Benzoimidazoles as prolyl hydroxylase inhibitors

Abstract

The present invention is directed to benzoimidazole compounds of the formula: and enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof. Compounds of the present invention are useful in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions modulated by prolyl hydroxylase activity.

What is claimed is: 
     
         1 . A compound having PHD inhibitor activity of the formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         n is 2-4; 
         each R 1  is independently selected from: H, halo, —C 1-4 alkyl, —C 1-4 perhaloalkyl, trifluoroC 1-4 alkoxy, —NO 2 , —CN, —OC 1-4 alkyl, —S—R c , —SO 2 —R c  and —NR a R b ; 
         R a  and R b  are each independently H; 
         R c  is phenyl optionally substituted with R d ; 
         each R d  is independently selected from the group consisting of: —H, halo, —C 1-4 alkyl or —C 1-4 perhaloalkyl, trifluoroC 1-4 alkoxy, and —OC 1-4 alkyl; 
         R 2  and R 3  are selected from: H, —CF 3 , or C 1-3 alkyl; and 
         each Z is C and 
         enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof. 
       
     
     
         2 . A compound of  claim 1 , where R 2  and R 3  are each —H. 
     
     
         3 . A compound of  claim 1  wherein each R 1  is independently selected from the group consisting of: H, halo, —CF 3 , —OCF 3 , benzylsulfanyl optionally substituted or unsubstituted with up to three halo, C 1-4 alkyl, —CF 3 , and —OCF 3 , and benzenesulfonyl optionally substituted or unsubstituted with up to three C 1-4 alkyl, C 1-4 alkoxy, halo, —CF 3 , and —OCF 3 . 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . A compound of  claim 1 , wherein each R 1  is independently selected from: H, halo, —C 1-4 alkyl, —CF 3 , —OCF 3 , —NO 2 , —NH 2  —CN, and —OC 1-4 alkyl. 
     
     
         7 . The compound of  claim 1 , wherein said compound is selected from the group consisting of:
 1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid;   1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5,6-Difluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-cyano-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-nitro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5-Amino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-m-tolylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(4-chloro-phenylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-phenylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(3,4-dichloro-phenylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(toluene-3-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-(5-Benzenesulfonyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(4-methoxy-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(4-chloro-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(4-trifluoromethoxy-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(3,4-dichloro-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-(6-Bromo-5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Ethoxy-5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5,6-Bis-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Fluoro-5-trifluoromethyl-1H-benzimidazol 2-yl)-1H-pyrazole-4 carboxylic acid;   and pharmaceutically acceptable salts thereof.   
     
     
         8 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of compound having PHD inhibitor activity of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         n is 2-4; 
         each R 1  is independently selected from: H, halo, —C 1-4 alkyl, —C 1-4 perhaloalkyl, trifluoroC 1-4 alkoxy, —NO 2 , —CN, —OC 1-4 alkyl, —S—R c , —SO 2 —R c , and —NR a R b ; 
         R a  and R b  are each independently H; 
         R c  is phenyl optionally substituted with R d ; 
         each R d  is independently selected from the group consisting of: —H, halo, —C 1-4 alkyl or —C 1-4 perhaloalkyl, trifluoroC 1-4 alkoxy, and —OC 1-4 alkyl; 
         R 2  and R 3  are selected from: H, —CF 3 , or C 1-3 alkyl; and 
         each Z is C and 
         enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof. 
       
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the composition comprises one or more compounds selected from the group consisting of:
 1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid;   1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5,6-Difluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-cyano-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-nitro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5-Amino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-m-tolylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(4-chloro-phenylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-phenylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(3,4-dichloro-phenylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(toluene-3-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazol-4-carboxylic acid;   1-(5-Benzenesulfonyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(4-methoxy-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(4-chloro-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(4-trifluoromethoxy-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(3,4-dichloro-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-(6-Bromo-5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Ethoxy-5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5,6-Bis-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Fluoro-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   and pharmaceutically acceptable salts thereof.   
     
     
         10 . A method for the treatment of anemia, hypoxia, ischemia, peripheral vascular disease, myocardial infarction, stroke, diabetes, obesity, inflammatory bowel disease, ulcerative colitis, Crohn's disease, wounds, infection, burns and bone fracture comprising the step of administering to a patient in need thereof a therapeutically effective amount of one or more compounds of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         n is 2-4; 
         each R 1  is independently selected from H, halo, —C 1-4 alkyl, —C 1-4 perhaloalkyl, trifluoroC 1-4 alkoxy, —NO 2 , —CN, —OC 1-4 alkyl, —S—R c , —SO 2 —R c , and —NR a R b ; 
         R a  and R b  are each independently H; 
         R c  is phenyl optionally substituted with R d ; 
         each R d  is independently selected from the group consisting of: —H, halo, —C 1-4 alkyl or —C 1-4 perhaloalkyl, trifluoroC 1-4 alkoxy, and —OC 1-4 alkyl; 
         R 2  and R 3  are selected from: H, —CF 3 , or C 1-3 alkyl; and 
         each Z is C; and 
         enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts thereof. 
       
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 10 , wherein the compound is selected from the group consisting of:
 1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid;   1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5,6-Difluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-cyano-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-nitro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5-Amino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-m-tolylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(4-chloro-phenylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-phenylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(3,4-dichloro-phenylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(toluene-3-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-(5-Benzenesulfonyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(4-methoxy-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(4-chloro-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(4-trifluoromethoxy-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[6-Chloro-5-(3,4-dichloro-benzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-(6-Bromo-5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Chloro-5-trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Ethoxy-5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5,6-Bis-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(6-Fluoro-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   and pharmaceutically acceptable salts thereof.