) 2 group, then R5 represents a hydrogen atom; and

when R5 represents a protected —OH group, then R3 and R4 represent hydrogen atoms.

15. The compound according to claim 14 wherein when R3 represents a protected —COOH group, said group is protected as a methyl ester and when R3 or R5 represents a protected —OH group, said R3 or R5 group is protected as a pivaloyl ester.

16. The compound according to claim 14 , wherein the compound is selected from the group consisting of the compound of Formula (C3) and the compound of Formula (D5):

17. The compound of formula (1) according to claim 2 , which is:

18. A process for preparing a compound of formula (I):

wherein:

R1 and R2 represent independently a hydrogen atom or a deuterium atom;

R3 represents a —COOH group;

R4 represents a hydrogen atom or a fluorine atom;

R5 represents a hydrogen atom;

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;

the process comprising deprotecting a compound of formula (Ib):

wherein R1, R2, R4 and R6 are as defined in Formula (I),

by treating the compound of Formula (Ib) in methanol with an aqueous solution of sodium hydroxide, and then acidifying with an aqueous solution of hydrochloric acid.

19. The process according to claim 18 , 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 and the compound of formula (Ib) 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 methyl ester.

20. The process according to claim 19 , where the treating step comprises adding a solution of NaOH 5M to a solution of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid methyl ester in methanol at 60° C. for 5 hours, removing the solvent under reduced pressure to give a residue, and

wherein the acidifying step comprises taking up the residue in water and aqueous hydrochloric acid 5 M added to pH 7.