4′-Substituted nucleoside reverse transcriptase inhibitors and preparations thereof
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. The present invention also provides processes for the preparation of 4′-substituted nucleoside derivatives of Formula (I) and derivatives thereof.
1. A compound of structural Formula I
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —H, —C(O)R 3 , —C(O)OR 3 , —C(O)N(R 3 ) 2 ,
or a pro-drug modification of the mono-, di- or triphosphate; and
R 2 is —H, —C(O)R 4 , —C(O)OR 4 or —C(O)N(R 4 ) 2 ;
R 3 and R 4 are each independently selected at each occurrence from —H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —(C 1 -C 3 alkylene) m -(C 3 -C 7 cycloalkyl), —(C 1 -C 3 alkylene) m -(aryl), —(C 1 -C 3 alkylene) m -(4 to 7-membered heterocycloalkyl), —(C 1 -C 3 alkylene) m -(5- or 6-membered monocyclic heteroaryl) or —(C 1 -C 3 alkylene) m -(9- or 10-membered bicyclic heteroaryl), wherein each of said —C 1 -C 6 alkyl, said —C 3 -C 7 cycloalkyl group, said aryl group, said 4 to 7-membered heterocycloalkyl group, said 5- or 6-membered monocyclic heteroaryl group or said 9- or 10-membered bicyclic heteroaryl group is unsubstituted or substituted with R 5 ;
m is an integer selected from 0 (zero) or 1; and
R 5 represents from one to five substituent groups, each independently selected from —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 1 -C 6 haloalkyl, aryl or a 5-6-member heteroaryl.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 1 is —H, —C(O)R 3 , —C(O)OR 3 , —C(O)N(R 3 ) 2 , or a pro-drug modification of one of the following mono-, di- or triphosphate moieties:
and
R 2 is —H, —C(O)R 4 , —C(O)OR 4 or —C(O)N(R 4 ) 2 .
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 1 is —H, —C(O)R 3 , —C(O)OR 3 , or —C(O)N(R 3 ) 2 ; and R 2 is —H, —C(O)R 4 , —C(O)OR 4 or —C(O)N(R 4 ) 2 .
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 1 is
and R 2 is —H.
5. The compound of claim 1 that is
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 that is
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
8. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and further comprising one or more anti-HIV agents selected from HIV antiviral agents, immunomodulators, and anti-infective agents.
9. The pharmaceutical composition of claim 8 , wherein the HIV antiviral agent is selected from one or more of HIV protease inhibitors, nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors and HIV maturation inhibitors.
10. A method for the treatment of infection by HIV or for the treatment or delay in the onset of AIDS in a subject in need thereof, which comprises administering to the subject the compound of claim 1 or a pharmaceutically acceptable salt thereof.
11. The method of claim 10 further comprising administering to the subject one or more additional HIV antiviral agents selected from HIV protease inhibitors, HIV integrase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, HIV fusion inhibitors, HIV entry inhibitors and HIV maturation inhibitors.
12. The method of claim 10 further comprising administering to the subject one or more additional HIV antiviral agents 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, emtricitabine+tenofovir disoproxil fumarate, emivirine, 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, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tipranavir, or vicriviroc.