Substituted benzimidazoles and methods of preparation

Abstract

Methods for preparing new substituted benzimidazole compounds having formula (I) useful for treating kinase mediated disorders are provided wherein R 1 , R 2 , R 3 , R 4 , a, b, and c are defined herein

1 . A method for preparing a compound of Formula (I) or a tautomer, stereoisomer, ester, metabolite, prodrug, or pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
       wherein,
 each R 1  is independently selected from hydroxy, halo, C 1-6  alkyl, C 1-6  alkoxy, (C 1-6  alkyl)sulfanyl, (C 1-6  alkyl)sulfonyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl; 
 R 2  is C 1-6  alkyl or halo(C 1-6  alkyl); 
 each R 3  is independently selected from halo, C 1-6  alkyl, and C 1-6  alkoxy; 
 each R 4  is independently selected from hydroxy, C 1-6  alkyl, C 1-6  alkoxy, halo, heterocycloalkylcarbonyl, carboxyl, (C 1-6  alkoxy)carbonyl, aminocarbonyl, C 1-6  alkylaminocarbonyl, carbonitrile, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl; 
 wherein R 1 , R 2 , R 3 , and R 4  may be optionally substituted with one or more substituents independently selected from hydroxy, halo, C 1-6  alkyl, halo(C 1-6  alkyl), C 1-6  alkoxy, and halo(C 1-6  alkoxy); 
 a is 1, 2, 3, 4, or 5; 
 b is 0, 1, 2, or 3; 
 c is 1 or 2; 
 the method comprising: 
 (a) reacting a compound of Formula (II) with a compound of Formula (III) to provide a compound of Formula (IV) 
 
       
         
           
           
               
               
           
         
       
       wherein Q is NH 2  or NO 2 ; one of L 1  or L 2  is halo and the other of L 1  or L 2  is OH or an anion thereof; Z is cyano, COOR 5 , CH 2 OR 5 , CHO, or imidazol-2-yl substituted with one or two R 4  groups and wherein R 5  is hydrogen or a hydroxy protecting group;
 (b) when in the compound of Formula (IV) Z is cyano, COOR 5  or CH 2 OR 5 , converting said compound to a compound of Formula (IV) wherein Z is CHO; 
 (c) when in the compound of Formula (IV) Z is cyano, converting the cyano functionality to an amidino functionality and reacting said amidino functionality with a compound of Formula (Va) under imidazole ring forming conditions; or when in the compound of Formula (IV) Z is CHO, reacting said compound with a compound of Formula (Vb) to provide a compound of Formula (VI) 
 
       
         
           
           
               
               
           
         
       
       wherein X a  in Formula (Va) is a leaving group and R 4p  and R 4q  in Formula (Vb) are independently H or R 4 , provided that at least one of R 4p  and R 4q  is R 4  and X b  is ═O or ═NHOH and provided that c is 1 when a compound of Formula (VI) is prepared from a compound of Formula (Va);
 (d) when in the compound of Formula (VI) Q is NO 2 , converting said compound to a compound of Formula (VI) wherein Q is NH 2 ; 
 (e) reacting the compound of Formula (VI) wherein Q is NH 2  with a compound of Formula (VII) to provide a compound of Formula (VIII) or a tautomer thereof 
 
       
         
           
           
               
               
           
         
         (f) reacting the compound of Formula (VIII) or a tautomer thereof with a desulfurizing agent to provide a compound of Formula (I); 
         (g) optionally reacting the compound of Formula (I) or a tautomer thereof with an acid to give a first pharmaceutically acceptable salt; 
         (h) optionally converting the first pharmaceutically acceptable salt of a compound of Formula (I) or a tautomer thereof to a second pharmaceutically acceptable salt; and 
         (i) optionally converting a compound of Formula (I) or a tautomer or pharmaceutically acceptable salt thereof to an ester, metabolite, or prodrug of Formula (I). 
       
     
     
         2 . The method of  claim 1  wherein part (a) is carried out with organic or inorganic base in polar solvent. 
     
     
         3 . The method of  claim 2  wherein the inorganic base is selected from the group consisting of NaOH, KOH, CaCO 3 , and K 2 CO 3 . 
     
     
         4 . The method of  claim 2  wherein the polar solvent is selected from the group consisting of dimethylsulfoxide and dimethylformamide. 
     
     
         5 . The method of  claim 1  wherein part (b) comprises reacting a compound of Formula (IV) when Z is COOR 5  with a reducing agent. 
     
     
         6 . The method of  claim 5  wherein R 5  is tert-butyl. 
     
     
         7 . The method of  claim 5  wherein the reducing agent is diisobutylaluminum hydride. 
     
     
         8 . The method of  claim 1  wherein part (c) is carried out with NH 4 OH in polar solvent. 
     
     
         9 . The method of  claim 8  wherein the polar solvent is a mixture of ethyl acetate and ethanol. 
     
     
         10 . The method of  claim 1  wherein part (d) comprises reacting a compound of Formula (VI) when Q is NO 2  with a reducing agent. 
     
     
         11 . The method of  claim 10  wherein the reducing agent is sodium dithionite. 
     
     
         12 . The method of  claim 1  wherein part (e) is carried out in acetonitrile. 
     
     
         13 . The method of  claim 1  wherein the desulfurizing agent in part (f) is selected from the group consisting of FeCl 3 , 2-chloro-1-methylpyridinium iodide, 2-chloro-1,3-dimethylimidazolium chloride, and POCl 3 . 
     
     
         14 . A method for preparing a pharmaceutically acceptable salt of a compound of Formula (I) or tautomer thereof 
       
         
           
           
               
               
           
         
       
       wherein,
 each R 1  is independently selected from hydroxy, halo, C 1-6  alkyl, C 1-6  alkoxy, (C 1-6  alkyl)sulfanyl, (C 1-6  alkyl)sulfonyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl; 
 R 2  is C 1-6  alkyl or halo(C 1-6  alkyl); 
 each R 3  is independently selected from halo, C 1-6  alkyl, and C 1-6  alkoxy; 
 each R 4  is independently selected from hydroxy, C 1-6  alkyl, C 1-6  alkoxy, halo, heterocycloalkylcarbonyl, carboxyl, (C 1-6  alkoxy)carbonyl, aminocarbonyl, C 1-6  alkylaminocarbonyl, carbonitrile, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl; 
 wherein R 1 , R 2 , R 3 , and R 4  may be optionally substituted with one or more substituents independently selected from hydroxy, halo, C 1-6  alkyl, halo(C 1-6  alkyl), C 1-6  alkoxy, and halo(C 1-6  alkoxy); 
 a is 1, 2, 3, 4, or 5; 
 b is 0, 1, 2, or 3; 
 c is 1 or 2; 
 the method comprising: 
 (a) reacting a compound of Formula (I) or a tautomer thereof with an acid to give a first pharmaceutically acceptable salt; or 
 (b) converting the first pharmaceutically acceptable salt of a compound of Formula (I) or a tautomer thereof to a second pharmaceutically acceptable salt. 
 
     
     
         15 . A method for preparing a compound of Formula (I) or a tautomer, stereoisomer, ester, metabolite, prodrug, or pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
       wherein,
 each R 1  is independently selected from hydroxy, halo, C 1-6  alkyl, C 1-6  alkoxy, (C 1-6  alkyl)sulfanyl, (C 1-6 alkyl)sulfonyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl; 
 R 2  is C 1-6  alkyl or halo(C 1-6  alkyl); 
 each R 3  is independently selected from halo, C 1-6  alkyl, and C 1-6  alkoxy; 
 each R 4  is independently selected from hydroxy, C 1-6  alkyl, C 1-6  alkoxy, halo, heterocycloalkylcarbonyl, carboxyl, (C 1-6  alkoxy)carbonyl, aminocarbonyl, C 1-6  alkylaminocarbonyl, carbonitrile, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl; 
 wherein R 1 , R 2 , R 3 , and R 4  may be optionally substituted with one or more substituents independently selected from hydroxy, halo, C 1-6  alkyl, halo(C 1-6 alkyl), C 1-6  alkoxy, and halo(C 1-6  alkoxy); 
 a is 1, 2, 3, 4, or 5; 
 b is 0, 1, 2, or 3; 
 c is 1 or 2; 
 the method comprising: 
 reacting a compound of Formula (XIII) with a compound of Formula (XIV) to provide a compound of Formula (I) 
 
       
         
           
           
               
               
           
         
       
       wherein one of L 3  or L 4  is halo and the other of L 3  or L 4  is OH or an anion thereof; or
 reacting a compound of Formula (XV) with a compound of Formula (Vb) to provide a compound of Formula (I) 
 
       
         
           
           
               
               
           
         
       
       wherein R 4p  and R 4q  are independently H or R 4 , provided that at least one of R 4p  and R 4q  is R 4 ; and X b  is ═O or ═NHOH; or
 reacting the compound of Formula (VIII) or a tautomer thereof with a desulfurizing agent to provide a compound of Formula (I) 
 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 1  wherein the compound of Formula (I) is selected from the group consisting of
 {1-Methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethylphenyl)-amine,   (2-Fluoro-5-pyridin-3-yl-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (2-Fluoro-5-pyridin-4-yl-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (4-tert-Butyl-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   {1-Methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(3-trifluoromethyl-phenyl)-amine,   (3-Ethyl-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (4-Chloro-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (4-Ethyl-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (4-Chloro-3-trifluoromethyl-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (4-Fluoro-3-trifluoromethyl-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   {1-Methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethoxy-phenyl)-amine,   (2-Fluoro-5-trifluoromethyl-phenyl)-(1-methyl-5-{2-[5-methyl-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-4-yloxy}-1H-benzoimidazol-2-yl)-amine,   (2-Fluoro-5-trifluoromethyl-phenyl)-(1-methyl-5-{2-[5-methyl-4-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyridin-4-yloxy}-1H-benzoimidazol-2-yl)-amine,   2-{4-[2-(2-Fluoro-5-trifluoromethyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-5-trifluoromethyl-1H-imidazole-4-carboxylic acid ethyl ester,   (2-{4-[2-(2-Fluoro-5-trifluoromethyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-5-trifluoromethyl-1H-imidazol-4-yl)-methanol,   2-{4-[1-Methyl-2-(4-trifluoromethyl-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridin-2yl}-3H-imidazole-4-carbonitrile,   (3-tert-Butyl-phenyl)-{1-methyl-5-[2-(5-phenyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   {1-Methyl-5-[2-(5-phenyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethylsulfanyl-phenyl)-amine,   (3-tert-Butyl-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   [4-Fluoro-3-(tetrahydro-furan-3-yl)-phenyl]-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (4-Bromo-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (4-Fluoro-3-isopropyl-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   {1-Methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(4-trifluoromethylsulfanyl-phenyl)-amine,   (2-Fluoro-5-isopropyl-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (2-Fluoro-5-trifluoromethyl-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (5-tert-Butyl-2-fluoro-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yl-oxy]-1H-benzoimidazol-2-yl}-amine,   (2-Fluoro-5-trifluoromethyl-phenyl)-{1-methyl-5-[2-(5-methyl-1H-imidazol-2-yl)-pyridin-4-yl-oxy]-1H-benzoimidazol-2-yl}-amine,   (2-Fluoro-5-pyridin-3-yl-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   2-{4-[2-(2-Fluoro-5-trifluoromethyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-3H-imidazole-4-carbonitrile,   (2-Chloro-4-trifluoromethyl-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (5-tert-Butyl-2-chloro-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (2-Fluoro-5-pyridin-4-yl-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (2-Fluoro-5-trifluoromethyl-phenyl)-{1-methyl-5-[2-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (2-Chloro-5-trifluoromethyl-phenyl)-{1-methyl-5-[2-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   {1-Methyl-5-[2-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(3-trifluoromethyl-phenyl)-amine,   (3-Ethyl-phenyl)-{1-methyl-5-[2-(4-phenyl-5-trifluoromethyl-1H-imidazol-2yl)-pyridin-4-yl-oxy]-1H-benzoimidazol-2-yl}-amine,   (4-tert-Butyl-phenyl)-{1-methyl-5-[2-(4-phenyl-5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (2-Chloro-5-trifluoromethyl-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (2-Fluoro-5-trifluoromethyl-phenyl)-{1-methyl-5-[2-(5-methyl-4-phenyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (2-Chloro-5-trifluoromethyl-phenyl)-{1-methyl-5-[2-(5-methyl-4-phenyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (4-tert-Butyl-phenyl)-{1-methyl-5-[2-(5-methyl-4-phenyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   {1-Methyl-5-[2-(5-methyl-4-phenyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(3-trifluoromethyl-phenyl)-amine,   (5-tert-Butyl-2-fluoro-phenyl)-{1-methyl-5-[2-(5-methyl-4-phenyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   [4-(4-Methyl-piperazin-1-yl)-phenyl]-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   2-{4-[2-(2-Fluoro-5-trifluoromethyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-3H-imidazole-4-carboxylic acid methyl ester,   2-{4-[2-(2-Chloro-5-trifluoromethyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-5-trifluoromethyl-1H-imidazole-4-carboxylic acid ethyl ester,   (2-Fluoro-4-trifluoromethyl-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (2-Chloro-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (2,5-Dimethoxy-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (3,5-Dimethoxy-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   {1-Methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(2-trifluoromethyl-phenyl)-amine,   (2-Ethyl-phenyl)-{1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   (4-Ethyl-piperazin-1-yl)-(2-{4-[2-(2-fluoro-5-trifluoromethyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-3H-imidazol-4-yl)-methanone,   2-{4-[2-(2-Fluoro -5-trifluoromethyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-3H-imidazole-4-carboxylic acid (2-hydroxy-ethyl)-amide,   {1-Ethyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-(2-fluoro-5-trifluoromethyl-phenyl)-amine,   (2-Fluoro-5-trifluoromethyl-phenyl)-{6-methoxy-1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-yl}-amine,   {6-Methoxy-1-methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-imidazol-2-yl}-(4-trifluoromethyl-phenyl)-amine,   (4-Ethyl-piperazin-1-yl)-(2-{4-[1-methyl-2-(4-trifluoromethyl-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-3H-imidazol-4-yl)-methanone,   {1-Ethyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2yl}-(4-trifluoromethyl-phenyl)-amine,   2-{4-[1-Methyl-2-(4-trifluoromethyl-phenylamino)-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-3H-imidazole-4-carboxylic acid (2-hydroxy-ethyl)-amide,   2-{1-Methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-ylamino}-5-trifluoromethyl-phenol, and   3-{1-Methyl-5-[2-(5-trifluoromethyl-1H-imidazol-2-yl)-pyridin-4-yloxy]-1H-benzoimidazol-2-ylamino}-6-trifluoromethyl-phenol;   or a tautomer, stereoisomer, ester, metabolite, prodrug, or pharmaceutically acceptable salt thereof.   
     
     
         17 . (canceled)