Treatment of HIV Infections with HIV Integrase Inhibitors

Patent Application Title:	Polycyclic Carbamoylpyridone Compounds and Their Pharmaceutical Use
Patent Application Number:	US 2016/0289246 A1	Publication date:	October 6, 2016
Priority Application:	US 62/142,338	Priority date:	April 2, 2015
Inventors:	Cai, Z. R.; Jin, H.; Scott E. Lazerwith, S. E.; Pyun, H.-J.
Applicant:	Gilead Sciences, Inc., Foster City, CA (US)
Disease Area:	Human immunodeficiency virus (HIV) infection	Biological Target:	HIV integrase

Summary:	The invention in this patent application relates to polycyclic carbamoylpyridone derivatives represented generally by Formula (I), which possess antiviral activities. These compounds may be used to treat HIV infections by inhibiting the activity of HIV integrase to reduce HIV replication.
	Human immunodeficiency virus (HIV) infections and related diseases remain as major public health problems worldwide. The replication of HIV type 1 (HIV-1) requires the actions of three essential enzymes: reverse transcriptase, protease, and integrase. There are many effective and widely used drugs that target reverse transcriptase and protease. These drugs are particularly useful and more effective when taken in combination; however, toxicity and development of resistant virus strains have limited their usefulness. Accordingly, there is a need to develop new drugs that inhibit the replication of resistant HIV without toxicity issues.
	The current standard of care according to the US Department of Health and Human Services requires the use of multiple different drug classes to suppress HIV. In addition, many of the HIV infected patients require treatments for other medical conditions and complications. Thus, there is a potential for drug–drug interactions. Therefore, there is a need for novel antiretroviral therapies having a decreased potential for drug interactions.
	In addition, there is a tendency of the HIV virus to mutate in infected subjects; therefore, there is a need for anti-HIV drugs that can be effective against a range of known HIV variants.
	Integrase inhibitors are antiretroviral drugs that can inhibit the actions of the viral enzyme integrase. This enzyme is responsible for inserting (integrating) the viral genome into the DNA of the host cells, which is a vital step in HIV replication. Inhibiting the function of this enzyme can stop or slow the spread of the virus and its replication process. The compounds described in this patent application are HIV integrase inhibitors that may be used to treat HIV infections. These compounds may also be effective against a range of known drug-resistant HIV mutants and may have less potential for drug–drug interactions when coadministered with other drugs.
Important Compound Classes:
Key Structures:	The inventors described synthetic procedures and listed structures of 28 compounds of Formula (I) including the following representative examples:
Biological Assay:	Antiviral Assays in MT4 Cells
Biological Data:	The biological data obtained from testing the above representative examples of Formula (I) are listed in the following table:
Recent Review Articles:	1. Gu S.-X.; Xue P.; Ju X.-L.; Zhu Y.-Y.. Bioorg. Med. Chem. 2016, 24 ( (21), ), 5007–5016.
	2. Blanco J. L.; Whitlock G.; Milinkovic A.; Moyle G.. Exp. Opin. Pharmacother. 2015, 16 ( (9), ), 1313–1324.
	3. Metifiot M.; Marchand C.; Pommier Y.. Adv. Pharmacol. 2013, 67 ( (Antiviral Agents), ), 75–105.
	4. Wainberg M. A.; Mesplede T.; Quashie P. K.. Curr. Opin. Virol. 2012, 2 ( (5), ), 656–662.

The author declares no competing financial interest.