Heterocyclyl polymethine ir chromophores

Abstract

The present disclosure provides NIR- and SWIR-active small molecule polymethine dyes with improved properties for use in optical imaging, photothermal therapy, and photodynamic therapy.

1 . A compound of formula I or formula II: 
       
         
           
           
               
               
           
         
       
       wherein:
 A and B are each independently selected from a bicyclic, tricyclic, or tetracyclic heteroaryl; wherein A and B are each independently substituted with one or more R 7a  and/or R 7b ; 
 each instance of p is independently 0, 1, or 2; 
 X is H, halo, aryl, heteroaryl, alkyl, alkenyl, cycloalkyl, alkynyl, N(R 3 ) 2 , P(R 3 ) 2 , PO(R 3 ) 2 , SR 4 , S(O)R 4 , S(O) 2 R 4 , OR 4 , SeR 4 , Se(O)R 4 , Se(O) 2 R 4 , azido, cyano, haloalkyl, or hydroxyl; 
 R 1  and R 2  are each independently F, D, or T; or R 1  and R 2  together complete a cycloalkenyl ring, a heterocyclyl ring, or a polycyclyl ring system; 
 R 3  is alkyl, aryl, or heteroaryl; and 
 R 4  is H, alkyl, or aryl; 
 wherein each R 7a  and/or R 7b  is independently selected from H, alkoxy, acyl, heteroaryl, sulfonate, carbonate, cyano, ester, amide, halo, aryl, amino, alkylamino, C 1-6  alkyl, C 3-10  cycloalkyl, haloalkyl, aralkenyl, aralkynyl, hetaralkenyl, hetaralkynyl, and heterocyclyl; or two adjacent R 7a  and/or R 7b  groups combine to form a carbocyclic or heterocyclic ring including the atoms to which they are attached; 
 and 
 i) the compound is not 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         2) at least one of A and B is not: 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , wherein R 1  is F, D, or T. 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . The compound of  claim 1 , wherein R 2  is F, D, or T. 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . The compound of  claim 1 , wherein the compound is of Formula Ia or IIa: 
       
         
           
           
               
               
           
         
         wherein: 
         A and B are each independently selected from a bicyclic, tricyclic, or tetracyclic heteroaryl; wherein A and B are each independently substituted with one or more R 7a  and/or R 7b ; 
         each instance of p is independently 0, 1, or 2; 
         X is H, halo, aryl, heteroaryl, alkyl, alkenyl, cycloalkyl, alkynyl, N(R 3 ) 2 , P(R 3 ) 2 , PO(R 3 ) 2 , SR 4 , OR 4 , SeR 4 , azido, cyano, haloalkyl, hydroxyl; 
         R 1  and R 2  together complete a cycloalkenyl ring, a heterocyclyl ring, or a polycyclyl ring system; 
         R 3  is alkyl, aryl, or heteroaryl; 
         R 4  is H, alkyl, or aryl; 
         wherein each R 7a  and/or R 7b  is independently selected from H, alkoxy, acyl, heteroaryl, sulfonate, carbonate, cyano, ester, amide, halo, aryl, amino, alkylamino, C 1-6  alkyl, C 3-10  cycloalkyl, haloalkyl, aralkenyl, aralkynyl, hetaralkenyl, hetaralkynyl, and heterocyclyl; and 
         or two adjacent R 7a  and/or R 7b  groups combine to form a carbocyclic or heterocyclic ring including the atoms to which they are attached. 
       
     
     
         10 - 12 . (canceled) 
     
     
         13 . The compound of  claim 9 , wherein R 1  and R 2  together complete a cycloalkenyl ring. 
     
     
         14 . (canceled) 
     
     
         15 . The compound of  claim 1 , wherein:
 A is substituted by one or more substituents independently selected from R 7a  and R 7b ;   B is substituted by one or more substituents independently selected from R 7a  and R 7b ;   Each instance of R 7a  and R 7b  is independently selected from alkyl, alkoxy, acyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, N(R 6 )R 6 , sulfonate, carbonate, cyano, ester, amide, and halo; and   each instance of R 6  is independently selected from H, alkyl, hydroxyl, alkyloxy, aryloxy, acyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; or two instances of R 6  connected to the same N complete a heterocyclyl.   
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . The compound of  claim 1 , wherein at least one R 7a  or R 7b  is a water-solubilizing group or an electron-withdrawing group. 
     
     
         19 - 27 . (canceled) 
     
     
         28 . The compound of  claim 1 , wherein: A and B are independently selected from 
       
         
           
           
               
               
           
         
         W is O, SO, SO 2 , PR 6 , PO 2 H, POR 6 , SeO, SeO 2 , TeO, TeO 2 , SiR 6   2 , GeR 6   2 , BH, BOH, or BR 6 ; 
         Y is O + , S + , Se + , Te + , SiR, GeR 6 , N, NR 6+ , or NO; and 
         A and B are independently optionally substituted with one or more R 7a  and/or R 7b , up to the limits of valence. 
       
     
     
         29 . The compound of  claim 1 , wherein: A and B are independently selected from 
       
         
           
           
               
               
           
         
         wherein Q is N(R 6 )R 6 OR 6 , SR 6 , SO(R 6 ) 2 , SeR 6 , SeOR 6 , SeO(R 6 ) 2 , P(R 6 )R 6 , PO(R 6 )R 6 , B(R 6 ) 2 , or halo; and 
         n is 0, 1, 2, 3, 4, or 5 subject to the limits of valence. 
       
     
     
         30 . (canceled) 
     
     
         31 . The compound of  claim 1 , wherein: A and B are independently selected from 
       
         
           
           
               
               
           
         
         wherein Q is N(R 6 )R 6  or OR 6 ; 
         R 71b  is C(R 31 )(R 32 ), arylene, heteroarylene, cycloalkylene, or heterocyclylene; 
         R 31  and R 32  are each independently H or alkyl; 
         n is 0, 1, 2, 3, 4, or 5 subject to the limits of valence; and 
         n 10  is 0, 1, 2, or 3. 
       
     
     
         32 - 35 . (canceled) 
     
     
         36 . The compound of  claim 29 , wherein at least one R 7a  or R 7b  is alkyloxy, aryl, trifluoromethyl, tert-butyl, H, aralkenyl, aralkynyl, cycloalkyl, or heterocyclyl. 
     
     
         37 - 42 . (canceled) 
     
     
         43 . The compound of  claim 1 , wherein the compound is selected from 
       
         
           
           
               
               
           
         
         wherein Ar is aryl; and 
         m is 0, 1, 2, 3, 4, or 5. 
       
     
     
         44 - 47 . (canceled) 
     
     
         48 . The compound of  claim 1 , wherein each R 6  is alkyl; or two instances of R 6  connected to the same N complete a heterocyclyl or a heteroaryl. 
     
     
         49 . (canceled) 
     
     
         50 . The compound of  claim 1 , wherein X is Cl. 
     
     
         51 - 54 . (canceled) 
     
     
         55 . The compound of  claim 1 , wherein at least one of A and B is 
       
         
           
           
               
               
           
         
       
       and
 wherein each instance of q is independently selected from 0, 1, 2, or 3. 
 
     
     
         56 . The compound of  claim 1 , wherein at least one of A and B is substituted with sulfate, sulfonate, fluoroalkyl, or carboxylate. 
     
     
         57 - 60 . (canceled) 
     
     
         61 . A pharmaceutical composition comprising a compound of  claim 1 . 
     
     
         62 . (canceled) 
     
     
         63 . A method of obtaining an image, comprising:
 illuminating a compound of  claim 1  with excitation light, thereby causing the compound to emit fluorescence; and   detecting the fluorescence.   
     
     
         64 . (canceled) 
     
     
         65 . (canceled) 
     
     
         66 . A method of administering a therapy, comprising administering a compound or composition of  claim 1 . 
     
     
         67 . (canceled) 
     
     
         68 . (canceled) 
     
     
         69 . A method of preparing a compound of  claim 1 , comprising:
 providing a starting material compound of formula I or formula II wherein A and B are different:   
       
         
           
           
               
               
           
         
         contacting the starting material compound with a basic amine, thereby producing a half-dye intermediate; 
         providing a compound of formula (IV):
   R 8 -D  (IV); and
 
 
         contacting the half-dye intermediate with the compound of formula (IV), thereby producing the compound; 
         wherein: 
         A and B are each independently selected from a bicyclic, tricyclic, or tetracyclic heteroaryl; wherein A and B are each independently substituted with one or more R 7a  and/or R 7b ; 
         each instance of p is independently 0, 1, or 2; 
         X is H, halo, aryl, heteroaryl, alkyl, alkenyl, cycloalkyl, alkynyl, N(R 3 ) 2 , P(R 3 ) 2 , PO(R 3 ) 2 , SR 4 , S(O)R 4 , S(O) 2 R 4 , OR 4 , SeR 4 , Se(O)R 4 , Se(O) 2 R 4 , azido, cyano, haloalkyl, hydroxyl; 
         R 1  and R 2  are each independently selected from F, D, or T; or R 1  and R 2  together complete a cycloalkenyl ring, a heterocyclyl ring, or a polycyclyl ring system; 
         R 3  is alkyl, aryl, or heteroaryl; and 
         R 4  is H, alkyl, or aryl; 
         wherein each R 7a  and/or R 7b  is independently selected from H, alkoxy, acyl, heteroaryl, sulfonate, carbonate, cyano, ester, amide, halo, aryl, amino, alkylamino, C 1-6  alkyl, C 3-10  cycloalkyl, haloalkyl, aralkenyl, aralkynyl, hetaralkenyl, hetaralkynyl, and heterocyclyl; 
         or two adjacent R 7a  and/or R 7b  groups combine to form a carbocyclic or heterocyclic ring including the atoms to which they are attached. 
       
     
     
         70 . (canceled)