IP Library Granted Patent US 8,158,675
Granted Patent B2
US 8,158,675 · App. 12/508,893 · Granted Apr 17, 2012

Compounds and methods for the treatment or prevention of

Assignee: Vertex Pharmaceuticals (Canada) Incorporated
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Quick Facts
Patent No.
US 8,158,675
App. No.
12/508,893
Granted
Apr 17, 2012
Kind
B2
Abstract

Compounds represented by formula I: or pharmaceutically acceptable salts and solvates thereof, wherein R 1 , X, Y, Y 1 , and Z are as defined herein, are useful for treating flaviviridae viral infections.

Claims (36)

1. A compound according to formula I:

wherein:

R 1 is optionally substituted C 3-12 cycloalkyl, optionally substituted C 4-12 cycloalkenyl, optionally substituted —C(O)—C 3-12 cycloalkyl, optionally substituted —C(O)—C 4-12 cycloalkenyl, optionally substituted 5 to 12 member spiroheterocycloalkyl, or optionally substituted 8 to 12 member spiroheterocycloalkenyl, wherein when R 1 is optionally substituted 5 to 12 member spiroheterocycloalkyl the cycloalkyl moiety is directly attached to the 5-position of the thiophene ring, and when R 1 is optionally substituted 8 to 12 member spiroheterocycloalkenyl the cycloalkenyl moiety is directly attached to the 5-position of the thiophene ring;

Z is H, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 alkynyl;

X is:

M is:

or a bond;

R 2 , R 3 and R 6 are each independently H, optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkenyl, optionally substituted C 2-12 alkynyl, optionally substituted C 6-14 aryl, optionally substituted C 7-16 aralkyl, optionally substituted 5-12 member heteroaryl, optionally substituted 6-18 member heteroaralkyl, optionally substituted 3-12 member heterocycle, or optionally substituted 4-18 member heterocycle-alkyl;

R 4 and R 5 are each independently H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 alkynyl;

Y 1 is a bond, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 alkynyl;

Y is COOR 9 , COCOOR 9 , P(O)OR a OR b , S(O)OR 9 , S(O) 2 OR 9 , tetrazole, CON(R 9 )CH(R 9 )COOR 9 , CONR 10 R 11 , CON(R 9 )—SO 2 —R 9 , CONR 9 OH, or halogen;

R 9 , R 10 and R 11 are each independently chosen from H, optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkenyl, optionally substituted C 2-12 alkynyl, optionally substituted C 6-14 aryl, optionally substituted C 7-16 aralkyl, optionally substituted 5-12 member heteroaryl, optionally substituted 6-18 member heteroaralkyl, optionally substituted 3-12 member heterocycle, or optionally substituted 4-18 member heterocycle-alkyl,

or R 10 and R 11 are taken together with the nitrogen atom to form an optionally substituted 3 to 10 member heterocycle or an optionally substituted 5-12 member heteroaryl; and

R a and R b are each independently H, optionally substituted C 1-12 alkyl, optionally substituted C 2-12 alkenyl, optionally substituted C 2-12 alkynyl, optionally substituted C 6-14 aryl, optionally substituted C 7-16 aralkyl, optionally substituted 5-12 member heteroaryl, optionally substituted 6-18 member heteroaralkyl, optionally substituted 3-12 member heterocycle, or optionally substituted 4-18 member heterocycle-alkyl,

or R a and R b are taken together with the oxygen atoms to form an optionally substituted 5 to 10 member heterocycle, or an optionally substituted 5-12 member heteroaryl; or

a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein said compound is of formula IA:

or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 , wherein said compound is of formula IC:

or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1 , wherein X is

and M is

or a bond.

5. A compound according to claim 3 , wherein M is

6. A compound according to claim 4 , wherein M is

7. A compound according to claim 1 , wherein Y 1 is CH 2 , C═CH, CH 2 —CH 2 or a bond.

8. A compound according to claim 1 , wherein Y 1 is a bond.

9. A compound according to claim 1 , wherein Y is COOR 9 , CONR 10 R 11 or CON(R 9 )CH(R 9 )—COOR 9 .

10. A compound according to claim 9 , wherein Y is COOR 9 , CONR 10 R 11 or CONR 9 CH 2 COOR 9 .

11. A compound according to claim 9 , wherein Y is COOH, CONH 2 , CONHCH 2 COOH, or COOCH 3 .

12. A compound according to claim 1 , wherein Y 1 —Y is COOH.

13. A compound according to claim 1 , wherein, R a , R b , R 9 , R 10 , and R 11 are each independently H or optionally substituted C 1-6 alkyl.

14. A compound according to claim 13 , wherein, R a , R b , R 9 , R 10 , and R 11 are each independently H or methyl.

15. A pharmaceutical combination comprising at least one compound according to claim 1 and at least one pharmaceutically acceptable carrier or excipient.

16. A pharmaceutical combination according to claim 15 , further comprising at least one additional agent selected from viral serine protease inhibitors, viral polymerase inhibitors, viral helicase inhibitors, immunomodulating agents, antioxidant agents, antibacterial agents, therapeutic vaccines, hepatoprotectant agents, antisense agents, inhibitors of HCV NS2/3 protease and inhibitors of internal ribosome entry site (IRES).

17. A method for treating a Flaviviridae viral infection in a host comprising administering to the host a therapeutically effective amount of at least one compound according to claim 1 .

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 23, 2010
From: DENIS, REAL; POISSON, CARL; DAS, SANJOY KUMAR; MOTORINA, IRINA; REJ, RABINDRA; YANNOPOULOS, CONSTANTIN G.; CHAN CHUN KONG, LAVAL
To: VIROCHEM PHARMA, INC.
Reel/Frame 025562/0483 →
MERGER Recorded Nov 10, 2010
From: VIROCHEM PHARMA INC.
To: VERTEX PHARMACEUTICALS (CANADA) INCORPORATED
Reel/Frame 025343/0812 →
Continuity (3)
Continuation 11433749 · May 15, 2006
Provisional Application 60680482 · May 13, 2005
Related Publication 20100093775A1 · Apr 15, 2010