Phenyl-substituted 2-imino-3-methyl pyrrolo pyrimidinone compounds as BACE-1 inhibitors, compositions, and their use
View Patent ↗In its many embodiments, the present invention provides certain 2-imino-3-methyl pyrrolo pyrimidone compounds, including compounds Formula (II): and include tautomers, steroisomers, or pharmaceutically acceptable salts or solvates of said compounds, stereoisomers, or said tautomers, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each selected independently and as defined herein. Pharmaceutical compositions comprising one or more such compounds, 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 deuterate thereof, or a tautomer of said compound or said deuterate, or a pharmaceutically acceptable salt of said compound, said deuterate, or said tautomer, said compound having the structural Formula (II-A):
wherein R 2 , R 3 , R 4 , R 5 , R 8 , R 7 , and R 8 are each selected independently and wherein:
R 2 is selected from hydrogen, fluorine, chlorine, and cyano;
R 3 is selected from hydrogen, fluorine, chlorine, and cyano;
R 4 is selected from hydrogen, fluorine, chlorine, and cyano;
R 5 is selected from hydrogen, fluorine, and chlorine;
R 6 is selected from lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, and lower alkyl-OH;
R 7 is selected from fluorine and chlorine; and
R 8 is selected from lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, and —O-alkyl-cycloalkyl.
2. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R 6 is selected from lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, and lower alkyl-OH;
R 7 is selected from fluorine and chlorine; and
R 8 is selected from lower alkyl, lower alkoxy, and cyclopropyl.
3. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R 6 is selected from methyl, ethyl, methoxy, ethoxy, —CH 2 OH, —CF 3 , and —CF 2 CH 3 ;
R 7 is selected from fluorine and chlorine; and
R 8 is selected from methoxy, ethoxy, cyclopropyl, and ethyl.
4. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R 6 is selected from methyl, ethyl, and methoxy;
R 7 is selected from fluorine and chlorine; and
R 8 is selected from methoxy and cyclopropyl.
5. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R 6 is selected from methyl, ethyl, methoxy, ethoxy, —CH 2 OH, —CF 3 , and —CF 2 CH 3 ;
R 7 is selected from fluorine and chlorine; and
R 8 is selected from methoxy, ethoxy, cyclopropyl, and ethyl;
and the moiety
shown in Formula (II-A) is selected from:
6. A compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
the moiety
shown in Formula (II-A) is selected from the group consisting of
7. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the structural Formula (II-AA):
wherein:
R 2 is selected from hydrogen, fluorine, chlorine, and cyano;
R 3 is selected from hydrogen, fluorine, chlorine, and cyano;
R 4 is selected from hydrogen, fluorine, chlorine, and cyano; and
R 5 is selected from hydrogen, fluorine, and chlorine.
8. A compound of claim 7 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: the moiety
shown in Formula (II-AA) is selected from:
9. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the structural Formula (II-AB):
wherein each variable is selected independently of the others and wherein: the moiety
shown in (II-AB) is selected from the group consisting of
either R 2 is F and R 3 is H or R 2 is H and R 3 is F.
10. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound being selected from:
Ex
No.
Compound
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
11. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having a structure selected from:
Ex
No.
Compound
1
2
8
9
10
15
16
17
18
19
20
31
35
38
39
12. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the following structure:
13. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the following structure:
14. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the following structure:
15. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the following structure:
16. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the following structure:
17. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the following structure:
18. A deuterated compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said deuterated compound or said tautomer, said deuterated compound having the following structure:
19. A deuterated compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said deuterated compound or said tautomer, said deuterated compound having the following structure:
20. A pharmaceutical composition comprising at least one compound of any one of claims 1 - 19 , or a tautomer thereof, or pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier or diluent.
21. A pharmaceutical composition comprising a compound of any one of claims 1 - 19 , or a tautomer thereof, or a stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt thereof, together with at least one additional therapeutic agent, wherein said at least one additional therapeutic agent is at least one agent selected from:
m 1 agonists; m 2 antagonists; cholinesterase inhibitors; galantamine; rivastigimine; N-methyl-D-aspartate receptor antagonists; combinations of cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists; gamma secretase modulators; gamma secretase inhibitors; non-steroidal anti-inflammatory agents; anti-inflammatory agents that can reduce neuroinflammation; anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists; CB1 receptor antagonists; antibiotics; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABA A inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors; Tau kinase inhibitors; Tau aggregation inhibitors; RAGE inhibitors; anti-Abeta vaccine; APP ligands; agents that upregulate insulin, cholesterol lowering agents; cholesterol absorption inhibitors; combinations of HMG-CoA reductase inhibitors and cholesterol absorption inhibitors; fibrates; combinations of fibrates and cholesterol lowering agents and/or cholesterol absorption inhibitors; nicotinic receptor agonists; niacin; combinations of niacin and cholesterol absorption inhibitors and/or cholesterol lowering agents; LXR agonists; LRP mimics; H3 receptor antagonists; histone deacetylase inhibitors; hsp90 inhibitors; 5-HT4 agonists; 5-HT6 receptor antagonists; mGluR1 receptor modulators or antagonists; mGluR5 receptor modulators or antagonists; mGluR2/3 antagonists; Prostaglandin EP2 receptor antagonists; PAI-1 inhibitors; agents that can induce Abeta efflux; Metal-protein attenuating compound; GPR3 modulators; and antihistamines.