Pyrimidone derivatives as selective cytotoxic agents against HIV infected cells
The present disclosure is directed to pyrimidone derivatives of Formula I and their use for selectively killing HIV infected GAG-POL expressing cells without concomitant cytotoxicity to HIV nave cells, and for the treatment or prophylaxis of infection by HIV, or for the treatment, prophylaxis or delay in the onset or progression of AIDS or AIDS Related Complex (ARC).
1. A compound which is:
5-(difluoromethyl)-2-methyl-3((1-((2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl)-6-oxo-4-(perfluoroethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 that is
3. A pharmaceutical composition comprising an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
4. The pharmaceutical composition of claim 3 further comprising an effective amount of one or more additional nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors and post-attachment inhibitors.
5. A method for the treatment or prophylaxis of infection by HIV, or for the treatment, prophylaxis or delay in the onset or progression of AIDS or ARC in a human subject in need thereof which comprises administering to the human subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
6. A method for eliciting GAG-POL dimerization in HIV-infected cells in a human subject in need thereof which comprises administering to the human subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
7. A method for selectively killing HIV infected GAG-POL expressing cells without concomitant cytotoxicity to HIV naïve cells in a human subject which comprises administering to the human subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
8. The method of claim 5 further comprising administering to the human subject an effective amount of one or more additional compatible HIV antiviral agent selected from nucleoside or nucleotide HIV reverse transcriptase inhibitors, nucleoside reverse transcriptase translocation inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV fusion inhibitors, HIV entry inhibitors, HIV maturation inhibitors and post-attachment inhibitors.
9. A method for augmenting the suppression of HIV viremia in a human subject whose viremia is being suppressed by administration of one or more compatible HIV antiviral agents, which comprises additionally administering to the human subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.