Thiophenyl-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 thiophenyl-substituted 2-imino-3-methyl pyrrolo pyrimidone compounds, including compounds (or tautomers or a pharmaceutically acceptable salts thereof) having the structural Formula (III): 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 tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the structural Formula (III):
wherein:
R 2 is selected from hydrogen, fluorine, chlorine, bromine, and cyano;
R 3 is selected from hydrogen, fluorine, chlorine, and cyano;
R 4 is selected from hydrogen, fluorine, chlorine, and cyano;
R 6 is selected from lower alkyl, lower alkoxy, lower haloalkyl, and lower haloalkoxy,
R 7 is selected from fluorine and chlorine;
R 8 is selected from lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, and —O-alkyl-cycloalkyl, and
R 9 is selected from hydrogen and lower alkyl.
2. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the structural Formula (III-A):
wherein R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 are each selected independently and wherein:
R 2 is selected from hydrogen, fluorine, chlorine, bromine, and cyano;
R 3 is selected from hydrogen, fluorine, chlorine, and cyano;
R 4 is selected from hydrogen, fluorine, chlorine, and cyano;
R 6 is selected from lower alkyl and lower alkoxy;
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 2 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R 2 is selected from chlorine and cyano;
R 3 is H;
R 4 is H;
R 6 is selected from lower alkyl and lower alkoxy;
R 7 is selected from fluorine and chlorine; and
R 8 is selected from lower alkyl, lower alkoxy, and cyclopropyl.
4. A compound of claim 2 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R 2 is H;
R 3 is selected from chlorine and cyano;
R 4 is H;
R 6 is selected from lower alkyl and lower alkoxy;
R 7 is selected from fluorine and chlorine; and
R 8 is selected from lower alkyl, lower alkoxy, and cyclopropyl.
5. A compound of claim 2 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R 2 is selected from chlorine and cyano;
R 3 is H;
R 4 is H;
R 6 is selected from methyl, ethyl, n-propyl, methoxy, and ethoxy;
R 7 is selected from chlorine and fluorine; and
R 8 is selected from methyl, ethyl, n-propyl, methoxy, ethoxy, and cyclopropyl.
6. A compound of claim 2 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R 2 is H;
R 3 is selected from chlorine and cyano;
R 4 is H;
R 6 is selected from methyl, ethyl, n-propyl, methoxy, and ethoxy;
R 7 is selected from chlorine and fluorine; and
R 8 is selected from methyl, ethyl, n-propyl, methoxy, ethoxy, and cyclopropyl.
7. A compound of claim 2 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R 2 is H;
R 3 is selected from chlorine and cyano;
R 4 is H;
R 6 is selected from selected from methyl, ethyl, and methoxy;
R 7 is selected from fluorine and chlorine; and
R 8 is selected from methoxy and cyclopropyl.
8. A compound of claim 2 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R 2 is selected from chlorine and cyano;
R 3 is H;
R 4 is H;
R 6 is selected from selected from methyl, ethyl, and methoxy;
R 7 is selected from fluorine and chlorine; and
R 8 is selected from methoxy and cyclopropyl.
9. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound selected from the group consisting of:
Example No.
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10. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound selected from the group consisting of:
Example No.
Structure
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11. A pharmaceutical composition comprising at least one compound of any one of claims 1 - 10 , or a tautomer thereof, or salt of said compound or said tautomer, and a pharmaceutically acceptable carrier or diluent.
12. A pharmaceutical composition comprising a compound of any one of claims 1 - 10 , or a tautomer thereof, or pharmaceutically acceptable salt of said compound or said tautomer, together with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier or diluent.
13. A pharmaceutical composition comprising a compound of any one of claims 1 - 10 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and one or more drugs 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; mGluR⅔antagonists; Prostaglandin EP2 receptor antagonists; PAI-1 inhibitors; agents that can induce Abeta efflux; Metal-protein attenuating compound; GPR3 modulators; and antihistamines.