Modulators of toll-like receptors for the treatment of hiv

Abstract

Provided are methods, uses, pharmaceutical regimens, pharmaceutical compositions, and kits comprising modulators of TLR7, including those of Formula II:and pharmaceutically acceptable salts thereof, useful in treating HIV infections.

1 .- 19 . (canceled) 
     
     
         20 . A method of treating an HIV infection in a virologically suppressed human in need thereof, the method comprising administering to the virologically suppressed human a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof, and a broadly neutralizing HIV antibody,
 wherein the TLR7 modulating compound is a compound of Formula III, or a pharmaceutically acceptable salt thereof:   
       
         
           
           
               
               
           
         
       
       wherein:
 the D ring represents a moiety selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         wherein, in each instance, the pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, or morpholinomethyl group is bound to the 3-position or 4-position of the phenyl ring to which it is bound; 
         L 1  is —O—; and 
         R 1  is unsubstituted C 1 -C 8  alkyl. 
       
     
     
         21 . The method of  claim 20 , wherein the measurable viral load in the human is less than 200 copies, less than 100 copies, less than 50 copies, less than 40 copies, less than 30 copies, or less than 20 copies of HIV-1 RNA per mL blood or plasma. 
     
     
         22 . The method of  claim 20 , wherein the TLR7 modulating compound is a compound of Formula III(a), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein the pyrrolidin-1-ylmethyl group is bound to the 3-position or 4-position of the phenyl ring. 
       
     
     
         23 . The method of  claim 20 , wherein the TLR7 modulating compound is a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The method of  claim 20 , wherein the TLR7 modulating compound is a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The method of  claim 20 , wherein the broadly neutralizing HIV antibody comprises a glycan V3-directed antibody. 
     
     
         26 . The method of  claim 25 , wherein the glycan V3-directed antibody is selected from the group consisting of PGT121, PGT122, PGT123, PGT124, PGT125, PGT126, PGT127, PGT128, PGT130, PGT131, PGT132, PGT135, PGT136, PGT137, and 2G12. 
     
     
         27 . The method of  claim 25 , wherein the glycan V3-directed antibody comprises a PGT121-series antibody. 
     
     
         28 . The method of  claim 20 , wherein the broadly neutralizing HIV antibody comprises a CD4-binding site-directed antibody. 
     
     
         29 . The method of  claim 28 , wherein the CD4-binding site-directed antibody is selected from the group consisting of VRC01, VRCO2, VRC03, VRC04, VR0007, b12, HJ16, NIH45-46, 3BNC60, BNC62, 3BNC117, 12A12, 12A21, 12A30, VRC-PG04, VRC-CH 30 , VRC-CH 31 , VRC-CH 32 , VRC-CH 33 , VRC-CH 34 , VRC-PG04b, 8ANC131, 8ANC37, 8ANC134, CH 103 , CH 104 , CH 105 , CH 106 , NIH45, NIH46, 1NC9, 1B2530, 7B2, and A32. 
     
     
         30 . The method of  claim 20 , wherein the broadly neutralizing HIV antibody comprises a gp-120 variable region 1 and variable region 2 (V1/V2)-directed antibody. 
     
     
         31 . The method of  claim 30 , wherein the V1/V2-directed antibody is selected from the group consisting of PG9, PG16, CH 01 -04, PGT141, PGT142, PGT143, PGT144, PGT145, and CAP256-VRC26. 
     
     
         32 . The method of  claim 20 , wherein the broadly neutralizing HIV antibody is selected from the group consisting of PGT-138, PGT-139, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-141, PGT-142, PGT-143, PGT-144, PGT-145, PGT-151, PGT-152, PGT-153, PGT-154, PGT-155, PGT-156, PGT-157, and PGT-158. 
     
     
         33 . The method of  claim 20 , further comprising the step of administering to the human in need thereof a pharmaceutically effective amount of a combination antiretroviral therapy regimen. 
     
     
         34 . The method of  claim 33 , wherein the combination antiretroviral therapy regimen comprises one or more agents selected from the group consisting of raltegravir, elvitegravir, soltegravir, GSK 1265744, dolutegravir, didanosine, tenofovir disoproxil fumarate, tenofovir alafenamide, emtricitabine, lamivudine, stavudine, zidovudine, abacavir, elvucitabine, CMX-157, festinavir, nevirapine, efavirenz, etravirine, rilpivirine, fosdevirine, MK-1439, lersivirine, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, fosamprenavir, maraviroc, enfuvirtide, BMS-663068, bevirimat, cobicistat, and ritonavir; or a pharmaceutically acceptable salt thereof. 
     
     
         35 . The method of  claim 20 , further comprising the step of administering to the human a pharmaceutically effective amount of a latency-reversing agent. 
     
     
         36 . A method of treating an HIV infection in a virologically suppressed human in need thereof, the method comprising administering to the virologically suppressed human a pharmaceutically effective amount of a TLR7 modulating compound and an HIV vaccine,
 wherein the TLR7 modulating compound is a compound of Formula III, or a pharmaceutically acceptable salt thereof:   
       
         
           
           
               
               
           
         
       
       wherein:
 the D ring represents a moiety selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         wherein, in each instance, the pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, or morpholinomethyl group is bound to the 3-position or 4-position of the phenyl ring to which it is bound;
 L 1  is —O—; and 
 
         R 1  is unsubstituted C 1 -C 8  alkyl. 
       
     
     
         37 . The method of  claim 36 , wherein the HIV vaccine comprises a viral vector. 
     
     
         38 . The method of  claim 37 , wherein the viral vector comprises a live vector vaccine, an inactivated vaccine, or a modified envelope vaccine. 
     
     
         39 . The method of  claim 37 , wherein the viral vector is developed from Adenoviridae, Poxviridae, Herpesviridae, Adeno-associated viruses, rubella poliovirus, Venezuelan equine encephalitis virus, lentivirus or Sendai vectors. 
     
     
         40 . The method of  claim 37 , wherein the viral vector is selected from the group consisting of tgAAC09 (a Gag-PR-RT AAV HIV vaccine), Ad35, Ad35-GRIN/ENV, Ad35-GRIN, Ad35-ENV, Ad4-EnvC150, MRKAd5 HIV-1 Gag, MRKAd5 HIV-1 gag/pol/nef, ADVAX e/g+ADVAX p/N-t (ADVAX), Ad26, Ad26.ENVA.01 (rAd26), Modified Vaccinia Ankara (MVA), Ad26/MVA, VRC rAd5 vaccine (rAd5 gag-pol/env A/B/C), rAd5 env A, rAd5 env B, rAd5 env C, rAd5 gag-pol, MRKAd5 (Clade B), MRKAd5 HIV-1 gag/pol/nef, Trivalent MRKAd5 HIV-1 gag/pol/nef, HIVAC-le, rAAV1-PG9DP, Ad5.ENVA.48 HIV-1, rAd5 Gag-Pol Env A B/C, Ad4-H5-VTN, Ad35-ENVA, Ad5HVR48.ENVA.01, ADVAX e/g, ADVAX p/n-t, and rAd35. 
     
     
         41 . The method of  claim 37 , wherein the viral vector comprises an Ad26 vector or a Modified Vaccinia Ankara (MVA) vector. 
     
     
         42 . A method of treating an HIV infection in a virologically suppressed human in need thereof, the method comprising administering to the virologically suppressed human a pharmaceutically effective amount of a TLR7 modulating compound, a broadly neutralizing HIV antibody, and an HIV vaccine,
 wherein the TLR7 modulating compound is a compound of Formula III, or a pharmaceutically acceptable salt thereof:   
       
         
           
           
               
               
           
         
       
       wherein:
 the D ring represents a moiety selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         wherein, in each instance, the pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, or morpholinomethyl group is bound to the 3-position or 4-position of the phenyl ring to which it is bound; 
         L 1  is —O—; and 
         R 1  is unsubstituted C 1 -C 8  alkyl. 
       
     
     
         43 . The method of  claim 42 , wherein the broadly neutralizing HIV antibody comprises a glycan V3-directed antibody. 
     
     
         44 . The method of  claim 43 , wherein the glycan V3-directed antibody comprises a PGT121-series antibody. 
     
     
         45 . The method of  claim 42 , wherein the broadly neutralizing HIV antibody comprises a CD4-binding site-directed antibody. 
     
     
         46 . The method of  claim 42 , wherein the broadly neutralizing HIV antibody is 3BNC117. 
     
     
         47 . The method of  claim 42 , wherein the HIV vaccine comprises a viral vector. 
     
     
         48 . The method of  claim 47 , wherein the viral vector is developed from Adenoviridae, Poxviridae, Herpesviridae, Adeno-associated viruses, rubella poliovirus, Venezuelan equine encephalitis virus, lentivirus or Sendai vectors. 
     
     
         49 . The method of  claim 47 , wherein the viral vector comprises an Ad26 vector or a Modified Vaccinia Ankara (MVA) vector.