Novel substituted 6,7-dihydro-5h-benzo[7]annulene compounds, processes for their preparation and therapeutic uses thereof

Abstract

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 .- 10 . (canceled) 
     
     
         11 . 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; 
 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. 
     
     
         12 . 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. 
 
 
 
     
     
         13 .- 27 . (canceled) 
     
     
         28 . The process according to  claim 11 , 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. 
     
     
         29 . The process according to  claim 11 , further comprising 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 11  for the compound of formula D. 
     
     
         30 . The process according to  claim 29 , 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. 
     
     
         31 . The process according to  claim 29 , comprising a Suzuki coupling of a compound of formula (B): 
       
         
           
           
               
               
           
         
       
       with a reagent of formula (1): 
       
         
           
           
               
               
           
         
       
       to give the compound of formula (C), wherein R1, R2, R3, R4 and R5 are as defined in  claim 29  and when R3 represents a —COOH or a —OH group or when R5 represents a —OH group, said R3 or R5 group is protected. 
     
     
         32 . The process according to  claim 29 , 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. 
     
     
         33 . The process according to  claim 11  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): 
       
         
           
           
               
               
           
         
       
     
     
         34 . The process according to  claim 33 , comprising brominating a compound of formula (C3) below: 
       
         
           
           
               
               
           
         
       
       to obtain a compound of formula (D5) as defined in  claim 33 . 
     
     
         35 . The process according to  claim 11 , comprising deprotecting a compound of formula (Ib): 
       
         
           
           
               
               
           
         
       
       wherein R1, R2, R4 and R6 are as defined in  claim 11  for a compound of formula (I). 
     
     
         36 . The process according to  claim 35 , 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 of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         37 . The process according to  claim 11 , 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. 
     
     
         38 . A process for preparing a compound of formula 51 as defined in  claim 33 , comprising 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 of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         38 . The compound according to  claim 12 , selected from the following formulae: 
       
         
           
           
               
               
           
         
       
       wherein R1, R2, R3, R4 and R5 are as defined in  claim 12 , wherein when R3 represents a —COOH or a —OH group or when R5 represents a —OH group, said R3 or R5 group is protected. 
     
     
         39 . The compound according to  claim 38  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. 
     
     
         40 . The compound according to  claim 39 , wherein the compound is selected from the group consisting of the compound of formula (C3) and the compound of formula (D5): 
       
         
           
           
               
               
           
         
       
     
     
         41 . The compound of formula (1) according to  claim 12 , which is: