Thiazole and thiadiazole inhibitors of tyrosine phosphatases

Abstract

Compounds and compositions are provided for modulating the activity of protein tyrosine phosphatases. In one embodiment, the compounds and compositions are thiazoles and thiadiazoles that inhibit the activity of protein tyrosine phosphatase 1B.

1 . A compound that has formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable derivative thereof, wherein: 
         D is H, alkyl or 
       
       
         
           
           
               
               
           
         
         E is CH 2 ; 
         s is 0 or 1; 
         R 8  and R 9  are H, or together form CH═CH—CH═CH; 
         R 10  is H, halo, haloalkyl, COOH, alkylsulfonyl, SO 2 NH 2  or COO-alkyl; 
         R 11  is H, COOH or halo; 
         R 12  is H; 
         R 13  is CF 2 PO 3 H 2 , NHC(O)COOH, OCH 2 COOH, CH═CHCOOH, CF 2 COOH, COOH, C(O)COOH or 3-COOH-5-isoxazolyl; 
         R 14  is halo or COOH; 
         R 15  is H, alkyl or CH 2 CONH 2 ; 
         R 16  is NHC(O)COOH, COOH, alkylsulfonyl, NHC(O)COO-alkyl, CH═CH—COOH, H, O(CH 2 ) t COOH, COOMe, O(CH 2 ) t COO-alkyl, 3-COOH-phenyl, OCMe 2 COOH, S(CH 2 ) t COO-alkyl, S(CH 2 )LCOOH, (CH 2 ) t COOH, SO 2 (CH 2 ) t COO-alkyl, SO 2 (CH 2 ) t COOH, OH, C(O)(OCH(H/Me)OC(═O)OiPr, C(O)(OCH(H/Me)OC(═O)tBu or ROCH 2 CHR′CH 2 O—C(O), where R is C 14-20 -n-alkyl and R′ is H, OH or OMe; 
         each t is independently 1, 2 or 3; and 
         R 17  is H, COO-alkyl, 3-COOH-phenyl, 2-COOH-phenoxy or OCH(Ph)COOH. 
       
     
     
         2 . The compound of  claim 1 , wherein D is H, methyl or 
       
         
           
           
               
               
           
         
         E is CH 2 ; 
         s is 0 or 1; 
         R 8  and R 9  are H, or together form CH═CH—CH═CH; 
         R 10  is H, Cl, CF 3 , COOH, SO 2 Me, SO 2 NH 2  or COOEt; 
         R 11  is H, COOH or Cl; 
         R 12  is H; 
         R 13  is CF 2 PO 3 H 2 , NHC(O)COOH, OCH 2 COOH, CH═CHCOOH, CF 2 COOH, COOH, C(O)COOH or 3-COOH-5-isoxazolyl; 
         R 14  is Cl, Br or COOH; 
         R 15  is H, CH 2 CONH 2  or Me; 
         R 16  is NHC(O)COOH, COOH, methanesulfonyl, NHC(O)COOEt, CH═CH—COOH, H, OCH 2 COOH, COOMe, OCH 2 COOEt, 3-COOH-phenyl, OCMe 2 COOH, SCH 2 COOMe, SCH 2 COOH, CH 2 CH 2 COOH, SO 2 CH 2 COOMe, SO 2 CH 2 COOH, OH or C(O)OCH(Me)OCOO-i-Pr; and 
         R 17  is H, COOMe, 3-COOH-phenyl, 2-COOH-phenoxy or OCH(Ph)COOH. 
       
     
     
         3 . The compound of  claim 1 , wherein R 8  and R 9  are H, or together form CH═CH—CH═CH. 
     
     
         4 . The compound of  claim 1 , wherein R 10  is H, Cl, CF 3 , COOH, SO 2 Me, SO 2 NH 2  or COOEt. 
     
     
         5 . The compound of  claim 1 , wherein R 11  is H, COOH or Cl. 
     
     
         6 . The compound of  claim 1 , wherein R 13  is CF 2 PO 3 H 2 . 
     
     
         7 . The compound of  claim 1 , wherein R 14  is Br. 
     
     
         8 . The compound of  claim 1 , wherein R 15  is H, CH 2 CONH 2  or Me. 
     
     
         9 . The compound of  claim 1 , wherein R 16  is NHC(O)COOH, COOH, methanesulfonyl, NHC(O)COOEt, CH═CH—COOH, H, OCH 2 COOH, COOMe, OCH 2 COOEt, 3-COOH-phenyl, OCMe 2 COOH, SCH 2 COOMe, SCH 2 COOH, CH 2 CH 2 COOH, SO 2 CH 2 COOMe, SO 2 CH 2 COOH, OH or C(O)OCH(Me)OCOO-i-Pr. 
     
     
         10 . The compound of  claim 1 , wherein R 17  is H, COOMe, 3-COOH-phenyl, 2-COOH-phenoxy or OCH(Ph)COOH. 
     
     
         11 . The compound of  claim 1 , wherein the compound is: 
       N-(4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-phenyl)-oxalamic acid; 
       (3-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-phenoxy)-phenyl-acetic acid; 
       4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(4′-carboxyphenyl amino]-thiazol-4-yl}-benzoic acid; 
       4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(4-trifluoromethyl-phenyl)-amino]-thiazol-4-yl}-benzoic acid; 
       4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-benzoic acid; 
       {[2-Bromo-4-({[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-phenyl-amino}-methyl)-phenyl]-difluoro-methyl}-phosphonic acid; 
       N-[4-(2-{[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-phenyl-amino}-thiazol-4-yl)-phenyl]-oxalamic acid ethyl ester; 
       {[2-Bromo-4-({(3,4-dichloro-phenyl)-[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-amino}-methyl)-phenyl]-difluoro-methyl}-phosphonic acid; 
       N-(4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-phenyl)-oxalamic acid ethyl ester; 
       4-(2-{[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-naphthalen-1-yl-amino}-thiazol-4-yl)-benzoic acid; 
       3-(4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-phenyl)-acrylic acid; 
       (4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-5-methyl-thiazol-4-yl}-phenoxy)-acetic acid; 
       4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(4′-ethoxycarbonylphenyl amino]-thiazol-4-yl}-benzoic acid methyl ester; 
       4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(4-trifluoromethyl-phenyl)amino]-thiazol-4-yl}-benzoic acid methyl ester; 
       4-(2-{[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-naphthalen-1-yl-amino}-thiazol-4-yl)-benzoic acid methyl ester; 
       5-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-2-hydroxy-benzoic acid methyl ester; 
       [(2-Bromo-4-{[(3,4-dichloro-phenyl)-(4-phenyl-thiazol-2-yl)-amino]-methyl}-phenyl)-difluoro-methyl]-phosphonic acid; 
       (4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-5-methyl-thiazol-4-yl}-phenoxy)-acetic acid ethyl ester; 
       4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-benzoic acid methyl ester; 
       [(2-Bromo-4-{[(3,4-dichloro-phenyl)-(4-naphthalen-2-yl-thiazol-2-yl)-amino]methyl}-phenyl)-difluoro-methyl]-phosphonic acid; 
       [2-Bromo-4-({(3,4-dichloro-phenyl)-[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-amino}-methyl)-phenoxy]-acetic acid; 
       3-[2-Bromo-4-({(3,4-dichloro-phenyl)-[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-amino}-methyl)-phenyl]-acrylic acid; 
       4-({(3,4-Dichloro-phenyl)-[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-amino}-methyl)-phenyl]-difluoro-acetic acid; 
       3-{3-[4-[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-5-(3-trifluoromethyl-benzoylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       4-{2-[(3-Bromo-4-carboxymethoxy-benzyl)-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-benzoic acid; 
       2-Bromo-4-{[[4-(4-carboxy-phenyl)-thiazol-2-yl]-(3,4-dichloro-phenyl)-amino]-methyl}-benzoic acid; 
       N-[4-(2-{[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-phenyl-amino}-thiazol-4-yl)-phenyl]-oxalamic acid; 
       [(4-{[(3,4-Dichloro-phenyl)-(4-phenyl-thiazol-2-yl)-amino]-methyl}-phenyl)-difluoro-methyl]-phosphonic acid; 
       5-({(3,4-Dichloro-phenyl)-[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-amino}-methyl)-2-(oxalyl-amino)-benzoic acid; 
       5-(4-{[[4-(4-Carboxy-phenyl)-thiazol-2-yl]-(3,4-dichloro-phenyl)-amino]-methyl}-phenyl)-isoxazole-3-carboxylic acid; 
       4-{2-[(3,4-Dichloro-phenyl)-(4-oxalyl-benzyl)-amino]-thiazol-4-yl}-benzoic acid; 
       4-(2-{[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-methyl-amino}-thiazol-4-yl)-benzoic acid; 
       4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-biphenyl-3-carboxylic acid; 
       4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-biphenyl-3-carboxylic acid; 
       2-(3-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-phenoxy)-benzoic acid; 
       4-({[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-amino}-methyl)-benzoic acid methyl ester; 
       4-({[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-amino}-methyl)-benzoic acid; 
       (3-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-phenoxy)-acetic acid; 
       2-(3-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-phenoxy)-2-methyl-propionic acid; 
       4-(2-{Benzenesulfonyl-[3-bromo-4-(difluoro-phosphono-methyl)-benzyl]-amino}-thiazol-4-yl)-benzoic acid methyl ester; 
       4-(2-{Benzenesulfonyl-[3-bromo-4-(difluoro-phosphono-methyl)-benzyl]-amino}-thiazol-4-yl)-benzoic acid; 
       (4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-phenylsulfanyl)-acetic acid methyl ester; 
       (4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-phenylsulfanyl)-acetic acid; 
       [(2-Bromo-4-{[[5-carbamoylmethyl-4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-(3,4-dichloro-phenyl)-amino]-methyl}-phenyl)-difluoro-methyl]-phosphonic acid; 
       [(2-Bromo-4-{[[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-(4-sulfamoyl-benzyl)-amino]-methyl}-phenyl)-difluoro-methyl]-phosphonic acid; 
       3-(4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-phenyl)-propionic acid; 
       {[2-Chloro-4-({(3,4-dichloro-phenyl)-[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-amino}-methyl)-phenyl]-difluoro-methyl}-phosphonic acid; 
       (4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-benzenesulfonyl)-acetic acid methyl ester; 
       (4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-benzenesulfonyl)-acetic acid; 
       (4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-phenoxy)-acetic acid; 
       (4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-phenoxy)-acetic acid; 
       (4-{2-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-phenoxy)-acetic acid; 
       [(2-Bromo-4-{[4-(4-methanesulfonyl-phenyl)-thiazol-2-ylamino]-methyl}-phenyl)-difluoro-methyl]-phosphonic acid; 
       [(2-Bromo-4-{2-(3,4-dichloro-phenyl)-2-[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-ethyl}-phenyl)-difluoro-methyl]-phosphonic acid; 
       [(2-Bromo-4-{[[4-(4-cyanomethylsulfanyl-phenyl)-thiazol-2-yl]-(3,4-dichloro-phenyl)-amino]-methyl}-phenyl)-difluoro-methyl]-phosphonic acid; 
       [(2-Bromo-4-{[[4-(4-cyanomethanesulfonyl-phenyl)-thiazol-2-yl]-(3,4-dichloro-phenyl)-amino]-methyl}-phenyl)-difluoro-methyl]-phosphonic acid; 
       ({2-Bromo-4-[((3,4-dichloro-phenyl)-{4-[4-(1H-tetrazol-5-ylmethylsulfanyl)-phenyl]-thiazol-2-yl}-amino)-methyl]-phenyl}-difluoro-methyl)-phosphonic acid; 
       [(2-Bromo-4-{[[4-(4-carbamoylmethylsulfanyl-phenyl)-thiazol-2-yl]-(3,4-dichloro-phenyl)-amino]-methyl}-phenyl)-difluoro-methyl]-phosphonic acid; 
       (4-{2-[{3-Bromo-4-[difluoro-(hydroxy-methyl-phosphinoyl)-methyl]-benzyl}-(3,4-dichloro-phenyl)-amino]-thiazol-4-yl}-phenylsulfanyl)-acetic acid; 
       (4-{2-[3-Bromo-4-(difluoro-phosphono-methyl)-benzylamino]-thiazol-4-yl}-phenylsulfanyl)-acetic acid; 
       [(2-Bromo-4-{[[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-(2-methoxy-phenyl)-amino]-methyl}-phenyl)-difluoro-methyl]-phosphonic acid; 
       {[2-Bromo-4-({(4-methanesulfonyl-benzyl)-[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-amino}-methyl)-phenyl]-difluoro-methyl}-phosphonic acid; 
       [(2-Bromo-4-{[[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-(3-methanesulfonyl-propyl)-amino]-methyl}-phenyl)-difluoro-methyl]-phosphonic acid; 
       4-{[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-amino}-butyric acid; 
       [(2-Bromo-4-{[[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-(3-methoxy-propyl)-amino]-methyl}-phenyl)-difluoro-methyl]-phosphonic acid; 
       {[2-Bromo-4-({(3-hydroxy-isoxazol-5-ylmethyl)-[4-(4-methanesulfonyl-phenyl)-thiazol-2-yl]-amino}-methyl)-phenyl]-difluoro-methyl}-phosphonic acid; 
       [4-(2-{1-[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-3-ethyl-ureido}-thiazol-4-yl)-phenylsulfanyl]-acetic acid; 
       4-(2-{Benzoyl-[3-bromo-4-(difluoro-phosphono-methyl)-benzyl]-amino}-thiazol-4-yl)-benzoic acid methyl ester; 
       4-(2-{Benzoyl-[3-bromo-4-(difluoro-phosphono-methyl)-benzyl]-amino}-thiazol-4-yl)-benzoic acid; or 
       4-{2-[3-Bromo-4-(difluoro-phosphono-methyl)-benzylamino]-thiazol-4-yl}-benzoic acid. 
     
     
         12 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable derivative thereof, wherein: 
         X is C═O, SO 2  or CH 2 ; 
         n is 0 or 1; 
         R 1  is H or halo; 
         R 2  is CF 2 PO 3 H 2 , CF 2 COOH, OCH(Me)COOH, COOH, CH═CHCOOH, OCH 2 COOH, cyclopropylene-COOH, tetrazolyl, OC(Me 2 )COOH or OCF 2 COOH; 
         R 3  is H, halo or pseudohalo; 
         Y is N or CR 4 , where R 4  is H, halo or CF 2 PO 3 H 2 ; 
         R 5  is H, halo or perhaloalkyl; 
         R 6  is H or alkylsulfonyl; and 
         R 7  is phenoxy which is optionally substituted with COOH or COO-alkyl, or R 7  is H, alkylsulfonyl or tetrazolyl. 
       
     
     
         13 . The compound of  claim 12 , wherein:
 X is C═O, SO 2  or CH 2 ;   n is 0 or 1;   R 1  is H or Br;   R 2  is CF 2 PO 3 H 2 , CF 2 COOH, OCH(Me)COOH, COOH, CH═CHCOOH, OCH 2 COOH, cyclopropylene-COOH, tetrazolyl, OC(Me 2 )COOH or OCF 2 COOH;   R 3  is H, F, Cl, Br or CN;   Y is N or CR 4 , where R 4  is H, Cl or CF 2 PO 3 H 2 ;   R 5  is H, Cl or CF 3 ;   R 6  is H or methanesulfonyl; and   R 7  is phenoxy which is optionally substituted with COOH or COOMe, or R 7  is H, methanesulfonyl or tetrazolyl.   
     
     
         14 . The compound of  claim 12  wherein R 1  is H or Br. 
     
     
         15 . The compound of  claim 12 , wherein R 2  is CF 2 PO 3 H 2 . 
     
     
         16 . The compound of  claim 12 , wherein R 3  is Br, CN or Cl. 
     
     
         17 . The compound of  claim 12 , wherein R 4  is H, Cl or CF 2 PO 3 H 2 . 
     
     
         18 . The compound of  claim 12 , wherein R 5  is H, Cl or CF 3 . 
     
     
         19 . The compound of  claim 12 , wherein R 6  is H or methanesulfonyl. 
     
     
         20 . The compound of  claim 12 , wherein R 7  is phenoxy which is optionally substituted with COOH, or R 7  is H or methanesulfonyl. 
     
     
         21 . The compound of  claim 12 , wherein the compound is: 
       3-(3-{5-Benzoylimino-4-[3-bromo-4-(difluoro-phosphono-methyl)-benzyl]-4,5-dihydro-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid; 
       3-{3-[4-[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-5-(3,4-dichloro-benzoylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       3-{3-[4-[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-5-(3-trifluoromethyl-benzoylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       3-{3-[4-[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-5-(3-chloro-phenylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       3-(3-{4-[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-5-phenylimino-4,5-dihydro-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid; 
       3-{3-[4-[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-5-(3,4-dichloro-phenylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       3-{3-[4-[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-5-(4-chloro-phenylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       3-{3-[4-[3-Chloro-4-(difluoro-phosphono-methyl)-benzyl]-5-(3,4-dichloro-phenylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       3-{3-[4-[3-Chloro-4-(difluoro-phosphono-methyl)-benzyl]-5-(3,4-dichloro-phenylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid methyl ester; 
       3-(3-{5-(3,4-Dichloro-phenylimino)-4-[4-(difluoro-phosphono-methyl)-3-fluoro-benzyl]-4,5-dihydro-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid; 
       3-(3-{5-(3,4-Dichloro-phenylimino)-4-[4-(difluoro-phosphono-methyl)-3-fluoro-benzyl]-4,5-dihydro-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid methyl ester; 
       3-{3-[4-[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-5-(3,4-dichloro-phenylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid methyl ester; 
       3-{3-[4-[3-Cyano-4-(difluoro-phosphono-methyl)-benzyl]-5-(3,4-dichloro-phenylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       ({2-Bromo-4-[2-[4-(difluoro-phosphono-methyl)-benzylimino]-5-(3-phenoxy-phenyl)-[1,3,4]thiadiazol-3-ylmethyl]-phenyl}-difluoro-methyl)-phosphonic acid; 
       ({2-Bromo-4-[2-(3,4-dichloro-phenylimino)-5-(4-methanesulfonyl-phenyl)-[1,3,4]thiadiazol-3-ylmethyl]-phenyl}-difluoro-methyl)-phosphonic acid; 
       [(2-Bromo-4-{2-(3,4-dichloro-phenylimino)-5-[3-(3-methanesulfonyl-phenoxy)-phenyl]-[1,3,4]thiadiazol-3-ylmethyl}-phenyl)-difluoro-methyl]-phosphonic acid; 
       3-{3-[4-[3,5-Dibromo-4-(difluoro-phosphono-methyl)-benzyl]-5-(3,4-dichloro-phenylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       3-(3-{5-(3,4-Dichloro-phenylimino)-4-[4-(difluoro-phosphono-methyl)-benzyl]-4,5-dihydro-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid; 
       3-{3-[4-[4-(Carboxy-difluoro-methyl)-benzyl]-5-(3,4-dichloro-phenylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       3-{3-[4-[3-Bromo-4-(1-carboxy-ethoxy)-benzyl]-5-(3,4-dichloro-phenylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       2-Bromo-4-[5-[3-(3-carboxy-phenoxy)-phenyl]-2-(3,4-dichloro-phenylimino)-[1,3,4]thiadiazol-3-ylmethyl]-benzoic acid; 
       3-(3-{5-Benzoylimino-4-[3-bromo-4-(2-carboxy-vinyl)-benzyl]-4,5-dihydro-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid; 
       3-{3-[4-(3-Bromo-4-carboxymethoxy-benzyl)-5-(pyridine-4-carbonylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       3-{3-[4-[3-Bromo-4-(carboxy-difluoro-methyl)-benzyl]-5-(3,4-dichloro-phenylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       3-{3-[4-[3-Bromo-4-(2-carboxy-cyclopropyl)-benzyl]-5-(3,4-dichloro-phenylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       (3-[3-Bromo-4-(1H-tetrazol-5-yl)-benzyl]-5-{3-[3-(1H-tetrazol-5-yl)-phenoxy]-phenyl}-3H-[1,3,4]thiadiazol-2-ylidene)-(3,4-dichloro-phenyl)-amine; 
       ({4-[2-(3,4-Dichloro-phenylimino)-5-(3-m-tolyloxy-phenyl)-[1,3,4]thiadiazol-3-ylmethyl]-phenyl}-difluoro-methyl)-phosphonic acid; 
       3-{3-[4-[3-Bromo-4-(1-carboxy-1-methyl-ethoxy)-benzyl]-5-(3,4-dichloro-phenylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       3-{3-[4-[3-Bromo-4-(carboxy-difluoro-methoxy)-benzyl]-5-(3,4-dichloro-phenylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       3-{3-[4-[3-Bromo-4-(1H-tetrazol-5-yl)-benzyl]-5-(3,4-dichloro-phenylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       3-(3-{5-Benzoylimino-4-[3-bromo-4-(difluoro-phosphono-methyl)-benzyl]-4,5-dihydro-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid methyl ester; 
       3-{3-[4-[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-5-(pyridine-4-carbonylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid methyl ester; or 
       3-{3-[4-[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-5-(pyridine-4-carbonylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid. 
     
     
         22 . A compound of formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable derivative thereof, wherein: 
         Z is CH 2 ; 
         m is 0 or 1; 
         R 18  is H or halo; 
         R 19  is CF 2 PO 3 H 2 , COOH, NHCOCOOH, CF 2 P(OH)OCH 2 OCO-t-butyl, CH═CH—COOH or 3-COOH-5-isoxazolyl; 
         R 20  is H, halo, pseudohalo or COOH; 
         R 21  is H, halo, CF 2 PO 3 H 2  or SO 2 -heterocyclyl; 
         R 22  is H or halo; 
         R 23  is H or phenoxy optionally substituted with COOH, tetrazolyl, COO-alkyl or alkylsulfonyl; and 
         R 24  is H or alkylsulfonyl. 
       
     
     
         23 . The compound of  claim 22 , wherein:
 Z is CH 2 ;   m is 0 or 1;   R 18  is H or Br;   R 19  is CF 2 PO 3 H 2 , COOH, NHCOCOOH, CF 2 P(OH)OCH 2 OCO-t-butyl, CH═CH—COOH or 3-COOH-5-isoxazolyl;   R 20  is H, Br, CN, Cl or COOH;   R 21  is H, Cl, CF 2 PO 3 H 2  or SO 2 -1-piperidinyl;   R 22  is H or Cl;   R 23  is H or phenoxy optionally substituted with COOH, tetrazolyl, COOMe or methanesulfonyl; and   R 24  is H or methanesulfonyl.   
     
     
         24 . The compound of  claim 22 , wherein Z is CH 2 . 
     
     
         25 . The compound of  claim 22 , wherein R 18  is H or Br. 
     
     
         26 . The compound of  claim 22 , wherein R 19  is CF 2 PO 3 H 2 . 
     
     
         27 . The compound of  claim 22 , wherein R 20  is Br, CN or Cl. 
     
     
         28 . The compound of  claim 22 , wherein R 21  is H, Cl, CF 2 PO 3 H 2  or SO 2 -1-piperidinyl. 
     
     
         29 . The compound of  claim 22 , wherein R 22  is H or Cl. 
     
     
         30 . The compound of  claim 22 , wherein R 23  is H or phenoxy optionally substituted with COOH, tetrazolyl, COOMe or methanesulfonyl. 
     
     
         31 . The compound of  claim 22 , wherein R 24  is H or methanesulfonyl. 
     
     
         32 . The compound of  claim 22 , wherein the compound is: 
       [(2-Bromo-4-{[(3,4-dichloro-phenyl)-(5-{3-[3-(1H-tetrazol-5-yl)-phenoxy]-phenyl}-[1,3,4]thiadiazol-2-yl)-amino]-methyl}-phenyl)-difluoro-methyl]-phosphonic acid; 
       3-(3-{5-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid; 
       3-(3-{5-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(4-chloro-phenyl)-amino]-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid; 
       3-[3-(5-{[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-phenyl-amino}-[1,3,4]thiadiazol-2-yl)-phenoxy]-benzoic acid; 
       3-(3-{5-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3-chloro-phenyl)-amino]-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid; 
       3-(3-{5-[[3-Chloro-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid; 
       3-(3-{5-[[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid methyl ester; 
       3-(3-{5-[[3-Chloro-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid methyl ester; or 
       3-[3-(5-{[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-[4-(piperidine-1-sulfonyl)-phenyl]-amino}-[1,3,4]thiadiazol-2-yl)-phenoxy]-benzoic acid; 
       3-{3-[4-[3-Chloro-4-(difluoro-phosphono-methyl)-benzyl]-5-(3,4-dichloro-phenylimino)-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxy}-benzoic acid; 
       3-(3-{5-[[3-Cyano-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid; 
       3-[3-(5-{Benzyl-[3-bromo-4-(difluoro-phosphono-methyl)-benzyl]-amino}-[1,3,4]thiadiazol-2-yl)-phenoxy]-benzoic acid; 
       3-(3-{5-[{3-Bromo-4-[difluoro-(hydroxy-methoxy-phosphoryl)-methyl]-benzyl}-(3,4-dichloro-phenyl)-amino]-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid; 
       {[2-Bromo-4-({(3,4-dichloro-phenyl)-[5-(4-methanesulfonyl-phenyl)-[1,3,4]thiadiazol-2-yl]-amino}-methyl)-phenyl]-difluoro-methyl}-phosphonic acid; 
       ({2-Bromo-4-[((3,4-dichloro-phenyl)-{5-[3-(3-methanesulfonyl-phenoxy)-phenyl]-[1,3,4]thiadiazol-2-yl}-amino)-methyl]-phenyl}-difluoro-methyl)-phosphonic acid; 
       3-(3-{5-[[3,5-Dibromo-4-(difluoro-phosphono-methyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid; 
       5-{[{5-[3-(3-Carboxy-phenoxy)-phenyl]-[1,3,4]thiadiazol-2-yl}-(3,4-dichloro-phenyl)-amino]-methyl}-2-(oxalyl-amino)-benzoic acid; 
       3-(3-{5-[(3-Bromo-4-{[(2,2-dimethyl-propionyloxymethoxy)-hydroxy-phosphoryl]-difluoro-methyl}-benzyl)-(3,4-dichloro-phenyl)-amino]-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid 2,2-dimethyl-propionyloxymethyl ester; 
       {[4-({[4-(Difluoro-phosphono-methyl)-benzyl]-[5-(3-phenoxy-phenyl)-[1,3,4]thiadiazol-2-yl]-amino}-methyl)-phenyl]-difluoro-methyl}-phosphonic acid; 
       3-(3-{5-[[3-Bromo-4-(2-carboxy-vinyl)-benzyl]-(3,4-dichloro-phenyl)-amino]-[1,3,4]thiadiazol-2-yl}-phenoxy)-benzoic acid; 
       4-({Benzoyl-[5-(3-phenoxy-phenyl)-[1,3,4]thiadiazol-2-yl]-amino}-methyl)-benzoic acid; or 
       5-(4-{[{5-[3-(3-Carboxy-phenoxy)-phenyl]-[1,3,4]thiadiazol-2-yl}-(3,4-dichloro-phenyl)-amino]-methyl}-phenyl)-isoxazole-3-carboxylic acid. 
     
     
         33 . A compound of formula IV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable derivative thereof, wherein: 
         G is H or 
       
       
         
           
           
               
               
           
         
         W is CO or SO 2 ; 
         k is 0 or 1; 
         R 25  is H or halo; 
         R 26  is CF 2 PO 3 H 2  or SO 2 NH 2 ; 
         R 27  is H or SO 2 -heterocyclyl; 
         R 28  is H or alkyl; and 
         R 29  is COO-alkyl, COOCH 2 OC(O)-t-Bu or OCH 2 COOH. 
       
     
     
         34 . The compound of  claim 33 , wherein:
 W is CO or SO 2 ;   k is 0 or 1;   R 25  is H or Br;   R 26  is CF 2 PO 3 H 2  or SO 2 NH 2 ;   R 27  is H or SO 2 -1-piperidinyl;   R 28  is H or Me; and   R 29  is COOMe or OCH 2 COOH.   
     
     
         35 . The compound of  claim 33  that is: 
       4-{2-Benzoylimino-3-[3-bromo-4-(difluoro-phosphono-methyl)-benzyl]-2,3-dihydro-thiazol-4-yl}-benzoic acid methyl ester; 
       4-{3-[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-2-imino-2,3-dihydro-thiazol-4-yl}-benzoic acid; 
       4-{2-Benzoylimino-3-[3-bromo-4-(difluoro-phosphono-methyl)-benzyl]-2,3-dihydro-thiazol-4-yl}-benzoic acid; 
       (4-{3-[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-2-imino-2,3-dihydro-thiazol-4-yl}-phenylsulfanyl)-acetic acid; 
       ({4-[2-Benzoylimino-4-(4-methanesulfonyl-phenyl)-thiazol-3-ylmethyl]-2-bromo-phenyl}-difluoro-methyl)-phosphonic acid; 
       ({2-Bromo-4-[2-imino-4-(4-methanesulfonyl-phenyl)-thiazol-3-ylmethyl]-phenyl}-difluoro-methyl)-phosphonic acid; 
       (4-{3-[3-Bromo-4-(difluoro-phosphono-methyl)-benzyl]-2-imino-2,3-dihydro-thiazol-4-yl}-benzenesulfonyl)-acetic acid; 
       3-Bromo-2-carboxymethoxy-5-[4-(4-carboxymethylsulfanyl-phenyl)-2-imino-thiazol-3-ylmethyl]-benzoic acid; 
       4-(2-{Benzoyl-[3-bromo-4-(difluoro-phosphono-methyl)-benzyl]-amino}-thiazol-4-yl)-benzoic acid; 
       4-[3-(3-Bromo-4-{difluoro-[hydroxy-(1-isopropoxycarbonyloxy-ethoxy)-phosphoryl]-methyl}-benzyl)-2-imino-2,3-dihydro-thiazol-4-yl]-benzoic acid 1-isopropoxycarbonyloxy-ethyl ester; or 
       4-[3-(3-Bromo-4-{[(2,2-dimethyl-propionyloxymethoxy)-hydroxy-phosphoryl]-difluoro-methyl}-benzyl)-2-imino-2,3-dihydro-thiazol-4-yl]-benzoic acid 2,2-dimethyl-propionyloxymethyl ester. 
     
     
         36 . A pharmaceutical composition, comprising the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         37 . The pharmaceutical composition of  claim 36  that is formulated for single dosage administration. 
     
     
         38 . A method of modulating the activity of a protein tyrosine phosphatase, comprising contacting the protein tyrosine phosphatase with a compound of  claim 1 . 
     
     
         39 . The method of  claim 38 , wherein the protein tyrosine phosphatase is protein tyrosine phosphatase 1B. 
     
     
         40 . The method of  claim 38 , wherein the protein tyrosine phosphatase is inhibited by the compound or composition. 
     
     
         41 . A method of increasing insulin sensitivity, comprising administering a compound of  claim 1 . 
     
     
         42 . A method of treating, preventing, or ameliorating one or more symptoms of a protein tyrosine phosphatase mediated disease, comprising administering a compound of  claim 1 . 
     
     
         43 . The method of  claim 42 , wherein the protein tyrosine phosphatase is protein tyrosine phosphatase 1B. 
     
     
         44 . The method of  claim 42 , wherein the disease is diabetes including Type 1 and Type 2 diabetes (and associated complications such as hypertension, ischemic diseases of the large and small blood vessels, blindness, circulatory problems, kidney failure and atherosclerosis), syndrome X, metabolic syndrome, glucose intolerance, insulin resistance, leptin resistance, obesity, cancer, neurodegenerative diseases, and other diseases in which the activity of a tyrosine phosphatase or multiple tyrosine phosphatases contributes to the symptoms or pathology thereof. 
     
     
         45 . A pharmaceutical composition, comprising a compound of  claim 1  and one or more of the following: antiobesity agents, antidiabetics, antihypertensive agents, agents for the treatment of complications resulting from or associated with diabetes and agents for the treatment of complications and disorders resulting from or associated with obesity. 
     
     
         46 . A pharmaceutical composition, comprising a compound of  claim 1  and one or more of the following: antiobesity agents or appetite regulating agents. 
     
     
         47 . A pharmaceutical composition, comprising a compound of  claim 1  and one or more of the following: CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, B3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR (peroxisome proliferator activated receptor) modulators, RXR (retinoid X receptor) modulators or TR B agonists. 
     
     
         48 . A pharmaceutical composition, comprising a compound of  claim 1  and one or more of the following: leptin, dexamphetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine, orlistat, mazindol or phentermine. 
     
     
         49 . A pharmaceutical composition, comprising a compound of  claim 1  and one or more of the following: insulin, GLP-1 (glucagons like peptide-1) derivatives, or orally active hypoglycemic agents. 
     
     
         50 . A pharmaceutical composition, comprising a compound of  claim 1  and one or more of the following: sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thizolidinediones, glucosidase inhibitors, glucagons antagonists, GLP-1 agonists, potassium channel openers, insulin sensitizers, DPP-IV (dipeptidyl peptidase-IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogensis and/or glycogenolysis, glucose uptake modulators, compounds modifying the lipid metabolism, antihyperlipidemic agents, antilipedimic agents, HMG CoA inhibitors (statins), compounds lowering food intake, PPAR agonists, RXR agonists and agents acting on the ATP-dependent potassium channel of the B-cells. 
     
     
         51 . A pharmaceutical composition, comprising a compound of  claim 1  and insulin. 
     
     
         52 . A pharmaceutical composition, comprising a compound of  claim 1  and one or more of the following: a sulphonylurea, a biguanide, a meglitinide, a thizolidinedione or a pharmaceutically acceptable salt thereof. 
     
     
         53 . A pharmaceutical composition, comprising a compound of  claim 1  and an insulin sensitizer. 
     
     
         54 . A pharmaceutical composition, comprising a compound of  claim 1  and one or more of the following: an α-glucosidase inhibitor, an agent acting on the ATP-dependent potassium channel of the B-cells, nateglinide, an antihyperlipidemic agent or antilipidemic agent. 
     
     
         55 . A pharmaceutical composition, comprising a compound of  claim 1  and one or more of the following: a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and lovastatin, or CART agonist and a CCK agonist. 
     
     
         56 . A pharmaceutical composition, comprising a compound of  claim 1  and one or more antihypertensive agents. 
     
     
         57 . A pharmaceutical composition, comprising a compound of  claim 1  and one or more of the following: β-blockers, ACE (angiotensin converting enzyme) inhibitors, calcium channel blockers, and α-blockers. 
     
     
         58 . A method of treating, preventing, or ameliorating one or more symptoms of a protein tyrosine phosphatase mediated disease, comprising administering a composition of  claim 45 . 
     
     
         59 . The method of  claim 58 , wherein the protein tyrosine phosphatase is protein tyrosine phosphatase 1B. 
     
     
         60 . The method of  claim 58 , wherein the disease is diabetes, syndrome X, metabolic syndrome, glucose intolerance, insulin resistance, leptin resistance, obesity, cancer, neurodegenerative diseases, and other diseases in which the activity of a tyrosine phosphatase or multiple tyrosine phosphatases contributes to the symptoms or pathology thereof. 
     
     
         61 . A prodrug of a compound of  claim 1 , wherein the prodrug has the formula ArCF 2 P(O)(OH)(OCH(H/Me)OC(═O)OiPr, ArCF 2 P(O)[(OCH(H/Me)OC(═O)OiPr] 2 , ArCF 2 P(O)(OH)(OCH(H/Me)OC(═O)tBu, or ArCF 2 P(O)[(OCH(H/Me)OC(═O)tBu] 2 . 
     
     
         62 . A prodrug of a compound of  claim 1  that is a mono- or bis-amidate prodrug, a mono- or di-lipid ester prodrug, a mono- or di-alpha-acyloxyalkyl ester or amide prodrug, a cytochrome P450 3A activated prodrug, a cyclic diester prodrug, a cyclic monoester monoamide prodrug, a cyclic diamide prodrug, or a carbohydrate prodrug. 
     
     
         63 . A prodrug of a compound of  claim 1 , wherein the prodrug has the formula ROCH 2 CHR′CH 2 O—P(O)(OH)CF 2 Ar or (ROCH 2 CHR′CH 2 O) 2 —P(O)CF 2 Ar, where R is C 14-20 -n-alkyl and R′ is H, OH or OMe.