Thiadiazole Compounds and Uses Thereof

Abstract

Thiadiazole compounds, compositions, bioconjugates, and methods for targeting and photoactivation at target sites.

1 . A compound of Formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 each of R 1 , R 2 , R 3 , and R 4  is independently hydrogen, C 1 -C 10  alkyl, C 5 -C 10  aryl, C 5 -C 10  heteroaryl, C 1 -C 10  acyl, halogen, nitro, cyano, —(CH 2 ) a OR 5 , —(CH 2 ) a CO 2 R 5 , —(CH 2 ) a NR 5 R 6 , —NR 6 COR 5 , —(CH 2 ) a CONR 5 R 6 , —(CH 2 ) a SR 5 , —(CH 2 ) a SOR 5 , —(CH 2 ) a SO 2 R 5 , —(CH 2 ) a CON(R 5 )E, —(CH 2 ) a N(R 5 )COE, —(CH 2 ) a N(R 5 )CON(R 6 )E, or —(CH 2 ) a N(R 5 )CSN(R 6 )E; or R 1  and R 2 , R 2  and R 3 , or R 3  and R 4 , together with the carbon atoms to which they are attached, independently form alicyclic or heterocyclic structures wherein a combination of R 1  and R 2 , or a combination of R 2  and R 3 , or a combination of R 3  and R 4  is —(CH 2 ) b X(CH 2 ) c —, —C(R 7 )═C(R 8 )—C(R 9 )═C(R 10 )—, —N═C(R 7 )—C(R 8 )═C(R 9 )—, —C(R 7 )═N—C(R 8 )═C(R 9 )—, —C(R 7 )═C(R 8 )—N═C(R 9 )—, —C(R 7 )═C(R 8 )—C(R 9 )═N—, —C(R 7 )═C(R 8 )—N(R 9 )—, —C(R 7 )═C(R 8 )—O—, —C(R 7 )═C(R 8 )—S—, —N═C(R 7 )—N(R 8 )—, —N═C(R 7 )O—, —N═C(R 7 )—S—, —C(R 7 )═N—N(R 8 )—, —C(R 7 )═N—N(R 8 )—, —C(R 7 )═N—O—, —N═N—N(R 8 )—, —N═N—O—, or —N═N—S—;  
 each of b and c independently varies from 0 to 3;  
 X is from —O—, —NR 11 —, —S—, —SO—, or —SO 2 —;  
 each of R 5  to R 11  is independently hydrogen, C 1 -C 10  alkyl, C 5 -C 10  aryl, C 1 -C 10  hydroxyalkyl, C 1 -C 10  alkoxyalkyl, C 5 -C 10  heteroaryl, C 1 -C 10  acyl, halogen, nitro, cyano, —(CH 2 ) a OR 12 , —(CH 2 ) a CO 2 R 12 , —(CH 2 ) a NR 12 R 13 , —NR 13 COR 12 , —(CH 2 ) a CONR 12 R 13 , —(CH 2 ) a SR 12 , —(CH 2 ) a SOR 12 , —(CH 2 ) a SO 2 R 12 , —(CH 2 ) a CON(R 12 )E, —(CH 2 ) a N(R 12 )COE, —(CH 2 ) a N(R 12 )CON(R 13 )E, or —(CH 2 ) a N(R 12 )CSN(R 13 )E;  
 wherein at least one of R 1  to R 4  is independently —(CH 2 ) a CON(R 5 )E, —(CH 2 ) a N(R 5 )COE, —(CH 2 ) a N(R 5 )CON(R 6 )E, or —(CH 2 ) a N(R 5 )CSN(R 6 )E; or wherein at least one of R 5  to R 11  is independently —(CH 2 ) a CON(R 12 )E, —(CH 2 ) a N(R 12 )COE, —(CH 2 ) a N(R 12 )CON(R 13 )E, or —(CH 2 ) a N(R 12 )CSN(R 13 )E;  
 a varies from 0 to 10;  
 each of R 12  and R 13  is independently hydrogen, C 1 -C 10  alkyl, C 5 -C 10  aryl, C 1 -C 10  hydroxyalkyl, C 1 -C 10  alkoxyalkyl, C 5 -C 10  heteroaryl, and C 1 -C 10  acyl; and  
 each E is independently a whole or fragmented somatostatin receptor binding molecule, a whole or fragmented ST receptor binding molecule, a whole or fragmented neurotensin receptor binding molecule, a whole or fragmented bombesin receptor binding molecule, a whole or fragmented CCK receptor binding molecule, a whole or fragmented steroid receptor binding molecule, or a whole or fragmented carbohydrate receptor binding molecule.  
 
     
     
         2 . The compound of  claim 1  wherein Formula I forms a structure of Formula II  
       
         
           
           
               
               
           
         
         wherein R 2  and R 3  of Formula I are combined to form A, and A is from —(CH 2 ) b X(CH 2 ) c —, —C(R 7 )═C(R 8 )—C(R 9 )═C(R 10 )—, —N═C(R 7 )—C(R 8 )═C(R 9 )—, —C(R 7 )═N—C(R 8 )═C(R 9 )—, —C(R 7 )═C(R 8 )—N═C(R 9 )—, —C(R 7 )═C(R 8 )—C(R 9 )═N—, —C(R 7 )═C(R 8 )—N(R 9 )—, —C(R 7 )═C(R 8 )—O—, —C(R 7 )═C(R 8 )—S—, —N═C(R 7 )—N(R 8 )—, —N═C(R 7 )—O—, —N═C(R 7 )—S—, —C(R 7 )═N—N(R 8 )—, —C(R 7 )═N—N(R 8 )—, —C(R 7 )═N—O—, —N═N—N(R 8 )—, —N═N—O—, or —N═N—S—; and  
         each of R 1  and R 4  is independently hydrogen, C 1 -C 10  alkyl, C 5 -C 10  aryl, C 5 -C 10  heteroaryl, C 1 -C 10  acyl, halogen, nitro, cyano, —(CH 2 ) a OR 5 , —(CH 2 ) a CO 2 R 5 , —(CH 2 ) a NR 5 R 6 , —NR 6 COR 5 , —(CH 2 ) a CONR 5 R 6 , —(CH 2 ) a SR 5 , —(CH 2 ) a SOR 5 , —(CH 2 ) a SO 2 R 5 , (CH 2 ) a CON(R 5 )E, —(CH 2 ) a N(R 5 )COE, —(CH 2 ) a N(R 5 )CON(R)E, or —(CH 2 ) a N(R 5 )CSN(R 6 )E.  
       
     
     
         3 . The compound of  claim 1  wherein Formula 1 forms a structure of Formula III  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  of Formula I are combined to form B, and B is —(CH 2 ) b X(CH 2 ) c —, —C(R 7 )═C(R 8 )—C(R 9 )═C(R 10 )—, —N═C(R 7 )—C(R 8 )═C(R 9 )—, —C(R 7 )═N—C(R 8 )═C(R 9 )—, —C(R 7 )═C(R 8 )—N═C(R 9 )—, —C(R 7 )═C(R 8 )—C(R 9 )═N—, —C(R 7 )═C(R 8 )—N(R 9 )—, —C(R 7 )═C(R 8 )—O—, —C(R 7 )═C(R 8 )—S—, —N═C(R 7 )—N(R 8 )—, —N═C(R 7 )—O—, —N═C(R 7 )—S—, —C(R 7 )═N—N(R 8 )—, —C(R 7 )═N—N(R 8 )—, —C(R 7 )═N—O—, —N═N—N(R 8 )—, —N═N—O— or —N═N—S—; and  
         each of R 3  and R 4  is independently hydrogen, C 1 -C 10  alkyl, C 5 -C 10  aryl, C 5 -C 10  heteroaryl, C 1 -C 10  acyl, halogen, nitro, cyano, —(CH 2 ) a OR 5 , —(CH 2 ) a CO 2 R 5 , —(CH 2 ) a NR 5 R 6 , —NR 6 COR 5 , —(CH 2 ) a CONR 5 R 6 , —(CH 2 ) a SR 5 , —(CH 2 ) a SOR 5 , —(CH 2 ) a SO 2 R 5 , —(CH 2 ) a CON(R 5 )E, —(CH 2 ) a N(R 5 )COE, —(CH 2 ) a N(R 5 )CON(R)E, or —(CH 2 ) a N(R 5 )CSN(R 6 )E.  
       
     
     
         4 . The compound of  claim 1  wherein Formula I forms a structure of Formula IV  
       
         
           
           
               
               
           
         
         wherein R 3  and R 4  of Formula I are combined to form D, and D is —(CH 2 ) b X(CH 2 ) c —, —C(R 7 )═C(R 8 )—C(R 9 )═C(R 10 )—, —N═C(R 7 )—C(R 8 )═C(R 9 )—, —C(R 7 )═N—C(R 8 )═C(R 9 )—, —C(R 7 )═C(R 8 )—N═C(R 9 )—, —C(R 7 )═C(R 8 )—C(R 9 )═N—, —C(R 7 )═C(R 8 )—N(R 9 )—, —C(R 7 )═C(R 8 )—O—, —C(R 7 )═C(R 8 )—S—, —N═C(R 7 )—N(R 8 )—, —N═C(R 7 )—O—, —N═C(R 7 )—S—, —C(R 7 )═N—N(R 8 )—, —C(R 7 )═N—N(R 8 )—, —C(R 7 )═N—O—, —N═N—N(R 8 )—, —N═N—O—, or —N═N—S—;  
         each of R 1  and R 2  is independently hydrogen, C 1 -C 10  alkyl, C 5 -C 10  aryl, C 5 -C 10  heteroaryl, C 1 -C 10  acyl, halogen, nitro, cyano, —CH 2 ) a OR 5 , —(CH 2 ) a CO 2 R 5 , —(CH 2 ) a NR 5 R 6 , —NR 6 COR 5 , —(CH 2 ) a CONR 5 R 6 , —(CH 2 ) a SR 5 , —(CH 2 ) a SOR 5 , —(CH 2 ) a SO 2 R 5 , —(CH 2 ) a CON(R 5 )E, —(CH 2 ) a N(R 5 )COE, —(CH 2 ) a N(R 5 )CON(R)E, or —(CH 2 ) a N(R 5 )CSN(R 6 )E; and  
         each of R 5  to R 11  is independently hydrogen, C 1 -C 10  alkyl, C 5 -C 10  aryl, C 1 -C 10  hydroxylakyl, C 1 -C 10  alkoxyalkyl, C 5 -C 10  heteroaryl, C 1 -C 10  acyl, halogen, nitro, cyano, —(CH 2 ) a OR 12 , —(CH 2 ) a CO 2 R 12 , —(CH 2 ) a NR 12 R 13 , —NR 13 COR 12 ; —(CH 2 ) a CONR 12 R 13 , —(CH 2 ) a SR 12 , —(CH 2 ) a SOR 12 , —(CH 2 ) a SO 2 R 12 , —(CH 2 ) a CON(R 12 )E, —(CH 2 ) a N(R 12 )COE, —(CH 2 ) a N(R 12 )CON(R 13 )E, or —(CH 2 ) a N(R 12 )CSN(R 13 )E.  
       
     
     
         5 . The compound of  claim 1  wherein Formula I forms a structure of Formula V  
       
         
           
           
               
               
           
         
         wherein R 2  and R 3  of Formula I are combined to form A, and A is —(CH 2 ) b X(CH 2 ) c —;  
         b is 2, and c is 1;  
         X is —NR 11 —;  
         R 4  is hydrogen;  
         R 1  is hydrogen, C 1 -C 10  alkyl, C 5 -C 10  aryl, C 5 -C 10  heteroaryl, C 1 -C 10  acyl, halogen, nitro, cyano, —(CH 2 ) a OR 5 , —(CH 2 ) a CO 2 R 5 , —(CH 2 ) a NR 5 R 6 , —NR 6 COR 5 , —(CH 2 ) a CONR 5 R 6 , —(CH 2 ) a SR 5 , —(CH 2 ) a SOR 5 , —(CH 2 ) a SO 2 R 5 , —(CH 2 ) a CON(R 5 )E, —(CH 2 ) a N(R 5 )COE, —(CH 2 ) a N(R 5 )CON(R 6 )E, or —(CH 2 ) a N(R 5 )CSN(R 6 )E; and  
         each of R 5 , R 6 , and R 11  is independently hydrogen, C 1 -C 10  alkyl, C 5 -C 10  aryl, C 1 -C 10  hydroxylakyl, or C 1 -C 10  alkoxyalkyl.  
       
     
     
         6 . The compound of  claim 1 , wherein E is a whole or fragmented somatostatin receptor binding molecule.  
     
     
         7 . The compound of  claim 1  further comprising at least one of an electron donating group, an electron withdrawing group, a lipophilic group, or a hydrophilic group.  
     
     
         8 . A biocompatible composition comprising a compound of  claim 1 , and a biocompatible excipient.  
     
     
         9 . The composition of  claim 8  wherein the excipient is at least one of a buffer, emulsifier, surfactant, or electrolyte.  
     
     
         10 - 19 . (canceled)  
     
     
         20 . The compound of  claim 1 , wherein E is a whole or fragmented ST receptor binding molecule.  
     
     
         21 . The compound of  claim 1 , wherein E is a whole or fragmented neurotensin receptor binding molecule.  
     
     
         22 . The compound of  claim 1 , wherein E is a whole or fragmented bombesin receptor binding molecule.  
     
     
         23 . The compound of  claim 1 , wherein E is a whole or fragmented CCK receptor binding molecule.  
     
     
         24 . The compound of  claim 1 , wherein E is a whole or fragmented steroid receptor binding molecule.  
     
     
         25 . The compound of  claim 1 , wherein E is a whole or fragmented carbohydrate receptor binding molecule.