Small Molecule Inhibitors of Toll-Like Receptor 9

Abstract

Small molecule compounds and compositions containing said compounds useful for inhibiting signaling by certain Toll-like receptors (TLRs), particularly TLR9, are provided. The compounds and compositions can be used to inhibit immune responses, including unwanted immune responses in particular. Compounds, compositions, and methods are provided to treat a variety of conditions involving unwanted immune responses, including for example autoimmune disease, inflammation, transplant rejection, and sepsis.

1 . A compound having a structure selected from 
       
         
           
           
               
               
           
         
       
       wherein
 X 1 , X 2 , X 3 , and X 4  are independently nitrogen or carbon; 
 R 1  and R 2  are independently absent, hydrogen, optionally substituted alkyl, optionally substituted alkoxy, or halide; 
 R 3  is absent, hydrogen, optionally substituted alkyl, optionally substituted alkoxy, halide, Y 1 , or Y 3 ; 
 R 4  is a group having the structure, 
 
       
         
           
           
               
               
           
         
         where R 9  is hydrogen or optionally substituted alkyl; L is optionally substituted alkyl; R 10  and R 11  are independently hydrogen or optionally substituted alkyl; and together R 10  and R 11  can be joined to form an optionally substituted heterocycle, or together R 9  and one of R 10  or R 11  can be joined to form an optionally substituted heterocycle; 
         R 5  is absent or hydrogen; 
         R 6  and R 7  are independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, halide, Y 1 , or Y 2 ; and 
         R 8  is hydrogen, optionally substituted alkyl, optionally substituted alkoxy, halide, Y 1 , or Y 3 ; 
       
       wherein
 Y 1  is Ar—Y 2 , where Ar is optionally substituted phenyl; 
 Y 2  is W-L 1 NR 12 R 13 , where W is O, S, or NR 14 ; L 1  is optionally substituted alkyl; R 12 , R 13 , and R 14  are independently hydrogen or optionally substituted alkyl; and together R 12  and R 13  can be joined to form an optionally substituted heterocycle, or together R 14  and one of R 12  or R 13  can be joined to form an optionally substituted heterocycle; 
 Y 3  is optionally substituted phenyl; and 
 at least one of R 3 , R 6 , R 7 , and R 8  is Y 1 ; or at least one of R 6  and R 7  is Y 2 ; and/or at least one of R 3  and R 8  is Y 3 . 
 
     
     
         2 .- 156 . (canceled) 
     
     
         157 . A compound having a structure selected from 
       
         
           
           
               
               
           
         
       
       wherein
 X 1 , X 3 , and X 4  are independently nitrogen or carbon; 
 R 3  is absent, hydrogen, optionally substituted alkyl, optionally substituted alkoxy, or halide; 
 R 4  is a group having the structure, 
 
       
         
           
           
               
               
           
         
         where R 9  is hydrogen or optionally substituted alkyl; L is optionally substituted alkyl; R 10  and R 11  are independently hydrogen or optionally substituted alkyl; and together R 10  and R 11  can be joined to form an optionally substituted heterocycle, or together R 9  and one of R 10  or R 11  can be joined to form an optionally substituted heterocycle; 
         R 5  is absent, hydrogen, optionally substituted alkyl, optionally substituted alkoxy, or halide; 
         R 6 , R 7 , and R 8  are independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, or halide; and 
         Y 1  is Ar—Y 2 , where Ar is optionally substituted phenyl; 
       
       wherein
 Y 2  is W-L 1 NR 12 R 13 , where W is O, S, or NR 14 ; L 1  is optionally substituted alkyl; R 12 , R 13 , and R 14  are independently hydrogen or optionally substituted alkyl; and together R 12  and R 13  can be joined to form an optionally substituted heterocycle, or together R 14  and one of R 12  or R 13  can be joined to form an optionally substituted heterocycle; 
 wherein, when the compound has the structure (IX) wherein X 3  is nitrogen, X 4  is nitrogen. 
 
     
     
         158 .- 172 . (canceled) 
     
     
         173 . A compound having a structure selected from 
       
         
           
           
               
               
           
         
       
       wherein
 X 1 , X 3 , and X 4  are independently nitrogen or carbon; 
 R 3  is absent, hydrogen, optionally substituted alkyl, optionally substituted alkoxy, or halide; 
 R 4  is a group having the structure, 
 
       
         
           
           
               
               
           
         
         where R 9  is hydrogen or optionally substituted alkyl; L is optionally substituted alkyl; R 10  and R 11  are independently hydrogen or optionally substituted alkyl; and together R 10  and R 11  can be joined to form an optionally substituted heterocycle, or together R 9  and one of R 10  or R 11  can be joined to form an optionally substituted heterocycle; 
         R 5  is absent or hydrogen; 
         R 6  and R 8  are independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, halide, or Y 3 ; 
         R 7  is hydrogen, optionally substituted alkyl, optionally substituted alkoxy, or halide; and 
         Y 2  is W-L 1 NR 12 R 13 , where W is O, S, or NR 14 ; L 1  is optionally substituted alkyl; R 12 , R 13 , and R 14  are independently hydrogen or optionally substituted alkyl; and together R 12  and R 13  can be joined to form an optionally substituted heterocycle, or together R 14  and one of R 12  or R 13  can be joined to form an optionally substituted heterocycle; 
       
       wherein
 Y 3  is optionally substituted phenyl. 
 
     
     
         174 .- 222 . (canceled) 
     
     
         223 . A compound having a structure selected from 
       
         
           
           
               
               
           
         
       
       wherein
 X 1 , X 3 , and X 4  are independently nitrogen or carbon; 
 R 3  is absent, hydrogen, optionally substituted alkyl, optionally substituted alkoxy, or halide; 
 R 4  is a group having the structure, 
 
       
         
           
           
               
               
           
         
         where R 9  is hydrogen or optionally substituted alkyl; L is optionally substituted alkyl; R 10  and R 11  are independently hydrogen or optionally substituted alkyl; and together R 10  and R 11  can be joined to form an optionally substituted heterocycle, or together R 9  and one of R 10  or R 11  can be joined to form an optionally substituted heterocycle; 
         R 5  is absent or hydrogen; 
         R 6  and R 7  are independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, halide, or Y 2 ; 
         R 8  is hydrogen, optionally substituted alkyl, optionally substituted alkoxy, or halide; and 
         Y 3  is optionally substituted phenyl; 
       
       wherein
 Y 2  is W-L 1 NR 12 R 13 , where W is O, S, or NR 14 ; L 1  is optionally substituted alkyl; R 12 , R 13 , and R 14  are independently hydrogen or optionally substituted alkyl; and together R 12  and R 13  can be joined to form an optionally substituted heterocycle, or together R 14  and one of R 12  or R 13  can be joined to form an optionally substituted heterocycle. 
 
     
     
         224 .- 272 . (canceled) 
     
     
         273 . A compound having a structure selected from 
       
         
           
           
               
               
           
         
       
       wherein
 X 1 , X 2 , X 3 , and X 4  are independently nitrogen or carbon; 
 R 1 , R 3 , and R 5  are independently absent, hydrogen, optionally substituted alkyl, optionally substituted alkoxy, or halide; 
 R 6  is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, halide, or Y 2 ; 
 R 7 , R 8 , and R 15  are independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, or halide; 
 each Q is independently optionally substituted alkyl or Y 2 ; and 
 n is an integer from 1-5; 
 
       wherein
 Y 2  is W-L 1 NR 12 R 13 , where W is O, S, or NR 14 ; L 1  is optionally substituted alkyl; R 12 , R 13 , and R 14  are independently hydrogen or optionally substituted alkyl; and together R 12  and R 13  can be joined to form an optionally substituted heterocycle, or together R 14  and one of R 12  or R 13  can be joined to form an optionally substituted heterocycle. 
 
     
     
         274 .- 340 . (canceled) 
     
     
         341 . A pharmaceutical composition, comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         342 .- 343 . (canceled) 
     
     
         344 . A pharmaceutical composition, comprising a compound of  claim 157  and a pharmaceutically acceptable carrier. 
     
     
         345 .- 346 . (canceled) 
     
     
         347 . A pharmaceutical composition, comprising a compound of  claim 173  and a pharmaceutically acceptable carrier. 
     
     
         348 .- 349 . (canceled) 
     
     
         350 . A pharmaceutical composition, comprising a compound of  claim 223  and a pharmaceutically acceptable carrier. 
     
     
         351 .- 352 . (canceled) 
     
     
         353 . A pharmaceutical composition, comprising a compound of  claim 273  and a pharmaceutically acceptable carrier. 
     
     
         354 .- 355 . (canceled) 
     
     
         356 . A method for reducing signaling by a Toll-like receptor (TLR), comprising: contacting a cell expressing a TLR, selected from TLR7, TLR8, and TLR9, with an effective amount of a compound of  claim 1  to reduce signaling by the TLR in response to an agonist of the TLR, compared to signaling by the TLR in response to the agonist in absence of the contacting. 
     
     
         357 .- 364 . (canceled) 
     
     
         365 . A method for reducing an immune response, comprising: contacting a population of immune cells expressing a Toll-like receptor (TLR), selected from TLR7, TLR8, and TLR9, with an effective amount of a compound of  claim 1  to reduce an immune response by the immune cells, compared to an immune response by the immune cells in absence of the contacting. 
     
     
         366 .- 377 . (canceled) 
     
     
         378 . A method for treating an autoimmune condition in a subject, comprising: administering to a subject having an autoimmune condition, wherein the autoimmune condition involves signaling by a Toll-like receptor (TLR) selected from TLR7, TLR8, and TLR9, an effective amount of a compound of  claim 1  to treat the autoimmune condition. 
     
     
         379 .- 385 . (canceled) 
     
     
         386 . A method for reducing signaling by a Toll-like receptor (TLR), comprising: contacting a cell expressing a TLR, selected from TLR7, TLR8, and TLR9, with an effective amount of a compound of  claim 157  to reduce signaling by the TLR in response to an agonist of the TLR, compared to signaling by the TLR in response to the agonist in absence of the contacting. 
     
     
         387 . A method for reducing signaling by a Toll-like receptor (TLR), comprising: contacting a cell expressing a TLR, selected from TLR7, TLR8, and TLR9, with an effective amount of a compound of  claim 173  to reduce signaling by the TLR in response to an agonist of the TLR, compared to signaling by the TLR in response to the agonist in absence of the contacting. 
     
     
         388 . A method for reducing signaling by a Toll-like receptor (TLR), comprising: contacting a cell expressing a TLR, selected from TLR7, TLR8, and TLR9, with an effective amount of a compound of  claim 223  to reduce signaling by the TLR in response to an agonist of the TLR, compared to signaling by the TLR in response to the agonist in absence of the contacting. 
     
     
         389 . A method for reducing signaling by a Toll-like receptor (TLR), comprising: contacting a cell expressing a TLR, selected from TLR7, TLR8, and TLR9, with an effective amount of a compound of  claim 273  to reduce signaling by the TLR in response to an agonist of the TLR, compared to signaling by the TLR in response to the agonist in absence of the contacting. 
     
     
         390 . A method for reducing an immune response, comprising: contacting a population of immune cells expressing a Toll-like receptor (TLR), selected from TLR7, TLR8, and TLR9, with an effective amount of a compound of  claim 157  to reduce an immune response by the immune cells, compared to an immune response by the immune cells in absence of the contacting. 
     
     
         391 . A method for reducing an immune response, comprising: contacting a population of immune cells expressing a Toll-like receptor (TLR), selected from TLR7, TLR8, and TLR9, with an effective amount of a compound of  claim 173  to reduce an immune response by the immune cells, compared to an immune response by the immune cells in absence of the contacting. 
     
     
         390 . A method for reducing an immune response, comprising: contacting a population of immune cells expressing a Toll-like receptor (TLR), selected from TLR7, TLR8, and TLR9, with an effective amount of a compound of  claim 223  to reduce an immune response by the immune cells, compared to an immune response by the immune cells in absence of the contacting. 
     
     
         391 . A method for reducing an immune response, comprising: contacting a population of immune cells expressing a Toll-like receptor (TLR), selected from TLR7, TLR8, and TLR9, with an effective amount of a compound of  claim 273  to reduce an immune response by the immune cells, compared to an immune response by the immune cells in absence of the contacting. 
     
     
         392 . A method for treating an autoimmune condition in a subject, comprising: administering to a subject having an autoimmune condition, wherein the autoimmune condition involves signaling by a Toll-like receptor (TLR) selected from TLR7, TLR8, and TLR9, an effective amount of a compound of  claim 157  to treat the autoimmune condition. 
     
     
         393 . A method for treating an autoimmune condition in a subject, comprising: administering to a subject having an autoimmune condition, wherein the autoimmune condition involves signaling by a Toll-like receptor (TLR) selected from TLR7, TLR8, and TLR9, an effective amount of a compound of  claim 173  to treat the autoimmune condition. 
     
     
         394 . A method for treating an autoimmune condition in a subject, comprising: administering to a subject having an autoimmune condition, wherein the autoimmune condition involves signaling by a Toll-like receptor (TLR) selected from TLR7, TLR8, and TLR9, an effective amount of a compound of  claim 223  to treat the autoimmune condition. 
     
     
         395 . A method for treating an autoimmune condition in a subject, comprising: administering to a subject having an autoimmune condition, wherein the autoimmune condition involves signaling by a Toll-like receptor (TLR) selected from TLR7, TLR8, and TLR9, an effective amount of a compound of  claim 273  to treat the autoimmune condition.