IP Library › Granted Patent US 8,350,042
Granted Patent B2
US 8,350,042 · App. 12/865,385 · Granted Jan 8, 2013

Antiviral compounds for the treatment of HCV infection

Assignee: The Regents of the University of California
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Quick Facts
Patent No.
US 8,350,042
App. No.
12/865,385
Granted
Jan 8, 2013
Kind
B2
Abstract

Disclosed are compounds and methods of synthesis of Formula I for the development of antiviral drugs for the treatment of HCV infection.

Claims (93)

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

X is NH, O, S, or (CH 2 ) n1 , wherein n 1 is 1 to 6;

A is O or S;

B is O or S;

each R 1 and R 2 , independently, is —CONH 2 , or a substituted or unsubstituted —C 1-6 alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted —(CH 2 ) n aryl, a substituted or unsubstituted —(CH 2 ) n heteroaryl, a substituted or unsubstituted —(CH 2 ) n heterocycloalkyl, a substituted or unsubstituted —(CH═CH) n aryl, a substituted or unsubstituted —(CH═CH) n heteroaryl, a substituted or unsubstituted —C 2-6 alkenyl-aryl, a substituted or unsubstituted —C 2-6 alkenyl-heteroaryl, a substituted or unsubstituted —(C≡C) n aryl, a substituted or unsubstituted —(C≡C) n heteroaryl, a substituted or unsubstituted —NR 3 —C 1-6 alkyl, a substituted or unsubstituted —NR 3 -aryl, a substituted or unsubstituted —NR 3 -heteroaryl, a substituted or unsubstituted —NR 3 -cycloalkyl, a substituted or unsubstituted —NR 3 -heterocycloalkyl, a substituted or unsubstituted —NHNH—C 1-6 alkyl, a substituted or unsubstituted —NHNH-aryl, a substituted or unsubstituted —NHNH-heteroaryl, a substituted or unsubstituted —NHNH-cycloalkyl, a substituted or unsubstituted —NHNH-heterocycloalkyl, a substituted or unsubstituted —O—C 1-6 alkyl, a substituted or unsubstituted —O-aryl, a substituted or unsubstituted —O-heteroaryl, a substituted or unsubstituted —O-cycloalkyl, a substituted or unsubstituted —O-heterocycloalkyl, —S(C 1-6 ) alkyl, a substituted or unsubstituted —S-aryl, a substituted or unsubstituted —S-heteroaryl, a substituted or unsubstituted —S-cycloalkyl, a substituted or unsubstituted —S-heterocycloalkyl, a substituted or unsubstituted —(C═O)(C 1-6 ) alkyl, a substituted or unsubstituted —(C═O) aryl, a substituted or unsubstituted —(C═O) heterocycloalkyl, n being an integer from 1 to 4; and

R 3 is —H or a substituted or unsubstituted alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.

2. The compound of claim 1 , wherein X is NH.

3. The compound of claim 1 , wherein X is CH 2 .

4. A compound of Formula (II) or a pharmaceutically acceptable salt thereof:

wherein:

A is O or S;

B is O or S;

Y is N or CH, or —(CH 2 ) n2 CH—, wherein n 2 is from 1 to 6;

Z is a lower alkylene group or a lower heteroalkylene group such that Z and Y together with the C atom between them form a 4-, 5-, or 6-membered substituted or unsubstituted cycloalkyl or heterocycloalkyl;

each R 2 is —CONH 2 , or a substituted or unsubstituted —C 1-6 alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted —(CH 2 ) n aryl, a substituted or unsubstituted —(CH 2 ) n heteroaryl, a substituted or unsubstituted —(CH 2 ) n heterocycloalkyl, a substituted or unsubstituted —(CH═CH) n aryl, a substituted or unsubstituted —(CH═CH) n heteroaryl, a substituted or unsubstituted —C 2-6 alkenyl-aryl, a substituted or unsubstituted —C 2-6 alkenyl-heteroaryl, a substituted or unsubstituted —(C≡C) n aryl, a substituted or unsubstituted —(C≡C) n heteroaryl, a substituted or unsubstituted —NR 3 —C 1-6 alkyl, a substituted or unsubstituted —NR 3 -aryl, a substituted or unsubstituted —NR 3 -heteroaryl, a substituted or unsubstituted —NR 3 -cycloalkyl, a substituted or unsubstituted —NR 3 -heterocycloalkyl, a substituted or unsubstituted —NHNH—C 1-6 alkyl, a substituted or unsubstituted —NHNH-aryl, a substituted or unsubstituted —NHNH-heteroaryl, a substituted or unsubstituted —NHNH-cycloalkyl, a substituted or unsubstituted —NHNH-heterocycloalkyl, a substituted or unsubstituted —O—C 1-6 alkyl, a substituted or unsubstituted —O-aryl, a substituted or unsubstituted —O-heteroaryl, a substituted or unsubstituted —O-cycloalkyl, a substituted or unsubstituted —O-heterocycloalkyl, a substituted or unsubstituted —S(C 1-6 ) alkyl, a substituted or unsubstituted —S-aryl, a substituted or unsubstituted —S-heteroaryl, a substituted or unsubstituted —S-cycloalkyl, a substituted or unsubstituted —S-heterocycloalkyl, a substituted or unsubstituted —(C═O)(C 1-6 ) alkyl, a substituted or unsubstituted —(C═O) aryl, a substituted or unsubstituted —(C═O) heterocycloalkyl, n being an integer from 1 to 4; and

R 3 is —H or a substituted or unsubstituted alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.

5. A compound of claim 1 , where the compound is:

6. A compound of claim 1 , wherein R 1 is:

—(CH 2 ) n3 —NH 2 , where n 3 is 1 to 6

where n 4 is 1 to 5

where n 5 is 1 to 3, and

R 2 is:

wherein R′ is an alkyl, aryl, heteroaryl, heterycycloalkyl, alkenyl-aryl, cycloalkyl, or alkenyl-heteroaryl.

7. A compound of claim 1 , wherein R 1 is:

and R 2 is

8. A compound of claim 1 , wherein R 1 is:

and R 2 is

9. A compound of claim 1 , wherein R 1 is:

and R 2 is

10. A compound of claim 1 , wherein R 1 is:

and R 2 is

11. A compound of claim 1 , wherein R 1 is:

and R 2 is

12. A compound of claim 1 , wherein R 1 is:

and R 2 is H.

13. A compound of claim 1 , wherein R 1 is:

and R 2 is

14. A compound of claim 1 , wherein R 1 is:

and R 2 is

15. A compound of claim 1 , wherein R 1 is:

and R 2 is

16. A compound of claim 1 , wherein R 1 is:

and R 2 is

17. A compound of claim 1 , wherein R 1 is:

and R 2 is

18. A compound of claim 1 , wherein R 1 is:

and R 2 is H.

19. A compound of claim 1 , wherein R 1 is:

and R 2 is

20. A compound of claim 1 , wherein R 1 is:

and R 2 is

21. A compound of claim 1 , wherein R 1 is:

and R 2 is

22. A compound of claim 1 , wherein R 1 is:

and R 2 is

23. A compound of claim 1 , wherein R 1 is:

and R 2 is

24. A compound of claim 1 , wherein R 1 is:

and R 2 is H.

25. A compound of claim 1 , wherein R 1 is:

and R 2 is

26. A compound of claim 1 , wherein R 1 is:

and R 2 is

27. A compound of claim 1 , wherein R 1 is:

and R 2 is

28. A compound of claim 1 , wherein R 1 is:

and R 2 is

29. A compound of claim 1 , wherein R 1 is:

and R 2 is

30. A compound of claim 1 , wherein R 1 is:

and R 2 is H.

31. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

X is NH, O, S, or (CH 2 ) n1 , wherein n 1 is 1 to 6;

A is O or S;

B is O or S;

each R 1 and R 2 , independently, is —CONH 2 , or a substituted or unsubstituted —C 1-6 alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted —(CH 2 ) n aryl, a substituted or unsubstituted —(CH 2 ) n heteroaryl, a substituted or unsubstituted —(CH 2 ) n heterocycloalkyl, a substituted or unsubstituted —(CH═CH) n aryl, a substituted or unsubstituted —(CH═CH) n heteroaryl, a substituted or unsubstituted —C 2-6 alkenyl-aryl, a substituted or unsubstituted —C 2-6 alkenyl-heteroaryl, a substituted or unsubstituted —(C≡C) n aryl, a substituted or unsubstituted —(C≡C) n heteroaryl, a substituted or unsubstituted —NR 3 —C 1-6 alkyl, a substituted or unsubstituted —NR 3 -aryl, a substituted or unsubstituted —NR 3 -heteroaryl, a substituted or unsubstituted —NR 3 -cycloalkyl, a substituted or unsubstituted —NR 3 -heterocycloalkyl, a substituted or unsubstituted —NHNH—C 1-6 alkyl, a substituted or unsubstituted —NHNH-aryl, a substituted or unsubstituted —NHNH-heteroaryl, a substituted or unsubstituted —NHNH-cycloalkyl, a substituted or unsubstituted —NHNH-heterocycloalkyl, a substituted or unsubstituted —O—C 1-6 alkyl, a substituted or unsubstituted —O-aryl, a substituted or unsubstituted —O-heteroaryl, a substituted or unsubstituted —O-cycloalkyl, a substituted or unsubstituted —O-heterocycloalkyl, —S(C 1-6 ) alkyl, a substituted or unsubstituted —S-aryl, a substituted or unsubstituted —S-heteroaryl, a substituted or unsubstituted —S-cycloalkyl, a substituted or unsubstituted —S-heterocycloalkyl, a substituted or unsubstituted —(C═O)(C 1-6 ) alkyl, a substituted or unsubstituted —(C═O) aryl, a substituted or unsubstituted —(C═O) heterocycloalkyl, n being an integer from 1 to 4; and

R 3 is —H or a substituted or unsubstituted alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.

32. The pharmaceutical composition of claim 31 , wherein said pharmaceutical composition is a pill comprising an effective amount of said compound of Formula (I).

33. An injection device comprising a compound of Formula (I).

34. The injection device of claim 33 , wherein said injection device is a syringe.

35. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof:

wherein:

A is O or S;

B is O or S;

Y is N or CH, or —(CH 2 ) n2 CH—, wherein n 2 is from 1 to 6;

Z is a lower alkylene group or a lower heteroalkylene group such that Z and Y together with the C atom between them form a 4-, 5-, or 6-membered substituted or unsubstituted cycloalkyl or heterocycloalkyl;

each R 2 is —CONH 2 , or a substituted or unsubstituted —C 1-6 alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted —(CH 2 ) n aryl, a substituted or unsubstituted —(CH 2 ) n heteroaryl, a substituted or unsubstituted —(CH 2 ) n heterocycloalkyl, a substituted or unsubstituted —(CH═CH) n aryl, a substituted or unsubstituted —(CH═CH) n heteroaryl, a substituted or unsubstituted —C 2-6 alkenyl-aryl, a substituted or unsubstituted —C 2-6 alkenyl-heteroaryl, a substituted or unsubstituted —(C≡C) n aryl, a substituted or unsubstituted —(C≡C) n heteroaryl, a substituted or unsubstituted —NR 3 —C 1-6 alkyl, a substituted or unsubstituted —NR 3 -aryl, a substituted or unsubstituted —NR 3 -heteroaryl, a substituted or unsubstituted —NR 3 -cycloalkyl, a substituted or unsubstituted —NR 3 -heterocycloalkyl, a substituted or unsubstituted —NHNH—C 1-6 alkyl, a substituted or unsubstituted —NHNH-aryl, a substituted or unsubstituted —NHNH-heteroaryl, a substituted or unsubstituted —NHNH-cycloalkyl, a substituted or unsubstituted —NHNH-heterocycloalkyl, a substituted or unsubstituted —O—C 1-6 alkyl, a substituted or unsubstituted —O-aryl, a substituted or unsubstituted —O-heteroaryl, a substituted or unsubstituted —O-cycloalkyl, a substituted or unsubstituted —O-heterocycloalkyl, a substituted or unsubstituted —S(C 1-6 ) alkyl, a substituted or unsubstituted —S-aryl, a substituted or unsubstituted —S-heteroaryl, a substituted or unsubstituted —S-cycloalkyl, a substituted or unsubstituted —S-heterocycloalkyl, a substituted or unsubstituted —(C═O)(C 1-6 ) alkyl, a substituted or unsubstituted —(C═O) aryl, a substituted or unsubstituted —(C═O) heterocycloalkyl, n being an integer from 1 to 4; and

R 3 is —H or a substituted or unsubstituted alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl.

36. The pharmaceutical composition of claim 31 , wherein said pharmaceutical composition is a pill comprising an effective amount of said compound of Formula (II).

37. An injection device comprising a compound of Formula (II).

38. The injection device of claim 33 , wherein said injection device is a syringe.

Assignments (3)
CONFIRMATORY LICENSE Recorded Feb 19, 2013
From: UNIVERSITY OF CALIFORNIA SAN DIEGO
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 029827/0241 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 17, 2012
From: HERMANN, THOMAS C.; CARNEVALI, MAIA
To: REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE
Reel/Frame 029012/0488 →
CONFIRMATORY LICENSE Recorded Aug 5, 2011
From: UNIVERSITY OF CALIFORNIA SAN DIEGO
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 026706/0231 →
Continuity (2)
Provisional Application 61025264 · Jan 31, 2008
Related Publication 20110003855A1 · Jan 6, 2011