Tlr agonists

Abstract

The present invention provides for TLR agonist conjugates (compounds) and compositions, as well as methods of using them. The compounds of the invention are broad-spectrum, long-lasting, and non-toxic combination of synthetic immunostimulatory agents, which are useful for activating the immune system of a mammal, preferably a human and can help direct the pharmacophore to the receptor within the endosomes of target cells and enhance the signal transduction induced by the pharmacophore.

1 . A compound having formula (IA): 
     
       
         
         
             
             
         
       
       wherein X 1  is —O—, —S—, or —NR c —; 
       wherein R c  is hydrogen, C 1-10 alkyl, or substituted C 1-10 alkyl, or R c  and R 1  taken together with the nitrogen atom can form a heterocyclic ring or a substituted heterocyclic ring, wherein the substituents on the alkyl, aryl or heterocyclic groups are hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkylene, C 1-6 alkoxy, C 3-6 cycloalkyl, C 1-6 alkoxyC 1-6 alkylene, amino, cyano, halogen, or aryl; 
       R 1  is hydrogen, (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )alkyl, C 6-10 aryl, or substituted C 6-10 aryl, C 5-9 heterocyclic, substituted C 5-9 heterocyclic; wherein the substituents on the alkyl, aryl or heterocyclic groups are hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkylene, C 1-6 alkoxy, C 3-6 cycloalkyl, C 1-6 alkoxyC 1-6 alkylene, amino, cyano, halogen, or aryl; 
       each R 2  is independently hydrogen, —OH, (C 1 -C 6 )alkyl, substituted (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, substituted (C 1 -C 6 )alkoxy, —C(O)—(C 1 -C 6 )alkyl (alkanoyl), substituted —C(O)—(C 1 -C 6 )alkyl, —C(O)—(C 6 -C 10 )aryl (aroyl), substituted —C(O)—(C 6 -C 10 )aryl, —C(O)OH (carboxyl), —C(O)O(C 1 -C 6 )alkyl (alkoxycarbonyl), substituted —C(O)O(C 1 -C 6 )alkyl, —NR a R b , —C(O)NR a R b  (carbamoyl), substituted —C(O)NR a R b , halo, nitro, or cyano; wherein the substituents on the alkyl, aryl or heterocyclic groups are hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkylene, C 1-6 alkoxy, C 3-6 cycloalkyl, C 1-6 alkoxyC 1-6 alkylene, amino, cyano, halogen, or aryl; 
       each R a  and R b  is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, hydroxy(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, Het, Het (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxycarbonyl; 
       X 2  is a bond or a linking group; and R 3  is an auxiliary group; 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       2 . The compound of  claim 1 , wherein X 1  is sulfur atom. 
   
   
       3 . The compound of  claim 1 , wherein X 1  is oxygen atom. 
   
   
       4 . The compound of  claim 1 , wherein X 1  is —NR c —, wherein R c  is hydrogen, C 1-6  alkyl or substituted C 1-6  alkyl;
 wherein the alkyl substituents are C 3-6 cycloalkyl, hydroxy, C 1-6 alkoxy, amino, cyano, or aryl.   
   
   
       5 . The compound of  claim 4 , wherein X 1  is —NH—. 
   
   
       6 . The compound of  claim 1 , wherein R 1  and R c  taken together form a heterocyclic ring or a substituted heterocyclic ring. 
   
   
       7 . The compound of  claim 6 , wherein R 1  and R c  taken together form a substituted or unsubstituted morpholino, piperidino, pyrrolidino, or piperazino ring. 
   
   
       8 . The compound of  claim 1 , wherein R 1  is hydrogen, C 1-4 alkyl, or substituted C 1-4 alkyl. 
   
   
       9 . The compound of  claim 8 , wherein R 1  is hydrogen, CH 3 —, CH 3 —CH 2 —, CH 3 CH 2 CH 2 —, hydroxyC 1-4 alkylene, or C 1-4 alkoxyC 1-4 alkylene. 
   
   
       10 . The compound of  claim 9 , wherein R 1  is hydrogen, CH 3 —, CH 3 —CH 2 —, CH 3 —O—CH 2 CH 2 — or CH 3 —CH 2 —O—CH 2 CH 2 —. 
   
   
       11 . The compound of  claim 1 , wherein R 2  is hydrogen, halogen, or C 1-4 alkyl. 
   
   
       12 . The compound of  claim 11 , wherein R 2  is hydrogen, chloro, bromo, CH 3 —, or CH 3 —CH 2 —. 
   
   
       13 . The compound of  claim 1 , wherein the substituents on the alkyl, aryl or heterocyclic groups are hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkylene, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkylene, C 3-6 cycloalkyl, amino, cyano, halogen, or aryl. 
   
   
       14 . The compound of  claim 1 , wherein X 2  is a bond or a chain having up to about 24 atoms; wherein the atoms are selected from the group consisting of carbon, nitrogen, sulfur, non-peroxide oxygen, and phosphorous. 
   
   
       15 . The compound of  claim 14 , wherein X 2  is a bond or a chain having from about 4 to about 12 atoms. 
   
   
       16 . The compound of  claim 14 , wherein X 2  is a bond or a chain having from about 6 to about 9 atoms. 
   
   
       17 . The compound of  claim 14 , wherein X 2  is 
     
       
         
         
             
             
         
       
     
   
   
       18 . The compound of  claim 1 , wherein the auxiliary group is an amino acid, a carbohydrate, a peptide, an antigen, a nucleic acid, a body substance, or a microbe. 
   
   
       19 . The compound of  claim 18 , wherein the peptide, has from 2 to about 200 amino acid residues. 
   
   
       20 . The compound of  claim 19 , wherein the peptide, has from 10 to about 200 amino acid residues. 
   
   
       21 . The compound of  claim 1 , wherein the auxiliary group is a carbohydrate. 
   
   
       22 . The compound of  claim 18 , wherein the nucleic acid is DNA, RNA or PNA. 
   
   
       23 . The compound of  claim 18 , wherein the body substance is a cell, lipid, vitamin, or co-factor. 
   
   
       24 . The compound of  claim 23 , wherein the body substance is a cell, or lipid. 
   
   
       25 . The compound of  claim 18 , wherein the antigen is a microbe. 
   
   
       26 . The compound of  claim 25 , wherein the microbe is a virus, bacteria, parasite, or fungi. 
   
   
       27 . The compound of  claim 26 , wherein the microbe is a virus or a bacteria. 
   
   
       28 . The compound of  claim 27 , wherein the bacteria is  Bacillus anthracis  (anthrax),  Listeria monocytogenes, Francisella tularensis , or  Salmonella.    
   
   
       29 . The compound of  claim 28 , wherein the  Salmonella  is  typhimurium  or  enteritidis.    
   
   
       30 . The compound of  claim 26 , wherein the virus is an RNA virus, a product of the RNA virus, or a DNA virus. 
   
   
       31 . The compound of  claim 30 , wherein the DNA virus is the Hepatitis B virus. 
   
   
       32 . A pharmaceutical composition comprising the compound of  claim 1 , and a pharmaceutically acceptable carrier. 
   
   
       33 . A therapeutic method for preventing or treating a pathological condition or symptom in a mammal, wherein the activity of TLR receptors is implicated and agonism of such activity is desired, comprising administering to a mammal in need of such therapy, an effective amount of the compound of  claim 1 . 
   
   
       34 . The method of  claim 33 , wherein the condition or symptom is cancer, bacterial disease, viral disease, autoimmune disease, or Crohn's Disease. 
   
   
       35 . The method of  claim 34 , wherein the bacteria is  Bacillus anthracis  (anthrax),  Listeria monocytogenes, Francisella tularensis , or  Salmonella.    
   
   
       36 . The method of  claim 35 , wherein the  Salmonella  is  typhimurium  or  enteritidis.    
   
   
       37 . The method of  claim 34 , wherein the virus is an RNA virus, a product of the RNA virus, or a DNA virus. 
   
   
       38 . The method of  claim 37 , wherein the DNA virus is the Hepatitis B virus. 
   
   
       39 . The method of  claim 34 , wherein cancer can be an interferon sensitive cancer, such as, for example, a leukemia, a lymphoma, a myeloma, a melanoma, or a renal cancer. 
   
   
       40 - 41 . (canceled) 
   
   
       42 . A method to treat cancer, bacterial disease, viral disease, autoimmune disease, or Crohn's Disease, comprising administering a composition comprising an effective amount of the compound of  claim 1 . 
   
   
       43 . The method of  claim 42 , wherein the composition includes a physiologically acceptable carrier. 
   
   
       44 . A compound of formula (II): 
     
       
         
         
             
             
         
       
       wherein X 1  is —O—, —S—, or —NR c —; 
       wherein R c  hydrogen, C 1-10 alkyl, or C 1-10 alkyl substituted by C 3-6 cycloalkyl, or R c  and R 1  taken together with the nitrogen atom can form a heterocyclic ring or a substituted heterocyclic ring, wherein the substituents are hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkylene, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkylene, or cyano; 
       R 1  is (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )alkyl, C 6-10 aryl, or substituted C 6-10 aryl, C 5-9 heterocyclic, substituted C 5-9 heterocyclic; 
       each R 2  is independently hydrogen, —OH, (C 1 -C 6 )alkyl, substituted (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, substituted (C 1 -C 6 )alkoxy, —C(O)—(C 1 -C 6 )alkyl (alkanoyl), substituted —C(O)—(C 1 -C 6 )alkyl, —C(O)—(C 6 -C 10 )aryl (aroyl), substituted —C(O)—(C 6 -C 10 )aryl, —C(O)OH (carboxyl), —C(O)O(C 1 -C 6 )alkyl (alkoxycarbonyl), substituted —C(O)O(C 1 -C 6 )alkyl, —NR a R b , —C(O)NR a R b  (carbamoyl), substituted —C(O)NR a R b , halo, nitro, or cyano; 
       each R a  and R b  is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, hydroxy(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, Het, Het (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxycarbonyl; 
       X 2  is a bond or a linking group; and R 3  is an auxiliary group; 
       n is 1, 2, 3, or 4; m is 1 or 2; q is 1 or 2; or 
       a pharmaceutically acceptable salt thereof. 
     
   
   
       45 . A compound of formula (III): 
     
       
         
         
             
             
         
       
       wherein X 1  is —O—, —S—, or —NR c —; 
       wherein R c  is hydrogen, C 1-10 alkyl, or substituted C 1-10 alkyl, or R c  and R 1  taken together with the nitrogen atom can form a heterocyclic ring or a substituted heterocyclic ring, wherein the substituents on the alkyl, aryl or heterocyclic groups are hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkylene, C 1-6 alkoxy, C 3-6 cycloalkyl, C 1-6 alkoxyC 1-6 alkylene, amino, cyano, halogen, or aryl; 
       R 1  is hydrogen, (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )alkyl, C 6-10 aryl, or substituted C 6-10 aryl, C 5-9 heterocyclic, substituted C 5-9 heterocyclic; wherein the substituents on the alkyl, aryl or heterocyclic groups are hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkylene, C 1-6 alkoxy, C 3-6 cycloalkyl, C 1-6 alkoxyC 1-6 alkylene, amino, cyano, halogen, or aryl; 
       each R 2  is independently hydrogen, —OH, (C 1 -C 6 )alkyl, substituted (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, substituted (C 1 -C 6 )alkoxy, —C(O)—(C 1 -C 6 )alkyl (alkanoyl), substituted —C(O)—(C 1 -C 6 )alkyl, —C(O)—(C 6 -C 10 )aryl (aroyl), substituted —C(O)—(C 6 -C 10 )aryl, —C(O)OH (carboxyl), —C(O)O(C 1 -C 6 )alkyl (alkoxycarbonyl), substituted —C(O)O(C 1 -C 6 )alkyl, —NR a R b , —C(O)NR a R b  (carbamoyl), substituted —C(O)NR a R b , halo, nitro, or cyano; wherein the substituents on the alkyl, aryl or heterocyclic groups are hydroxy, C 1-6 alkyl, hydroxyC 1-6 alkylene, C 1-6 alkoxy, C 3-6 -cycloalkyl, C 1-6 alkoxyC 1-6 alkylene, amino, cyano, halogen, or aryl; 
       each R a  and R b  is independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, hydroxy(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, Het, Het (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxycarbonyl; 
       X 2  is a bond or a linking group; and R 3  is an auxiliary group; 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       46 . The compound of  claim 45  wherein if m is 2, a linker (L) links each R 3 .