Acyclic antivirals
Disclosed herein are nucleotide analogs, methods of synthesizing nucleotide analogs and methods of treating diseases and/or conditions such as a HBV and/or HDV and/or HIV infection with one or more nucleotide analogs.
1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:
wherein:
B 1 is selected from the group consisting of: an optionally substituted
an optionally substituted
an optionally substituted
an optionally substituted
an optionally substituted
an optionally substituted
an optionally substituted
an optionally substituted
an optionally substituted
an optionally substituted
and an optionally substituted
R 1 and R 2 are each independently selected from the group consisting of O − , —OH, an optionally substituted —O—C 1-24 alkyl, an optionally substituted —O—C 2-24 alkenyl, an optionally substituted —O—C 2-24 alkynyl, an optionally substituted —O—C 3-6 cycloalkyl, an optionally substituted —O—C 3-6 cycloalkenyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl, an optionally substituted —O-aryl(C 1-6 alkyl), an optionally substituted —O—(CR 4 R 5 ) p —O—C 1-24 alkyl, an optionally substituted —O—(CR 6 R 7 ) q —O—C 1-24 alkenyl,
an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative; or
R 1 is
and R 2 is O − or OH; or
R 1 and R 2 are taken together to form a moiety selected from the group consisting of an optionally substituted
and an optionally substituted
wherein the phosphorus and the moiety form a six-membered or ten-membered ring system;
R 3a and R 3b are each independently selected from the group consisting of hydrogen, halogen, an unsubstituted C 1-4 alkyl, an unsubstituted C 3-6 cycloalkyl, cyano, halogen(C 1-4 alkyl), hydroxy(C 1-4 alkyl), alkoxy(C 1-4 alkyl), acyl(C 1-4 alkyl) and cyano(C 1-4 alkyl); or
R 3a and R 3b are taken together with the carbon to which they are connected to form an optionally substituted C 3-6 cycloalkyl;
each R 4 , each R 5 , each R 6 and each R 7 are independently hydrogen, an optionally substituted C 1-24 alkyl or alkoxy;
R 8 , R 9 , R 11 and R 12 are each independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl;
R 10 and R 13 are each independently selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl, an optionally substituted aryl, an optionally substituted —O—C 1-24 alkyl, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl and an optionally substituted —O-monocyclic heterocyclyl;
R 14 is selected from the group consisting of hydrogen, an optionally substituted C 1-24 alkyl and an optionally substituted aryl;
R 15 and R 16 are each independently selected from the group consisting of —C≡N, an optionally substituted C 2-8 organylcarbonyl, an optionally substituted C 2-8 alkoxycarbonyl and an optionally substituted C 2-8 organylaminocarbonyl;
R 17 is selected from the group consisting of hydrogen, an optionally substituted C 1-24 -alkyl, an optionally substituted C 2-24 alkenyl, an optionally substituted C 2-24 alkynyl, an optionally substituted C 3-6 cycloalkyl and an optionally substituted C 3-6 cycloalkenyl;
R 19 , R 20 and R 21 are each independently absent or hydrogen;
m is 0 or 1;
n is 1 or 2;
p and q are each independently selected from the group consisting of 1, 2 and 3;
r is 1 or 2;
s is 0 or 1;
Z 1 is oxygen (O) or sulfur (S).
2. The compound of claim 1 , wherein B 1 is selected from the group consisting of: an unsubstituted
an unsubstituted
an unsubstituted
an unsubstituted
an unsubstituted
an unsubstituted
an unsubstituted
an unsubstituted
an unsubstituted
an unsubstituted
and an unsubstituted
3. The compound of claim 1 , wherein R 1 and R 2 are each independently selected from the group consisting of O − , —OH, an optionally substituted —O-aryl, an optionally substituted —O-heteroaryl, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester derivative.
4. The compound of claim 1 , wherein the optionally substituted N-linked amino acid ester derivative of R 1 and R 2 is independently selected from the group consisting of:
5. The compound of claim 1 , wherein R 3a and R 3b are each hydrogen.
6. The compound of claim 1 , wherein at least one of R 3a and R 3b is an unsubstituted C 1-4 alkyl.
7. The compound of claim 1 , wherein one of R 3a and R 3b is hydrogen; and other of R 3a and R 3b is halogen(C 1-4 alkyl).
8. The compound of claim 1 , wherein one of R 3a and R 3b is hydrogen; and other of R 3a and R 3b is hydroxy(C 1-4 alkyl).
9. The compound of claim 1 , wherein one of R 3a and R 3b is hydrogen; and other of R 3a and R 3b is alkoxy(C 1-4 alkyl).
10. The compound of claim 1 , wherein R 3a and R 3b are each independently selected from the group consisting of hydrogen, fluoro, CH 3 , CH 2 F, CHF 2 , CH 2 OH and CH 2 —O—CH 3 , or wherein R 3a and R 3b are taken together with the carbon to which they are connected form an optionally substituted cyclopropyl.
11. The compound of claim 1 , wherein n is 1.
12. The compound of claim 1 , wherein m is 1.
13. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
14. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
15. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
16. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
17. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
18. A method of ameliorating or treating an HBV and/or HDV infection, comprising administering to a subject suffering from the HBV and/or HDV infection an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 17 .
19. A method of ameliorating or treating an HIV infection comprising administering to a subject suffering from the HIV infection an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 17 .