Kappa opioid receptor antagonists and products and methods related thereto
Compounds are provided that antagonize the kappa-opioid receptor (KOR) and products containing such compounds, as well as to methods of their use and synthesis. Such compounds have the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof: wherein X, Y, R 1 , R 2 , R 4 , R 5 R 6 , R 7 , R 8 and R 11 are as defined herein.
1. A compound having the structure of Formula (XI) or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof:
wherein
R 1 is H, F, or lower alkyl;
R 2 is H or lower alkyl;
R 4 is lower alkyl;
R 8 is halo or cyano;
R 5 and R 7 are both; and
R 6 is lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, cycloalkoxy, lower alkynyl, cycloalkyl, halo or cyano.
2. The compound of claim 1 , wherein the compound having the structure of Formula (XI) is a compound having one of the following structures, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof:
3. A compound having the following structure, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope or salt thereof:
wherein
X is O when Y is N or X is N when Y is O;
R 1 is H, F, or lower alkyl;
R 2 is H or lower alkyl; and
R 6 is lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, cycloalkoxy, lower alkynyl, cycloalkyl, halo or cyano.
4. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 1, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
5. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 12, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
6. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 30, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
7. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 36, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
8. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 54, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
9. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 55, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
10. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 56, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
11. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 57, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
12. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 80, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
13. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 88, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
14. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 94, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
15. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 97, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
16. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 98, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
17. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 99, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
18. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 109, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
19. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 111, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
20. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 116, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
21. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 118, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
22. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 121, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
23. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 122, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
24. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 127, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
25. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 128, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
26. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 134, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
27. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 135, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
28. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 136, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
29. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 137, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
30. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 142, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
31. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 172, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
32. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 173, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
33. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 174, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
34. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 177, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
35. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 181, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
36. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 186, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
37. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 189, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
38. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 190, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
39. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 193, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
40. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 197, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
41. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 200, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
42. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 208, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
43. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 211, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
44. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 215, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
45. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 218, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
46. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 221, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
47. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 226, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
48. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 229, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
49. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 232, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
50. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 235, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
51. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 240, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
52. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 243, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
53. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 244, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
54. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 248, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
55. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 256, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
56. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 259, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
57. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 260, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
58. The compound of claim 2 , wherein the compound having the structure of Formula (XI) is Compound 265, or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope, or salt thereof.
59. A composition comprising a compound of any one of claim 1 , 2 , 3 , 4 - 11 , 12 - 30 , or 31 - 58 , or a pharmaceutically acceptable stereoisomer, racemate, hydrate, solvate, isotope or salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.