Compositions and Methods for Enhancing Immune Responses to Vaccines

Abstract

The disclosure provides adjuvants, immunogenic compositions, and methods useful for vaccination and immune response. In particular, the disclosure provides a class of adjuvants comprising cationic lipid:co-lipid mixtures and methods for delivering formulated compositions.

1 . A compound having formula I: 
       
         
           
           
               
               
           
         
       
       or an enantiomer, diastereomer, or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  and R 2  are each independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted carboxyalkyl, wherein R 1  and R 2  are each optionally independently substituted with 1 to 5 R 16  groups; 
 L 1  and L 2  are each independently a direct bond, O, NH, N(C 1 -C 6  alkyl), or S(O) m , wherein m is an integer from 0 to 2; 
 n is an integer from 0 to 6; 
 Q is independently -Z 1 N + Z 2 - or -Z 1 P + Z 2 -; 
 Z 1  and Z 2  are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted carboxyalkyl, or substituted or unsubstituted —(CH 2 ) m —R 3  wherein m is an integer from 1 to 6, and wherein Z 1  and 
 Z 2  are each optionally independently substituted with 1 to 5 R 16  groups; 
 T is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted carboxyalkyl; wherein T is optionally independently substituted with 1 to 5 R 16  groups; and 
 R 3  is independently —OR 4 , —S(O) m R 5 , —NR 6 R 7 , —N + R 8 R 9 R 10 , —PR 11 R 12 , or —P + R 13 R 14 R 15 ; 
 R 4  and R 5  are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted carboxyalkyl, wherein R 4  and R 5  are each optionally independently substituted with 1 to 5 R 16  groups; 
 R 6  and R 7  are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted carboxyalkyl, or R 6  and R 7 , together with the N atom to which they are attached, form substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl, wherein R 6  and R 7  are each optionally independently substituted with 1 to 5 R 16  groups; 
 R 8 , R 9  and R 10  are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted carboxyalkyl, or R 8  is as described, and R 9  and R 10 , together with the N atom to which they are attached, form substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl, wherein R 8 , R 9  and R 10  are each optionally independently substituted with 1 to 5 R 16  groups; 
 R 11 , R 12  and R 13  are each independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted carboxyalkyl, or R 1  is as described, and R 12  and R 13 , together with the P atom to which they are attached, form substituted or unsubstituted heterocycloalkyl, wherein R 11 , R 12  and R 13  are each optionally independently substituted with 1 to 5 R 16  groups; 
 R 16  is hydrogen, halogen, nitro, cyano, hydroxyl, alkyl, cycloalkyl, perfluoroalkyl, heteroalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —(CH 2 ) j CN, —(CH 2 ) j OR 17 —(CH 2 ) j C(O)R 17 , —(CH 2 ) j C(O)OR 17 , —(CH 2 ) j NR 18 R 19 , —(CH 2 ) j C(O)NR 18 R 19 , —(CH 2 ) j OC(O)NR 18 R 19 , —(CH 2 ) j NR 20 C(O)R 17 , —(CH 2 ) j NR 20 C(O)OR 17 , —(CH 2 ) j N 20 C(O)NR 18 R 19 , —(CH 2 ) j S(O) m R 21 , —(CH 2 ) j S(O) 2 NR 18 R 19  or —(CH 2 ) j NR 20 S(O) 2 R 21 , wherein each j is independently an integer from 0 to 6, and each m is independently an integer from 0 to 2; 
 R 17 , R 18 , R 19 , R 20  and R 21  are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, perfluoroalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted —O-aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted —O-heteroaryl, or substituted or unsubstituted heteroarylalkyl, or 
 R 17 , R 20  and R 21  are as described above, and R 18  and R 19 , together with the N atom to which they are attached, form substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl; 
 with the proviso that the compound of formula I is not GAP-DMORIE; and 
 one or more counter ions. 
 
     
     
         2 . An adjuvant composition comprising a mixture of one or more cationic lipids having formula I: 
       
         
           
           
               
               
           
         
       
       or an enantiomer, diastereomer, or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  and R 2  are each independently substituted or unsubstituted alkyl (includes alkenyl and alkynyl), substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted carboxyalkyl, wherein R 1  and R 2  are each optionally independently substituted with 1 to 5 R 6  groups; 
 L 1  and L 2  are each independently a direct bond, O, NH, N(C 1 -C 6  alkyl), Se, Te, or S(O) m , wherein m is an integer from 0 to 2; 
 n is an integer from 0 to 6; 
 Q is independently -Z 1 N + Z 2 - or -Z 1 P + Z 2 -; 
 Z 1  and Z 2  are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted carboxyalkyl, or substituted or unsubstituted —(CH 2 ) m —R 3  wherein m is an integer from 1 to 6, and wherein Z 1  and Z 2  are each optionally independently substituted with 1 to 5 R 16  groups; 
 T is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted carboxyalkyl; wherein T is optionally independently substituted with 1 to 5 R 16  groups; and 
 R 3  is independently-OR 4 , —S(O) m R 5 , —NR 6 R 7 , —N + R 8 R 9 R 10 , —PR 11 R 12 , or —P + R 13 R 14 R 15 ; 
 R 4  and R 5  are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted carboxyalkyl, wherein R 4  and R 5  are each optionally independently substituted with 1 to 5 R 16  groups; 
 R 6  and R 7  are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted carboxyalkyl, or R 6  and R 7 , together with the N atom to which they are attached, form substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl, wherein R 6  and R 7  are each optionally independently substituted with 1 to 5 R 16  groups; 
 R 8 , R 9  and R 10  are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted carboxyalkyl, or R 8  is as described, and R 9  and R 10 , together with the N atom to which they are attached, form substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl, wherein R 8 , R 9  and R 10  are each optionally independently substituted with 1 to 5 R 16  groups; 
 R 11 , R 12  and R 13  are each independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted carboxyalkyl, or R 11  is as described, and R 12  and R 13 , together with the P atom to which they are attached, form substituted or unsubstituted heterocycloalkyl, wherein R 11 , R 12  and R 13  are each optionally independently substituted with 1 to 5 R 16  groups; 
 R 16  is hydrogen, halogen, nitro, cyano, hydroxyl, alkyl, cycloalkyl, perfluoroalkyl, heteroalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —(CH 2 ) j CN, —(CH 2 ) j OR 17 , —(CH 2 ) j C(O)R 17 , —(CH 2 ) j C(O)OR 17 , —(CH 2 ) j NR 17 R 18 , —(CH 2 ) j C(O)NR 18 R 19 , —(CH 2 ) j OC(O)NR 18 R 19 , —(CH 2 ) j NR 20 C(O)R 17 , —(CH 2 ) j NR 20 C(O)OR 27 —(CH 2 ) j N 20 C(O)NR 18 R 19 , —(CH 2 ) j S(O) m R 21 , —(CH 2 ) j S(O) 2 NR 18 R 19 , or —(CH 2 ) j NR 20 S(O) 2 R 21 , wherein each j is independently an integer from 0 to 6, and each m is independently an integer from 0 to 2; 
 R 17 , R 18 , R 19 , R 20  and R 21  are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, perfluoroalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted —O-aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted —O-heteroaryl, or substituted or unsubstituted heteroarylalkyl, or 
 R 17 , R 20  and R 21  are as described above, and R 18  and R 19 , together with the N atom to which they are attached, form substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl; 
 with the proviso that the compound of formula I is not GAP-DMORIE; 
 one or more counter ions, and 
 one or more co-lipids. 
 
     
     
         3 . The adjuvant composition of  claim 2 , wherein:
 R 1  and R 2  are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;   L 1  and L 2  are each independently O or NH;   n is 1; and   Q is independently -Z 1 N + Z 2 -.   
     
     
         4 . The adjuvant composition of  claim 3 , wherein R 1  and R 2  are each independently substituted or unsubstituted (C 1 -C 20 )alkyl, substituted or unsubstituted (C 2 -C 20 )alkenyl, or substituted or unsubstituted (C 2 -C 20 )alkynyl. 
     
     
         5 . The adjuvant composition of  claim 4 , wherein R 1  and R 2  are each independently: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The adjuvant composition of  claim 3 , wherein:
 Z 1  and Z 2  are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted carboxyalkyl; and   T is substituted or unsubstituted alkyl.   
     
     
         7 . The adjuvant composition of  claim 6 , wherein:
 Z 1  and Z 2  are each independently (C 1 -C 6 )alkyl; and   T is independently (C 1 -C 6 )alkyl.   
     
     
         8 . The adjuvant composition of  claim 3 , wherein:
 Z 1  and Z 2  are each independently substituted or unsubstituted —(CH 2 ) m —R 3 ;   T is substituted or unsubstituted alkyl; and   R 3  is independently —NR 6 R 7  or —N + R 8 R 9 R 10 .   
     
     
         9 . The adjuvant composition of  claim 8 , wherein:
 T is independently (C 1 -C 6 )alkyl;   R 3  is independently —NR 6 R 7 ; and   R 6  and R 7  are each independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or R 6  and R 7 , together with the N atom to which they are attached, form substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl.   
     
     
         10 . The adjuvant composition of  claim 9 , wherein R 6  and R 7  are each independently substituted or unsubstituted (C 1 -C 6 )alkyl. 
     
     
         11 . The adjuvant composition of  claim 9 , wherein R 6  and R 7 , together with the N atom to which they are attached, form substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrazolinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted thiomorpholinyl. 
     
     
         12 . The adjuvant composition of  claim 8 , wherein:
 T is independently (C 1 -C 6 )alkyl;   R 3  is independently —N + R 8 R 9 R 10 ; and   R 8 , R 9  and R 10  are each independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or R 8  is as described, and R 9  and R 10 , together with the N atom to which they are attached, form substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl.   
     
     
         13 . The adjuvant composition of  claim 12 , wherein R 8 , R 9  and R 10  are each independently substituted or unsubstituted (C 1 -C 6 )alkyl. 
     
     
         14 . The adjuvant composition of  claim 12 , wherein R 9  and R 10 , together with the N atom to which they are attached, form substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrazolinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted thiomorpholinyl. 
     
     
         15 . The adjuvant composition of  claim 2 , wherein the counter ion is negatively charged. 
     
     
         16 . The adjuvant composition of  claim 15 , wherein the negatively charged counter ion is F − , Cl − , Br − , I − , CH 3 COO − , CF 3 COO − , or any pharmaceutically acceptable negatively charged counter ion. 
     
     
         17 . The adjuvant composition of  claim 2 , wherein the co-lipid is a neutral lipid. 
     
     
         18 . The adjuvant composition of  claim 17 , wherein the neutral lipid is a phosphatidylethanolamine, and/or a phosphatidylcholine, and/or a mono-, di-, or trialkylglycerol, and/or a mono-, di-, or triacylglycerol. 
     
     
         19 . The adjuvant composition of  claim 18 , wherein the phosphatidylethanolamine is 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and/or 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (DPyPE), and/or 1,2-dimyristoyl-glycero-3-phosphoethanolamine (DMPE). 
     
     
         20 . The adjuvant composition of  claim 19 , wherein the phosphatidylethanolamine is 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (DPyPE). 
     
     
         21 . The adjuvant composition of  claim 2 , wherein the compound of formula I and the co-lipid ratio is from about 9:1 to about 1:9. 
     
     
         22 . The adjuvant composition of  claim 2 , wherein the compound of formula I and the co-lipid are in molar ratio of from about 4:1 to about 1:4. 
     
     
         23 . The adjuvant composition of  claim 2 , wherein the compound of formula I and the co-lipid are in molar ratio of from about 2:1 to about 1:2. 
     
     
         24 . The adjuvant composition of  claim 2 , wherein the compound of formula I and the co-lipid are in molar ratio of about 1:1. 
     
     
         25 . The adjuvant composition of  claim 2 , wherein the compound of formula I and DPyPE are in molar ratio of from about 2:1 to about 1:2. 
     
     
         26 . The adjuvant composition of  claim 2 , wherein the compound of formula I and DPyPE are in molar ratio of about 1:1. 
     
     
         27 . The adjuvant composition of  claim 2 , wherein the compound of formula I has formulae: 
       
         
           
           
               
               
           
         
       
     
     
         28 . A method for immunizing a vertebrate comprising administering into a tissue or cavity of the vertebrate an immunogenic composition comprising (a) one or more immunogen-encoding polynucleotide, peptides or polypeptides, or polysaccharides in an amount sufficient to generate an immune response to the one or more peptides or polypeptides, or polysaccharides, and (b) the adjuvant composition of  claim 2 . 
     
     
         29 . The method of  claim 28 , wherein the immunogen-encoding polynucleotide, upon incorporation into the cells of the vertebrate, produces an immunologically effective amount of an immunogen (e.g., an immunogenic protein). 
     
     
         30 . The method of  claim 29 , wherein the adjuvant composition of  claim 2  enhances the immune response of the vertebrate to the immunogen. 
     
     
         31 . A method for immunizing a vertebrate comprising intradermally administering an immunogenic composition comprising (a) one or more immunogen-encoding polynucleotide, peptides or polypeptides, or polysaccharides in an amount sufficient to generate an immune response to the one or more peptides or polypeptides, or polysaccharides, and (b) an adjuvant composition. 
     
     
         32 . The method of  claim 31 , wherein the adjuvant composition comprises formula I or formula II and one or more co-lipids. 
     
     
         33 . The method of  claim 31 , wherein the adjuvant composition comprises GAP-DMORIE and DPyPE. 
     
     
         34 . A compound having formula II: 
       
         
           
           
               
               
           
         
       
       or an enantiomer, diastereomer, or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1  and R 2  are each independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted carboxyalkyl, wherein R 1  and R 2  are each optionally independently substituted with 1 to 5 R 16  groups; 
 L 1  and L 2  are each independently a direct bond, O, NH, N(C 1 -C 6  alkyl), or S(O) m , wherein m is an integer from 0 to 2; 
 n is an integer from 1 to 3; 
 Q′ is independently —N + Z 1 - or —P + Z 1 -; 
 Z 1  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted carboxyalkyl, or substituted or unsubstituted —(CH 2 ) m —R 3  wherein m is an integer from 1 to 6, and wherein Z 1  is optionally independently substituted with 1 to 5 R 16  groups; 
 T is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted carboxyalkyl; wherein Q is optionally independently substituted with 1 to 5 R 16  groups; and 
 R 3  is independently —OR 4 , —S(O) m R 5 , —NR 6 R 7 , —N + R 8 R 9 R 10 , —PR 11 R 12 , or —P + R 13 R 14 R 15 ; 
 R 4  and R 5  are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted carboxyalkyl, wherein R 4  and R 5  are each optionally independently substituted with 1 to 5 R 16  groups; 
 R 6  and R 7  are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted carboxyalkyl, or R 6  and R 7 , together with the N atom to which they are attached, form substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl, wherein R 6  and R 7  are each optionally independently substituted with 1 to 5 R 16  groups; 
 R 8 , R 9  and R 1  are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted carboxyalkyl, or R 8  is as described, and R 9  and R 10 , together with the N atom to which they are attached, form substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl, wherein R 8 , R 9  and R 10  are each optionally independently substituted with 1 to 5 R 16  groups; 
 R 11 , R 12  and R 13  are each independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted carboxyalkyl, or R 11  is as described, and R 12  and R 13 , together with the P atom to which they are attached, form substituted or unsubstituted heterocycloalkyl, wherein R 11 , R 12  and R 13  are each optionally independently substituted with 1 to 5 R 16  groups; 
 R 16  is hydrogen, halogen, nitro, cyano, hydroxyl, alkyl, cycloalkyl, perfluoroalkyl, heteroalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —(CH 2 ) j CN, —(CH 2 ) j OR 17 , —(CH 2 ) j C(O)R 17 , —(CH 2 ) j C(O)OR 17 , —(CH 2 ) j NR 18 R 19 , —(CH 2 ) j C(O)NR 18 R 19 , —(CH 2 ) j OC(O)NR 18 R 19 , —(CH 2 ) j NR 20 C(O)R 17 , —(CH 2 ) j NR 20 C(O)OR 17 , —(CH 2 ) j N 20 C(O)NR 18 R 19 , —(CH 2 ) j S(O) m R 21 , —(CH 2 ) j S(O) 2 NR 18 R 19 , or —(CH 2 ) j NR 20 S(O) 2 R 21 , wherein each j is independently an integer from 0 to 6, and each m is independently an integer from 0 to 2; 
 R 17 , R 18 , R 19 , R 20  and R 21  are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, perfluoroalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted —O-aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted —O-heteroaryl, or substituted or unsubstituted heteroarylalkyl, or 
 R 17 , R 20  and R 21  are as described above, and R 18  and R 19 , together with the N atom to which they are attached, form substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl; and 
 one or more counter ions.