Kappa opioid receptor ligands

1. A kappa opioid receptor antagonist compound represented by the formula (I):

wherein

G is H, OH, OC 1-6 alkyl, OCOC 1-8 alkyl, CONH 2 , NHCHO, NH 2 , NHSO 2 C 1-8 alkyl, or NHCO 2 C 1-8 alkyl;

R 1 is C 1-8 alkyl, or one of the following structures:

each Y 1 is, independently, H, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR 8 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , or CH 2 (CH 2 ) n Y 2 ,

or two adjacent Y 1 groups form a —O—CH 2 —O— or —O—CH 2 CH 2 —O— group;

each Y 2 is, independently, H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ;

Y 3 is H, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR 8 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , or CH 2 (CH 2 ) n Y 2 ;

R 2 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl or CH 2 -aryl substituted by one or more groups Y 1 ;

R 3 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl or CH 2 -aryl substituted by one or more groups Y 1 ;

wherein R 2 and R 3 may be bonded together to form a C 2-8 , alkyl group;

R 4 is hydrogen, C 1-8 alkyl, CO 2 C 1-8 alkylaryl substituted by one or more groups Y 1 , CH 2 -aryl substituted by one or more groups Y 1 or CO 2 C 1-8 alkyl;

Z is N, O or S, wherein when Z is O or S, there is no R 5 ;

R 5 is H, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, CH 2 CO 2 C 1-8 alkyl, CO 2 C 1-8 alkyl or CH 2 -aryl substituted by one or more groups Y 1 ;

n is 0, 1, 2 or 3;

o is 0, 1, 2, or 3;

R 6 is a group selected from the group consisting of structures (a)-(p):

Q is NR 7 , CH 2 , O, S, SO, or SO 2 ;

each Y 4 is, independently, H, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR 8 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , or CH 2 (CH 2 ) n Y 2 ,

or two adjacent Y 4 groups form a —O—CH 2 —O— or —O—CH 2 CH 2 —O— group;

p is 0, 1, 2, or 3;

Y 5 is H, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , OR 8 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , or CH 2 (CH 2 ) n Y 2 ;

X 1 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, or C 3-8 alkynyl;

X 2 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, or C 3-8 alkynyl;

or X 1 and X 2 together form ═O, ═S, or ═NH;

R 7 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents Y 1 , NR 10 R 11 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , CH 2 (CH 2 ) n Y 2 , or C(═NH)NR 16 R 17 ;

each of R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 is, independently, H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents H, OH, Br, Cl, F, CN, CF 3 , NO 2 , N 3 , C 1-6 alkyl, or CH 2 (CH 2 ) n Y 2 ′;

Y 2 ′ is H, CF 3 , or C 1-6 alkyl;

R 18 is C 1-8 alkyl, C 2-8 alkenyl, C 3-8 alkenyl, CH 2 OR 5 , or CH 2 -aryl substituted by one or more substituents Y 1 ;

or a pharmaceutically acceptable salt thereof.

2. The kappa opioid receptor antagonist of claim 1 , wherein Y 3 is H.

3. The kappa opioid receptor antagonist of claim 1 , wherein

R 1 is C 1-8 alkyl, or one of the following structures:

Y 3 is H;

R 2 and R 3 are each, independently, H or C 1-8 alkyl, wherein R 2 and R 3 cannot both be H at the same time; and

R 7 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents Y 1 , NR 10 R 11 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , or CH 2 (CH 2 ) n Y 2 .

4. The kappa opioid receptor antagonist of claim 1 , wherein

R 1 is C 1-8 alkyl;

Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCOR 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ;

Y 3 is H;

R 2 and R 3 are each, independently, H or methyl, wherein R 2 and R 3 cannot both be H at the same time;

R 4 is H, C 1-8 alkyl, CO 2 C 1-8 alkyl, or CH 2 -aryl substituted by one or more substituents Y 1 and the stereocenter adjacent to R 4 is in an (S) configuration;

R 5 is H, C 1-8 alkyl, or CH 2 CO 2 C 1-8 alkyl;

R 6 is a group having a formula selected from the group consisting of structures (a)-(c) and (h)-(p); and

R 7 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents Y 1 , NR 10 R 11 , NHCOR 12 , NHCO 2 R 13 , CONR 14 R 15 , or CH 2 (CH 2 ) n Y 2 .

5. The kappa opioid receptor antagonist of claim 1 , wherein

R 1 is methyl,

Y 2 is H, CF 3 , CO 2 R 9 , C 1-6 alkyl, NR 10 R 11 , NHCO 2 R 12 , NHCO 2 R 12 , CONR 13 R 14 , CH 2 OH, CH 2 OR 8 , or COCH 2 R 9 ;

Y 3 is H;

R 2 and R 3 are each H or methyl, such that when R 2 is H, R 3 is methyl and vice versa;

R 4 is C 1-8 alkyl, or CO 2 C 1-8 alkyl, and the stereocenter adjacent to R 4 has a configuration of (S);

R 5 is H;

R 6 is a group having a formula selected from the group consisting of structures (a) and (b); and

R 7 is H, C 1-8 alkyl, CH 2 -aryl substituted by one or more substituents Y 1 or CH 2 (CH 2 ) n Y 2 .

6. The kappa opioid receptor antagonist of claim 1 , which is represented by formula 14, 15, 16, 17 or 18:

wherein Q and R 18 are as defined in claim 1 .

7. The kappa opioid receptor antagonist of claim 1 , wherein Q is NH and R 18 is C 1-8 alkyl.

8. The kappa opioid receptor antagonist of claim 1 , wherein Q is NH and R 18 is C 2-8 alkenyl.

9. The kappa opioid receptor antagonist of claim 1 , wherein Q is NH and R 18 is C 3-8 alkenyl.

10. The kappa opioid receptor antagonist of claim 1 , wherein Q is NH and R 18 is CH 2 -aryl substituted by one or more groups Y 1 .

11. The kappa opioid receptor antagonist of claim 1 , wherein Q is NH and R 18 is C 1-4 alkyl.

12. The kappa opioid receptor antagonist of claim 1 , wherein Q is NH and R 18 is methyl.

13. The kappa opioid receptor antagonist of claim 6 , wherein Q is NH and R 18 is C 1-8 alkyl.

14. The kappa opioid receptor antagonist of claim 6 , wherein Q is NH and R 18 is C 2-8 alkenyl.

15. The kappa opioid receptor antagonist of claim 6 , wherein Q is NH and R 18 is C 3-8 alkenyl.

16. The kappa opioid receptor antagonist of claim 6 , wherein Q is NH and R 18 is CH 2 -aryl substituted by one or more groups Y 1 .

17. The kappa opioid receptor antagonist of claim 6 , wherein Q is NH.

18. The kappa opioid receptor antagonist of claim 6 , wherein Q is NH and R 18 is C 1-4 alkyl.

19. The kappa opioid receptor antagonist of claim 6 , wherein Q is NH and R 18 is methyl.

20. The kappa opioid receptor antagonist of claim 1 , which has a κ/μ selectivity of at least 2:1.

21. The kappa opioid receptor antagonist of claim 1 , which has a κ/μ selectivity of at least 50:1.

22. The kappa opioid receptor antagonist of claim 1 , which has a κ/μ selectivity of at least 100:1.

23. The kappa opioid receptor antagonist of claim 1 , which has a κ/δ selectivity of at least 2:1.

24. The kappa opioid receptor antagonist of claim 1 , which has a κ/δ selectivity of at least 20:1.

25. The kappa opioid receptor antagonist of claim 1 , which has a κ/δ selectivity of at least 250:1.

26. The kappa opioid receptor antagonist of claim 1 , which has a κ/μ selectivity of at least 100:1 and which has a κ/δ selectivity of at least 200:1.

27. A pharmaceutical composition comprising an effective amount of the kappa opioid receptor antagonist of claim 1 and a physiologically acceptable carrier.

28. The pharmaceutical composition of claim 27 , which is an injectable composition.

29. The pharmaceutical composition of claim 27 , which is an orally administrable composition.

30. The pharmaceutical composition of claim 27 , which is an orally administrable composition in a form selected from the group consisting of tablets, capsules, troches, powders, solutions, dispersions, emulsions and suspensions.

31. A method of making the pharmaceutical composition of claim 27 , comprising combining the kappa opioid receptor antagonist and the physiologically acceptable carrier.

32. A method of binding a kappa opioid receptor in a subject in need thereof, comprising administering to the subject an effective amount of the kappa opioid receptor antagonist of claim 1 .