US2016264610A1PendingUtilityA1

Azido nucleosides and nucleotide analogs

56
Assignee: ALIOS BIOPHARMA INCPriority: Sep 22, 2010Filed: May 23, 2016Published: Sep 15, 2016
Est. expirySep 22, 2030(~4.2 yrs left)· nominal 20-yr term from priority
C07H 19/19C07H 19/073A61K 31/7105A61K 31/7068C07H 19/09C07H 19/20A61K 45/06C07H 19/10A61K 31/708C07H 19/167C07H 19/11C07H 19/056A61K 31/7056C07H 19/06A61K 31/7076A61P 31/16A61P 31/12C07H 19/067A61K 31/7072A61P 31/14C07H 19/16
56
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Claims

Abstract

Disclosed herein are nucleosides, nucleotides and analogs thereof, pharmaceutical compositions that include one or more of nucleosides, nucleotides and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an infection from a paramyxovirus and/or an orthomyxovirus, with a nucleoside, a nucleotide and an analog thereof. Examples of viral infections include a respiratory syncytial viral (RSV) and influenza infection.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method of ameliorating or treating a viral infection selected from a paramyxovirus viral infection and an orthomyxovirus viral infection comprising administering a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, to a subject suffering from the viral infection, wherein the compound of Formula (II) has the structure: 
       
         
           
           
               
               
           
         
         wherein: 
         B 1a  is selected from the group consisting of an optionally substituted heterocyclic base and an optionally substituted heterocyclic base with a protected amino group; 
         R 1a  is selected from the group consisting of hydrogen, an optionally substituted acyl, 
       
       
         
           
           
               
               
           
         
         n a  is 0, 1, or 2; 
         R 2a  and R 1a  are independently selected from the group consisting of hydrogen, an optionally substituted C 1-6  alkyl and an optionally substituted C 1-6  haloalkyl; 
         R 4a  is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6  alkyl, —OR 18a  and —OC(═O)R 19a ; 
         R 5a  is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6  alkyl, —OR 20a  and —OC(═O)R 21a ; 
         R 6a  is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6  alkyl, —OR 22a  and —OC(═O)R 23a ;
 or R 5a  and R 6a  are both oxygen atoms and linked together by a carbonyl group; 
 
         R 7a  is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6  alkyl, —OR 24a  and —OC(═O)R 25a ; 
         R 8a  is selected from the group consisting of hydrogen, an optionally substituted C 1-6  alkyl and an optionally substituted C 1-6  haloalkyl; 
         R 9a  and R 12a  are independently absent or hydrogen; 
         R 10a  is absent or hydrogen; 
         each R 11a  is independently absent or hydrogen; 
         R 13a  is absent or hydrogen; 
         R 14a  is selected from the group consisting of an —O— optionally substituted aryl, an —O— optionally substituted heteroaryl and an —O— optionally substituted heterocyclyl, and R 15a  is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; or 
         R 14a  is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative, and R 15a  is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; or 
         R 14a  is O − , hydroxy or an —O— optionally substituted C 1-6  alkyl, and R 15a  and R 5a  together are O; 
         R 16a  is selected from the group consisting of an —O— optionally substituted aryl, an —O— optionally substituted heteroaryl and an —O— optionally substituted heterocyclyl, and R 17a  is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; or 
         R 16a  is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative, and R 17a  is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; or 
         R 16a  is O − , hydroxy or an —O— optionally substituted C 1-6  alkyl, and R 17a  and R 5a  together are O; 
         R 18a , R 20a , R 22a  and R 24  are independently hydrogen or an optionally substituted C 1-6  alkyl; and 
         R 19a , R 21a , R 23a  and R 25a  are independently selected from the group consisting of an optionally substituted C 1-6  alkyl and an optionally substituted C 3-6  cycloalkyl. 
       
     
     
         2 . The method of  claim 1 , wherein R 2a  and R 3a  are hydrogen. 
     
     
         3 . The method of  claim 1 , wherein at least one of R 2a  and R 3a  is hydrogen; and the other of R 2a  and R 3a  is an optionally substituted C 1-6  alkyl or an optionally substituted C 1-6  haloalkyl. 
     
     
         4 . The method of  claim 1 , wherein R 1a  is hydrogen or an optionally substituted acyl. 
     
     
         5 . The method of  claim 1 , wherein R 1a  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 5 , wherein R 1a  is 
       
         
           
           
               
               
           
         
       
       and R 14a  is an optionally substituted aryl, an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative. 
     
     
         7 . The method of  claim 6 , wherein R 15a  is an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative. 
     
     
         8 . The method of  claim 5 , wherein R 1a  is 
       
         
           
           
               
               
           
         
       
       and R 14a  and R 15a  each independently have the structure: 
       
         
           
           
               
               
           
         
         wherein R 26a  is hydrogen or an optionally substituted C 1-4 -alkyl; R 27a  is selected from the group consisting of hydrogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 1-6  haloalkyl, an optionally substituted C 3-6  cycloalkyl, an optionally substituted C 6  aryl, an optionally substituted C 10  aryl, and an optionally substituted aryl(C 1-6  alkyl); and R 28a  is selected from the group consisting of hydrogen, an optionally substituted C 1-6 -alkyl, an optionally substituted C 3-6  cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C 1-6  alkyl), and an optionally substituted haloalkyl, or R 26a  and R 27a  are taken together to form an optionally substituted C 3-6  cycloalkyl. 
       
     
     
         9 . The method of  claim 8 , wherein R 26a  is hydrogen; R 27a  is hydrogen or methyl; and R 28a  is methyl or benzyl. 
     
     
         10 . The method of  claim 5 , wherein R 1a  is 
       
         
           
           
               
               
           
         
       
       and R 14a  is O − , hydroxy or an —O— optionally substituted C 1-6  alkyl, and R 15a  and R 5a  together are O. 
     
     
         11 . The method of  claim 5 , wherein R 1a  is 
       
         
           
           
               
               
           
         
       
       and R 16a  is an —O— optionally substituted aryl, an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative. 
     
     
         12 . The method of  claim 11 , wherein R 17a  is an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative. 
     
     
         13 . The method of  claim 5 , wherein R 1a  is 
       
         
           
           
               
               
           
         
       
       and R 16a  and R 17a  each independently have the structure: 
       
         
           
           
               
               
           
         
         wherein: R 29a  is selected from the group consisting of hydrogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 1-6  haloalkyl, an optionally substituted C 3-6  cycloalkyl, an optionally substituted C 6  aryl, an optionally substituted C 10  aryl and an optionally substituted aryl(C 1-6  alkyl); R 30a  is hydrogen or an optionally substituted C 1-4 -alkyl; and R 31a  is selected from the group consisting of hydrogen, an optionally substituted C 1-6 -alkyl, an optionally substituted C 3-6  cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C 1-6  alkyl) and an optionally substituted C 1-6  haloalkyl, or R 29a  and R 30a  are taken together to form an optionally substituted C 3-6  cycloalkyl. 
       
     
     
         14 . The method of  claim 13 , wherein R 29a  is hydrogen; R 30a  is hydrogen or methyl; and R 31a  is methyl or benzyl. 
     
     
         15 . The method of  claim 1 , wherein R 1a  is 
       
         
           
           
               
               
           
         
       
       and R 16a  is O − , hydroxy or an —O— optionally substituted C 1-6  alkyl; and R 17a  and R 5a  together are O. 
     
     
         16 . The method of  claim 1 , wherein B 1a  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein: 
         R A2a  is selected from the group consisting of hydrogen, halogen and NHR J2a , wherein R J2a  is selected from the group consisting of hydrogen, —C(═O)R K2a  and —C(═O)OR L2a ; 
         R B2a  is halogen or NHR W2a , wherein R W2a  is selected from the group consisting of hydrogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 2-6  alkenyl, an optionally substituted C 3-8  cycloalkyl, —C(═O)R M2a  and —C(═O)OR N2a ; 
         R C2a  is hydrogen or NHR O2a , wherein R O2a  is selected from the group consisting of hydrogen, —C(═O)R P2a  and —C(═O)OR Q2a ; 
         R D2a  is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 2-6  alkenyl and an optionally substituted C 2-6  alkynyl; 
         R E2a  is selected from the group consisting of hydrogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 3-8  cycloalkyl, —C(═O)R R2a  and —C(═O)OR S2a ; 
         R F2a  is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 2-6  alkenyl and an optionally substituted C 2-6  alkynyl; 
         Y 2a  is N or CR I2a , wherein R I2a  is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 -alkyl, an optionally substituted C 2-6 -alkenyl and an optionally substituted C 2-6 -alkynyl; 
         R G2a  is an optionally substituted C 1-6  alkyl; 
         R H2a  is hydrogen or NHR T2a , wherein R T2a  is independently selected from the group consisting of hydrogen, —C(═O)R U2a  and —C(═O)OR V2a , 
         R Y2a  is hydrogen or NHR Z2a , wherein R Z2a  is selected from the group consisting of hydrogen, —C(═O)R AA2a  and —C(═O)OR BB2a ; 
         R K2a , R L2a , R M2a , R N2a , R P2a , R Q2a , R R2a , R S2a , R U2a , R V2a , R AA2a  and R BB2a  are independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, C 3-6  cycloalkenyl, C 3-6  cycloalkynyl, C 6-10  aryl, heteroaryl, heteroalicyclyl, aryl(C 1-6  alkyl), heteroaryl(C 1-6  alkyl) and heteroalicyclyl(C 1-6  alkyl). 
       
     
     
         17 . The method of  claim 16 , wherein B 1a  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method of  claim 1 , wherein R 7a  is —OR 24a  or an optionally substituted C 1-6  alkyl; and R 8a  is hydrogen. 
     
     
         19 . The method of  claim 1  wherein R 7a  is hydrogen or a halogen; and R 8a  is hydrogen. 
     
     
         20 . The method of  claim 1 , wherein R 5a  is —OR 20a . 
     
     
         21 . The method of  claim 1 , wherein R 6a  is —OR 22a , hydrogen or a halogen. 
     
     
         22 . The method of  claim 1 , wherein R 5a  and R 6a  are both oxygen atoms and linked together by a carbonyl group. 
     
     
         23 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         24 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         25 . The method of  claim 1 , wherein the paramyxovirus viral infection is a human respiratory syncytial virus infection. 
     
     
         26 . The method of  claim 1 , wherein the orthomyxovirus viral infection is an influenza virus infection (influenza A, B and/or C). 
     
     
         27 . A method of inhibiting replication of a virus selected from paramyxovirus and orthomyxovirus comprising contacting a cell infected with the virus with an effective amount of a compound selected from a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof. 
     
     
         28 . A method of ameliorating or treating a viral infection selected from paramyxovirus viral infection and orthomyxovirus viral infection comprising contacting a cell infected with the virus with an effective amount of a compound selected from a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof. 
     
     
         29 . A method of ameliorating or treating a viral infection selected from a paramyxovirus viral infection and an orthomyxovirus viral infection comprising administering a therapeutically effective amount of a compound selected from a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, in combination with one or more agents to a subject suffering from the viral infection. 
     
     
         30 . The method of  claim 29 , wherein the paramyxovirus viral infection is a human respiratory syncytial virus infection; and wherein the one or more agents is selected from the group consisting of ribavirin, palivizumab, RSV-IGIV, ALN-RSV01, BMS-433771, RFI-641, RSV604, MDT-637, BTA9881, TMC-353121, MBX-300 and YM-53403. 
     
     
         31 . A method of treating or ameliorating a viral infection selected from a paramyxovirus viral infection and an orthomyxovirus viral infection comprising contacting a cell infected with the virus with an effective amount of a compound selected from a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, in combination with one or more agents. 
     
     
         32 . The method of  claim 31 , wherein the orthomyxovirus viral infection is an influenza virus infection; and wherein the one or more agents is selected from the group consisting of amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir, favipirvir, fludase, ADS-8902, IFN-b and beraprost. 
     
     
         33 . A compound of Formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         B 1  is selected from the group consisting of an optionally substituted heterocyclic base and an optionally substituted heterocyclic base with a protected amino group; 
         R 1  is selected from the group consisting of hydrogen, an optionally substituted acyl, 
       
       
         
           
           
               
               
           
         
         n is 0, 1 or 2; 
         R 2  and R 3  are independently selected from the group consisting of hydrogen, an optionally substituted C 1-6  alkyl and an optionally substituted C 1-6  haloalkyl; 
         R 4  is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6  alkyl, —OR 18  and —OC(═O)R 19 ; 
         R 5  is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6  alkyl, —OR 20  and —OC(═O)R 21 ; 
         R 6  is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6  alkyl, —OR 22  and —OC(═O)R 23 ;
 or R 5  and R 6  are both oxygen atoms and linked together by a carbonyl group; 
 
         R 7  is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6  alkyl, —OR 24  and —OC(═O)R 25 ; 
         R 8  is selected from the group consisting of hydrogen, an optionally substituted C 1-6  alkyl and an optionally substituted C 1-6  haloalkyl; 
         R 9 , R 10 , each R 11 , R 12  and R 13  are independently absent or hydrogen; 
         R 14  is selected from the group consisting of an —O— optionally substituted aryl, an —O— optionally substituted heteroaryl and an —O— optionally substituted heterocyclyl, and R 15  is 
       
       
         
           
           
               
               
           
         
          or 
         R 14  is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative, and R 15  is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; or 
         R 14  is O − , hydroxy or an —O— optionally substituted C 1-6  alkyl, and R 15  and R 5  together are O; 
         R 16  is selected from the group consisting of an —O— optionally substituted aryl, an —O— optionally substituted heteroaryl and an —O— optionally substituted heterocyclyl, and R 17  is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; or 
         R 16  is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative, and R 17  is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester derivative; or 
         R 16  is O − , hydroxy or an —O— optionally substituted C 1-6  alkyl, and R 17  and R 5  together are O; 
         R 18 , R 20 , R 22  and R 24  are independently selected from the group consisting of hydrogen and an optionally substituted C 1-6  alkyl; 
         R 19 , R 21 , R 23  and R 25  are independently selected from the group consisting of an optionally substituted C 1-6  alkyl and an optionally substituted C 3-6  cycloalkyl; 
         R 26  is hydrogen or an optionally substituted C 1-4 -alkyl; 
         R 27  is selected from the group consisting of hydrogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 1-6  haloalkyl, an optionally substituted C 3-6  cycloalkyl, an optionally substituted C 6  aryl, an optionally substituted C 10  aryl and an optionally substituted aryl(C 1-6  alkyl); and 
         R 28  is selected from the group consisting of hydrogen, an optionally substituted C 1-6 -alkyl, an optionally substituted C 3-6  cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C 1-6  alkyl) and an optionally substituted haloalkyl, 
         or R 26  and R 27  are taken together to form an optionally substituted C 3-6  cycloalkyl; 
         provided that when R 2 , R 3 , R 4 , and R 8  are all hydrogen, R 1  cannot be hydrogen; 
         provided that when R 2  and R 3  are both hydrogen, R 5  is hydroxy, R 4  and R 6  are both hydrogen, R 7  is halogen, R 8  is hydrogen, and B 1  is 
       
       
         
           
           
               
               
           
         
          then R 1  cannot be 
       
       
         
           
           
               
               
           
         
          wherein n is 0 or 2; and R 9 , R 10  and R 11  are hydrogen; 
         provided that when R 1  is 
       
       
         
           
           
               
               
           
         
          R 2  and R 3  are both hydrogen, R 4  is hydrogen, R 5  is OH, R 6  is selected from the group consisting of halogen, hydrogen, and hydroxy, R 7  is selected from the group consisting of halogen, hydrogen, methyl, and hydroxy, R 8  is hydrogen, B 1  selected from the group consisting of 
       
       
         
           
           
               
               
           
         
          R 14  is an —O— optionally substituted aryl, then R 15  cannot be 
       
       
         
           
           
               
               
           
         
          wherein R 26  is hydrogen or an optionally substituted C 1-4  alkyl; R 27  is selected from the group consisting of hydrogen, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 CH 2 SCH 3 , —CH 2 CH 2 COOCH 2 CH 3 , —CH 2 C(═O)OCH 2 CH 3 , —CH 2 -indol-3-yl, —CH 2 phenyl, unsubstituted cyclopentyl and —CH(CH 2 CH 3 )CH 3 ; and R 28  is selected from the group consisting of unsubstituted C 1-4 -alkyl, unsubstituted benzyl and CH 2 CF 3 ; 
         provided that when R 1  is 
       
       
         
           
           
               
               
           
         
          R 2 , R 3 , R 4 , R 7  and R 8  are all hydrogen, R 5  is hydroxy, R 6  is hydroxy, R 14  is —O-naphthyl, R 15  is 
       
       
         
           
           
               
               
           
         
          wherein R 26  is hydrogen, R 27  is methyl and R 28  is benzyl, then B 1  cannot be 
       
       
         
           
           
               
               
           
         
         provided that when R 1  is 
       
       
         
           
           
               
               
           
         
          R 2 , R 3 , R 4 , R 7  and R 8  are all hydrogen, R 5  is hydroxy, R 6  is hydroxy, R 14  is —O-phenyl, R 15  is 
       
       
         
           
           
               
               
           
         
          wherein R 26  and R 27  are taken together to form an substituted cyclopentyl ring and R 28  is an unsubstituted C 1-4  alkyl or benzyl, then B 1  cannot be 
       
       
         
           
           
               
               
           
         
         provided that B 1  cannot be adenine or an optionally substituted adenine when at least one of R 2  and R 3  is not hydrogen; and 
         provided that a compound of Formula (I) cannot have the following structure: 
       
       
         
           
           
               
               
           
         
       
     
     
         34 . The compound of  claim 33 , wherein R 2  and R 3  are hydrogen; or wherein at least one of R 2  and R 3  is hydrogen; and the other of R 2  and R 3  is an optionally substituted C 1-6  alkyl or an optionally substituted C 1-6  haloalkyl. 
     
     
         35 . The compound of  claim 33 , wherein R 1  is selected from the group consisting of hydrogen, an optionally substituted acyl, 
       
         
           
           
               
               
           
         
       
     
     
         36 . The compound of  claim 33 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       and R 14  is an —O— optionally substituted aryl; and R 26  is hydrogen; R 27  is hydrogen or methyl; and R 28  is methyl or benzyl; or R 1  is 
       
         
           
           
               
               
           
         
       
       R 14  is an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative; and R 15  is an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative; or R 1  is 
       
         
           
           
               
               
           
         
       
       R 14  is O − , hydroxy or an —O— optionally substituted C 1-6  alkyl, and R 15  and R 5  together are O. 
     
     
         37 . The compound of  claim 33 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       R 16  is an —O— optionally substituted aryl; and R 17  is an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative; or R 1  is 
       
         
           
           
               
               
           
         
       
       R 16  is an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative; and R 17  is an optionally substituted N-linked α-amino acid or an optionally substituted N-linked α-amino acid ester derivative; or R 1  is 
       
         
           
           
               
               
           
         
       
       R 16  is O − , hydroxy or an —O— optionally substituted C 1-6  alkyl; and R 17  and R 5  together are O. 
     
     
         38 . The compound of  claim 33 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       and R 16  and R 17  each independently have the structure: 
       
         
           
           
               
               
           
         
         wherein: R 29  is selected from the group consisting of hydrogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 1-6  haloalkyl, an optionally substituted C 3-6  cycloalkyl, an optionally substituted C 6  aryl, an optionally substituted C 10  aryl and an optionally substituted aryl(C 1-6  alkyl); R 30  is hydrogen or an optionally substituted C 1-4 -alkyl; and R 31  is selected from the group consisting of hydrogen, an optionally substituted C 1-6 -alkyl, an optionally substituted C 3-6  cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C 1-6  alkyl) and an optionally substituted C 1-6  haloalkyl, or R 29  and R 30  are taken together to form an optionally substituted C 3-6  cycloalkyl. 
       
     
     
         39 . The compound of  claim 33 , wherein B 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein: 
         R A2  is selected from the group consisting of hydrogen, halogen and NHR J2 , wherein R J2  is selected from the group consisting of hydrogen, —C(═O)R K2  and —C(═O)OR L2 ; 
         R B2  is halogen or NHR W2 , wherein R W2  is selected from the group consisting of hydrogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 2-6  alkenyl, an optionally substituted C 3-8  cycloalkyl, —C(═O)R M2  and —C(═O)OR N2 ; 
         R C2  is hydrogen or NHR O2 , wherein R O2  is selected from the group consisting of hydrogen, —C(═O)R P2  and —C(═O)OR Q2 ; 
         R D2  is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 2-6  alkenyl and an optionally substituted C 2-6  alkynyl; 
         R E2  is selected from the group consisting of hydrogen, an optionally substituted C 1-6  alkyl, an optionally substituted C 3-8  cycloalkyl, —C(═O)R R2  and —C(═O)OR S2 ; 
         R F2  is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 2-6  alkenyl and an optionally substituted C 2-6  alkynyl; 
         Y 2  is N or CR I2 , wherein R I2  is selected from the group consisting of hydrogen, halogen, an optionally substituted C 1-6 -alkyl, an optionally substituted C 2-6 -alkenyl and an optionally substituted C 2-6 -alkynyl; 
         R G2  is an optionally substituted C 1-6  alkyl; 
         R H2  is hydrogen or NHR T2 , wherein R T2  is independently selected from the group consisting of hydrogen, —C(═O)R U2  and —C(═O)OR V2 , 
         R Y2  is hydrogen or NHR Z2 , wherein R is selected from the group consisting of hydrogen, —C(═O)R AA2  and —C(═O)OR BB2 ; 
         R K2 , R L2 , R M2 , R N2 , R P2 , R Q2 , R R2 , R S2 , R U2 , R V2 , R AA2  and R BB2  are independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, C 3-6  cycloalkenyl, C 3-6  cycloalkynyl, C 6-10  aryl, heteroaryl, heteroalicyclyl, aryl(C 1-6  alkyl), heteroaryl(C 1-6  alkyl) and heteroalicyclyl(C 1-6  alkyl). 
       
     
     
         40 . The compound of  claim 39 , wherein B 1  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         41 . The compound of  claim 33 , wherein R 7  is —OR 24  or an optionally substituted C 1-6  alkyl; and R 8  is hydrogen. 
     
     
         42 . The compound of  claim 33 , wherein R 7  is hydrogen or a halogen; and R 8  is hydrogen. 
     
     
         43 . The compound of  claim 33 , wherein R 5  is —OR 20 . 
     
     
         44 . The compound of  claim 33 , wherein R 6  is —OR 22 , hydrogen or a halogen. 
     
     
         45 . The compound of  claim 33 , wherein R 5  and R 6  are both oxygen atoms and linked together by a carbonyl group. 
     
     
         46 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 33 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

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