4'-substituted nucleoside reverse transcriptase inhibitors

Abstract

The present invention is directed to 4′-substituted nucleoside derivatives of Formula I and their use in the inhibition of HIV reverse transcriptase, the prophylaxis of infection by HIV, the treatment of infection by HIV, and the prophylaxis, treatment, and delay in the onset or progression of AIDS and/or ARC.

1 - 65 . (canceled) 
     
     
         66 . A pharmaceutical composition comprising an effective amount of a compound that is:
 1) (2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   2) (2R,3S,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   3) (2R,3S,5R)-5-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   4) (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   5) (2R,3S,5R)-5-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   6) (2R,3S,5R)-5-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   7) (2R,3S,5R)-5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   8) (2R,3S,5R)-5-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   9) (2R,3S,5R)-5-(4-amino-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   10) (2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxy-2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile;   11) (2R,3S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   12) (2R,3S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-hydroxy-2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile;   13) ((2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   14) ((2R,3S,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   15) ((2R,3S,5R)-5-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   16) ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   17) ((2R,3S,5R)-5-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   18) ((2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-cyano-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   19) ((2R,3S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   20) ((2R,3S,5R)-5-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   21) ((2R,3S,5R)-5-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   22) (2R,3S,5R)-5-(4-aminoimidazo[2, 1-f][1,2,4]triazin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol; or   23) (2R,3S,5R)-5-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   or a pharmaceutically acceptable salt thereof, and an effective amount of one or more HIV antiviral agent selected from:   abacavir, abacavir sulfate, abacavir+lamivudine, abacavir+lamivudine+zidovudine, amprenavir, atazanavir, atazanavir sulfate, AZT, capravirine, darunavir, dideoxycytidine, dideoxyinosine, delavirdine, delavirdine mesylate, dolutegravir, doravirine, efavirenz, efavirenz+emtricitabine+tenofovir disoproxil fumarate, 4′-ethynyl-2-fluoro-2′-deoxyadenosine, elvitegravir, emtricitabine, emvirine, enfuvirtide, etravirine, fosamprenavir calcium, indinavir, indinavir sulfate, lamivudine, lamivudine+zidovudine, lopinavir, lopinavir+ritonavir, maraviroc, nelfinavir, nelfinavir mesylate, nevirapine, PPL-100, raltegravir, rilpivirine, ritonavir, saquinavir, saquinavir mesylate, stavudine, tipranavir or vicriviroc,   and a pharmaceutically acceptable carrier.   
     
     
         67 . A method for the treatment of infection by HIV or for the treatment or delay in the onset of AIDS in a human subject in need thereof which comprises administering to the subject an effective amount of a compound that is:
 1) (2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   2) (2R,3S,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   3) (2R,3S,5R)-5-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   4) (2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   5) (2R,3S,5R)-5-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   6) (2R,3S,5R)-5-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   7) (2R,3S,5R)-5-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   8) (2R,3S,5R)-5-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   9) (2R,3S,5R)-5-(4-amino-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   10) (2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxy-2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile;   11) (2R,3S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   12) (2R,3S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-hydroxy-2-(hydroxymethyl)tetrahydrofuran-2-carbonitrile;   13) ((2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   14) ((2R,3S,5R)-5-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   15) ((2R,3S,5R)-5-(4-amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   16) ((2R,3S,5R)-5-(4-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   17) ((2R,3S,5R)-5-(4-amino-5-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   18) ((2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-cyano-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   19) ((2R,3S,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   20) ((2R,3S,5R)-5-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   21) ((2R,3S,5R)-5-(4-aminoimidazo[2,1-f][1,2,4]triazin-7-yl)-2-ethynyl-3-hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate;   22) (2R,3S,5R)-5-(4-aminoimidazo[2, 1-f][1,2,4]triazin-7-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol; or   23) (2R,3S,5R)-5-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol;   or a pharmaceutically acceptable salt thereof,   and an effective amount of one or more HIV antiviral agent selected from:   abacavir, abacavir sulfate, abacavir+lamivudine, abacavir+lamivudine+zidovudine, amprenavir, atazanavir, atazanavir sulfate, AZT, capravirine, darunavir, dideoxycytidine, dideoxyinosine, delavirdine, delavirdine mesylate, dolutegravir, doravirine, efavirenz, efavirenz+emtricitabine+tenofovir disoproxil fumarate, 4′-ethynyl-2-fluoro-2′-deoxyadenosine, elvitegravir, emtricitabine, emvirine, enfuvirtide, etravirine, fosamprenavir calcium, indinavir, indinavir sulfate, lamivudine, lamivudine+zidovudine, lopinavir, lopinavir+ritonavir, maraviroc, nelfinavir, nelfinavir mesylate, nevirapine, PPL-100, raltegravir, rilpivirine, ritonavir, saquinavir, saquinavir mesylate, stavudine, tipranavir or vicriviroc.   
     
     
         68 . A pharmaceutical composition comprising an effective amount of a compound that is: 
       
         
           
           
               
               
           
         
         or a compound that is a pharmaceutically acceptable salt thereof, 
         and an effective amount of one or more HIV antiviral agent selected from: 
         abacavir, abacavir sulfate, abacavir+lamivudine, abacavir+lamivudine+zidovudine, amprenavir, atazanavir, atazanavir sulfate, AZT, capravirine, darunavir, dideoxycytidine, dideoxyinosine, delavirdine, delavirdine mesylate, dolutegravir, doravirine, efavirenz, efavirenz+emtricitabine+tenofovir disoproxil fumarate, 4′-ethynyl-2-fluoro-2′-deoxyadenosine, elvitegravir, emtricitabine, emvirine, enfuvirtide, etravirine, fosamprenavir calcium, indinavir, indinavir sulfate, lamivudine, lamivudine+zidovudine, lopinavir, lopinavir+ritonavir, maraviroc, nelfinavir, nelfinavir mesylate, nevirapine, PPL-100, raltegravir, rilpivirine, ritonavir, saquinavir, saquinavir mesylate, stavudine, tipranavir or vicriviroc, 
         and a pharmaceutically acceptable carrier. 
       
     
     
         69 . The pharmaceutical composition of  claim 68  wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         70 . The pharmaceutical composition of  claim 68  wherein the compound is a pharmaceutically acceptable salt of 
       
         
           
           
               
               
           
         
       
     
     
         71 . A method for the treatment of infection by HIV or for the treatment or delay in the onset of AIDS in a human subject in need thereof which comprises administering to the subject an effective amount of a compound that is 
       
         
           
           
               
               
           
         
         or a compound that is a pharmaceutically acceptable salt thereof, 
         and an effective amount of one or more HIV antiviral agent selected from: 
         abacavir, abacavir sulfate, abacavir+lamivudine, abacavir+lamivudine+zidovudine, amprenavir, atazanavir, atazanavir sulfate, AZT, capravirine, darunavir, dideoxycytidine, dideoxyinosine, delavirdine, delavirdine mesylate, dolutegravir, doravirine, efavirenz, efavirenz+emtricitabine+tenofovir disoproxil fumarate, 4′-ethynyl-2-fluoro-2′-deoxyadenosine, elvitegravir, emtricitabine, emvirine, enfuvirtide, etravirine, fosamprenavir calcium, indinavir, indinavir sulfate, lamivudine, lamivudine+zidovudine, lopinavir, lopinavir+ritonavir, maraviroc, nelfinavir, nelfinavir mesylate, nevirapine, PPL-100, raltegravir, rilpivirine, ritonavir, saquinavir, saquinavir mesylate, stavudine, tipranavir or vicriviroc. 
       
     
     
         72 . The method of  claim 71  wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         73 . The method of  claim 71  wherein the compound is a pharmaceutically acceptable salt of