Dihydrobenzopyrans, dihydrobenzothiopyrans, and tetrahydroquinolines for the treatment of COX-2-mediated disorders

Abstract

A class of dihydrobenzopyrans, dihydrobenzothiopyrans, tetrahydroquinolines, tetrahydronaphthalenes, and analogs thereof, is described for use in treating cyclooxygenase-2 mediated disorders. Compounds of particular interest are defined by Formula (I) wherein X, A 1 , A 2 , A 3 , A 4 , R, R″, R 1 and R 2 are as described in the specification.

1 . A compound of Formula I  
       
         
           
           
               
               
           
         
         wherein X is selected from O, S, CR c R b  and NR a ;  
         wherein R a  is selected from hydrido, C 1 -C 3 -alkyl, phenyl-C 1 -C 3 -alkyl, (substituted phenyl)-C 1 -C 3 -alkyl, C 1 -C 3 -alkoxycarbonyl-C 1 -C 3 -alkyl and carboxy-C 1 -C 6 -alkyl;  
         wherein each of R b  and R c  is independently selected from hydrido, C 1 -C 3 -alkyl, substituted or unsubstituted phenyl-C 1 -C 3 -alkyl, C 1 -C 3 -perfluoroalkyl, chloro, C 1 -C 6 -alkylthio, C 1 -C 6 -alkoxy, nitro, cyano and cyano-C 1 -C 3 -alkyl; or wherein CR b R c  forms a 3-6 membered cycloalkyl ring;  
         wherein R is selected from carboxyl, aminocarbonyl, C 1 -C 6 -alkylsulfonylaminocarbonyl and C 1 -C 6 -alkoxycarbonyl;  
         wherein R″ is selected from hydrido, phenyl, thienyl, C 1 -C 6 -alkyl and C 2 -C 6 -alkenyl;  
         wherein R 1  is selected from C 1 -C 3 -perfluoroalkyl, chloro, C 1 -C 6 -alkylthio, C 1 -C 6 -alkoxy, nitro, cyano and cyano-C 1 -C 3 -alkyl;  
         wherein R 2  is one or more radicals independently selected from hydrido, halo, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, halo-C 2 -C 6 -alkynyl, aryl-C 1 -C 3 -alkyl, aryl-C 2 -C 4 -alkynyl, aryl-C 2 -C 6 -alkenyl, C 1 -C 6 -alkoxy, methylenedioxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, aryl-C 1 -C 6 -alkoxy, heteroaryl-C 1 -C 6 -alkoxy, aryl-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, C 1 -C 6 -haloalkylthio, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -haloalkylsulfonyl, C 1 -C 3 -(haloalkyl)-C 1 -C 3 -hydroxyalkyl, C 1 -C 6 -hydroxyalkyl, hydroxyimino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, arylamino, N-aryl-N-C 1 -C 6 -alkylamino, heteroarylamino, N-heteroaryl-N—C 1 -C 6 -alkylamino, nitro, cyano, amino, aminosulfonyl, C 1 -C 6 -alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, N-aryl-C 1 -C 6 -alkylaminosulfonyl, N-heteroaryl-C 1 -C 6 -alkylaminosulfonyl, heterocyclylsulfonyl, C 1 -C 6 -alkylsulfonyl, aryl-C 1 -C 6 -alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-C 1 -C 6 -alkylcarbonyl, heteroaryl-C 1 -C 6 -alkylcarbonyl; heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C 1 -C 6 -alkoxycarbonyl, formyl, C 2 -C 6 -haloalkylcarbonyl and C 1 -C 6 -alkylcarbonyl; and  
         wherein the A ring atoms A 1 , A 2 , A 3  and A 4  are independently selected from carbon and nitrogen with the proviso that at least two of A 1 , A 2 , A 3  and A 4  are carbon;  
         or wherein R 2  together with ring A forms a radical selected from naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuryl;  
         or an isomer or pharmaceutically acceptable salt thereof.  
       
     
     
         2 . A compound of  claim 1  wherein X is selected from O, S, CR a R b  and NR a ; wherein R a  is selected from hydrido, C 1 -C 3 -alkyl, phenyl-C 1 -C 6 -alkyl, (substituted phenyl)-C 1 -C 3 -alkyl, C 1 -C 3 -alkoxycarbonyl-C 1 -C 3 -alkyl and carboxy-C 1 -C 6 -alkyl; wherein each of R b  and R c  is independently selected from hydrido, C 1 -C 3 -alkyl, phenyl-C 1 -C 3 -alkyl, (substituted phenyl)-C 1 -C 3 -alkyl, C 2 -C 3 -perfluoroalkyl, chloro, C 1 -C 4 -alkylthio, C 1 -C 4 -alkoxy, nitro, cyano and cyano-C 1 -C 3 -alkyl; or wherein CR b R c  forms a cyclopropyl ring; wherein R is selected from carboxyl, aminocarbonyl, C 1 -C 4 -alkyl sulfonylaminocarbonyl and C 1 -C 4 -alkoxycarbonyl; wherein R″ is selected from hydrido, phenyl, thienyl, C 1 -C 4 -alkyl and C 2 -C 4 -alkenyl; wherein R 1  is selected from C 1 -C 3 -perfluoroalkyl, chloro, C 1 -C 4 -alkylthio, C 1 -C 4 -alkoxy, nitro, cyano and cyano-C 1 -C 3 -alkyl; wherein R 2  is one or more radicals independently selected from hydrido, halo, C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 6 -alkynyl, halo-C 2 -C 6 -alkynyl, aryl-C 1 -C 3 -alkyl, aryl-C 2 -C 6 -alkynyl, aryl-C 2 -C 4 -alkenyl, C 1 -C 4 -alkoxy, methylenedioxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, aryl-C 1 -C 4 -alkoxy, heteroaryl-C 1 -C 4 -alkoxy, aryl-C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy, C 1 -C 4 -haloalkylthio, C 1 -C 4 -haloalkylsulfinyl, C 1 -C 4 -haloalkylsulfonyl, C 1 -C 3 -(haloalkyl)-C 1 -C 3 -hydroxyalkyl, C 1 -C 4 -hydroxyalkyl, hydroxyimino-C 1 -C 4 -alkyl, C 1 -C 4 -alkylamino, arylamino, N-aryl-N—C 1 -C 4 -alkylamine, heteroarylamino, N-heteroaryl-N—C 1 -C 4 -alkylamino, nitro, cyano, amino, aminosulfonyl, C 1 -C 4 -alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-C 1 -C 4 -alkylaminosulfonyl, heteroaryl-C 1 -C 4 -alkylaminosulfonyl, heterocyclylsulfonyl, C 1 -C 4 -alkylsulfonyl, aryl-C 1 -C 4 -alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-C 1 -C 4 -alkylcarbonyl, heteroaryl-C 1 -C 4 -alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C 1 -C 4 -alkoxycarbonyl, formyl, C 1 -C 4 -haloalkylcarbonyl and C 1 -C 4 -alkylcarbonyl; and wherein the A ring atoms A 1 , A 2 , A 3  and A 4  are independently selected from carbon and nitrogen with the proviso that at least three of A 1 , A 2 , A 3  and A 4  are carbon; or wherein R 2  together with ring A forms a naphthyl or quinolyl radical; or an isomer or pharmaceutically acceptable salt thereof.  
     
     
         3 . A compound of  claim 2  wherein X is selected from O, S and NR a ; wherein R a  is selected from hydrido, C 1 -C 3 -alkyl and (optionally substituted phenyl)methyl; wherein R is carboxyl; wherein R″ is selected from hydrido, C 1 -C 3 -alkyl and C 2 -C 3 -alkenyl; wherein R 1  is selected from C 1 -C 3 -perfluoroalkyl; wherein R 2  is one or more radicals independently selected from hydrido, halo, C 1 -C 4 -alkyl, C 2 -C 3 -alkenyl, C 2 -C 6 -alkynyl, halo-C 2 -C 5 -alkynyl, optionally substituted phenyl-C 1 -C 3 -alkyl, optionally substituted phenyl-C 2 -C 3 -alkynyl, phenyl-C 2 -C 3 -alkenyl, C 2 -C 3 -alkoxy, methylenedioxy, C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkylthio, C 1 -C 3 -alkylsulfinyl, optionally substituted phenyloxy, optionally substituted phenylthio, optionally substituted phenylsulfinyl, C 1 -C 3 -haloalkyl-C 1 -C 3 -hydroxyalkyl, phenyl-C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, C 1 -C 3 -haloalkoxy, C 1 -C 3 -haloalkylthio, C 1 -C 3 -hydroxyalkyl, C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl, hydroxyimino-C 1 -C 3 -alkyl, C 1 -C 6 -alkylamino, nitro, cyano, amino, aminosulfonyl, N-alkylaminosulfonyl, N-arylaminosulfonyl, N-heteroarylaminosulfonyl, N-(phenyl-C 1 -C 6 -alkyl)aminosulfonyl, N-(heteroaryl-C 1 -C 6 -alkyl) aminosulfonyl, phenyl-C 1 -C 3 -alkylsulfonyl, 5- to 8-membered heterocyclylsulfonyl, C 1 -C 3 -alkylsulfonyl, optionally substituted phenyl, optionally substituted 5- to 9-membered heteroaryl, phenyl-C 1 -C 3 -alkylcarbonyl, phenylcarbonyl, 4-chlorophenylcarbonyl, 4-hydroxyphenylcarbonyl, 4-trifluoromethylphenylcarbonyl, 4-methoxyphenylcarbonyl, aminocarbonyl, formyl, and C 1 -C 6 -alkylcarbonyl; wherein the A ring atoms A 1 , A 2 , A 3  and A 4  are independently selected from carbon and nitrogen with the proviso that at least three of A 1 , A 2 , A 3  and A 4  are carbon; or wherein R 2  together with ring A forms a naphthyl, benzofurylphenyl, or quinolyl radical; or an isomer or pharmaceutically acceptable salt thereof.  
     
     
         4 . A compound of  claim 3  wherein X is selected from O, S and NR a ; wherein R a  is selected from hydrido, methyl, ethyl, (4-trifluoromethyl)benzyl, (4-chloromethyl)benzyl, (4-methoxy)benzyl, (4-cyano)benzyl, and (4-nitro)benzyl; wherein R is carboxyl; wherein R″ is selected from hydrido, ethyl and ethenyl; wherein R 1  is trifluoromethyl or pentafluoroethyl; wherein R 2  is one or more radicals independently selected from hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl, ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl, 3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl, 4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy, methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl, methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethylthio, hydroxymethyl, hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl, N-methylamino, nitro, cyano, amino, aminosulfonyl, N-methylaminosulfonyl, N-phenylaminosulfonyl, N-furylaminosulfonyl, N-(benzyl)aminosulfonyl, N-(furylmethyl)aminosulfonyl, benzylsulfonyl, phenylethylaminosulfonyl, furylsulfonyl, methylsulfonyl, phenyl, phenyl substituted with one or more radicals selected from chloro, fluoro, bromo, methoxy, methylthio and methylsulfonyl benzimidazolyl, thienyl, thienyl substituted with chloro, furyl, furyl substituted with chloro, benzylcarbonyl, optionally substituted phenylcarbonyl, aminocarbonyl, formyl and methylcarbonyl; wherein the A ring atoms A 1 , A 2 , A 3  and A 4  are independently selected from carbon and nitrogen with the proviso that at least three of A 1 , A 2 , A 3  and A 4  are carbon; or wherein R 2  together with ring A forms a naphthyl, or quinolyl radical; or an isomer or pharmaceutically acceptable salt thereof.  
     
     
         5 . A compound of  claim 4  selected from compounds, and their isomers and pharmaceutically-acceptable salts, of the group consisting of 
 rel-(2R,3S)-6,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid;    (2S,3R)-6,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;    rel-(2R,3S)-5,6-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;    (2S,3R)-6-chloro-3,4-dihydro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;    rel-(2R,3S)-3,4-dihydro-5,6,7-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;    (2S,3R)-6-chloro-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid;    rel-(2R,3S)-3,4-dihydro-6,7,8-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;    rel-(2R,3S)-5,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;    (2S,3R)-6-chloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;    rel-(2R,3S)-6-cyano-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid; and    rel-(2R,3S)-3,4-dihydro-6-trifluoromethoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.    
     
     
         6 . A compound of Formula II  
       
         
           
           
               
               
           
         
         wherein R 3  is selected from hydrido, C 1 -C 3 -alkyl, C 1 -C 3 -hydroxyalkyl, C 1 -C 3 -alkoxy and halo;  
         wherein R 4  is selected from hydrido, halo, C 1 -C 4 -alkyl, C 1 -C 3 -alkylthio, C 1 -C 3 -haloalkyl, amino, aminosulfonyl, C 1 -C 3 -alkylsulfonyl, C 1 -C 3 -alkylsulfinyl, C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkylcarbonyl, formyl, cyano, C 1 -C 3 -haloalkylthio, substituted or unsubstituted phenylcarbonyl, C 1 -C 3 -haloalkoxy, C 1 -C 3 -alkoxy, aryl-C 1 -C 3 -alkylcarbonyl, di-C 1 -C 3 -alkylaminosulfonyl, C 1 -C 3 -alkylaminosulfonyl, aryl-C 1 -C 3 -alkylaminosulfonyl, 5- or 6-heteroaryl-C 1 -C 3 -alkylaminosulfonyl, 5- or 6-membered heteroaryl, C 1 -C 3 -hydroxyalkyl, substituted or unsubstituted phenyl and 5- or 6-membered nitrogen-containing heterocyclylsulfonyl;  
         wherein R 5  is selected from hydrido, C 1 -C 4 -alkyl, halo, C 1 -C 3 -haloalkyl, C 1 -C 3 -hydroxyalkyl, C 2 -C 3 -alkynyl, C 2 -C 3 -alkenyl, C 1 -C 3 -alkoxy, phenoxy, phenoxy independently substituted with one or more radicals selected from C 1 -C 3 -haloalkyl, nitro, carboxyl, C 1 -C 3 -haloalkoxy, C 1 -C 3 -alkoxy, cyano, C 1 -C 3 -alkyl and halo, naphthyloxy, naphthyloxy substituted with one or more halo radicals, phenylthio, phenylthio substituted with one or more halo radicals, phenylsulfinyl, phenylsulfinyl substituted with one or more halo radicals, phenylsulfonyl, phenylsulfonyl substituted with one or more halo radicals, pyridinyloxy, pyridinyloxy substituted with one or more halo radicals, and phenyl; and  
         wherein R 6  is selected from hydrido, halo, cyano, hydroxyiminomethyl, C 1 -C 3 -hydroxyalkyl, C 1 -C 3 -alkynyl, phenyl-C 2 -C 3 -alkynyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, formyl and phenyl; or an isomer or pharmaceutically acceptable salt thereof.  
       
     
     
         7 . Compound of  claim 6  wherein R 1  is hydrido or chloro; wherein R 4  is selected from hydrido, chloro, methyl, tert-butyl, methylthio, trifluoromethyl, difluoromethyl, pentafluoromethyl, trifluoromethylthio, trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl, and substituted or unsubstituted phenyl; wherein R 5  is selected from hydrido, methyl, tert-butyl, 2,2,2-trifluoroethoxy, 2-hydroxy-1,1-dimethylethyl, phenoxy, 4-methoxyphenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 2-chlorophenoxy, 4-cyanophenoxy, 2,6-dimethylphenoxy, 2,4-dichlorophenoxy, 3,4-difluorophenoxy, 4-chloro-3-fluorophenoxy, 4-(trifluoromethyl)phenoxy, 4-nitrophenoxy, 4-carboxyphenoxy, 3-carboxyphenoxy, 2-chloro-4-carboxyphenoxy, 4-(trifluoromethoxy)phenoxy, 2-bromo-4-chlorophenoxy, (6-bromo-2-naphthalenyl)oxy, phenylthio, (4-methoxyphenyl)thio, (4-chlorophenyl)thio, (4-chlorophenyl)sulfinyl, (4-chlorophenyl)sulfonyl, (6-chloro-2-pyridinyl)oxy, (2-chloro-3-pyridinyl)oxy, (3-pyridinyl)oxy, (2-pyridinyl)oxy, iodo, ethenyl, ethynyl, chloro; and wherein R is selected from hydrido, chloro, thienyl, hydroxyiminomethyl, substituted or unsubstituted phenylethynyl, phenyl and substituted phenyl; or an isomer or pharmaceutically acceptable salt thereof.  
     
     
         8 . A compound of  claim 7  selected from compounds, and their isomers and pharmaceutically-acceptable salts, of the group consisting of 
 (2S,3R)-6,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;    rel-(2R,3S)-5,6-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;    (2S,3R)-6-chloro-3,4-dihydro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;    rel-(2R,3S)-3,4-dihydro-5,6,7-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;    rel-(2R,3S)-3,4-dihydro-6,7,8-trichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;    rel-(2R,3S)-5,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;    (2S,3R)-6-chloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid;    rel-(2R,3S)-6-cyano-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid; and    rel-(2R,3S)-3,4-dihydro-6-trifluoromethoxy-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.    
     
     
         9 . A compound of Formula III  
       
         
           
           
               
               
           
         
         wherein R a  is selected from hydrido and lower aralkyl;  
         wherein R 3  is selected from hydrido, C 1 -C 3 -alkyl, C 1 -C 3 -hydroxyalkyl, C 1 -C 3 -alkoxy and halo;  
         wherein R 4  is selected from hydrido, halo, C 1 -C 4 -alkyl, C 1 -C 3 -alkylthio, C 1 -C 3 -haloalkyl, amino, aminosulfonyl, C 1 -C 3 -alkylsulfonyl, C 1 -C 3 -alkylsulfinyl, C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkylcarbonyl, formyl, cyano, C 1 -C 3 -haloalkylthio, substituted or unsubstituted phenylcarbonyl, C 1 -C 3 -haloalkoxy, C 1 -C 3 -alkoxy, aryl-C 1 -C 3 -alkylcarbonyl, di-C 1 -C 3 -alkylaminosulfonyl, C 1 -C 3 -alkylaminosulfonyl, aryl-C 1 -C 3 -alkylaminosulfonyl,  5 - or 6-heteroaryl-C 1 -C 3 -alkylaminosulfonyl, 5- or 6-membered heteroaryl, C 1 -C 3 -hydroxyalkyl, substituted or unsubstituted phenyl and 5- or 6-membered nitrogen-containing heterocyclylsulfonyl;  
         wherein R 5  is selected from hydrido, C 1 -C 4 -alkyl, halo, C 1 -C 3 -haloalkyl, C 1 -C 4 -hydroxyalkyl, C 2 -C 3 -alkynyl, C 2 -C 3 -alkenyl, C 1 -C 3 -alkoxy, phenoxy, phenoxy independently substituted with one or more radicals selected from C 1 -C 3 -haloalkyl, nitro, carboxyl, C 1 -C 3 -haloalkoxy, C 1 -C 3 -alkoxy, cyano, C 1 -C 3 -alkyl and halo, naphthyloxy, naphthyloxy substituted with one or more halo radicals, phenylthio, phenylthio substituted with one or more halo radicals, phenylsulfinyl, phenylsulfinyl substituted with one or more halo radicals, phenylsulfonyl, phenylsulfonyl substituted with one or more halo radicals, pyridinyloxy, pyridinyloxy substituted with one or more halo radicals, and phenyl; and  
         wherein R 6  is selected from hydrido, halo, cyano, hydroxyiminomethyl, C 1 -C 3 -hydroxyalkyl, C 2 -C 3 -alkynyl, phenyl-C 2 -C 3 -alkynyl, C 1 -C 4 -alkyl, C 2 -C 3 -alkoxy, formyl and phenyl; or an isomer or pharmaceutically acceptable salt thereof.  
       
     
     
         10 . Compound of  claim 9  R 3  is hydrido or chloro; wherein R 4  is selected from hydrido, chloro, methyl, tert-butyl, methylthio, trifluoromethyl, difluoromethyl, pentafluoromethyl, trifluoromethylthio, trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl, and substituted or unsubstituted phenyl; wherein R 5  is selected from hydrido, methyl, tert-butyl, 2,2,2-trifluoroethoxy, 2-hydroxy-1,1-dimethylethyl, phenoxy, 4-methoxyphenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 2-chlorophenoxy, 4-cyanophenoxy, 2,6-dimethylphenoxy, 2,4-dichlorophenoxy, 3, 4-difluorophenoxy, 4-chloro-3-fluorophenoxy, 4-(trifluoromethyl)phenoxy, 4-nitrophenoxy, 4-carboxyphenoxy, 3-carboxyphenoxy, 2-chloro-4-carboxyphenoxy, 4-(trifluoromethoxy)phenoxy, 2-bromo-4-chlorophenoxy, (6-bromo-2-naphthalenyl)oxy, phenylthio, (4-methoxyphenyl)thio, (4-chlorophenyl)thio, (4-chlorophenyl)sulfinyl, (4-chlorophenyl)sulfonyl, (6-chloro-2-pyridinyl)oxy, (2-chloro-3-pyridinyl)oxy, (3-pyridinyl)oxy, (2-pyridinyl)oxy, iodo, ethenyl, ethynyl, chloro; and wherein R 6  is selected from hydrido, chloro, thienyl, hydroxyiminomethyl, substituted or unsubstituted phenylethynyl, phenyl and substituted phenyl; or an isomer or pharmaceutically acceptable salt thereof.  
     
     
         11 . A compound of  claim 10  selected from compounds, and their isomers and pharmaceutically-acceptable salts, of the group consisting of 
 (2S,3R)-6-chloro-1,2,3,4-tetrahydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid.    
     
     
         12 . A compound of Formula IV  
       
         
           
           
               
               
           
         
         wherein R 3  is selected from hydrido, C 1 -C 3 -alkyl, C 1 -C 3 -hydroxyalkyl, C 1 -C 3 -alkoxy and halo;  
         wherein R 4  is selected from hydrido, halo, C 1 -C 4 -alkyl, C 1 -C 3 -alkylthio, C 1 -C 3 -haloalkyl, amino, aminosulfonyl, C 1 -C 3 -alkylsulfonyl, C 1 -C 3 -alkylsulfinyl, C 2 -C 3 -alkoxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkylcarbonyl, formyl, cyano, C 1 -C 3 -haloalkylthio, substituted or unsubstituted phenylcarbonyl, C 1 -C 3 -haloalkoxy, C 1 -C 3 -alkoxy, aryl-C 1 -C 3 -alkylcarbonyl, di-C 1 -C 3 -alkylaminosulfonyl, C 1 -C 3 -alkylaminosulfonyl, aryl-C 2 -C 3 -alkylaminosulfonyl, 5- or 6-heteroaryl-C 1 -C 3 -alkylaminosulfonyl, 5- or 6-membered heteroaryl, C 1 -C 3 -hydroxyalkyl, substituted or unsubstituted phenyl and 5- or 6-membered nitrogen-containing heterocyclylsulfonyl;  
         wherein R 5  is selected from hydrido, C 1 -C 4 -alkyl, halo, C 1 -C 3 -haloalkyl, C 1 -C 4 -hydroxyalkyl, C 2 -C 3 -alkynyl, C 2 -C 3 -alkenyl, C 1 -C 3 -alkoxy, phenoxy, phenoxy independently substituted with one or more radicals selected from C 1 -C 3 -haloalkyl, nitro, carboxyl, C 1 -C 3 -haloalkoxy, C 1 -C 3 -alkoxy, cyano, C 1 -C 3 -alkyl and halo, naphthyloxy, naphthyloxy substituted with one or more halo radicals, phenylthio, phenylthio substituted with one or more halo radicals, phenylsulfinyl, phenylsulfinyl substituted with one or more halo radicals, phenylsulfonyl, phenylsulfonyl substituted with one or more halo radicals, pyridinyloxy, pyridinyloxy substituted with one or more halo radicals, and phenyl; and  
         wherein R 6  is selected from hydrido, halo, cyano, hydroxyiminomethyl, C 2 -C 3 -hydroxyalkyl, C 2 -C 3 -alkynyl, phenyl-C 2 -C 3 -alkynyl, C 1 -C 4 -alkyl, C 2 -C 3 -alkoxy, formyl and phenyl; or an isomer or pharmaceutically acceptable salt thereof.  
       
     
     
         13 . Compound of  claim 12  R 3  is hydrido or chloro; wherein R 4  is selected from hydrido, chloro, methyl, tert-butyl, methylthio, tri fluoromethyl, difluoromethyl, pentafluoromethyl, trifluoromethylthio, trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl, and substituted or unsubstituted phenyl; wherein R 5  is selected from hydrido, methyl, tert-butyl, 2,2,2-trifluoroethoxy, 2-hydroxy-1,1-dimethylethyl, phenoxy, 4-methoxyphenoxy, 4-chlorophenoxy, 3-chlorophenoxy, 2-chlorophenoxy, 4-cyanophenoxy, 2,6-dimethylphenoxy, 2,4-dichlorophenoxy, 3,4-difluorophenoxy, 4-chloro-3-fluorophenoxy, 4-(trifluoromethyl)phenoxy, 4-nitrophenoxy, 4-carboxyphenoxy, 3-carboxyphenoxy, 2-chloro-4-carboxyphenoxy, 4-(trifluoromethoxy)phenoxy, 2-bromo-4-chlorophenoxy, (6-bromo-2-naphthalenyl)oxy, phenylthio, (4-methoxyphenyl)thio, (4-chlorophenyl)thio, (4-chlorophenyl)sulfinyl, (4-chlorophenyl)sulfonyl, (6-chloro-2-pyridinyl)oxy, (2-chloro-3-pyridinyl)oxy, (3-pyridinyl)oxy, (2-pyridinyl)oxy, iodo, ethenyl, ethynyl, chloro; and wherein R 6  is selected from hydrido, chloro, thienyl, hydroxyiminomethyl, substituted or unsubstituted phenylethynyl, phenyl and substituted phenyl; or an isomer or pharmaceutically acceptable salt thereof.  
     
     
         14 . A compound of  claim 13 , rel-(2R,3S)-6,8-dichloro-3,4-dihydro-2-(trifluoromethyl)-2H-1-benzothiopyran-3-carboxylic acid, and isomers and pharmaceutically-acceptable salts, thereof.  
     
     
         15 . A method of treating or preventing a cyclooxygenase-2 mediated disorder in a subject, said method comprising treating the subject having or susceptible to said disorder with a therapeutically-effective amount of a compound of claims  1 - 14 ; or a pharmaceutically-acceptable salt thereof.  
     
     
         16 . The method of  claim 15  wherein the cyclooxygenase-2 mediated disorder is inflammation.  
     
     
         17 . The method of  claim 15  wherein the cyclooxygenase-2 mediated disorder is arthritis.  
     
     
         18 . The method of  claim 15  wherein the cyclooxygenase-2 mediated disorder is pain.  
     
     
         19 . The method of  claim 15  wherein the cyclooxygenase-2 mediated disorder is cancer.  
     
     
         20 . A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from a family of compounds of claims  1 - 14 ; or a pharmaceutically-acceptable salt thereof.  
     
     
         21 . A process for the preparation of compounds of compound of Formula I  
       
         
           
           
               
               
           
         
         wherein X is selected from O, S, CR c R b  and NR a ;  
         wherein R a  is selected from hydrido, C 1 -C 3 -alkyl, (optionally substituted phenyl)-C 1 -C 3 -alkyl, alkoxycarbonylalkyl and carboxy-C 1 -C 6 -alkyl;  
         wherein each of R b  and R c  is independently selected from hydrido, C 1 -C 3 -alkyl, phenyl-C 1 -C 3 -alkyl, C 1 -C 3 -perfluoroalkyl, chloro, C 1 -C 6 -alkylthio, C 1 -C 6 -alkoxy, nitro, cyano and cyano-C 1 -C 3 -alkyl; or wherein CR b R c  forms a 3-6 membered cycloalkyl ring;  
         wherein R is selected from carboxyl, aminocarbonyl, C 1 -C 6 -alkylsulfonylaminocarbonyl and C 1 -C 6 -alkoxycarbonyl;  
         wherein R″ is selected from hydrido, phenyl, thienyl, C 1 -C 6 -alkyl and C 2 -C 6 -alkenyl;  
         wherein R 1  is selected from C 1 -C 6 -perfluoroalkyl, chloro, C 1 -C 6 -alkylthio, C 1 -C 6 -alkoxy, nitro, cyano and cyano-C 1 -C 6 -alkyl;  
         wherein R 2  is one or more radicals independently selected from hydrido, halo, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, halo-C 2 -C 6 -alkynyl, aryl-C 1 -C 3 -alkyl, aryl-C 2 -C 6 -alkynyl, aryl-C 2 -C 6 -alkenyl, C 1 -C 6 -alkoxy, methylenedioxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, aryl-C 1 -C 6 -alkoxy, heteroaryl-C 1 -C 6 -alkoxy, aryl-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, C 1 -C 6 -haloalkylthio, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -haloalkylsulfonyl, C 1 -C 3 -(haloalkyl-C 1 -C 3 -hydroxyalkyl, C 1 -C 6 -hydroxyalkyl, hydroxyimino-C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino, arylamino, aryl-C 1 -C 6 -alkylamino, heteroarylamino, heteroaryl-C 1 -C 6 -alkylamino, nitro, cyano, amino, aminosulfonyl, C 1 -C 6 -alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-C 1 -C 6 -alkylaminosulfonyl, heteroaryl-C 1 -C 6 -alkylaminosulfonyl, heterocyclylsulfonyl, C 1 -C 6 -alkylsulfonyl, aryl-C 1 -C 6 -alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-C 1 -C 6 -alkylcarbonyl, heteroaryl-C 1 -C 6 -alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C 1 -C 6 -alkoxycarbonyl, formyl, C 1 -C 6 -haloalkylcarbonyl and C 1 -C 6 -alkylcarbonyl; and  
         wherein the A ring atoms A 1 , A 2 , A 3  and A 4  are independently selected from carbon and nitrogen with the proviso that at least two of A 1 , A 2 , A 3  and A 4  are carbon;  
         or wherein R 2  together with ring A forms a radical selected from naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuryl;  
         or an isomer or pharmaceutically acceptable salt thereof;  
         Said process comprising reducing a compound of Formula 41.