Preparation and use of biphenyl-4-yl-carbonylamino acid derivatives for the treatment of obesity

Abstract

This invention relates to certain biphenyl-4-yl carbonylamino acid compounds, compositions, and methods for treating or preventing obesity and related diseases.

1 . A method of treating obesity, type 1 diabetes, type 2 diabetes, maturity-onset diabetes, latent autoimmune diabetes, gestational diabetes, hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, insulin resistance, atherosclerosis, coronary heart disease, coronary artery disease, or hypertension in a mammal, the method comprising the step of administering to a mammal a therapeutically effective amount of a compound of Formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         Q is O, NR 11 , or S; 
       
       
         
           
           
               
               
           
         
       
       is a fused ring selected from
 an aromatic 6-membered ring containing 0 or 1 N atoms; 
 R 1  is independently selected from 
 halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, nitro, cyano, (C 1 -C 6 )haloalkyl, 
 (C 1 -C 6 )haloalkoxy, aminocarbonyl, (C 1 -C 6 )alkylaminocarbonyl, 
 bis[(C 1 -C 6 )alkyl]aminocarbonyl, aminosulfonyl, (C 1 -C 6 )alkylaminosulfonyl, 
 bis[(C 1 -C 6 )alkyl]aminosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylsulfonyl, 
 (C 1 -C 6 )alkylsulfonylamino, hydroxy-(C 2 -C 6 )alkylaminocarbonyl, 
 1-morpholinylcarbonyl, and 1-piperidinylcarbonyl, 
 and 
 when two of said R 1  substituents are (C 1 -C 6 )alkyl and are attached to adjacent carbon atoms of the Ring A, they may be joined together to form a 5-7-membered carbocyclic ring; 
 n is 0, 1, or 2; 
 R 2  and R 3  are independently selected from hydrogen, halo, hydroxy, (C 1 -C 6 )alkyl, trifluoromethyl, (C 1 -C 6 )alkoxy, and trifluoromethoxy; 
 R 4  is selected from 
 
       
         
           
           
               
               
           
         
         wherein 
         R 6  is H or CH 3 ; 
         and 
         R 7  is 
       
       
         
           
           
               
               
           
         
         wherein 
         R 9  is selected from 
         (C 1 -C 6 )alkyl optionally substituted with one or two groups selected from vinyl, CF 3 , OH, methoxy, SCH 3 , NH 2 , —CO 2 H, and —CONH 2 , 
         (CH 2 ) m phenyl wherein m is 0 to 3, and 
         where the phenyl ring is optionally substituted with one or two groups selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OH, nitro, and cyano, 
         piperidinyl optionally substituted on C with halo and optionally substituted on C or N with (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, nitro, or cyano, 
         tetrahydropyran-4-yl; 
         R 10  is H or methyl; 
         or 
         R 9  and R 10  may form, together with the carbon to which they are attached, a 3- to 6-membered carbocyclic ring, 
         R 8  is hydrogen, (C 1 -C 4 )alkyl, hydroxy, or methoxy; 
         R 5  is selected from H, (C 1 -C 6 )alkyl, and hydroxy-(C 2 -C 6 )alkyl; 
         R 11  is selected from H, (C 1 -C 6 )alkyl, and hydroxy-(C 2 -C 6 )alkyl; 
       
       and the pharmaceutically acceptable salts and esters thereof. 
     
     
         2 . The method of  claim 1 , wherein
 Q is O, NR 11 , or S;   
       
         
           
           
               
               
           
         
       
       is a fused ring selected from
 an aromatic 6-membered ring containing 0 or 1 N atoms; 
 R 1  is independently selected from 
 halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, nitro, cyano, (C 1 -C 6 )haloalkyl, 
 (C 1 -C 6 )haloalkoxy, aminocarbonyl, (C 1 -C 6 )alkylaminocarbonyl, 
 bis[(C 1 -C 6 )alkyl]aminocarbonyl, aminosulfonyl, (C 1 -C 6 )alkylaminosulfonyl, 
 bis[(C 1 -C 6 )alkyl]aminosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylsulfonyl, 
 (C 1 -C 6 )alkylsulfonylamino, hydroxy-(C 2 -C 6 )alkylaminocarbonyl, 
 1-morpholinylcarbonyl, and 1-piperidinylcarbonyl; 
 n is 0, 1, or 2; 
 R 2  and R 3  are independently selected from hydrogen, halo, hydroxy, (C 1 -C 6 )alkyl, trifluoromethyl, (C 1 -C 6 )alkoxy, and trifluoromethoxy; 
 R 4  is selected from 
 
       
         
           
           
               
               
           
         
         wherein 
         R 6  is H or CH 3 ; 
         and 
         R 7  is 
       
       
         
           
           
               
               
           
         
         wherein 
         R 9  is selected from 
         (C 1 -C 6 )alkyl optionally substituted with one or two groups selected from vinyl, CF 3 , OH, methoxy, SCH 3 , NH 2 , —CO 2 H, and —CONH 2 , 
         (CH 2 ) m phenyl wherein m is 0 to 3, and 
         where the phenyl ring is optionally substituted with one or two groups selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OH, nitro, and cyano, 
         piperidinyl optionally substituted on C with halo and optionally substituted on C or N with (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, nitro, or cyano, 
         tetrahydropyran-4-yl; 
         R 10  is H or methyl; 
         or 
         R 9  and R 10  may form, together with the carbon to which they are attached, a 3- to 6-membered carbocyclic ring, 
         R 8  is hydrogen, (C 1 -C 4 )alkyl, hydroxy, or methoxy; 
         R 5  is selected from H, (C 1 -C 6 )alkyl, and hydroxy-(C 2 -C 6 )alkyl; and 
         R 11  is selected from H, (C 1 -C 6 )alkyl, and hydroxy-(C 2 -C 6 )alkyl. 
       
     
     
         3 . The method of  claim 1 , wherein
 Q is O, NR 11 , or S;   
       
         
           
           
               
               
           
         
       
       is a fused ring selected from
 an aromatic 6-membered ring containing 0 or 1 N atoms; 
 R 1  is independently selected from 
 halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, nitro, cyano, (C 1 -C 6 )haloalkyl, 
 (C 1 -C 6 )haloalkoxy, aminocarbonyl, (C 1 -C 6 )alkylaminocarbonyl, 
 bis[(C 1 -C 6 )alkyl]aminocarbonyl, aminosulfonyl, (C 1 -C 6 )alkylaminosulfonyl, 
 bis[(C 1 -C 6 )alkyl]aminosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylsulfonyl, 
 (C 1 -C 6 )alkylsulfonylamino, hydroxy-(C 2 -C 6 )alkylaminocarbonyl, 
 1-morpholinylcarbonyl, and 1-piperidinylcarbonyl; 
 n is 0, 1, or 2; 
 R 2  and R 3  are independently selected from hydrogen, halo, hydroxy, (C 1 -C 6 )alkyl, trifluoromethyl, (C 1 -C 6 )alkoxy, and trifluoromethoxy; 
 R 4  is selected from 
 
       
         
           
           
               
               
           
         
         wherein 
         R 6  is H or CH 3 ; 
         and 
         R 7  is 
       
       
         
           
           
               
               
           
         
         wherein 
         R 9  is selected from 
         (C 1 -C 6 )alkyl optionally substituted with one or two groups selected from vinyl, CF 3 , OH, methoxy, SCH 3 , NH 2 , —CO 2 H, and —CONH 2 , 
         (CH 2 ) m phenyl wherein m is 0 to 3, and 
         where the phenyl ring is optionally substituted with one or two groups selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OH, nitro, and cyano, 
         piperidinyl optionally substituted on C with halo and optionally substituted on C or N with (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, nitro, or cyano, 
         tetrahydropyran-4-yl; 
         R 10  is H or methyl; 
         or 
         R 9  and R 10  may form, together with the carbon to which they are attached, a 3- to 6-membered carbocyclic ring, 
         R 8  is hydrogen, (C 1 -C 4 )alkyl, hydroxy, or methoxy; 
         R 5  is selected from H, (C 1 -C 6 )alkyl, and hydroxy-(C 2 -C 6 )alkyl; and 
         R 11  is selected from H, (C 1 -C 6 )alkyl, and hydroxy-(C 2 -C 6 )alkyl. 
       
     
     
         4 . The method of  claim 1 , wherein
 Q is S;   
       
         
           
           
               
               
           
         
       
       is a fused ring selected from
 an aromatic 6-membered ring containing 0 or 1 N atoms; 
 R 1  is independently selected from 
 halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, nitro, cyano, (C 1 -C 6 )haloalkyl, 
 (C 1 -C 6 )haloalkoxy, aminocarbonyl, (C 1 -C 6 )alkylaminocarbonyl, 
 bis[(C 1 -C 6 )alkyl]aminocarbonyl, aminosulfonyl, (C 1 -C 6 )alkylaminosulfonyl, 
 bis[(C 1 -C 6 )alkyl]aminosulfonyl, (C 1 -C 6 )alkylcarbonylamino, (C 1 -C 6 )alkylsulfonyl, 
 (C 1 -C 6 )alkylsulfonylamino, hydroxy-(C 2 -C 6 )alkylaminocarbonyl, 
 1-morpholinylcarbonyl, and 1-piperidinylcarbonyl; 
 n is 0, 1, or 2; 
 R 2  and R 3  are independently selected from hydrogen, halo, hydroxy, (C 1 -C 6 )alkyl, trifluoromethyl, (C 1 -C 6 )alkoxy, and trifluoromethoxy; 
 R 4  is 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 6  is H or CH 3 ; 
 and 
 R 7  is 
 
       
         
           
           
               
               
           
         
         wherein 
         R 9  is selected from 
         (C 1 -C 6 )alkyl optionally substituted with one or two groups selected from vinyl, CF 3 , OH, methoxy, SCH 3 , NH 2 , —CO 2 H, and —CONH 2 , 
         (CH 2 ) m phenyl wherein m is 0 to 3, and 
         where the phenyl ring is optionally substituted with one or two groups selected from halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OH, nitro, and cyano, 
         piperidinyl optionally substituted on C with halo and optionally substituted on C or N with (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, nitro, or cyano, 
         tetrahydropyran-4-yl; 
         R 10  is H or methyl; 
         or 
         R 9  and R 10  may form, together with the carbon to which they are attached, a 3- to 6-membered carbocyclic ring, 
         R 8  is hydrogen, (C 1 -C 4 )alkyl, hydroxy, or methoxy; 
         R 5  is selected from H, (C 1 -C 6 )alkyl, and hydroxy-(C 2 -C 6 )alkyl; and 
         R 11  is selected from H, (C 1 -C 6 )alkyl, and hydroxy-(C 2 -C 6 )alkyl. 
       
     
     
         5 . The method of  claim 1 , wherein the compound is
 N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-valine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-alanine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-alanine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-valine;   N-({3-chloro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-valine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-yl}carbonyl)-L-valine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-L-valine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-leucine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-leucine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-L-leucine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-L-leucine;   N-({3-chloro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-leucine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-yl}carbonyl)-L-leucine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-yl}carbonyl)-L-leucine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-D-leucine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-D-leucine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-isoleucine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-isoleucine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-L-isoleucine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-phenylalanine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-phenylalanine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-L-phenylalanine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-yl}carbonyl)-L-phenylalanine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-yl}carbonyl)-L-phenylalanine;   N-({3-chloro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-phenylalanine;   1-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-proline;   1-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-proline;   1-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-L-proline;   1-({3-chloro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-proline;   1-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-yl}carbonyl)-L-proline;   1-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-yl}carbonyl)-L-proline;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-2-methylalanine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-2-methylalanine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-2-methylalanine;   N-({3-chloro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-2-methylalanine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-yl}carbonyl)-2-methylalanine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-yl}carbonyl)-2-methylalanine;   1-[({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino]cyclopropanecarboxylic acid;   1-[({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino]cyclopropanecarboxylic acid;   1-[({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)amino]cyclopropanecarboxylic acid;   1-[({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino]cyclopentanecarboxylic acid;   1-[({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino]cyclopentanecarboxylic acid;   1-[({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino]cyclohexanecarboxylic acid;   (2S)-2-[({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino]butanoic acid;   (2S)-2-[({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino]butanoic acid;   (2S)-2-[({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)amino]butanoic acid;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-norvaline;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-norvaline;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-L-norvaline;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-3-methyl-L-valine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-3-methyl-L-valine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-3-methyl-L-valine;   4-chloro-N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)phenylalanine;   (2S)-cyclohexyl[({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino]acetic acid;   [({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino](tetrahydro-2H-pyran-4-yl)acetic acid;   [1-(tert-butoxycarbonyl)piperidin-4-yl][({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino]acetic acid;   [1-(tert-butoxycarbonyl)piperidin-3-yl][({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino]acetic acid;   [({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino](piperidin-3-yl)acetic acid;   1-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)piperidine-2-carboxylic acid;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-L-valine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-yl}carbonyl)-L-valine;   N-({4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-yl}carbonyl)-L-valine;   N-{[4′-(1,3-benzothiazol-2-ylamino)-3-methylbiphenyl-4-yl]carbonyl}-L-valine;   N-({4′-[(6-isopropyl-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-yl}carbonyl)-L-valine;   N-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-yl}carbonyl)-L-valine,   N-({4′-[(7-fluoro-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-yl}carbonyl)-L-valine;   N-({4′-[(7-chloro-1,3-benzothiazol-2-yl)amino]-3-methylbiphenyl-4-yl}carbonyl)-L-valine,   N-{[4′-(1,3-benzothiazol-2-ylamino)-3-methoxybiphenyl-4-yl]carbonyl}-L-valine;   N-{[4′-(1,3-benzothiazol-2-ylamino)biphenyl-4-yl]carbonyl}-L-valine;   N-{[4′-(1,3-benzothiazol-2-ylamino)biphenyl-4-yl}carbonyl]-D-valine;   N-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-L-valine,   N-({4′-[(7-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-L-valine,   N-({4′-[(7-chloro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-L-valine,   N-({4′-[(6-isopropyl-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-L-valine,   N-{[4′-(1,3-benzothiazol-2-ylamino)-3-chlorobiphenyl-4-yl]carbonyl}-L-valine,   N-({3-chloro-4′-[(6-isopropyl-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-valine,   N-({3-chloro-4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-valine,   N-({3-chloro-4′-[(7-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-valine,   N-({3-chloro-4′-[(7-chloro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-valine,   N-{[4′-(1,3-benzothiazol-2-ylamino)-3-methoxybiphenyl-4-yl]carbonyl}-L-leucine,   N-({3-methoxy-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-leucine,   N-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-L-leucine,   N-({4′-[(4-chloro-6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-L-leucine,   N-({3-methoxy-4′-[(6-nitro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-leucine,   N-[(3-methoxy-4′-{[6-(methylsulfonyl)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-L-leucine,   N-({4′-[(6-isopropyl-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-yl}carbonyl)-L-leucine,   N-({4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-2-methylalanine;   N-{[4′-(1,3-benzothiazol-2-ylamino)biphenyl-4-yl}carbonyl]-2-methylalanine;   N-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-2-methylalanine;   N-{[4′-(1,3-benzothiazol-2-ylamino)biphenyl-4-yl}carbonyl]-N-methyl-L-alanine;   N-{[4′-(1,3-benzothiazol-2-ylamino)biphenyl-4-yl}carbonyl]-N-methyl-L-valine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-allothreonine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-allothreonine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-threonine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-threonine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-serine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-β-methyl-L-serine;   3-cyclopropyl-N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-alanine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-O-methyl-L-serine;   3-cyclopropyl-N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-alanine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-N-methyl-L-valine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-N-methyl-L-valine;   N-({3-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-valine;   N-({3-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-leucine;   N-({3-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-3-methyl-L-valine;   N-({3-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-isoleucine;   N-({3-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-norvaline;   (2S)-2-[({3-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino]butanoic acid;   3-cyclopropyl-N-({3-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-alanine;   N-({3,3′-difluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-valine;   N-({3,3′-difluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-leucine;   N-({3,3′-difluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-3-methyl-L-valine;   N-({3,3′-difluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-norvaline;   (2S)-2-[({3,3′-difluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino]butanoic acid;   3-cyclopropyl-N-({3,3′-difluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-alanine;   N-[(3′-fluoro-4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-L-valine;   N-[(3′-fluoro-4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-L-leucine; N-[(3′-fluoro-4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-L-norvaline;   N-[(3′-fluoro-4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-L-isoleucine;   N-[(3′-fluoro-4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-3-methyl-L-valine;   3-cyclopropyl-N-[(3′-fluoro-4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-L-alanine;   (2S)-2-{[(3′-fluoro-4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]amino}butanoic acid;   N-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-3′-fluorobiphenyl-4-yl}carbonyl)-L-leucine;   N-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-valine;   N-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-leucine;   N-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-norvaline;   N-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-isoleucine;   N-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-3-methyl-L-valine;   N-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-3′-fluorobiphenyl-4-yl}carbonyl)-L-valine;   N-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-3′-fluorobiphenyl-4-yl}carbonyl)-L-norvaline;   (2S)-2-[({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-3′-fluorobiphenyl-4-yl}carbonyl)amino]butanoic acid;   N-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-3-cyclopropyl-L-alanine;   N-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-3′-fluorobiphenyl-4-yl}carbonyl)-3-methyl-L-valine;   (2S)-2-[({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino]butanoic acid;   N-{[4′-([1,3]thiazolo[5,4-b]pyridin-2-ylamino)biphenyl-4-yl]carbonyl}-L-valine;   N-{[4′-([1,3]thiazolo[4,5-c]pyridin-2-ylamino)biphenyl-4-yl]carbonyl}-L-valine;   N-{[4′-([1,3]thiazolo[4,5-b]pyridin-2-ylamino)biphenyl-4-yl]carbonyl}-L-valine;   N-[(3′-fluoro-4′-{[6-(trifluoromethyl)[1,3]thiazolo[4,5-b]pyridin-2-yl]amino}biphenyl-4-yl)carbonyl]-L-valine;   N-{[3′-fluoro-4′-([1,3]thiazolo[4,5-c]pyridin-2-ylamino)biphenyl-4-yl]carbonyl}-L-valine;   N-{[3′-fluoro-4′-([1,3]thiazolo[4,5-b]pyridin-2-ylamino)biphenyl-4-yl]carbonyl}-L-valine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-O-methyl-L-allothreonine;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-N-methyl-L-norvaline;   4,4,4-trifluoro-2-[({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino]butanoic acid;   N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-4-methylene-L-norvaline;   3-cyclobutyl-N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-alanine;   (2S)-[({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino](phenyl)acetic acid;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-O-methyl-L-allothreonine;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-N-methyl-L-norvaline;   1-[({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)(methyl)amino]cyclopropanecarboxylic acid;   (4R)-3-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid;   4,4,4-trifluoro-2-[({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino]butanoic acid;   N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-4-methylene-L-norvaline;   3-cyclobutyl-N-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-alanine;   (2S)-[({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino](phenyl)acetic acid;   N-[(3′-fluoro-4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-L-valine;   N-[(3′-fluoro-4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-L-leucine;   N-[(3′-fluoro-4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-L-norvaline;   N-[(3′-fluoro-4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-3-methyl-L-valine;   (2S)-2-{[(3′-fluoro-4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]amino}butanoic acid; N-[(3′-fluoro-4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-L-isoleucine;   3-cyclopropyl-N-[(3′-fluoro-4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-L-alanine;   N-[(4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-L-valine; N-[(4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-L-leucine;   N-[(4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-L-norvaline;   3-methyl-N-[(4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-L-valine;   (2S)-2-{[(4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]amino}butanoic acid;   N-[(4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-L-isoleucine;   3-cyclopropyl-N-[(4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}biphenyl-4-yl)carbonyl]-L-alanine;   N-({3′-fluoro-4′-[(6-isopropyl-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-valine;   N-({3′-fluoro-4′-[(6-isopropyl-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-leucine;   N-({3′-fluoro-4′-[(6-isopropyl-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-norvaline;   (2S)-2-[({3′-fluoro-4′-[(6-isopropyl-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)amino]butanoic acid;   N-({3′-fluoro-4′-[(6-isopropyl-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-3-methyl-L-valine;   N-({3′-fluoro-4′-[(6-isopropyl-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-isoleucine;   3-cyclopropyl-N-({3′-fluoro-4′-[(6-isopropyl-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-alanine;   N-[(4′-{[6-(trifluoromethyl)[1,3]thiazolo[4,5-b]pyridin-2-yl]amino}biphenyl-4-yl)carbonyl]-L-leucine;   N-[(4′-{[6-(trifluoromethyl)[1,3]thiazolo[4,5-b]pyridin-2-yl]amino}biphenyl-4-yl)carbonyl]-L-norvaline;   3-methyl-N-[(4′-{[6-(trifluoromethyl)[1,3]thiazolo[4,5-b]pyridin-2-yl]amino}biphenyl-4-yl)carbonyl]-L-valine;   (2S)-2-{[(4′-{[6-(trifluoromethyl)[1,3]thiazolo[4,5-b]pyridin-2-yl]amino}biphenyl-4-yl)carbonyl]amino}butanoic acid;   N-[(4′-{[6-(trifluoromethyl)[1,3]thiazolo[4,5-b]pyridin-2-yl]amino}biphenyl-4-yl)carbonyl]-L-isoleucine;   3-cyclopropyl-N-[(4′-{[6-(trifluoromethyl)[1,3]thiazolo[4,5-b]pyridin-2-yl]amino}biphenyl-4-yl)carbonyl]-L-alanine;   N-[(3′-fluoro-4′-{[6-(trifluoromethyl)[1,3]thiazolo[4,5-b]pyridin-2-yl]amino}biphenyl-4-yl)carbonyl]-L-leucine;   N-[(3′-fluoro-4′-{[6-(trifluoromethyl)[1,3]thiazolo[4,5-b]pyridin-2-yl]amino}biphenyl-4-yl)carbonyl]-L-norvaline;   N-[(3′-fluoro-4′-{[6-(trifluoromethyl)[1,3]thiazolo[4,5-b]pyridin-2-yl]amino}biphenyl-4-yl)carbonyl]-3-methyl-L-valine;   (2S)-2-{[(3′-fluoro-4′-{[6-(trifluoromethyl)[1,3]thiazolo[4,5-b]pyridin-2-yl]amino}biphenyl-4-yl)carbonyl]amino}butanoic acid;   N-[(3′-fluoro-4′-{[6-(trifluoromethyl)[1,3]thiazolo[4,5-b]pyridin-2-yl]amino}biphenyl-4-yl)carbonyl]-L-isoleucine; or   N-({4′-[(7-chloro[1,3]thiazolo[5,4-c]pyridin-2-yl)amino]-3′-fluorobiphenyl-4-yl}carbonyl)-L-valine.   
     
     
         6 - 32 . (canceled)