POLYSUBSTITUTED DERIVATIVES OF 2-HETEROARYL-6-PHENYLIMIDAZO[1,2-a]PYRIDINES, AND PREPARATION AND THERAPEUTIC USE THEREOF

Abstract

Compounds of formula (I): wherein R, R 1 , R 2 , R 3 , R 4 and X are as defined in the disclosure, or an acid addition salt thereof, and the therapeutic use and process of synthesis thereof.

What is claimed is: 
     
         1 . A method for treating a pathology selected from the group consisting of cerebral trauma, epilepsy, a psychiatric disease, an inflammatory disease, osteoporosis, cancer, Parkinson's disease, Alzheimer's disease, tauopathies, multiple sclerosis, schizophrenia, depression, substance dependence and attention deficit hyperactivity disorders, said method comprising administering to a patient an effective amount of a compound of formula (I): 
       wherein: 
       
         
           
           
               
               
           
         
         R 1  represents:
 a heteroaryl or heterocyclic group, wherein this group is optionally substituted with one or more atoms or groups chosen, independently of one another, from the following atoms or groups: halogen, (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, oxo, (C 1 -C 10 )thioalkyl, —S(O)(C 1 -C 10 )alkyl, —S(O) 2 (C 1 -C 10 -alkyl), hydroxyl, cyano, nitro, hydroxy(C 1 -C 10 )alkylene, NRaRb(C 1 -C 10 )alkylene, (C 1 -C 10 )alkoxy(C 1 -C 10 )alkyleneoxy, NRaRb, CONRaRb, SO 2 NRaRb, NRcCORd, OC(O)NRaRb, OCO(C 1 -C 10 )alkyl, NRcC(O)ORe, NRcSO 2 Re, aryl(C 1 -C 10 )alkylene, monocyclic heteroaryl and aryl, wherein the monocyclic heteroaryl and aryl are optionally substituted with one or more substituents chosen from a halogen, and a (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, NRaRb, hydroxyl, oxo, nitro, cyano or OCO(C 1 -C 10 )alkyl group, and R1 is linked to the imidazo[1,2-a]pyridine by an aromatic carbon; 
 
         X represents from 1 to 4 substituents, which may be identical to or different from one another, chosen from hydrogen, a halogen, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, NRaRb, nitro, and cyano, wherein the (C 1 -C 10 )alkyl group is optionally substituted with one or more groups chosen from a halogen, (C 1 -C 10 )alkoxy, (C 1 -C 10 )haloalkoxy, NRaRb and hydroxyl; 
         R represents, at position 3, 5, 7 or 8 of the imidazo[1,2-a]pyridine, from 1 to 4 substituents, which may be identical to or different from one another, chosen from a hydrogen, a halogen, (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, and (C 1 -C 10 )alkoxy; 
         R 2  and R 3  represent, independently of one another, a hydrogen atom,
 a (C 1 -C 10 )alkyl group, optionally substituted with an Rf group; or 
 an aryl group, optionally substituted with one or more substituents chosen from a halogen, and a (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, NRaRb, hydroxyl, nitro or cyano group; 
 
         R 2  and X can form, together with the carbon atoms which bear them, a carbon-based ring containing from 5 to 7 carbon atoms; 
         R 4  represents:
 a hydrogen atom; 
 a (C 1 -C 10 )alkyl group, optionally substituted by an Rf group; or 
 an aryl group, optionally substituted with one or more substituents chosen from a halogen, and a (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, NRaRb, hydroxyl, nitro, cyano, (C 1 -C 10 )alkyl(CO)—, CONRaRb, NRcCORd, OC(O)NRaRb, OCO(C 1 -C 10 )alkyl, NRcC(O)ORe or aryl group, wherein the aryl is optionally substituted with one or more substituents chosen from a halogen, and a (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, NRaRb, hydroxyl, nitro or cyano group; 
 
         Ra and Rb represent, independently of one another, a hydrogen atom or a (C 1 -C 10 )alkyl, aryl(C 1 -C 10 )alkylene or aryl group; 
         or Ra and Rb form, together with the nitrogen atom which bears them, an azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, this group being optionally substituted with a (C 1 -C 10 )alkyl, aryl or aryl(C 1 -C 10 )alkylene group; 
         Rc and Rd represent, independently of one another, a hydrogen atom or a (C 1 -C 10 )alkyl, aryl(C 1 -C 10 )alkylene or aryl group, 
         or Rc and Rd together form a (C 2 -C 5 )alkylene group; 
         Re represents a (C 1 -C 10 )alkyl, aryl(C 1 -C 10 )alkylene or aryl group, 
         or Rc and Re together form a (C 2 -C 5 )alkylene group; and 
         Rf represents a halogen atom, or a (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, hydroxyl, cyano, NRaRb, C(O)NRaRb, NRcCORd, OC(O)NRaRb, OCO(C 1 -C 10 )alkyl, NRcCOORe, SO 2 NRaRb, NRcSO 2 Re, aryl(C 1 -C 10 )alkylene or aryl group, wherein the aryl is optionally substituted with one or more substituents chosen from a halogen, and a (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, NRaRb, hydroxyl, nitro, cyano or OCO(C 1 -C 10 )alkyl group; 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method according to  claim 1 , wherein for the compound of formula (I):
 R 1  represents an isoxazolyl, pyridinyl, thiazolyl, quinolinyl, benzo[1,3]dioxolyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzoxazolyl, furyl, thienyl, pyrrolo[2,3-b]pyridinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, benzimidazolyl, indazolyl, benzisoxazolyl, isoquinolinyl or pyrazolyl group;   wherein these groups are optionally substituted with one or more atoms or groups chosen, independently of one another, from halogen, (C 1 -C 10 )alkyl, oxo, NRaRb, (C 1 -C 10 )alkoxy, aryl and CONRaRb; and   Ra and Rb represent, independently of one another, a hydrogen atom or a (C 1 -C 10 )alkyl group;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The method according to  claim 1 , wherein for the compound of formula (I):
 X represents 1 or 2 hydrogen or halogen atoms;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The method according to  claim 1 , wherein for the compound of formula (I):
 R represents, at position 3, 5, 7 or 8 of the imidazo[1,2-a]pyridine, a hydrogen atom or a (C 1 -C 10 )alkyl group;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The method according to  claim 1 , wherein for the compound of formula (I):
 R 2  and R 3  represent, independently of one another, a hydrogen atom or a (C 1 -C 10 )alkyl group;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The method according to  claim 1 , wherein for the compound of formula (I):
 R 4  represents a hydrogen atom, or a (C 1 -C 10 )alkyl group optionally substituted with an Rf group; and   Rf represents a (C 1 -C 10 )alkoxy group;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The method according to  claim 1 , wherein for the compound of formula (I): 
       the group 
       
         
           
           
               
               
           
         
       
       is at position 2, 3 or 4 of the phenyl which bears it; 
       or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method according to  claim 1 , wherein for the compound of formula (I):
 R 1  represents an isoxazolyl, pyridinyl, thiazolyl, quinolinyl, benzo[1,3]dioxolyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzoxazolyl, furyl, thienyl, pyrrolo[2,3-b]pyridinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, benzimidazolyl, indazolyl, benzisoxazolyl, isoquinolinyl or pyrazolyl group;   wherein these groups are optionally substituted with one or more atoms or groups chosen, independently of one another, from halogen, (C 1 -C 10 )alkyl, oxo, NRaRb, (C 1 -C 10 )alkoxy, aryl and CONRaRb;   Ra and Rb represent, independently of one another, a hydrogen atom or a (C 1 -C 10 )alkyl group;   X represents 1 or 2 hydrogen or halogen atoms;   R represents, at position 3, 5, 7 or 8 of the imidazo[1,2-a]pyridine, a hydrogen atom or a (C 1 -C 10 )alkyl group;   R 2  and R 3  represent, independently of one another, a hydrogen atom or a (C 1 -C 10 )alkyl group;   R 4  represents a hydrogen atom, or a (C 1 -C 10 )alkyl group optionally substituted with an Rf group; and   Rf represents a (C 1 -C 10 )alkoxy group;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The method according to  claim 1 , wherein for the compound of formula (I):
 R 1  represents an isoxazolyl, pyridinyl, thiazolyl, quinolinyl, benzo[1,3]dioxolyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzoxazolyl, furyl, thienyl, pyrrolo[2,3-b]pyridinyl, pyrimidinyl, benzothiazolyl, benzothiophenyl, benzimidazolyl, indazolyl, benzisoxazolyl, isoquinolinyl or pyrazolyl group;   wherein these groups are optionally substituted with one or more atoms or groups chosen, independently of one another, from halogen, (C 1 -C 10 )alkyl, oxo, NRaRb, (C 1 -C 10 )alkoxy, aryl and CONRaRb;   Ra and Rb represent, independently of one another, a hydrogen atom or a (C 1 -C 10 )alkyl group;   X represents 1 or 2 hydrogen or halogen atoms;   R represents, at position 3, 5, 7 or 8 of the imidazo[1,2-a]pyridine, a hydrogen atom or a (C 1 -C 10 )alkyl group;   R 2  and R 3  represent, independently of one another, a hydrogen atom or a (C 1 -C 10 )alkyl group;   R 4  represents a hydrogen atom, or a (C 1 -C 10 )alkyl group optionally substituted with an Rf group;   Rf represents a (C 1 -C 10 )alkoxy group; and   
       the group 
       
         
           
           
               
               
           
         
       
       being at position 2, 3 or 4 of the phenyl which bears it; 
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The method according to  claim 1 , wherein for the compound of formula (I):
 R 1  represents an isoxazolyl, pyridinyl, thiazolyl, quinolinyl, benzo[1,3]dioxolyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzoxazolyl, furyl, thienyl or pyrrolo[2,3-b]pyridinyl group, wherein these groups are optionally substituted with one or more atoms or groups chosen, independently of one another, from halogen, (C 1 -C 10 )alkyl, oxo, NRaRb and aryl;   X represents a hydrogen;   R represents a hydrogen or a (C 1 -C 10 )alkyl group;   R 2  and R 3  represent, independently of one another, a hydrogen atom;   R 4  represents a hydrogen atom or a (C 1 -C 10 )alkyl group, this group being optionally substituted with an Rf group;   Ra and Rb represent, independently of one another, a hydrogen atom or a (C 1 -C 10 )alkyl group; and   Rf represents a (C 1 -C 10 )alkoxy group;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method according to  claim 1 , wherein the pathology is cerebral trauma or epilepsy. 
     
     
         12 . The method according to  claim 1 , wherein the pathology is a psychiatric disease. 
     
     
         13 . The method according to  claim 1 , wherein the pathology is an inflammatory disease. 
     
     
         14 . The method according to  claim 1 , wherein the pathology is osteoporosis or cancer. 
     
     
         15 . The method according to  claim 1 , wherein the pathology is Parkinson's disease, Alzheimer's disease, tauopathies or multiple sclerosis. 
     
     
         16 . The method according to  claim 1 , wherein the pathology is schizophrenia, depression, substance dependence or an attention deficit hyperactivity disorder. 
     
     
         17 . A process for synthesizing the compound of formula (I): 
       wherein: 
       
         
           
           
               
               
           
         
         R 1  represents:
 a heteroaryl or heterocyclic group, wherein this group is optionally substituted with one or more atoms or groups chosen, independently of one another, from the following atoms or groups: halogen, (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, oxo, (C 1 -C 10 )thioalkyl, —S(O)(C 1 -C 10 )alkyl, —S(O) 2 (C 1 -C 10 -alkyl), hydroxyl, cyano, nitro, hydroxy(C 1 -C 10 )alkylene, NRaRb(C 1 -C 10 )alkylene, (C 1 -C 10 )alkoxy(C 1 -C 10 )alkyleneoxy, NRaRb, CONRaRb, SO 2 NRaRb, NRcCORd, OC(O)NRaRb, OCO(C 1 -C 10 )alkyl, NRcC(O)ORe, NRcSO 2 Re, aryl(C 1 -C 10 )alkylene, monocyclic heteroaryl and aryl, wherein the monocyclic heteroaryl and aryl are optionally substituted with one or more substituents chosen from a halogen, and a (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, NRaRb, hydroxyl, oxo, nitro, cyano or OCO(C 1 -C 10 )alkyl group, and R1 is linked to the imidazo[1,2-a]pyridine by an aromatic carbon; 
 
         X represents from 1 to 4 substituents, which may be identical to or different from one another, chosen from hydrogen, a halogen, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, NRaRb, nitro, and cyano, wherein the (C 1 -C 10 )alkyl group is optionally substituted with one or more groups chosen from a halogen, (C 1 -C 10 )alkoxy, (C 1 -C 10 )haloalkoxy, NRaRb and hydroxyl; 
         R represents, at position 3, 5, 7 or 8 of the imidazo[1,2-a]pyridine, from 1 to 4 substituents, which may be identical to or different from one another, chosen from a hydrogen, a halogen, (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, and (C 1 -C 10 )alkoxy; 
         R 2  and R 3  represent, independently of one another,
 a hydrogen atom, 
 a (C 1 -C 10 )alkyl group, optionally substituted with an Rf group; or 
 an aryl group, optionally substituted with one or more substituents chosen from a halogen, and a (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, NRaRb, hydroxyl, nitro or cyano group; 
 
         R 2  and X can form, together with the carbon atoms which bear them, a carbon-based ring containing from 5 to 7 carbon atoms; 
         R 4  represents:
 a hydrogen atom; 
 a (C 1 -C 10 )alkyl group, optionally substituted by an Rf group; or 
 an aryl group, optionally substituted with one or more substituents chosen from a halogen, and a (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, NRaRb, hydroxyl, nitro, cyano, (C 1 -C 10 )alkyl(CO)—, CONRaRb, NRcCORd, OC(O)NRaRb, OCO(C 1 -C 10 )alkyl, NRcC(O)ORe or aryl group, wherein the aryl is optionally substituted with one or more substituents chosen from a halogen, and a (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, NRaRb, hydroxyl, nitro or cyano group; 
 
         Ra and Rb represent, independently of one another, a hydrogen atom or a (C 1 -C 10 )alkyl, aryl(C 1 -C 10 )alkylene or aryl group; 
         or Ra and Rb form, together with the nitrogen atom which bears them, an azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, this group being optionally substituted with a (C 1 -C 10 )alkyl, aryl or aryl(C 1 -C 10 )alkylene group; 
         Rc and Rd represent, independently of one another, a hydrogen atom or a (C 1 -C 10 )alkyl,
 aryl(C 1 -C 10 )alkylene or aryl group, 
 
         or Rc and Rd together form a (C 2 -C 5 )alkylene group; 
         Re represents a (C 1 -C 10 )alkyl, aryl(C 1 -C 10 )alkylene or aryl group, 
         or Rc and Re together form a (C 2 -C 5 )alkylene group; and 
         Rf represents a halogen atom, or a (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, hydroxyl, cyano, NRaRb, C(O)NRaRb, NRcCORd, OC(O)NRaRb, OCO(C 1 -C 10 )alkyl, NRcCOORe, SO 2 NRaRb, NRcSO 2 Re, aryl(C 1 -C 10 )alkylene or aryl group, wherein the aryl is optionally substituted with one or more substituents chosen from a halogen, and a (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, NRaRb, hydroxyl, nitro, cyano or OCO(C 1 -C 10 )alkyl group; or an acid addition salt thereof;
 said method comprising reacting a compound of formula (XI): 
 
       
       
         
           
           
               
               
           
         
         
           wherein R, X, R3 and R2 are as defined for the compound of formula (I) and GP is a hydroxyl-function-protecting group, 
         
         with R1-W wherein R1 is as defined for the compound of formula (I) and W is a boron or tin derivative; and then deprotecting the product obtained. 
       
     
     
         18 . A process for synthesizing the compound of formula (I): 
       wherein: 
       
         
           
           
               
               
           
         
         R 1  represents:
 a heteroaryl or heterocyclic group, wherein this group is optionally substituted with one or more atoms or groups chosen, independently of one another, from the following atoms or groups: halogen, (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, oxo, (C 1 -C 10 )thioalkyl, —S(O)(C 1 -C 10 )alkyl, —S(O) 2 (C 1 -C 10 -alkyl), hydroxyl, cyano, nitro, hydroxy(C 1 -C 10 )alkylene, NRaRb(C 1 -C 10 )alkylene, (C 1 -C 10 )alkoxy(C 1 -C 10 )alkyleneoxy, NRaRb, CONRaRb, SO 2 NRaRb, NRcCORd, OC(O)NRaRb, OCO(C 1 -C 10 )alkyl, NRcC(O)ORe, NRcSO 2 Re, aryl(C 1 -C 10 )alkylene, monocyclic heteroaryl and aryl, wherein the monocyclic heteroaryl and aryl are optionally substituted with one or more substituents chosen from a halogen, and a (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, NRaRb, hydroxyl, oxo, nitro, cyano or OCO(C 1 -C 10 )alkyl group, and R1 is linked to the imidazo[1,2-a]pyridine by an aromatic carbon; 
 
         X represents from 1 to 4 substituents, which may be identical to or different from one another, chosen from hydrogen, a halogen, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, NRaRb, nitro, and cyano, wherein the (C 1 -C 10 )alkyl group is optionally substituted with one or more groups chosen from a halogen, (C 1 -C 10 )alkoxy, (C 1 -C 10 )haloalkoxy, NRaRb and hydroxyl; 
         R represents, at position 3, 5, 7 or 8 of the imidazo[1,2-a]pyridine, from 1 to 4 substituents, which may be identical to or different from one another, chosen from a hydrogen, a halogen, (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, and (C 1 -C 10 )alkoxy; 
         R 2  and R 3  represent, independently of one another,
 a hydrogen atom, 
 a (C 1 -C 10 )alkyl group, optionally substituted with an Rf group; or 
 an aryl group, optionally substituted with one or more substituents chosen from a halogen, and a (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, NRaRb, hydroxyl, nitro or cyano group; 
 
         R 2  and X can form, together with the carbon atoms which bear them, a carbon-based ring containing from 5 to 7 carbon atoms; 
         R 4  represents:
 a hydrogen atom; 
 a (C 1 -C 10 )alkyl group, optionally substituted by an Rf group; or 
 an aryl group, optionally substituted with one or more substituents chosen from a halogen, and a (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, NRaRb, hydroxyl, nitro, cyano, (C 1 -C 10 )alkyl(CO)—, CONRaRb, NRcCORd, OC(O)NRaRb, OCO(C 1 -C 10 )alkyl, NRcC(O)ORe or aryl group, wherein the aryl is optionally substituted with one or more substituents chosen from a halogen, and a (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, NRaRb, hydroxyl, nitro or cyano group; 
 
         Ra and Rb represent, independently of one another, a hydrogen atom or a (C 1 -C 10 )alkyl, aryl(C 1 -C 10 )alkylene or aryl group; 
         or Ra and Rb form, together with the nitrogen atom which bears them, an azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, this group being optionally substituted with a (C 1 -C 10 )alkyl, aryl or aryl(C 1 -C 10 )alkylene group; 
         Rc and Rd represent, independently of one another, a hydrogen atom or a (C 1 -C 10 )alkyl, aryl(C 1 -C 10 )alkylene or aryl group, 
         or Rc and Rd together form a (C 2 -C 5 )alkylene group; 
         Re represents a (C 1 -C 10 )alkyl, aryl(C 1 -C 10 )alkylene or aryl group, 
         or Rc and Re together form a (C 2 -C 5 )alkylene group; and 
         Rf represents a halogen atom, or a (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, hydroxyl, cyano, NRaRb, C(O)NRaRb, NRcCORd, OC(O)NRaRb, OCO(C 1 -C 10 )alkyl, NRcCOORe, SO 2 NRaRb, NRcSO 2 Re, aryl(C 1 -C 10 )alkylene or aryl group, wherein the aryl is optionally substituted with one or more substituents chosen from a halogen, and a (C 1 -C 10 )alkyl, halo(C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, halo(C 1 -C 10 )alkoxy, NRaRb, hydroxyl, nitro, cyano or OCO(C 1 -C 10 )alkyl group; or an acid addition salt thereof;
 said method comprising: 
 a) reacting a compound of formula (IX): 
 
       
       
         
           
           
               
               
           
         
         
           wherein R, X, R3, R4 and R2 are as defined for the compound of formula (I), with R1-W wherein R1 is as defined for the compound of formula (I) and W is a boron or tin derivative; or 
           b) reacting a compound of formula (VIII): 
         
       
       
         
           
           
               
               
           
         
         
           wherein R is as defined for the compound of formula (I) and Y represents a boron derivative, 
         
         with a compound of formula (VII) wherein R6 represents R4, and R2, R3, R4 and X are as defined for the compound of formula (I) and Z is a halogen; or
 c) reacting a compound of formula (XIII): 
 
       
       
         
           
           
               
               
           
         
         
           wherein R2, R3, R4 and X are as defined for the compound of formula (I), with a compound of formula (VI) wherein R1 and R are as defined for the compound of formula (I) and Hal is a halogen; or 
           d) reacting a compound of formula (XIV) 
         
       
       
         
           
           
               
               
           
         
         
           wherein R2, R3, and X are as defined for the compound of formula (I) and GP is a hydroxyl-function-protecting group, with a compound of formula (VI) wherein R1 and R are as defined for the compound of formula (I) and Hal is a halogen; and then deprotecting the product obtained.