Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
View Patent ↗In its many embodiments, the present invention provides certain iminothiadiazine dioxide compounds, including compounds Formula (I): and include stereoisomers thereof, and pharmaceutically acceptable salts of said compounds stereoisomers, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , ring A, ring B, m, n, p, -L 1 -, -L 2 -, and -L 3 - is selected independently and as defined herein. The novel iminothiadiazine dioxide compounds of the invention have surprisingly been found to exhibit properties which are expected to render them advantageous as BACE inhibitors and/or for the treatment and prevention of various pathologies related to β-amyloid (“Aβ”) production. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use in treating pathologies associated with amyloid beta (Aβ) protein, including Alzheimer's disease, are also disclosed.
1. A compound, or a tautomer thereof, said compound having a structure:
2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 1 or a tautomer thereof.
3. A pharmaceutically acceptable salt of a compound or a tautomer thereof, said compound having a structure:
4. The pharmaceutically acceptable salt of claim 3 , wherein said salt is selected from the group consisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, and toluenesulfonate.
5. The pharmaceutically acceptable salt of claim 3 , wherein said salt is a hydrochloride salt.
6. The pharmaceutically acceptable salt of claim 3 , wherein said salt is a toluenesulfonate salt.
7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a pharmaceutically acceptable salt of claim 3 .
8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 5 .
9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 6 .
10. A compound, or a tautomer thereof, said compound having a structure:
11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 10 or a tautomer thereof.
12. A pharmaceutically acceptable salt of a compound or a tautomer thereof, said compound having a structure:
13. The pharmaceutically acceptable salt of the compound or tautomer of claim 12 , wherein said salt is selected from the group consisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, and toluenesulfonate.
14. The pharmaceutically acceptable salt of claim 12 , wherein said salt is a hydrochloride salt.
15. The pharmaceutically acceptable salt of claim 12 , wherein said salt is a toluenesulfonate salt.
16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a pharmaceutically acceptable salt of claim 12 .
17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 14 .
18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 15 .
19. A compound, or a tautomer thereof, said compound having a structure:
20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 19 or a tautomer thereof.
21. A pharmaceutically acceptable salt of a compound or a tautomer thereof, said compound having a structure:
22. The pharmaceutically acceptable salt of claim 21 , wherein said salt is selected from the group consisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, and toluenesulfonate.
23. The pharmaceutically acceptable salt of claim 21 , wherein said salt is a hydrochloride salt.
24. The pharmaceutically acceptable salt of claim 21 , wherein said salt is a toluenesulfonate salt.
25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a pharmaceutically acceptable salt of claim 21 .
26. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 23 .
27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 24 .
28. A compound, or a tautomer thereof, said compound having a structure:
29. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 28 or a tautomer thereof.
30. A pharmaceutically acceptable salt of a compound or a tautomer thereof, said compound having a structure:
31. The pharmaceutically acceptable salt of claim 30 , wherein said salt is selected from the group consisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, and toluenesulfonate.
32. The pharmaceutically acceptable salt of claim 30 , wherein said salt is a hydrochloride salt.
33. The pharmaceutically acceptable salt of claim 30 , wherein said salt is a toluenesulfonate salt.
34. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a pharmaceutically acceptable salt of claim 30 .
35. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 32 .
36. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 33 .
37. A compound, or a tautomer thereof, said compound having a structure:
38. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 37 or a tautomer thereof.
39. A pharmaceutically acceptable salt of a compound or a tautomer thereof, said compound having a structure:
40. The pharmaceutically acceptable salt of claim 39 , wherein said salt is selected from the group consisting of acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartarate, thiocyanate, and toluenesulfonate.
41. The pharmaceutically acceptable salt of claim 39 , wherein said salt is a hydrochloride salt.
42. The pharmaceutically acceptable salt of claim 39 , wherein said salt is a toluenesulfonate salt.
43. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a pharmaceutically acceptable salt of claim 39 .
44. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 41 .
45. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the pharmaceutically acceptable salt of claim 42 .