Pyrimidine phosphonic acid esters
This invention relates to compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , and Y 3b are each independently selected from hydrogen and deuterium, Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11a , Y 11b , Y 12a , Y 12b , Y 13a , Y 13b , Y 14a , Y 14b , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18a , and Y 18b are each deuterium, X 1a , X 1b , X 2a , X 2b , X 3 , X 4a , X 4b , X 5 , and X 6 are each independently selected from hydrogen and deuterium; and R is CD 3 . This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering a viral DNA polymerase inhibitor.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein
Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , and Y 3b are each independently selected from hydrogen and deuterium;
Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7a , Y 7b , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11a , Y 11b , Y 12a , Y 12b , Y 13a , Y 13b , Y 14a , Y 14b , Y 15a , Y 15b , Y 16a , Y 16b , Y 17a , Y 17b , Y 18a , and Y 18b are each deuterium;
X 1a , X 1b , X 2a , X 2b , X 3 , X 4a , X 4b , X 5 , and X 6 are each independently selected from hydrogen and deuterium; and
R is CD 3 ,
wherein the deuterium incorporation at each designated deuterium atom is at least 50.1%.
2. The compound of claim 1 , wherein X 1a and X 1b are the same.
3. The compound of claim 1 , wherein X 2a and X 2b are the same.
4. The compound of claim 1 , wherein X 4a and X 4b are the same.
5. The compound of claim 1 , wherein X 5 and X 6 are the same.
6. The compound of claim 1 , wherein, X 1a and X 1b are the same; X 2a and X 2b are the same; X 4a and X 4b are the same; and X 5 and X 6 are the same.
7. The compound of claim 1 , wherein Y 1a , Y 1b , Y 2a , Y 2b , Y 3a and Y 3b are all the same.
8. The compound of claim 1 , wherein each of X 1a , X 1b , X 2a , X 2b , X 3 , X 4a , X 4b , X 5 , and X 6 is hydrogen; and the compound is a compound of Formula II:
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
10. The compound of claim 8 , wherein Y 1a , Y 1b , Y 2a , Y 2b , Y 3a and Y 3b are all the same; and the compound is selected from any one of the compounds in the table below:
Compound
Y 1a -Y 3b
Y 4a -Y 18b
R
105
H
D
CD 3
107
D
D
CD 3
or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
11. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
12. A method of inhibiting the activity of viral DNA polymerase in a cell, comprising contacting the cell with a compound of claim 1 , or a composition of claim 11 .
13. A method of treating a dsDNA viral infection, comprising the step of administering to the subject in need thereof a compound of claim 1 , or a composition of claim 11 .
14. The method of claim 13 , wherein the dsDNA viral infection is selected from Ebola virus infection, cytomegalovirus infection, adenovirus infection, smallpox virus infection, Herpes simplex virus infection, vaccinia infection, varicella zoster virus infection, and monkeypox virus infection.
15. The method of claim 14 , comprising the additional step of co-administering a second therapeutic agent.
16. The compound of claim 1 , wherein the deuterium incorporation at each designated deuterium atom is at least 90%.
17. The compound of claim 1 , wherein the deuterium incorporation at each designated deuterium atom is at least 95%.
18. The compound of claim 1 , wherein the deuterium incorporation at each designated deuterium atom is at least 97%.
19. The method of claim 15 , wherein the second therapeutic agent is probenecid.