Toll like receptor modulator compounds

Abstract

The present disclosure relates generally to toll like receptor modulator compounds, such as diamino pyrido[3,2 D] pyrimidine compounds and pharmaceutical compositions which, among other things, modulate toll-like receptors (e.g. TLR-8), and methods of making and using them.

1 .- 102 . (canceled) 
     
     
         103 . A compound of Formula (IVd), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is selected from the group consisting of hydrogen, halogen, C 1-6  alkyl, CN, and OR a , wherein C 1-6  alkyl is optionally substituted with 1 to 5 R 20  groups; 
         R 2  is selected from the group consisting of hydrogen, halogen, C 1-6  alkyl, CN, and OR a , wherein C 1-6  alkyl is optionally substituted with 1 to 5 R 20  groups; 
         R 3  is selected from the group consisting of hydrogen, halogen, C 1-6  alkyl, CN, and OR a , wherein C 1-6  alkyl is optionally substituted with 1 to 5 R 20  groups; 
         R 11  is selected from the group consisting of hydrogen, and C 1-2  alkyl; 
         R 12a  is selected from the group consisting of hydrogen, C 1-2  alkyl and C 1-3  haloalkyl; 
         R 13  is C 3-6  alkyl; 
         each R 20  is independently selected from the group consisting of halogen, CN, —NR a R b , and OR a ; and 
         each R a  and R b  is independently selected from the group consisting of hydrogen and C 1-3  alkyl, wherein each C 1-3  alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl, amino, and C 1-6  haloalkyl. 
       
     
     
         104 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is selected from the group consisting of hydrogen, halogen, and C 1-3  alkyl, wherein C 1-3  alkyl is optionally substituted with 1 to 5 halogen groups;   R 2  is selected from the group consisting of hydrogen, halogen, C 1-3  alkyl, CN and OR a , wherein C 1-3  alkyl is optionally substituted with 1 to 5 halogen groups; and   R 3  is selected from the group consisting of hydrogen, halogen, and C 1-3  alkyl.   
     
     
         105 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is selected from the group consisting of hydrogen, methyl, fluoro, chloro, and CF 3 ;   R 2  is selected from the group consisting of hydrogen, methyl, ethyl, fluoro, chloro, bromo, CF 3 , CN, OH, OMe, and OEt; and   R 3  is selected from the group consisting of hydrogen, methyl, fluoro, and chloro.   
     
     
         106 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen;   R 2  is selected from the group consisting of hydrogen and fluoro; and   R 3  is selected from the group consisting of hydrogen and methyl.   
     
     
         107 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein R 11  is methyl. 
     
     
         108 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein R 11  is hydrogen. 
     
     
         109 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein
 each R a  and R b  is independently selected from the group consisting of hydrogen and C 1-3  alkyl, wherein each C 1-3  alkyl is optionally substituted with 1 to 3 substituents independently selected from hydroxyl and amino.   
     
     
         110 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein R 13  is propyl, butyl or pentyl. 
     
     
         111 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein R 13  is propyl or butyl. 
     
     
         112 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein:
 R 11  is methyl; and   R 13  is selected from the group consisting of propyl, butyl and pentyl.   
     
     
         113 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein
 R 2  is hydrogen or fluoro; and   R 13  is selected from the group consisting of propyl and butyl.   
     
     
         114 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein
 R 1  is selected from the group consisting of hydrogen, halogen, and C 1-3  alkyl;   R 2  is selected from the group consisting of hydrogen, halogen, and C 1-3  alkyl;   R 3  is selected from the group consisting of hydrogen, halogen, and C 1-3  alkyl;   R 11  is C 1-2  alkyl;   R 12a  is selected from the group consisting of hydrogen, C 1-2  alkyl and C 1-3  haloalkyl;   R 13  is C 3-6  alkyl; and   each R a  and R b  is independently selected from the group consisting of hydrogen and C 1-3  alkyl, wherein each C 1-3  alkyl is optionally substituted with 1 to 3 substituents independently selected from hydroxyl and amino.   
     
     
         115 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (IVd) has the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 R 2  is selected from the group consisting of hydrogen, methyl, fluoro, and chloro; 
 R 3  is selected from the group consisting of hydrogen and methyl; 
 R 12a  is selected from the group consisting of hydrogen, C 1-2  alkyl and C 1-3  haloalkyl; 
 R 13  is C 3-6  alkyl; and 
 R b  is methyl or ethyl, each optionally substituted with hydroxyl or amino. 
 
     
     
         116 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (IVd) has the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 R 13  is C 3-6  alkyl. 
 
     
     
         117 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (IVd) has the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 R 2  is selected from the group consisting of hydrogen, Cl, and F; and 
 R 13  is C 3-6  alkyl. 
 
     
     
         118 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (IVd) has the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 R 3  is selected from the group consisting of hydrogen and methyl; and 
 R 13  is C 3-6  alkyl. 
 
     
     
         119 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, having the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of hydrogen, halogen, and C 1-3  alkyl; 
 R 2  is selected from the group consisting of hydrogen, halogen, and C 1-3  alkyl; 
 R 3  is selected from the group consisting of hydrogen, halogen, and C 1-3  alkyl; 
 R 12a  is selected from the group consisting of hydrogen, C 1-2  alkyl and C 1-3  haloalkyl; 
 R 13  is C 3-6  alkyl; and 
 each R a  and R b  is independently selected from the group consisting of hydrogen and C 1-3  alkyl, wherein each C 1-3  alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxyl, amino, and C 1-6  haloalkyl. 
 
     
     
         120 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein R 1  is hydrogen, halogen, or C 1-6  alkyl optionally substituted with 1 to 5 R 20  groups. 
     
     
         121 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein R 1  is hydrogen, halogen, or C 1-3  alkyl optionally substituted with 1 to 5 halogens. 
     
     
         122 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein R 1  is hydrogen, Cl, CH 3 , or CF 3 . 
     
     
         123 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein R 2  is hydrogen, halogen, —OH, CN, or C 1-6  alkyl optionally substituted with 1 to 5 R 20  groups. 
     
     
         124 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein R 2  is hydrogen, halogen, —OH, CN or C 1-3  alkyl optionally substituted with 1 to 5 halogens. 
     
     
         125 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein R 2  is hydrogen, CH 3 , —OH, —CF 3 , —CH 2 CH 3 , F, Br, Cl, or CN. 
     
     
         126 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein R 3  is hydrogen, halogen, or C 1-6  alkyl optionally substituted with 1 to 5 R 20  groups. 
     
     
         127 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein R 3  is hydrogen, halogen, or C 1-3  alkyl optionally substituted with 1 to 5 R 20  groups. 
     
     
         128 . The compound of  claim 103 , or a pharmaceutically acceptable salt thereof, wherein R 3  is hydrogen, Cl, or CH 3 . 
     
     
         129 . The compound of  claim 103 , selected from 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         130 . A pharmaceutical composition for treating or preventing a disease or condition responsive to the modulation of TLR-8 comprising a compound of  claim 103 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         131 . The pharmaceutical composition of  claim 130 , further comprising one or more additional therapeutic agents selected from the group consisting of HBV DNA polymerase inhibitors, toll-like receptor 7 modulators, toll-like receptor 8 modulators, toll-like receptor 7 and 8 modulators, toll-like receptor 3 modulators, interferon alpha ligands, HBsAg inhibitors, compounds targeting HbcAg, cyclophilin inhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines, HBV viral entry inhibitors, NTCP inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA), hepatitis B virus E antigen inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), stimulators of retinoic acid-inducible gene 1, stimulators of NOD2, recombinant thymosin alpha-1 and hepatitis B virus replication inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, IDO inhibitors, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, selected from the group consisting of adefovir (Hepsera®), tenofovir disoproxil fumarate+emtricitabine (Truvada®), tenofovir disoproxil fumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®), Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b (PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferon alpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®), interferon alfa-n1 (Humoferon®), ribavirin, interferon beta-la (Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b (Axxo), Alfaferone, interferon alfa-2b (BioGeneric Pharma), Feron, interferon-alpha 2 (CJ), Bevac, Laferonum, Vipeg, Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b (Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b (Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant human interleukin-2, Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, Intefen, Sinogen, Fukangtai, Alloferon, and celmoleukin, and combinations thereof. 
     
     
         132 . A method of treating a hepatitis B viral infection, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of  claim 103 , or a pharmaceutically acceptable salt thereof. 
     
     
         133 . The method of  claim 132 , further comprising administering one or more additional therapeutic agents selected from the group consisting of HBV DNA polymerase inhibitors, toll-like receptor 7 modulators, toll-like receptor 8 modulators, Toll-like receptor 7 and 8 modulators, Toll-like receptor 3 modulators, interferon alpha ligands, HBsAg inhibitors, compounds targeting HbcAg, cyclophilin inhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines, HBV viral entry inhibitors, NTCP inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA), hepatitis B virus E antigen inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), stimulators of retinoic acid-inducible gene 1, stimulators of NOD2, recombinant thymosin alpha-1 and hepatitis B virus replication inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, IDO inhibitors, and combinations thereof, selected from the group consisting of adefovir (Hepsera®), tenofovir disoproxil fumarate+emtricitabine (Truvada®), tenofovir disoproxil fumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®), Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b (PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferon alpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®), interferon alfa-n1 (Humoferon®), ribavirin, interferon beta-1a (Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b (Axxo), Alfaferone, interferon alfa-2b, Feron, interferon-alpha 2 (CJ), Bevac, Laferonum, Vipeg, Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa-2b, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b, Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant human interleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin.