Benzoimidazoles as prolyl hydroxylase inhibitors

Abstract

Certain Benzoimidazole compounds are described, which are useful as prolyl hydroxylase inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by prolyl hydroxylase activity. Thus, the compounds may be administered to treat, e.g., Anemia, vascular disorders, metabolic disorders, and wound healing.

What is claimed is: 
     
         1 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof, wherein
 X is an optionally substituted heteroaryl selected from pyrazole, pyridine, pyrimidine, and pyridazine; 
 A is a bond or optionally substituted methylene; 
 each Z is independently C or N; 
 n is 0-4; and 
 R 1  is independently selected from hydrogen, halogen, nitro, —C 1-4 alkyl, alkoxy, cycloalkoxy, CON(R y )(R z ), trifluoromethyl, trifluoromethoxy, N(R y )R z  (wherein R y  and R z  are independently hydrogen, aryl, arylsulfonyl, —C 1-6 alkyl, and —C 1-6 alkenyl, or R y  and R z  may be taken together with the nitrogen of attachment to form an otherwise aliphatic hydrocarbon ring, said ring being optionally substituted and having 4 to 7 members, optionally having one carbon replaced with >O, ═N, >NH, or >N(C 1-4 alkyl), and optionally substituted Ar wherein said Ar is aryl or heteroaryl. 
 
     
     
         2 . The compound of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
       and each R 2  is independently hydrogen, halo, hydroxyl, methyl, or CF 3 . 
     
     
         3 . The compound of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
       and each R 2  is independently hydrogen, halo, hydroxyl, methyl, or CF 3 . 
     
     
         4 . The compound of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
       R 2  is hydrogen, halo, hydroxyl, methyl, or CF 3 , each Z is independently C or N wherein R 3  is hydrogen, halo, hydroxyl, methyl, or CF 3  when Z is C and R 3  is a lone electron pair when Z is N. 
     
     
         5 . The compound of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
       R 2  is hydrogen, halo, hydroxyl, methyl, or CF 3 , each Z is independently C or N wherein R 3  is hydrogen, halo, hydroxyl, methyl, or CF 3  when Z is C and R 3  is a lone electron pair when Z is N. 
     
     
         6 . The compound of  claim 1  wherein A is a methlyene optionally substituted with hydrogen, hydroxymethyl, or —C 1-4 alkyl. 
     
     
         7 . The compound of  claim 1 , wherein A is a bond. 
     
     
         8 . The compound of  claim 1 , wherein Z is C. 
     
     
         9 . The compound of  claim 1  wherein R 1  is selected from the group consisting of phenyl, benzyl, quinolinyl, napthalenyl, dichlorophenyl, hydroxyphenyl, trifluoromethylphenyl, benzylamine-, benzyloxy-, benzamide-, chlorobenzyloxy phenyl, benzyloxyphenyl, phenoxy phenyl, benzamide having a ring member as a point of attachment and a benzyl substitutent on its N, propyloxy phenyl, and benzenesulfonylamine. 
     
     
         10 . The compound of  claim 1 , wherein R 1  is selected from hydrogen, methyl, Br, CI, F, CF 3 , methyl, methoxy, OCF 3 , Ar, and alkoxy, cycloalkoxy, aryloxy, piperidino, pyrrolidino, and morpholino. 
     
     
         11 . A compound selected from the group consisting of:
 1-(1H-Benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5-Trifluoromethyl-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-Bromo-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5-Methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(4-Chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5,6-Dimethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5-Trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-{5-[3-(3-Chloro-benzyloxy)-phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid;   1-{5-[3-(2-Chloro-benzyloxy)-phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid;   1-{5-[3-(4-Chloro-benzyloxy)-phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid;   1-[5-(3-Benzyloxy-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[5-(4-Benzyloxy-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[5-(3-Trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[5-(3,4-Dichloro-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-(5-Bromo-1H-benzoimidazol-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid;   1-(5,6-dichloro-1H-benzoimidazol-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid;   1-(5-Bromo-1H-benzoimidazol-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid;   1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid;   1-[5-(4-Hydroxy-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[5-(3-Hydroxy-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-(5-Chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5-Bromo-6,7-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid; and   
       pharmaceutically acceptable salts thereof. 
     
     
         12 . A pharmaceutical composition comprising:
 (a) an effective amount of a chemical entity selected from a compound of  claim 1 , a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable prodrug of said compound, and a pharmaceutically active metabolite of said compound; and   (b) a pharmaceutically acceptable excipient.   
     
     
         13 . A pharmaceutical composition comprising one or more compounds selected from the group consisting of:
 1-(1H-Benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5-Trifluoromethyl-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-Bromo-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5-Methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(4-Chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5,6-Dimethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(4,5-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5-Trifluoromethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-{5-[3-(3-Chloro-benzyloxy)-phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid;   1-{5-[3-(2-Chloro-benzyloxy)-phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid;   1-{5-[3-(4-Chloro-benzyloxy)-phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid;   1-[5-(3-Benzyloxy-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[5-(4-Benzyloxy-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[5-(3-Trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[5-(3,4-Dichloro-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-(5-Bromo-1H-benzoimidazol-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid;   1-(5,6-dichloro-1H-benzoimidazol-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid;   1-(5-Bromo-1H-benzoimidazol-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid;   1-(5,6-Dichloro-1H-benzoimidazol-2-yl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid;   1-[5-(4-Hydroxy-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-[5-(3-Hydroxy-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;   1-(5-Chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;   1-(5-Bromo-6,7-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid; and   
       pharmaceutically acceptable salts thereof. 
     
     
         14 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof, wherein
 each Z is independently C or N; 
 n is 0-4; and 
 R 1  is independently selected from hydrogen, halogen, nitro, —C 1-4 alkyl, alkoxy, cycloalkoxy, CON(R y )(R z ), trifluoromethyl, trifluoromethoxy, N(R y )R z  (wherein R y  and R z  are independently hydrogen, aryl, arylsulfonyl, —C 1-6 alkyl, and —C 1-6 alkenyl, or R y  and R z  may be taken together with the nitrogen of attachment to form an otherwise aliphatic hydrocarbon ring, said ring being optionally substituted and having 4 to 7 members, optionally having one carbon replaced with >O, ═N, >NH, or >N(C 1-4 alkyl), and optionally substituted Ar wherein said Ar is aryl or heteroaryl; 
 R 2  is hydrogen, hydroxymethyl or (C 1-4 )alkyl. 
 
     
     
         15 . The compound of  claim 14 , wherein each R 2  is independently hydrogen, hydroxymethyl, or (C 1-4 )alkyl. 
     
     
         16 . The compound of  claim 14 , wherein Z is C. 
     
     
         17 . The compound of  claim 14 , wherein R 1  is selected from the group consisting of phenyl, benzyl, quinolinyl, napthalenyl, dichlorophenyl, hydroxyphenyl, trifluoromethylphenyl, benzylamine-, benzyloxy-, benzamide-, chlorobenzyloxy phenyl, benzyloxyphenyl, phenoxy phenyl, benzamide having a ring member as a point of attachment and a benzyl substitutent on its N, propyloxy phenyl, and benzenesulfonylamine. 
     
     
         18 . The compound of  claim 14 , wherein R 1  is selected from hydrogen, methyl, Br, CI, F, CF 3 , methyl, methoxy, OCF 3 , Ar, and alkoxy, cycloalkoxy, aryloxy, piperidino, pyrrolidino, and morpholino. 
     
     
         19 . A compound selected from the group consisting of:
 [(1H-Benzoimidazole-2-carbonyl)-amino]-acetic acid;   (S)-2-[(1H-Benzoimidazole-2-carbonyl)-amino]-propionic acid;   [(5,6-Dichloro-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   (S)-2-[(5,6-Dichloro-1H-benzoimidazole-2-carbonyl)-amino]-propionic acid;   [(6-Nitro-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   [(5,7-Bis-trifluoromethyl-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   (S)-2-[(5,7-Bis-trifluoromethyl-1H-benzoimidazole-2-carbonyl)-amino]-propionic acid;   [(5-Iodo-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   [(6-Bromo-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   (S)-2-[(6-Fluoro-1H-benzoimidazole-2-carbonyl)-amino]-propionic acid;   (R)-2-[(6-Fluoro-1H-benzoimidazole-2-carbonyl)-amino]-propionic acid;   [(6-Methoxy-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   ({5-[3-(3-Chloro-benzyloxy)-phenyl]-1H-benzoimidazole-2-carbonyl}-amino)-acetic acid;   ({5-[3-(2-Chloro-benzyloxy)-phenyl]-1H-benzoimidazole-2-carbonyl}-amino)-acetic acid;   ({5-[3-(4-Chloro-benzyloxy)-phenyl]-1H-benzoimidazole-2-carbonyl}-amino)-acetic acid;   ({5-[3-(3-Fluoro-benzyloxy)-phenyl]-1H-benzoimidazole-2-carbonyl}-amino)-acetic acid;   ({5-[3-(2-Fluoro-benzyloxy)-phenyl]-1H-benzoimidazole-2-carbonyl}-amino)-acetic acid;   {[5-(4-Phenoxy-phenyl)-1H-benzoimidazole-2-carbonyl]-amino}-acetic acid;   {[5-(3-Benzyloxy-5-fluoro-phenyl)-1H-benzoimidazole-2-carbonyl]-amino}-acetic acid;   [(5-Quinolin-3-yl-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   ({5-[3-Chloro-4-(3-chloro-benzyloxy)phenyl]-1H-benzoimidazole-2-carbonyl}-amino)-acetic acid;   ({5-[4-(3-Chloro-benzyloxy)-3,5-dimethyl-phenyl]-1H-benzoimidazole-2-carbonyl}-amino)-acetic acid;   {[5-(3-Methoxy-phenyl)-1H-benzoimidazole-2-carbonyl]-amino}-acetic acid;   {[5-(5-Benzylcarbamoyl-2-fluoro-phenyl)-1H-benzoimidazole-2-carbonyl]-amino}-acetic acid;   [(5-Naphthalen-2-yl-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   {[5-(4-Propoxy-phenyl)-1H-benzoimidazole-2-carbonyl]-amino}-acetic acid;   {[5-(4-Chloro-3-methyl-phenyl)-1H-benzoimidazole-2-carbonyl]-amino}-acetic acid;   {[5-(5-Chloro-2-fluoro-phenyl)-1H-benzoimidazole-2-carbonyl]-amino}-acetic acid;   [(5-Benzoylamino-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   [(6-Benzenesulfonylamino-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   [(6-Benzylamino-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   (R)-2-[(1H-Benzoimidazole-2-carbonyl)-amino]-propionic acid;   (R)-2-[(1H-Benzoimidazole-2-carbonyl)-amino]-3-hydroxy-propionic acid;   (R)-2-[(5,7-Bis-trifluoromethyl-1H-benzoimidazole-2-carbonyl)-amino]-propionic acid;   (R)-2-[(5,6-Dichloro-1H-benzoimidazole-2-carbonyl)-amino]-propionic acid;   (R)-2-[(5-Iodo-1H-benzoimidazole-2-carbonyl)-amino]-propionic acid;   
       and pharmaceutically acceptable salts thereof. 
     
     
         20 . A pharmaceutical composition comprising:
 (a) an effective amount of a chemical entity selected from a compound of  claim 14 , a pharmaceutically acceptable salt of said compound, a pharmaceutically acceptable prodrug of said compound, and a pharmaceutically active metabolite of said compound; and   (b) a pharmaceutically acceptable excipient.   
     
     
         21 . A pharmaceutical composition comprising one or more compounds selected from the group consisting of:
 [(1H-Benzoimidazole-2-carbonyl)-amino]-acetic acid;   (S)-2-[(1H-Benzoimidazole-2-carbonyl)-amino]-propionic acid;   [(5,6-Dichloro-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   (S)-2-[(5,6-Dichloro-1H-benzoimidazole-2-carbonyl)-amino]-propionic acid;   [(6-Nitro-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   [(5,7-Bis-trifluoromethyl-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   (S)-2-[(5,7-Bis-trifluoromethyl-1H-benzoimidazole-2-carbonyl)-amino]-propionic acid;   [(5-Iodo-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   [(6-Bromo-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   (S)-2-[(6-Fluoro-1H-benzoimidazole-2-carbonyl)-amino]-propionic acid;   (R)-2-[(6-Fluoro-1H-benzoimidazole-2-carbonyl)-amino]-propionic acid;   [(6-Methoxy-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   ({5-[3-(3-Chloro-benzyloxy)-phenyl]-1H-benzoimidazole-2-carbonyl}-amino)-acetic acid;   ({5-[3-(2-Chloro-benzyloxy)-phenyl]-1H-benzoimidazole-2-carbonyl}-amino)-acetic acid;   ({5-[3-(4-Chloro-benzyloxy)-phenyl]-1H-benzoimidazole-2-carbonyl}-amino)-acetic acid;   ({5-[3-(3-Fluoro-benzyloxy)-phenyl]-1H-benzoimidazole-2-carbonyl}-amino)-acetic acid;   ({5-[3-(2-Fluoro-benzyloxy)-phenyl]-1H-benzoimidazole-2-carbonyl}-amino)-acetic acid;   {[5-(4-Phenoxy-phenyl)-1H-benzoimidazole-2-carbonyl]-amino}-acetic acid;   {[5-(3-Benzyloxy-5-fluoro-phenyl)-1H-benzoimidazole-2-carbonyl]-amino}-acetic acid;   [(5-Quinolin-3-yl-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   ({5-[3-Chloro-4-(3-chloro-benzyloxy)phenyl]-1H-benzoimidazole-2-carbonyl}-amino)-acetic acid;   ({5-[4-(3-Chloro-benzyloxy)-3,5-dimethyl-phenyl]-1H-benzoimidazole-2-carbonyl}-amino)-acetic acid;   {[5-(3-Methoxy-phenyl)-1H-benzoimidazole-2-carbonyl]-amino}-acetic acid;   {[5-(5-Benzylcarbamoyl-2-fluoro-phenyl)-1H-benzoimidazole-2-carbonyl]-amino}-acetic acid;   [(5-Naphthalen-2-yl-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   {[5-(4-Propoxy-phenyl)-1H-benzoimidazole-2-carbonyl]-amino}-acetic acid;   {[5-(4-Chloro-3-methyl-phenyl)-1H-benzoimidazole-2-carbonyl]-amino}-acetic acid;   {[5-(5-Chloro-2-fluoro-phenyl)-1H-benzoimidazole-2-carbonyl]-amino}-acetic acid;   [(5-Benzoylamino-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   [(6-Benzenesulfonylamino-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   [(6-Benzylamino-1H-benzoimidazole-2-carbonyl)-amino]-acetic acid;   (R)-2-[(1H-Benzoimidazole-2-carbonyl)-amino]-propionic acid;   (R)-2-[(1H-Benzoimidazole-2-carbonyl)-amino]-3-hydroxy-propionic acid;   (R)-2-[(5,7-Bis-trifluoromethyl-1H-benzoimidazole-2-carbonyl)-amino]-propionic acid;   (R)-2-[(5,6-Dichloro-1H-benzoimidazole-2-carbonyl)-amino]-propionic acid;   (R)-2-[(5-Iodo-1H-benzoimidazole-2-carbonyl)-amino]-propionic acid;   
       and pharmaceutically acceptable salts thereof. 
     
     
         22 . A method for treating a hypoxic disorder comprising administering a therapeutically effective amount of a compound of  claim 1  or  14  to a patient in need thereof. 
     
     
         23 . The method of  claim 22 , wherein said hypoxic disorder is anemia. 
     
     
         24 . A method for treating diabetes comprising administering a therapeutically effective amount of a compound of  claim 1  or  14  to a patient in need thereof. 
     
     
         25 . A method for wound treatment comprising administering a therapeutically effective amount of a compound of  claim 1  or  14  to a patient in need thereof. 
     
     
         26 . A method for treating a metabolic disorder comprising administering a therapeutically effective amount of a compound of  claim 1  or  14  to a patient in need thereof. 
     
     
         27 . The method of  claim 26 , wherein said metabolic disorder is obesity or diabetes.