Novel nitrogen-containing heteroaryl compounds and methods of use thereof

Abstract

The present invention relates to compounds suitable for use in mediating hypoxia inducible factor and for treating erythropoietin-associated conditions by increasing endogenous erythropoietin in vitro and in vivo.

1 - 2 . (canceled)  
     
     
         3 . A compound as represented by formula IB:  
       
         
           
           
               
               
           
         
         wherein  
         q is zero or one;  
         W is selected from the group consisting of oxygen, —S(O) n — and —NR 9 — where n is zero, one or two, R 9 , is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and R 8  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, or when W is —NR 9 — then R 8  and R 9 , together with the nitrogen atom to which they are bound, can be joined to form a heterocyclic or a substituted heterocyclic group, provided that when W is —S(O) n — and n is one or two, then R 8  is not hydrogen;  
         R 1  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, halo, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and —XR 6  where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6  is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7  is hydrogen, alkyl or aryl or, when X is —NR 7 —, then R 7  and R 6 , together with the nitrogen atom to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic group;  
         R 2 and R 3  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —S(O) n —N(R 6 )—R 6 where n is 0, 1, or 2, —NR 6 C(O)NR 6 R 6 , —XR 6  where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, each R 6  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic provided that when X is —SO— or —SO 2 —, then R 6  is not hydrogen, and R 7  is selected from the group consisting of hydrogen, alkyl, aryl, or R 2 , R 3  together with the carbon atom pendent thereto, form an aryl substituted aryl, heteroaryl, or substituted heteroaryl;  
         R 4 and R 5  are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6  is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7  is hydrogen, alkyl or aryl or, when X is —NR 7 —, then R 7  and R 6 , together with the nitrogen atom to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic group;  
         R″ is selected from the group consisting of hydrogen and alkyl;  
         R′″ is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, acyloxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, aryl, —S(O) n —R 10  wherein R 10  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl and n is zero, one or two;  
         and pharmaceutically acceptable salts, esters and prodrugs thereof;  
         with the proviso that when R″ is hydrogen, q is zero, W is oxygen, and R 8  is hydrogen then at least one of the following occurs:  
         1) R 1  is fluoro, bromo, iodo, alkyl, substituted alkyl, alkoxy, aminoacyl, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and —XR 6  where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6  is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7  is hydrogen alkyl or aryl; or  
         2) R 2  is substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, fluoro, bromo, iodo, cyano, —XR 6  where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6  is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7  is hydrogen, alkyl or aryl provided that: 
 a) when R 2  is substituted alkyl such a substituent does not include trifluoromethyl;  
 b) —XR 6  is not alkoxy; and  
 c) when —XR 6  is substituted alkoxy such a substituent does not include benzyl or benzyl substituted by a substituent selected from the group consisting of (C 1 -C 5 ) alkyl and (C 1 -C 5 ) alkoxy or does not include a fluoroalkoxy substituent of the formula:  
   —O—[CH 2 ] x —C f H (2f−1+g) F g    
 where x is zero or one, f is an integer of from 1 to 5: and g is an integer of from 1 to (2f+1); or  
 
         3) R 3  is substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, bromo, iodo, —XR 6 where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two R 6  is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7  is hydrogen, alkyl or aryl provided that: 
 a) when R 3  is substituted alkyl such a substituent does not include trifluoromethyl;  
 b) —XR 6  is not alkoxy: and  
 c) when —XR 6  is substituted alkoxy such a substituent does not include benzyl or benzyl substituted by a substituent selected from the group consisting of (C 1 -C 5 ) and (C 1 -C 5 ) alkoxy or does not include a fluoroalkoxy substituent of the formula:  
   —O—[CH 2 ] x —C f H (2f−1+g) F g    
 where x is zero or one; f is an integer of from 1 to 5; and g is an integer of from 1 to (2f+1); or  
 
         4) R 4  is iodo, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, —XR 6  where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6  is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7  is hydrogen, alkyl or aryl provided that: 
 a) when R 4  is substituted alkyl such a substituent does not include trifluoromethyl;  
 b) —XR 6  is not alkoxy; and  
 c) when —XR 6  is substituted alkoxy such a substituent does not include a fluoroalkoxy substituent of the formula:  
   —O—[CH 2 ] x —C f H (2f−1+g) F g    
 where x is zero or one; f is an integer of from 1 to 5; and g is an integer of form 1 to (2f+1); or  
 
         5) R 5 is iodo, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, —XR 6  where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6  is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7  is hydrogen, alkyl or aryl provided that: 
 a) when R 5  is substituted alkyl such a substituent does not include trifluoromethyl;  
 b) —XR 6  is not alkoxy; and  
 c) when —XR 6  is substituted alkoxy such a substituent does not include a fluoroalkoxy substituent of the formula:  
   —O—[CH 2 ] x —C f H (2f−1+g) F g    
 where x is zero or one; f is an integer of from 1 to 5, and g is an integer of from 1 to (2f+1);  
 
         and with the further following proviso:  
         that when R 1 , R 3 , R 4 , and R 5  are hydrogen, then R 2  is not bromo.  
       
     
     
         4 - 5 . (canceled)  
     
     
         6 . A compound as in  claim 3 , wherein R 1  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, halo, alkoxy, aryloxy, substituted aryloxy, substituted aryl, alkylthio, aminoacyl, aryl, substituted amino, heteroaryl, heteroaryloxy, —S(O) n -aryl, —S(O) n -substituted aryl, —S(O) n -heteroaryl, and —S(O) n -substituted heteroaryl, where n is zero, one or two.  
     
     
         7 . A compound as in  claim 6 , wherein R 1  is selected from the group consisting of: 
 (4-methoxy)phenylsulfonylamino;    2,6-dimethylphenoxy;    3,4-difluorophenoxy;    3,5-difluorophenoxy;    3-chloro-4-fluorophenoxy;    3-methoxy-4-fluorophenoxy;    3-methoxy-5-fluorophenoxy;    4-(methylsulfonamido)phenoxy;    4-(phenylsulfonamido)phenoxy;    4-CF 3 —O-phenoxy;    4-CF 3 -phenoxy;    4-chlorophenoxy;    4-fluorophenoxy;    4-(4-fluorophenoxy)phenoxy;    4-methoxyphenoxy;    4-nitrophenoxy;    benzyloxy;    bromo;    butoxy;    CF 3 ;    chloro;    cyclohexyloxy;    cyclohexylsulfanyl;    cyclohexylsulfonyl;    fluoro;    hydrogen;    iodo;    isopropoxy;    methyl;    phenoxy;    phenyl;    phenylsulfanyl;    phenylsulfinyl;    phenylsulfonyl;    phenylurea;    pyridin-1-ylsulfanyl;    pyridin-3-yloxy; and    pyridin-4-ylsulfanyl.    
     
     
         8 . A compound as in  claim 3 , wherein R 2  is selected from the group consisting of substituted amino, aryloxy, substituted aryloxy, alkoxy, substituted alkoxy, halo, hydrogen, alkyl, substituted alkyl, aryl, —S(O) n -aryl, —S(O) n -substituted aryl, —S(O) n -cycloalkyl, where n is zero, one or two, aminocarbonylamino, heteroaryloxy, and cycloalkyloxy.  
     
     
         9 . A compound as in  claim 8 , wherein R 2  is selected from the group consisting of: 
 (4-methoxy)phenylsulfonylamino;    2,6-dimethylphenoxy;    3,4-difluorophenoxy;    3,5-difluorophenoxy;    3-chloro-4-fluorophenoxy;    3-methoxy-4-fluorophenoxy;    3-methoxy-5-fluorophenoxy;    4-(methylsulfonamido)phenoxy;    4-(phenylsulfonamido)phenoxy;    4-CF 3 —O-phenoxy;    4-CF 3 -phenoxy;    4-chlorophenoxy;    4-fluorophenoxy;    4-(4-fluorophenoxy)phenoxy;    4-methoxyphenoxy;    4-nitrophenoxy;    benzyloxy;    bromo;    butoxy;    CF 3 ;    chloro;    cyclohexyloxy;    cyclohexylsulfanyl;    cyclohexylsulfonyl;    fluoro;    hydrogen;    iodo;    isopropoxy;    methyl;    phenoxy;    phenyl;    phenylsulfanyl;    phenylsulfinyl;    phenylsulfonyl;    phenylurea;    pyridin-1-ylsulfanyl;    pyridin-3-yloxy; and    pyridin-4-ylsulfanyl.    
     
     
         10 . A compound as in  claim 3 , wherein R 3  is selected from the group consisting of: substituted aryloxy, substituted alkoxy, alkoxy, substituted alkyl, alkyl, amino, cycloalkyloxy, hydrogen, halo, aryl, —S(O) n -aryl, —S(O) n -substituted aryl, —S(O) n -heteroaryl, and —S(O) n -substituted heteroaryl, where n is zero, one or two, aminocarbonylamino, and heteroaryloxy.  
     
     
         11 . A compound as in  claim 10 , wherein R 3  is selected from the group consisting of: 
 amino;    (4-methyl)phenylsulfonylaminophenoxy;    3,4-difluorophenoxy;    3,5-difluorophenoxy;    3-fluoro-5-methoxy-phenoxy;    3-chloro-4-fluorophenoxy 4-CF 3 —O-phenoxy;    4-CF 3 -phenoxy;    4-chlorophenoxy;    4-fluorophenoxy;    4-(4-fluorophenoxy)phenoxy;    4-methoxyphenoxy;    benzyloxy;    bromo;    butoxy;    CF 3 ;    chloro;    cyclohexyloxy;    hydrogen;    iodo;    isopropoxy;    phenoxy;    phenyl;    phenylsulfanyl;    phenylsulfonyl;    phenylsulfinyl;    phenylurea;    pyridin-1-ylsulfanyl;    pyridin-3-yloxy; and    pyridin-4-ylsulfanyl.    
     
     
         12 . A compound as in  claim 3 , wherein R 2  and R 3 , combined with the carbon atom pendent thereto, join to form an aryl group.  
     
     
         13 . A compound as in  claim 12 , wherein said aryl group is phenyl.  
     
     
         14 . A compound as in  claim 3 , wherein R 4  is selected from the group consisting of substituted arylthio, halo, hydrogen, substituted alkyl and aryl.  
     
     
         15 . A compound as in  claim 14 , wherein R 4  is selected from the group consisting of: 
 4-chlorophenyl sulfanyl;    chloro;    hydrogen;    methoxymethyl; and    phenyl.    
     
     
         16 . A compound as in  claim 3 , wherein R 5  is hydrogen or aryl.  
     
     
         17 . A compound as in  claim 16 , wherein R 5  phenyl.  
     
     
         18 - 23 . (canceled)  
     
     
         24 . A compound as in  claim 3 , wherein R″ is hydrogen.  
     
     
         25 - 26 . (canceled)  
     
     
         27 . A compound as in  claim 3 , wherein R′″ is selected from the group consisting of hydrogen, hydroxy, alkoxy, substituted alkoxy, thiol, acyloxy and aryl.  
     
     
         28 . A compound as in  claim 27 , wherein R′″ is selected from the group consisting of: 
 hydroxy;    benzyloxy;    ethoxy;    hydrogen;    thiol;    methoxy;    methylcarbonyloxy; and    phenyl.    
     
     
         29 . A compound as in  claim 3 , wherein WR 8  is preferably selected from the group consisting of amino, substituted amino, hydroxy, and alkoxy.  
     
     
         30 . A compound as in  claim 29 , wherein WR 8  is selected from the group consisting of: 
 amino:    dimethylamino;    hydroxy;    methoxy; and    methylcarbonylamino.    
     
     
         31 . (canceled)  
     
     
         32 . A compound as in  claim 3 , wherein said compound is represented by formula IIB:  
       
         
           
           
               
               
           
         
         wherein:  
         q is zero or one;  
         W is selected from the group consisting of oxygen, —S(O) n — and —NR 9 — where n is zero, one or two, R 9  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 8  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;  
         R″ is selected from hydrogen and alkyl;  
         R 1  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, halo, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and —XR 6  where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6  is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7  is hydrogen, alkyl or aryl;  
         R 2  and R 3  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —XR 6  where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6  is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7  is hydrogen, alkyl or aryl;  
         R 4  and R 5  are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —XR 6  where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6  is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7  is hydrogen, alkyl or aryl; or  
         pharmaceutically acceptable salts and/or prodrugs thereof.  
       
     
     
         33 - 34 . (canceled)  
     
     
         35 . A compound selected from the group consisting of: 
 1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid(2-amino-ethyl)-amide(trifluoro-acetic acid salt);    1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid(2-methoxy-ethyl)-amide;    1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid(2-hydroxy-ethyl)-amide;    1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid(2-dimethylamino-ethyl)-amide;    1-Chloro-4-hydroxy-isoquinoline-3-carboxylic acid(2-acetylamino-ethyl)-amide;    1-Chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid(2-hydroxy-ethyl)-amide;    1-Chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid(2-methoxy-ethyl)-amide;    1-Chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid(2-amino-ethyl)-amide(trifluoro-acetic acid salt);    1-Chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid(2-dimethylamino-ethyl)-amide;    1-Chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid(2-amino-ethyl)-amide(trifluoro-acetic acid salt);    1-Chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid(2-methoxy-ethyl)-amide;    1-Chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid(2-dimethylamino-ethyl)-amide;    1-Chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid(2-hydroxy-ethyl)-amide;    
     
     
         36 . A pharmaceutical composition comprising a compound of  claim 3  and a pharmaceutically acceptable carrier or excipient.  
     
     
         37 . A method of treating, preventing or pretreating a condition mediated at least in part by hypoxia inducible factor (HIF) and/or erythropoietin (EPO) is provided, said method comprises administering to a mammalian patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of  claim 3  and pharmaceutically acceptable excipient or carrier.  
     
     
         38 . The method according to  claim 37 , wherein said condition is selected from the group consisting of anemic disorders; neurological disorders and/or injuries; including cases of stroke, trauma, epilepsy, neurodegenerative disease, myocardial infarction, liver ischemia, renal ischemia, and stroke; peripheral vascular disorders, ulcers, burns, and chronic wounds; pulmonary embolism; and ischemic-reperfusion injury.  
     
     
         39 . A method of inhibiting the activity hydroxylase enzyme which modifies the alpha subunit of hypoxia inducible factor comprising which methods comprises contacting said enzyme with a inhibiting effective amount of a compound of  claim 3 .  
     
     
         40 . A composition comprising the compound of  claim 3  or a mixture of compounds of  claim 3  in combination with at least one additional therapeutic agent.  
     
     
         41 . The composition of  claim 40  wherein the additional therapeutic agent is erythropoietin.  
     
     
         42 . A compound represented by formula:  
       
         
           
           
               
               
           
         
         wherein:  
         R 2  and R 3  are independently selected from hydrogen or alkoxy;  
         W is selected from the group consisting of oxygen, and —NR 9 — where R 9  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, and acyl;  
         R 8  is selected from the group consisting of hydrogen, and alkyl;  
         and pharmaceutically acceptable salts, esters and prodrugs thereof;  
         with the proviso that when W is oxygen and R 8  is hydrogen then at least one of the following occurs:  
         1) R 2  is substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, fluoro, bromo, iodo, cyano, —XR 6  where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6  is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7  is hydrogen, alkyl or aryl provided that:  
         a) when R 2  is substituted alkyl such a substituent does not include trifluoromethyl;  
         b) —XR 6  is not alkoxy; and  
         c) when —XR 6  is substituted alkoxy such a substituent does not include benzyl or benzyl substituted by a substituent selected from the group consisting of (C 1 -C 5 ) alkyl and (C 1 -C 5 ) alkoxy or does not include a fluoroalkoxy substituent of the formula:  
           —O—[CH 2 ] x —C f H (2f+1−g) F g    
         where x is zero or one; f is an integer of from 1 to 5; and g is an integer of from 1 to (2f+1); or  
         2) R 3  is substituted alkyl aryl, substituted aryl, heteroaryl, substituted heteroaryl, bromo, iodo, —XR 6  where X is oxygen, —S(O) n — or —NR 7 — where n is zero, one or two, R 6  is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 7  is hydrogen, alkyl or aryl provided that:  
         a) when R 3  is substituted alkyl such a substituent does not include trifluoromethyl;  
         b) —XR 6  is not alkoxy; and  
         c) when —XR 6  is substituted alkoxy such a substituent does not include benzyl or benzyl substituted by a substituent selected from the group consisting of (C 1 -C 5 ) alkyl and (C 1 -C 5 ) alkoxy or does not include a fluoroalkoxy substituent of the formula:  
           —O—[CH 2 ] x —C f H (2f+1−g) F g    
         where x is zero or one; f is an integer of from 1 to 5; and g is an integer of from 1 to (2f+1).  
       
     
     
         43 . A compound as in  claim 42 , wherein R 2  is hydrogen or isopropoxy.  
     
     
         44 . A compound as in  claim 42 , wherein R 3  is hydrogen or isopropoxy.  
     
     
         45 . A compound as in  claim 42 , wherein WR 8  is selected from the group consisting of methoxy, amino, hydroxyl, dimethylamino, and methylcarbonylamino.  
     
     
         46 . A compound represented by formula:  
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters, prodrugs thereof.  
       
     
     
         47 . A compound represented by formula:  
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters, prodrugs thereof.  
       
     
     
         48 . A compound represented by formula:  
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters, prodrugs thereof.  
       
     
     
         49 . A compound represented by formula:  
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters, prodrugs thereof.  
       
     
     
         50 . A compound represented by formula:  
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters, prodrugs thereof  
       
     
     
         51 . A compound represented by formula:  
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters, prodrugs thereof.  
       
     
     
         52 . A compound represented by formula:  
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters, prodrugs thereof.  
       
     
     
         53 . A compound represented by formula:  
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters, prodrugs thereof.  
       
     
     
         54 . A compound represented by formula:  
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters, prodrugs thereof.  
       
     
     
         55 . A compound represented by formula:  
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, esters, prodrugs thereof.