Prostaglandin endoperoxide H synthase biosynthesis inhibitors

Abstract

The present invention describes pyridazinone compounds which are cyclooxygenase (COX) inhibitors, and in particular, are selective inhibitors of cyclooxygenase-2 (COX-2). COX-2 is the inducible isoform associated with inflammation, as opposed to the constitutive isoform, cyclooxygenase-1 (COX-1) which is an important “housekeeping” enzyme in many tissues, including the gastrointestinal (GI) tract and the kidneys. The selectivity of these compounds for COX-2 minimizes the unwanted GI and renal side-effects seen with currently marketed non-steroidal anti inflammatory drugs (NSAIDs).

We claim:  
     
         1 . A compound of formula I:  
       
         
           
           
               
               
           
         
       
       where 
 X is selected from the group consisting of O, S, NR 4 , N—OR a , and N—NR b R c , wherein R 4  is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic (alkyl), and arylalkyl; and R a , R b , and R c  are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;  
 R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylcarbonylalkyl, heterocyclic, heterocyclic (alkyl), heterocyclic (alkoxy), heterocyclic (oxy), —C(O)R 5,  —(CH 2 ) n C(O)R 5 , —R 6 —R 7 , —(CH 2 ) n CH(OH)R 5 , —(CH 2 ) n CH(OR d )R 5 , —(CH 2 ) n C(NOR d )R 5 , —(CH 2 ) n C(NR d )R 5 , —(CH 2 ) n CH(NOR d )R 5 , —(CH 2 ) n CH(NR d R e )R 5 , —(CH 2 ) n C≡C—R 7 , —(CH 2 ) n [CH(CX′ 3 )] m —(CH 2 ) n —CX′ 3 , —(C H 2 ) n (CX′ 2 ) m —(CH 2 ) n —CX′ 3 , —(CH 2 ) n [CH(CX′ 3 )] m —(CH 2 ) n —R 8 , —(CH 2 ) n (CX′ 2 ) m —(CH 2 ) n R 8 , —(CH 2 ) n (CHX′) m —(CH 2 ) n —CX′ 3 , —(CH 2 ) n (CHX′) m —(CH 2 ) n —R 8 , and —(C H 2 ) n —R 20 ,  
 wherein R 5  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, and heterocyclic (alkyl);  
 wherein R 6  is alkylene or alkenylene;  
 R 7  and R 8  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl);  
 R 20  is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic (alkyl);  
 R d  and R e  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl);  
 X′ is halogen;  
 n is from 0 to about 10, and m is 0 to about 5; at least one of R 1 , R 2  and R 3  is a group, substituted with a substituent having a group —X 1 —R 9 , having the formula:  
                     
 where X 1  is selected from the group consisting of —SO 2 —, —SO(NR 10 )—, —PO(OR 11 )—, and —PO(NR 12 R 13 )—,  
 R 9  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, —NHNH 2 , alkylamino, dialkylamino, alkoxy, thiol, alkylthiol, and protecting groups,  
 X 2  is selected from the group consisting of hydrogen or halogen;  
 R 10 , R 11 , R 12 , and R 13  are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R 12  and R 13  can be taken together, with the nitrogen to which they are attached, to form a heterocyclic ring having from 3 to 6 atoms.  
 The remaining two of the groups of R 1 , R 2 , and R 3 , are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclic, heterocyclic (alkyl), cyano, nitro, and —Y—R 14 , wherein Y is selected from the group consisting of, —O—, —S—, —C(R 16 ) (R 17 )—,  
 C(O)NR 21 —, —C(O)—, —C(O)O—, —NH—, —NC(O)—, and —NR 19- . R 14  is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl),  
 R 16 , R 17 , and R 19  are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; and  
 R 21  is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
 
     
     
         2 . A compound of the formula II:  
       
         
           
           
               
               
           
         
       
       wherein Z is a group having the formula:  
       
         
           
           
               
               
           
         
         where X 1  is selected from the group consisting of —SO 2 —, and SO(NR 10 )—, and R 9  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino;  
         X 2  is selected from the group consisting of hydrogen or halogen;  
         X is selected from the group consisting of O, S, NR 4 , N—OR a , and N—NR b R c , wherein R 4  is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, hetrocyclic (alkyl), and arylalkyl; and R a , R b , and R c . are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;  
         R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylcarbonylalkyl, heterocyclic, heterocyclic (alkyl), heterocyclic (alkoxy), heterocyclic (oxy), —C(O)R 5,  —(CH 2 ) n C(O)R 5 , —(CH 2 ) n C≡C—R 7,  (CH 2 ) n [CH(CX′ 3 )] m —(CH 2 ) n —CX′ 3 , —(CH 2 ) n (CX′ 2 ) m —(CH 2 ) n —CX′ 3 , —(CH 2 ) n [CH(CX′ 3 )] m —(CH 2 ) n —R 8 , —(CH 2 ) n (CX′ 2 ) m —(CH 2 ) n R 8 , —(CH 2 ) n (CHX′) m —(CH 2 ) n —CX′ 3 , —(CH 2 ) n (CHX′) m —(CH 2 ) n —R 8 , and —(CH 2 ) n —R 20 ,  0   
         wherein R 5  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl);  
         R 7  and R 8  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl),  
         R 20  is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic (alkyl);  
         X′ is halogen;  
         n is from 0 to about 10, m is from 0 to about 5;  
         R 1  and R 2  are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclic, hetreocyclic (alkyl), cyano, nitro, and —Y—R 14 , wherein Y is selected from the group consisting of, —O—, —S—, —CH 2 —, —C(R 16 ) (R 17 )—, —C(O)—, —C(O)O—, —NH—, and —NR 19- . R 14  is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl), and  
         R 16 , R 17 , and R 19  are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, hetrocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
       
     
     
         3 . A compound according to  claim 1  having the formula III:  
       
         
           
           
               
               
           
         
         wherein X, X 1 , X 2 , R, R 1 , R 3 , and R 9  are as defined above in Formula I; or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
       
     
     
         4 . A compound of the formula III:  
       
         
           
           
               
               
           
         
         wherein X 1  is selected from the group consisting of —SO 2 —, and —SO(NR 10 )—, and R 9  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;  
         X 2  is selected from the group consisting of hydrogen and halogen,  
         X is selected from the group consisting of O, S, NR 4 , N—OR a , and N—NR b R c , wherein R 4  is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic (alkyl), and arylalkyl; and R a , R b , and R c . are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;  
         R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl, arylalkynyl, heterocyclic, heterocyclic (alkyl), arylalkyl, —(CH 2 ) n C(O)R 5,  —(CH 2 ) n C≡C—R 7,  —(CH 2 ) n [CH(CX′ 3 )] m —(CH 2 ) n —R 8  and —(CH 2 ) n —R 20 ;  
         wherein R 5  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl);  
         R 7  and R 8  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl),  
         R 20  is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic (alkyl);  
         X′ is halogen;  
         n is from 0 to about 10, m is from 0 to about 5;  
         R 1  and R 3  are independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclcic, heterocyclic (alkyl), cyano, and —Y—R 14 , wherein Y is selected from the group consisting of, —O—, —S—, —C(R 16 ) (R 17 )—,  
         —C(O)—, —C(O)O—, —NH—, —NC(O)—, and —NR 19- . R 14  is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl), and  
         R 16 , R 17 , and R 19  are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
       
     
     
         5 . A compound according to  claim 4  wherein X 1  is selected from the group consisting of —SO 2 —, and —SO(NR 10 )—, and R 9  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; 
 X 2  is selected from the group consisting of hydrogen and halogen;  
 X is selected from the group consisting of O, S, NR 4 , N—OR a , and N—NR b R c , wherein R 4  is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl, heteroaryl, and arylalkyl; and R a , R b , and R c . are independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, aryl, and arylalkyl;  
 R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl, arylalkynyl, heterocyclic, heterocyclic (alkyl), arylalkyl, —(CH 2 ) n C(O)R 5,  and —(CH 2 ) n —R 20 ;  
 wherein R 5  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl);  
 R 20  is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic (alkyl);  
 n is from 0 to about 10;  
 R 1  and R 2  are independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclcic, heterocyclic (alkyl), cyano, and —Y—R 14 , wherein Y is selected from the group consisting of, —O—, —S—, —C(R 16 ) (R 17 )—,  
 —C(O)—, —C(O)O—, —NH—, —NC(O)—, and —NR 19- . R 14  is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl), and  
 R 16 , R 17 , and R 19  are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
 
     
     
         6 . A compound according to  claim 4  wherein X 1  is selected from the group consisting of —SO 2 -, and —SO(NR 10 )—, and R 9  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; 
 X 2  is selected from the group consisting of hydrogen and halogen,  
 X is selected from the group consisting of O, S, NR 4 , N—OR a , and N—NR b R c , wherein R 4  is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl, heteroaryl, and arylalkyl; and R a , R b , and R c . are independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, aryl, and arylalkyl;  
 R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkynyl, heterocyclic, heterocyclic (alkyl), arylalkyl, and —(CH 2 ) n C(O)R 5, ;  
 wherein R 5  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl); and  
 n is from 0 to about 10;  
 R 1  and R 2  are independently selected from the group consisting of hydrogen, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and —Y—R 14 , wherein Y is selected from the group consisting of, —O—, —S—, —C(R 16 ) (R 17 )—,  
 —C(O)—, —C(O)O—, —NH—, —NC(O)—, and —NR 19- . R 14  is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl), and  
 R 16 , R 17 , and R 19  are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
 
     
     
         7 . A compound according to  claim 4  wherein X 1  is selected from the group consisting of —SO 2 —, and —SO(NR 10 )—, and R 9  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; 
 X 2  is selected from the group consisting of hydrogen and halogen,  
 X is selected from the group consisting of O, S, NR 4 , N—OR a , and N—NR b R c , wherein R 4  is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl, heteroaryl, and arylalkyl; and R a , R b , and R c . are independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, aryl, and arylalkyl;  
 R is selected from haloalkyl, aryl, heterocyclic, heterocyclic (alkyl), and —(CH 2 ) n —R 20  where is R 20  is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen;  
 n is from 0 to about 10;  
 R 1  and R 2  are independently selected from the group consisting of hydrogen, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and —Y—R 14 , wherein Y is selected from the group consisting of, —O—, —S—, —C(R 16 ) (R 17 )—,  
 —C(O)—, —C(O)O—, —NH—, —NC(O)—, and —NR 19- . R 14  is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl), and  
 R 16 , R 17 , and R 19  are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
 
     
     
         8 . A compound according to  claim 4  wherein X 1  is selected from the group consisting of —SO 2 —, and —SO(NR 10 )—, and R 9  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; 
 X 2  is selected from the group consisting of hydrogen and halogen,  
 X is selected from the group consisting of O, S, NR 4 , N—OR a , and N—NR b R c , wherein R 4  is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl, heteroaryl, and arylalkyl; and R a , R b , and R c . are independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, aryl, and arylalkyl;  
 R is selected from haloalkyl, aryl, heterocyclic, heterocyclic (alkyl), and —(CH 2 ) n —R 20  where is R 20  is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen;  
 n is from 0 to about 10;  
 R 1  and R 2  are independently selected from the group consisting of hydrogen, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl); or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
 
     
     
         9 . A compound according to  claim 4  wherein X 1  is —SO 2 —, and R 9  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; 
 X 2  is selected from the group consisting of hydrogen and halogen,  
 X is selected from the group consisting of O, S, NR 4 , N—OR a , and N—NR b R c , wherein R 4  is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkylcycloalkyl, alkylcycloalkenyl, aryl, heteroaryl, and arylalkyl; and R a , R b , and R c . are independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, aryl, and arylalkyl;  
 R is selected from haloalkyl, aryl, heterocyclic, heterocyclic (alkyl), and —(CH 2 ) n —R 20  where is R 20  is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen;  
 n is from 0 to about 10;  
 R 1  and R 2  are independently selected from the group consisting of unsubstituted aryl and substituted aryl with one, two, or three substituents selected from the group consisting of alkyl, alkoxy, fluorine and chlorine; or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
 
     
     
         10 . A compounds of formula IV:  
       
         
           
           
               
               
           
         
         wherein X 1  is selected from the group consisting of —SO 2 —, and —SO(NR 10 )—, and R 9  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;  
         X 2  is selected from the group consisting of hydrogen and halogen,  
         R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylcarbonylalkyl, heterocyclic, heterocyclic (alkyl), heterocyclic (alkoxy), heterocyclic (oxy), —(CH 2 ) n C(O)R 5,  —(CH 2 ) n C≡C—R 7,  —(CH 2 ) n [CH(CX′ 3 )] m —(CH 2 ) n —R 8  and —(CH 2 ) n —R 20 ;  
         wherein R 5  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl);  
         R 7  and R 8  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl), R 20  is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic (alkyl);  
         X′ is halogen;  
         n is from 0 to about 10, m is from 0 to about 5;  
         R 1  and R 2  are independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclcic, heterocyclic (alkyl), cyano, nitro, and —Y—R 14 , wherein Y is selected from the group consisting of, —O—, —S—, —C(R 16 ) (R 17 )—,  
         —C(O)—, —C(O)O—, —NH—, —NC(O)—, and —NR 19- . R 14  is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl), and  
         R 16 , R 17 , and R 19  are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
       
     
     
         11 . A compound according to  claim 10  wherein X 1  is selected from the group consisting of —SO 2 —, and —SO(NR 10 )—, and R 9  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; 
 X 2  is selected from the group consisting of hydrogen and halogen,  
 R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl, arylalkynyl, heterocyclic, heterocyclic (alkyl), arylalkyl, —(CH 2 ) n C(O)R 5,  and —(C H 2 ) n —R 20 ;  
 wherein R 5  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl);  
 R 20  is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic (alkyl);  
 n is from 0 to about 10;  
 R 1  is hydrogen and R 2  is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclcic, heterocyclic (alkyl), cyano, nitro, and —Y—R 14 , wherein Y is selected from the group consisting of, —O—, —S—, —C(R 16 ) (R 17 )—,  
 —C(O)—, —C(O)O—, —NH—, —NC(O)—, and —NR 19- . R 14  is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl), and  
 R 16 , R 17 , and R 19  are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
 
     
     
         12 . A compound according to  claim 10  wherein X 1  is selected from the group consisting of —SO 2 —, and —SO(NR 10 )—, and R 9  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; 
 X 2  is selected from the group consisting of hydrogen and halogen,  
 R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkynyl, heterocyclic, heterocyclic (alkyl), arylalkyl, and —(CH 2 ) n C(O)R 5, ;  
 wherein R 5  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic (alkyl); and  
 n is from 0 to about 10;  
 R 1  is hydrogen and R 2  is selected from the group consisting of hydrogen, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and —Y—R 14 , wherein Y is selected from the group consisting of, —O—, —S—, —C(R 16 ) (R 17 )—,  
 —C(O)—, —C(O)O—, —NH—, —NC(O)—, and —NR 19- . R 14  is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl), and  
 R 16 , R 17 , and R 19  are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
 
     
     
         13 . A compound according to  claim 10  wherein X 1  is selected from the group consisting of —SO 2 —, and —SO(NR 10 )—, and R 9  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; 
 X 2  is selected from the group consisting of hydrogen and halogen,  
 R is selected from haloalkyl, aryl, heterocyclic, heterocyclic (alkyl), and —(CH 2 ) n —R 20  where is R 20  is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen;  
 n is from 0 to about 10;  
 R 1  is hydrogen and R 2  is selected from the group consisting of hydrogen, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and —Y—R 14 , wherein Y is selected from the group consisting of, —O—, —S—, —C(R 16 ) (R 17 )—,  
 —C(O)—, —C(O)O—, —NH—, —NC(O)—, and —NR 19- . R 14  is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl), and  
 R 16 , R 17 , and R 19  are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
 
     
     
         14 . A compound according to  claim 10  wherein X 1  is selected from the group consisting of —SO 2 —, and —SO(NR 10 )—, and R 9  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; 
 X 2  is selected from the group consisting of hydrogen and halogen,  
 R is selected from haloalkyl, aryl, heterocyclic, heterocyclic (alkyl), and —(CH 2 ) n —R 20  where is R 20  is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen;  
 n is from 0 to about 10;  
 R 1  is hydrogen and R 2  is selected from the group consisting of hydrogen, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl); or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
 
     
     
         15 . A compound according to  claim 10  wherein X 1  is selected from the group consisting of —SO 2 —, and —SO(NR 10 )—, and R 9  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; 
 X 2  is selected from the group consisting of hydrogen and halogen,  
 R is selected from haloalkyl, aryl, heterocyclic, heterocyclic (alkyl), and —(CH 2 ) n —R 20  where is R 20  is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen;  
 n is from 0 to about 10;  
 R 1  is hydrogen and R 2  is selected from the group consisting of hydrogen, aryl substituted with one, two, or three substituents selected from the group consisting of alkyl, alkoxy, fluorine and chlorine including, but not limited to, p-chlorophenyl, p-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, and the like; or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
 
     
     
         16 . A compound according to  claim 10  wherein X 1  is —SO 2 —, and R 9  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; 
 X 2  is selected from the group consisting of hydrogen and halogen,  
 R is haloalkyl and R 1  is hydrogen and R 2  is selected from the group consisting of unsubstituted aryl and aryl substituted with one, two, or three substituents selected from the group consisting of alkyl, alkoxy, fluorine and chlorine; or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
 
     
     
         17 . A compound according to  claim 10  wherein X 1  is selected from the group consisting of —SO 2 , and R 9  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; 
 X 2  is selected from the group consisting of hydrogen and halogen,  
 R is substituted and unsubstituted aryl and R 1  is hydrogen and R 2  is selected from the group consisting of unsubstituted aryl and aryl substituted with one, two, or three substituents selected from the group consisting of alkyl, alkoxy, fluorine and chlorine; or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
 
     
     
         18 . A compound according to  claim 10  wherein X′ is SO 2 , R 9  is selected from alkyl and amino, X 2  is selected from the group consisting of hydrogen and halogen, R is substituted and unsubstituted aryl and R 1  is hydrogen and R 2  is selected unsubstituted aryl and aryl substituted with one, two, or three substituents selected from the group consisting of alkyl, alkoxy, fluorine and chlorine; or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
     
     
         19 . A compound according to  claim 10 , selected from the group consisting of: 
 5-(4-Methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;    2-Benzyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;    2-Methyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;    2-Ethyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;    2-(4-Fluorobenzyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;    2-(n-Butyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;    2-(2,2,2-Trifluoroethyl)-5-(4-methylsulfonylphenyl)-6-(4-flurophenyl)-3(2H)-pyridazinone;    2-(4-Fluoro-α-methylbenzyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;    2-(n-Propyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;    2-(n-Pentyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;    2-Cyclohexylmethyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;    2-Phenacyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;    2-Propargyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;    2-Cyclohexyl-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;    2-(2-Butynyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone;    2-(Cyclobutanylmethyl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone; and    2-(3-Methylbuten-2-yl)-5-(4-methylsulfonylphenyl)-6-(4-fluorophenyl)-3(2H)-pyridazinone; or a pharmaceutically acceptable salt or ester thereof.    
     
     
         20 . A pharmaceutical composition for inhibiting prostaglandin biosynthesis comprising a therapeutically effective amount of the compound of  claim 1  and a pharmaceutrically acceptable carrier.  
     
     
         21 . A pharmaceutical composition for inhibiting prostaglandin biosynthesis comprising a therapeutically effective amount of the compound of  claim 2  and a pharmaceutrically acceptable carrier.  
     
     
         22 . A pharmaceutical composition for inhibiting prostaglandin biosynthesis comprising a therapeutically effective amount of the compound of  claim 4  and a pharmaceutrically acceptable carrier.  
     
     
         23 . A pharmaceutical composition for inhibiting prostaglandin biosynthesis comprising a therapeutically effective amount of the compound of  claim 10  and a pharmaceutrically acceptable carrier.  
     
     
         24 . A method for inhibiting prostaglandin biosynthesis comprising administering to a mammal in need of such teratment a therapeutically effective amount of a compound of  claim 1 .  
     
     
         25 . A method for inhibiting prostaglandin biosynthesis comprising administering to a mammal in need of such teratment a therapeutically effective amount of a compound of  claim 2 .  
     
     
         26 . A method for inhibiting prostaglandin biosynthesis comprising administering to a mammal a therapeutically effective amount of a compound of  claim 4 .  
     
     
         27 . A method for inhibiting prostaglandin biosynthesis comprising administering to a mammal a therapeutically effective amount of a compound of  claim 10 .  
     
     
         28 . A method for treating pain, fever, inflamation, rheumatoid arthritis, osteoarthritis, and cancer comprising administering to a therapeutically effective amount of a compound of  claim 1 .  
     
     
         29 . A method for treating pain, fever, inflamation, rheumatoid arthritis, osteoarthritis, and cancer comprising administering to a mammal in need of such teratment a therapeutically effective amount of a compound of  claim 1 .  
     
     
         30 . A method for treating pain, fever, inflamation, rheumatoid arthritis, osteoarthritis, and cancer comprising administering to a mammal a therapeutically effective amount of a compound of  claim 2 .  
     
     
         31 . A method for treating pain, fever, inflamation, rheumatoid arthritis, osteoarthritis, and cancer comprising administering to a mammal a therapeutically effective amount of a compound of  claim 4 .  
     
     
         32 . A method for treating pain, fever, inflamation, rheumatoid arthritis, osteoarthritis, and cancer comprising administering to a mammal a therapeutically effective amount of a compound of  claim 10.