2′-alkynyl substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
View Patent ↗The present invention relates to 2′-Alkynyl Substituted Nucleoside Derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein B, X, R1, R2, R3 and R4 are as defined herein. The present invention also relates to compositions comprising at least one 2′-Alkynyl Substituted Nucleoside Derivative, and methods of using the 2′-Alkynyl Substituted Nucleoside Derivatives for treating or preventing HCV infection in a patient.
1. A compound having the structure:
or a pharmaceutically acceptable salt thereof,
wherein:
B is a pyrimidine base;
X is O, S or CH 2 ;
R 1 is H,
R 2 is H, —C(O)—(C 1 -C 6 alkyl) or
or R 1 and R 2 join to form a group having the formula:
R 3 is H, F, —OR 12 , NH 2 , —CN, N 3 , —SR 12 or —C≡CR 5 ;
R 4 is F, —OR 12 , NH 2 , —CN, N 3 , —SR 12 , —O—(C 6 -C 10 aryl) or —C≡CR 5 , such that at least one of R 3 and R 4 must be —C≡CR 5 ;
R 5 is selected from H, C 1 -C 6 alkyl, ethynyl, and C 3 -C 7 cycloalkyl, wherein said C 1 -C 6 alkyl group, said ethynyl group and said C 3 -C 7 cycloalkyl group can be optionally substituted with one or more R 6 groups;
each occurrence of R 6 is independently selected from C 1 -C 6 alkyl, halo, —OR 12 , N(R 12 ) 2 , —CN, C 3 -C 7 cycloalkyl, phenyl and benzyl;
R 7 is H, C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl, wherein said C 6 -C 10 aryl group, said 5- or 6-membered monocyclic heteroaryl group and said 9- or 10-membered bicyclic heteroaryl group can be optionally substituted with halo, C 1 -C 6 alkyl, —O—(C 1 -C 6 alkyl) or —(C 1 -C 3 alkylene)-C(O)O—(C 1 -C 6 alkyl);
R 8 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl or benzyl;
R 9 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl or benzyl;
R 10 is H, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, —(C 1 -C 3 alkylene) m -(C 3 -C 7 cycloalkyl) or —(C 1 -C 3 alkylene) m -(C 6 -C 10 aryl);
R 11 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, —(C 1 -C 3 alkylene) m -C 6 -C 10 aryl, 5- or 6-membered monocyclic heteroaryl, 9- or 10-membered bicyclic heteroaryl;
each occurrence of R 12 is independently H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or C 6 -C 10 aryl; and
each occurrence of m is independently 0 or 1,
such that when R 3 is —C≡CR 5 and R 4 is —OR 12 , then R 1 and R 2 join to form a group having the formula:
2. The compound of claim 1 , wherein X is O.
3. The compound of claim 1 , wherein B is uridine.
4. The compound of claim 1 , wherein R 3 is —C≡CR 5 .
5. The compound of claim 1 , wherein R 4 is —C≡CR 5 .
6. The compound of claim 1 having the formula:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 and R 2 join to form a group having the formula:
R 5 is H or C 3 -C 7 cycloalkyl; and
R 11 is C 1 -C 6 alkyl.
7. The compound of claim 1 , wherein R 1 is:
8. The compound of claim 7 , wherein R 1 is:
9. The compound of claim 1 , wherein R 1 and R 2 join to form a group having the formula:
and R 11 is C 1 -C 6 alkyl.
10. The compound of claim 9 , wherein R 1 and R 2 join to form a group having the structure:
11. A compound having the structure:
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. The pharmaceutical composition according to claim 12 , further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
14. The pharmaceutical composition according to claim 13 , further comprising a third therapeutic agent selected from the group consisting of HCV protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.
15. A method of treating a patient infected with HCV comprising the step of administering an amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, effective to treat infection by HCV in said patient.
16. The method according to claim 15 , further comprising the step of administering to said patient a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
17. The method according to claim 16 further comprising the step of further comprising the step of administering to said patient a third therapeutic agent selected from the group consisting of HCV protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.