Biaryl Sulfonamides and Methods for Using Same

Abstract

The present invention relates to biaryl sulfonamides and their use as, for example, metalloproteinase inhibitors.

1 . A compound the formula 1: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 2  are, independently, H, CH(OH)R 4 , phenyl, heteroaryl, or C 1 -C 6  alkyl, with the proviso that when R 1  or R 2  is CH(OH)R 4 , then Z is substituted with NR 4 SO 2 R 5 , SO 2 NR 4 R 5 , heterocycloalkyl, heteroaryl, or C 3 -C 6  cycloalkyl; 
       R 3  is H or C 1 -C 6  alkyl; 
       R 4  and R 5  are, independently with respect to each occurrence, a bond to the other, H, C 1 -C 6  alkyl, or phenyl; 
       G and E are, independently, S, O, N(R 4 ), C(R 6 )═C(R 6 ), or N═C(R 6 ); 
       R 6  is, independently with respect to each occurrence, H, halogen, NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NR 4 SO 2 R 5 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , OR 4 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, phenyl, heteroaryl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
       X is N(R 3 )C(═O), OC(═O), OS(O) 2 , NHSO 2 , OCH 2 , CH 2 S(O), or CH 2 S(O) 2 ; and 
       Z is at least one heteroaryl moiety; 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       2 . The compound of  claim 1  wherein R 1  is substituted with halogen, CO 2 R 4 , C(═O)NR 4 R 5 , phenyl, or heteroaryl. 
   
   
       3 . The compound of  claim 1  wherein R 3  is substituted with NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NR 4 SO 2 R 5 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , OR 4 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl. 
   
   
       4 . The compound of  claim 1  wherein R 6  is each optionally substituted with NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NR 4 SO 2 R 5 , NR 4 C(═O)R 5 , NR 4 C(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , OR 4 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, phenyl, or heteroaryl. 
   
   
       5 . The compound of  claim 1  wherein Z is a 5 membered ring. 
   
   
       6 . The compound of  claim 1  wherein Z is bicyclic. 
   
   
       7 . The compound of  claim 1  wherein Z is furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, isothiazole, thiazole, 1,2,5-thiadiazole, 1,2,3-triazole, 1,3,4-thiadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazan, or 
     
       
         
         
             
             
         
       
       wherein: 
       U is selected from S, O, and N(R 4 ); 
       W is selected from C(R 6 ), and N; 
       M is selected from C(R 6 ), and N; 
       L is C(R 6 )═C(R 6 ), C(R 6 )═N, or N(R 4 ); 
       R 7  is a bond to R 6 , H, halogen, NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NHSO 2 R 4 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , OR 4 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, phenyl, heteroaryl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl, each optionally substituted with NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NHSO 2 R 4 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , OR 8 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; and 
       R 8  is H, phenyl, heteroaryl, or C 1 -C 6  alkyl, optionally substituted with NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NR 4 SO 2 R 5 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl. 
     
   
   
       8 . The compound of  claim 1  wherein Z is: 
     
       
         
         
             
             
         
       
       wherein: 
       U is S, O, or N(R 4 ); 
       W is C(R 6 ), or N; 
       M is C(R 6 ), or N; 
       L is C(R 6 )═C(R 6 ), C(R 6 )═N, or N(R 4 ); 
       R 7  is a bond to R 6 , H, halogen, NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NHSO 2 R 4 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , OR 4 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, phenyl, heteroaryl, and C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl, each optionally substituted with NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NHSO 2 R 4 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , OR 8 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; and 
       R 8  is H, phenyl, heteroaryl, or C 1 -C 6  alkyl, optionally substituted with NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NR 4 SO 2 R 5 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl. 
     
   
   
       9 . The compound of  claim 1  wherein:
 R 3  is H;   G is C(H)═C(H);   E is C(H)═C(H) or N═C(H);   X is NHC(═O), or OCH 2 ; and   
     
       
         
         
             
             
         
       
       Z is 
       wherein: 
       U is S, O, or N(R 4 ); 
       W is C(R 6 ), or N; 
       M is C(R 6 ), or N; 
       L is C(R 6 )═C(R 6 ), C(R 6 )═N, or N(R 4 ); 
       R 7  is a bond to R 6 , H, halogen, NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NHSO 2 R 4 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , OR 4 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, phenyl, heteroaryl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl, each optionally substituted with NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NHSO 2 R 4 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , OR 8 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; and 
       R 8  is H, phenyl, heteroaryl, and C 1 -C 6  alkyl, optionally substituted with NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NR 4 SO 2 R 5 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl. 
     
   
   
       10 . The compound of  claim 9  wherein:
 E is C(H)═C(H);   U is O;   W is C(H), or C(CH 3 );   M is C(R 9 ), wherein R 9  is H, halogen, C 1 -C 6  alkyl, or CN; and   L is C(H)═C(H).   
   
   
       11 . The compound of  claim 1  wherein at least one of R 1  or R 2  is C 1 -C 6  alkyl. 
   
   
       12 . The compound of  claim 1  wherein R 3  is H. 
   
   
       13 . The compound of  claim 1  wherein R 4  and R 5  are each C 1 -C 6  alkyl. 
   
   
       14 . The compound of  claim 1  wherein G and E are each C(H)═C(H). 
   
   
       15 . The compound of  claim 1  wherein U is O or S. 
   
   
       16 . The compound of  claim 1  wherein W is C(H) or C(CH 3 ). 
   
   
       17 . The compound of  claim 1  wherein M is CR 6 . 
   
   
       18 . The compound of  claim 1  wherein L is CH═CH. 
   
   
       19 . The compound of  claim 1  wherein R 7  is other than H. 
   
   
       20 . The compound of  claim 1  that is
 N-({4′-[(1H-indol-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)glycine;   4′-[(Benzo[β]thiophene-2-carbonyl)-amino]-biphenyl-4-sulfonyl-L-valine;   L-3-Methyl-2-(4′-{[3-methyl-4-(3-methyl-isoxazol-5-yl)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-butyric acid;   L-3-Hydroxy-2-(4-{5-[(4-methanesulfonylamino-3-methyl-b enzofuran-2-carbonyl)-amino]-pyridin-2-yl}-benzenesulfonylamino)-butyric acid;   L-2-(4-{5-[(4-Methanesulfonylamino-3-methyl-benzofuran-2-carbonyl)-amino]-pyridin-2-yl}-benzenesulfonylamino)-3-methyl-butyric acid;   L-2-(4-{5-[(4-Cyano-3-methyl-benzofuran-2-carbonyl)-amino]-pyridin-2-yl}-benzenesulfonylamino)-3-methyl-butyric acid;   L-2-{4′-[(1H-Benzoimidazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid;   L-3-Methyl-2-(4′-{[3-methyl-4-(2H-tetrazol-5-yl)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-butyric acid;   L-3-Methyl-2-{4′-[(3-methyl-4-pyrrolidin-1-yl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   (S)-3-Methyl-2-(4′-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-amino}-biphenyl-4-sulfonylamino)-butyric acid;   L-3-Methyl-2-(4′-{[3-methyl-4-(thiophene-2-sulfonylamino)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-butyric acid;   L-2-(4′-{[4-(1,1-Dioxo-1-58 6-isothiazolidin-2-yl)-3-methyl-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-3-methyl-butyric acid;   4-{5-[(Benzofuran-2-carbonyl)-amino]-pyridin-2-yl}-benzenesulfonyl-L-valine;   (S)-2-{4′-[(1,3-Dimethyl-1H-thieno[2,3-c]pyrazole-5-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid;   N-({4′-[(1-Benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-N-(pyridin-3-ylmethyl)-L-valine;   N-({4′-[(1-Benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-N-(2-morpholin-4-ylethyl)-L-valine;   N-[(4′-{[(4-Methyl-3,4,5,6-tetrahydrofuro[4,3,2-e][3]benzazepin-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine;   N-{[4′-({[4-(2,2-Dimethyl-1,3-dioxolan-4-yl)-3-methyl-1-benzofuran-2-yl]carbonyl}amino)-1,1′-biphenyl-4-yl]sulfonyl}-L-valine;   (S)-3-methyl-2-{4′-[(3-methyl-4-pyridin-3-yl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   (S)-3-Methyl-2-{4′-[(3-methyl-4-pyridin-4-yl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   (S)-2-{4′-[(4-Furan-3-yl-3-methyl-b enzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid;   (S)-3-methyl-2-{4′-[(3-methyl-4-morpholin-4-yl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   (S)-3-Methyl-2-{4′-[(benzooxazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   (S)-3-Methyl-2-{4′-[(4-methyl-benzooxazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   (S)-3-Methyl-2-{4′-[(5-methyl-benzooxazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   (S)-3-Methyl-2-{4′-[(5-chloro-benzothiazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   (S)-3-Methyl-2-{4′-[(5-trifluoromethyl-benzothiazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   D-2-[4′-(Benzothiazol-2-ylmethoxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid;   D-3-Methyl-2-[4′-(1-methyl-1H-benzoimidazol-2-ylmethoxy)-biphenyl-4-sulfonylamino]-butyric acid;   N-{[4′-(2-Furoyloxy)-1,1′-biphenyl-4-yl]sulfonyl}-D-valine;   N-{[4′-(3-Furoyloxy)-1,1′-biphenyl-4-yl]sulfonyl}-D-valine;   L-2-{4′-[(Benzothiazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid;   D-2-{4′-[(Benzothiazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid;   L-3-Methyl-2-{4′-[(naphtho[2,1-b]furan-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   L-3-Methyl-2-{4′-[(1-methyl-naphtho[2,1-b]furan-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   L-3-Methyl-2-(4′-{[3-methyl-4-(pyridin-3-ylmethoxy)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-butyric acid;   L-2-(4-{5-[(1-Ethyl-1H-benzimidazole-2-carbonyl)-amino]-pyridin-2-yl}-benzenesulfonylamino)-3-methyl-butyric acid;   N-({4′-[(1,2,3-thiadiazol-4-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-L-valine;   (S)-2-(4′-{[3-(4-Chloro-phenyl)-isoxazole-5-carbonyl]-amino}-biphenyl-4-sulfonylamino)-3-methyl-butyric acid;   (S)-3-Methyl-2-{4′-[(1-methyl-3-phenyl-1H-thieno[2,3-c]pyrazole-5-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   (S)-3-Methyl-2-{4′-[(5-methyl-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   (S)-3-Methyl-2-{4′-[(2-pyridin-4-yl-thiazole-4-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   (S)-3-Methyl-2-[4′-(thiophene-2-sulfonylamino)-biphenyl-4-sulfonylamino]-butyric acid;   (R)-3-Methyl-2-[4′-(thiophene-2-sulfonylamino)-biphenyl-4-sulfonylamino]-butyric acid;   (R)-2-{4′-[(Furan-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid;   (R)-3-Methyl-2-{4′-[(thiophene-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   (S)-3-Methyl-2-{4′-[(thiophene-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   (S)-2-{4′-[(Furan-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid;   (S)-3-Methyl-2-(4′-{[3-methyl-4-(pyridin-2-ylmethoxy)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-butyric acid;   (S)-3-Methyl-2-(4′-{[3-methyl-4-(pyridin-4-ylmethoxy)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-butyric acid;   N-({4′-[(5-Bromo-2-furoyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-L-valine;   N-[(4′-{[(7-Nitro-1H-indol-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine;   N-[(4′-{[(2-Pyridin-4-yl-1,3-thiazol-5-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine;   N-[(4′-{[5-(2-Nitrophenyl)-2-furoyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine;   N-{[4′-({[2-(2,3-Dihydro-1,4-benzodioxin-2-yl)-1,3-thiazol-4-yl]carbonyl}amino)-1,1′-biphenyl-4-yl]sulfonyl}-L-valine;   N-[(4′-{[(5-Methyl-3-phenylisoxazol-4-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine;   N-[(4′-{[(4-Methyl-1,2,3-thiadiazol-5-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine;   N-[(4′-{[(1-tert-Butyl-3-methyl-1H-pyrazol-5-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine;   N-[(4′-{[(3-Chloro-1-benzothien-2-yl)carbonyl]amino}-1,1′-biphenyl-4-yl)sulfonyl]-L-valine;   N-{[4′-([3-(2-Chlorophenyl)-5-methylisoxazol-4-yl]carbonyl}amino)-1,1′-biphenyl-4-yl]sulfonyl}-L-valine;   N-({4′-[(1-Benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-L-histidine;   N-({4′-[(1-Benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-D-histidine;   1-({4′-[(1-Benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-L-proline;   1-({4′-[(1-Benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-D-proline;   N-({4′-[(1-Benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-L-tryptophan;   N-({4′-[(1-Benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-D-tryptophan;   [({4′-[(1-Benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)amino](thien-2-yl)acetic acid;   (2S)-[({4′-[(1-Benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)amino](2,3-dihydro-1H-inden-2-yl)acetic acid;   [({4′-[(1-Benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)amino](1-methyl-1H-indol-5-yl)acetic acid;   [({4′-[(1-Benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)amino](1-benzothien-5-yl)acetic acid;   N-({4′-[(1-Benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-N-methyl-L-tryptophan;   N-({4′-[(1-Benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-1-benzyl-L-histidine; or   a pharmaceutically acceptable salt thereof.   
   
   
       21 . The compound of  claim 1  that is
 L-3-Methyl-2-(4′-{[3-methyl-4-(3-methyl-isoxazol-5-yl)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-butyric acid;   L-3-Methyl-2-(4′-{[3-methyl-4-(2H-tetrazol-5-yl)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-butyric acid;   L-3-Methyl-2-(4′-{[3-methyl-4-(thiophene-2-sulfonylamino)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-butyric acid;   N-{[4′-([4-(2,2-Dimethyl-1,3-dioxolan-4-yl)-3-methyl-1-benzofuran-2-yl]carbonyl}amino)-1,1′-biphenyl-4-yl]sulfonyl}-L-valine;   (S)-3-methyl-2-{4′-[(3-methyl-4-pyridin-3-yl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   (S)-3-Methyl-2-{4′-[(3-methyl-4-pyridin-4-yl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   (S)-2-{4′-[(4-Furan-3-yl-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid;   (S)-3-Methyl-2-{4′-[(5-methyl-benzooxazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid;   L-3-Methyl-2-(4′-{[3-methyl-4-(pyridin-3-ylmethoxy)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-butyric acid;   (S)-3-Methyl-2-{4′-[(1-methyl-3-phenyl-1H-thieno[2,3-c]pyrazole-5-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid; or   (S)-3-Methyl-2-(4′-{[3-methyl-4-(pyridin-4-ylmethoxy)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-butyric acid; or   a pharmaceutically acceptable salt thereof.   
   
   
       22 . A composition comprising:
 one or more compounds of  claim 1 ; and   one or more pharmaceutically acceptable carriers.   
   
   
       23 . A method for treating a patient suspected of suffering from a disease associated with excessive metalloproteinase activity, comprising the step of administering to the patient a therapeutically effective amount of the compound of  claim 1 . 
   
   
       24 . The method of  claim 23 , wherein said disease is cancer, osteoarthritis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, atherosclerosis, age-related macular degeneration, myocardial infarction, corneal ulceration and other ocular surface diseases, hepatitis, aortic aneurysms, tendonitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft versus host disease, diabetes, inflammatory bowel disease, shock, invertebral disc degeneration, stroke, osteopenia, or periodontal diseases. 
   
   
       25 . The method of  claim 23 , wherein said disease is osteoarthritis, rheumatoid arthritis, asthma, or chronic obstructive pulmonary disease. 
   
   
       26 . A method for modulating the activity of a metalloproteinase comprising contacting said metalloproteinase with an effective amount of a biaryl sulfonamide linked to a heteroaryl moiety. 
   
   
       27 . The method of  claim 26  further comprising determining the activity of said metalloproteinase. 
   
   
       28 . The method of  claim 27  wherein said determination is made before said contacting step. 
   
   
       29 . The method of  claim 27  wherein said determination is made after said contacting step. 
   
   
       30 . The method of  claim 26 , wherein the metalloproteinase is Gelatinase A, Macrophage metalloelastase, Collagenase-3, or Aggrecanase-1. 
   
   
       31 . The method of  claim 26 , wherein the metalloproteinase is Macrophage metalloelastase or Collagenase-3. 
   
   
       32 . The method of  claim 26 , wherein the compound is the formula 1: 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  and R 2  are, independently, H, CH(OH)R 4 , phenyl, heteroaryl, or C 1 -C 6  alkyl, with the proviso that when R 1  or R 2  is CH(OH)R 4 , then Z is substituted with NR 4 SO 2 R 5 , SO 2 NR 4 R 5 , heterocycloalkyl, heteroaryl, or C 3 -C 6  cycloalkyl; 
       R 3  is H or C 1 -C 6  alkyl; 
       R 4  and R 5  are, independently with respect to each occurrence, a bond to the other, H, C 1 -C 6  alkyl, or phenyl; 
       G and E are, independently, S, O, N(R 4 ), C(R 6 )═C(R 6 ), or N═C(R 6 ); 
       R 6  is, independently with respect to each occurrence, H, halogen, NR 4 R 5 , N[(CH 2 ) 2 ] 2 O, N[(CH 2 ) 2 ] 2 NR 4 , NR 4 SO 2 R 5 , NR 4 C(═O)R 5 , NHC(═O)OR 4 , NO 2 , SO 2 NR 4 R 5 , SO 2 R 4 , OR 4 , C(═O)R 4 , COOR 4 , CONR 4 R 5 , CN, phenyl, heteroaryl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
       X is N(R 3 )C(═O), OC(═O), OS(O) 2 , NHSO 2 , OCH 2 , CH 2 S(O), or CH 2 S(O) 2 ; and 
       Z is at least one heteroaryl moiety; 
     
     or a pharmaceutically acceptable salt thereof. 
   
   
       33 . A method for treating a patient suspected of suffering from a disease associated with excessive metalloproteinase activity, comprising the step of administering to the patient a therapeutically effective amount of biaryl sulfonamide linked to a heteroaryl moiety.