Novel Substituted N-(3-Fluoropropyl)-Pyrrolidine Compounds, Processes for their Preparation and Therapeutic Uses Thereof

Abstract

The present invention relates to novel substituted N-(3-fluoropropyl)-pyrrolidine compounds of formula (I-A): wherein R1 and R2 represent independently a hydrogen atom or a deuterium atom; A represents an oxygen or nitrogen atom; and SERM-F represents a selective estrogen receptor modulator fragment comprising an aryl or heteroaryl group linked to the adjacent “A” group. The invention also relates to the preparation and to the therapeutic uses of the compounds of formula (I-A) as inhibitors and degraders of estrogen receptors.

1 . A compound of the formula (I-A): 
       
         
           
           
               
               
           
         
         wherein:
 R1 and R2 represent independently a hydrogen atom or a deuterium atom; 
 A represents an oxygen or nitrogen atom; and 
 SERM-F represents a selective estrogen receptor modulator fragment comprising an aryl or heteroaryl group linked to the adjacent “A” group; 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of formula (I-A) according to  claim 1 , with the proviso that the compounds of formula (I-B) below are excluded: 
       
         
           
           
               
               
           
         
         wherein, in formula (I-B):
 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; 
 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 (such as 1, 2 or 3) fluorine atoms; a halogen atom; a —OH group; a (C 1 -C 6 )-alkoxy group unsubstituted or substituted with one or more (such as 1, 2 or 3) 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 (such as 2 or 3) fluorine atoms; a sulfonyl-(C 1 -C 6 )-alkyl group wherein said (C 1 -C 6 )-alkyl group are unsubstituted or substituted with two or more (such as 2 or 3) fluorine atoms; 
 a silane group substituted with 3 (C 1 -C 6 )-alkyl groups; an amine group unsubstituted or substituted with one or more (such as 1 or 2) (C 1 -C 6 )-alkyl groups; an amide group unsubstituted or substituted with one or more (such as 1 or 2) (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 or sulphur; or a heteroaryl group comprising 2 to 4 carbon atoms and comprising 1 to 3 heteroatoms selected from oxygen, nitrogen or 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 or 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 a (C 1 -C 6 )-alkyl group; or an oxo group; 
 
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         3 . The compound of formula (I-A) according to  claim 1 , wherein SERM-F is selected from the following structures (aI), (bII), (cIII) and (dIV), provided that when A represents a nitrogen atom then SERM-F represents the structure (aI): 
       
         
           
           
               
               
           
         
         wherein:
 B, D, E and G represent independently ═CH— or nitrogen atoms; 
 n is an integer selected from 0 and 1; 
 X represents —CH 2 —, —O—, —S—, —SO— or —SO 2 —; 
 when n=1 and X=CH 2 , then at least one of A, B, D, E or G is a nitrogen atom; 
 R3 represents a hydrogen atom or an —OH, —COOH or —OPO(OH) 2  group; 
 R4 represents a hydrogen, fluorine or chlorine atom or a methyl group; 
 R5 represents a hydrogen, fluorine or chlorine atom, or a methyl or —OH group; 
 wherein R3 and R5 do not simultaneously represent —OH groups or hydrogen atoms; 
 R6 is selected from:
 a phenyl group, which is 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 or —OH groups; a halogen atom; an —OH group; a (C 1 -C 6 )-alkoxy group unsubstituted or substituted with one or more fluorine atoms, (C 1 -C 6 )-alkoxy or heterocycloalkyl groups; a cyano group; a sulphur group substituted with 5 fluorine atoms or with a (C 1 -C 6 )-alkyl group 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 three (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 or (C 1 -C 6 )-alkoxy 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; 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; a —SO 2 NH 2  group; a —COOH group; a —O-cycloalkyl group; a —O-heterocycloalkyl group; and a —OCD 3  group;
 a heteroaryl group comprising 3 to 9 carbon atoms and comprising between 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, said heteroaryl group 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; an —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 with a (C 1 -C 6 )-alkyl group 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 three (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 or (C 1 -C 6 )-alkoxy 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; 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; a —COO—(C 1 -C 6 )-alkyl group; and an oxo group;
 a cycloalkyl group comprising 4 to 9 carbon atoms, which is saturated or partially saturated, and which is unsubstituted or substituted with 1 to 4 substituents independently selected from: 
 a fluorine atom; an —OH group; a (C 1 -C 6 )-alkyl group; a —COOR7 group wherein R7 is a (C 1 -C 6 )-alkyl group; and an oxo group;
 and
 a heterocycloalkyl group comprising 4 to 9 carbon atoms and comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulphur, said heterocycloalkyl group being saturated or partially saturated and being unsubstituted or substituted with 1 to 4 substituents independently selected from: 
 
 
 a fluorine atom; an —OH group; a (C 1 -C 6 )-alkyl group; a —COOR7 group wherein R7 is a (C 1 -C 6 )-alkyl group; and an oxo group;
 or a pharmaceutically acceptable salt thereof. 
 
 
     
     
         4 . The compound according to  claim 3 , wherein the compound is a compound of formula (I), wherein R1, R2, R3, R4, R5, R6, A, B, D, E, G, X and n are as defined in  claim 3 : 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The compound according to  claim 3 , characterized in that R6 is selected from:
 a phenyl group, which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from:   
       a (C 1 -C 6 )-alkyl group unsubstituted or substituted with one or more fluorine atoms or —OH groups; a halogen atom; an —OH group; a (C 1 -C 6 )-alkoxy group unsubstituted or substituted with one or more fluorine atoms, (C 1 -C 6 )-alkoxy or heterocycloalkyl groups; a sulphur group substituted with a (C 1 -C 6 )-alkyl group substituted with two or more fluorine atoms; a sulfonyl-(C 1 -C 6 )-alkyl group; an amine group unsubstituted or substituted with one or more (C 1 -C 6 )-alkyl groups; an amide group substituted with an (C 1 -C 6 )-alkoxy group; a —SO 2 NH 2  group; a —COOH group; a —O-cycloalkyl group; a —O-heterocycloalkyl group; and a —OCD 3  group;
 a heteroaryl group selected from an indole, pyridinyl, benzofuran, isoxazole, quinolyl and thiazolyl group, said heteroaryl group being unsubstituted or substituted with 1 to 3 substituents independently selected from: 
 
       a (C 1 -C 6 )-alkyl group; a halogen atom; an —OH group; a (C 1 -C 6 )-alkoxy group; an amine group; an amide group substituted with a (C 1 -C 6 )-alkoxy group; and
 a heterocycloalkyl group selected from an indolinyl, dihydroazaindolinyl, dihydrobenzodioxinyl, benzodioxolyl, 2,3-dihydrobenzofuranyl, dihydrobenzoxazinyl and 5,6-dihydro-2H-pyranyl group, said heterocycloalkyl group being unsubstituted or substituted with 1 to 4 substituents independently selected from: 
 
       a fluorine atom; a (C 1 -C 6 )-alkyl group; a —COOR7 group wherein R7 is a (C 1 -C 6 )-alkyl group; and 
       an oxo group;
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         6 . The compound according to  claim 3 , wherein the compound is a compound of formula (I-2), wherein X, n, R1, R2, R3, R4, R5, R6, B, D, E and G are as defined in  claim 3 : 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . The compound according to  claim 3 , wherein the compound is a compound of formula (I-3), wherein R1, R2, R3, R4, R5 and R6 are as defined in  claim 3 : 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The compound according to  claim 3 , wherein the compound is a compound of formula (I-4), wherein R1, R2, R3, R4, R5 and R6 are as defined in  claim 3 : 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . The compound according to  claim 3 , wherein the compound is a compound of formula (I-5), wherein E, D, R1, R2, R3, R4, R5 and R6 are as defined in  claim 3  and wherein one or two of E and D represent nitrogen atoms: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         10 . The compound according to  claim 3 , wherein the compound is a compound of formula (I-6), wherein R1, R2, R3, R4, R5 and R6 are as defined in  claim 3 : 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         11 . The compound according to  claim 3 , wherein the compound is a compound of formula (I-7), wherein n, R1, R2, R3, R4, R5 and R6 are as defined in  claim 3 : 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The compound according to  claim 3 , wherein the compound is a compound of formula (I-8), wherein R1, R2, R3, R4, R5 and R6 are as defined in  claim 3 : 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 . The compound according to  claim 3 , wherein the compound is a compound of formula (I-9), wherein D, R1, R2, R3, R4, R5 and R6 are as defined in  claim 3 : 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         14 . The compound according to  claim 3 , wherein the compound is a compound of formula (I-10), wherein R1, R2, R3, R4, R5 and R6 are as defined in  claim 3 : 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         15 . The compound according to  claim 3 , characterized in that they respond to wherein the compound is a compound of formula (I-11), wherein R1, R2, R3, R4, R5 and R6 are as defined in  claim 3 : 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         16 . The compound according to  claim 3 , wherein the compound is a compound of formula (I-12), wherein B, D, E, G, R1, R2, R3, R4, R5 and R6 are as defined in  claim 3 : 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . (canceled) 
     
     
         18 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         19 . A method for inhibiting and/or degrading estrogen receptors, comprising administering to a person a compound according to  claim 1 . 
     
     
         20 . A method of treating a disease or disorder, comprising administering to a patient in need thereof a compound according to  claim 1  wherein the disease or disorder is chosen from ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy and inflammation. 
     
     
         21 . The method according to  claim 20 , wherein the disease or disorder is an estrogen receptor dependent cancer. 
     
     
         22 . The method according to  claim 20 , wherein the disease or disorder is breast, ovarian, endometrial, prostate, uterine, cervical or lung cancer, or a metastasis thereof. 
     
     
         23 . The method according to  claim 20 , a wherein the cancer is resistant to anti-hormonal treatment.