Heterocyclic aspartyl protease inhibitors
View Patent ↗Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein each variable in Formula I are as defined in the specification; and pharmaceutical compositions comprising the compounds of formula I. Also disclosed are methods of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymes. Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic m 1 agonist or m 2 antagonist.
1. A method of treating or ameliorating a disease or disorder for which the inhibition of an aspartyl protease is therapeutic, said method comprising administering to a patient in need thereof with an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is selected from the group consisting of:
Str #
Structure
1928
1945
1990
2055
2089
2106
2107
2118
2130
2131
2174
2178
2190
2196
2218
2219
2230
2253
2267
2314
2330
2340
2341
2357
2388
2438
2444
2455
2459
2470
2479
2489
2516
2522
2561
2562
2588
2598
2723
2733
2739
2759
2782
2801
2811
2833
2867
2870
2937
2983
3042
3044
3054
3104
3108
3112
3126
3149
3182
3189
3206
3241
3243
3251
3256
3259
3275
3306
3346
3368
3383
3411
3422
3426
3435
3540
3630
3659
3680
3735
3745
3763
3783
3873
3884
3888
3939
3963
3986
4018
4069
4070
4088
4098
4105
4115
4160
4165
4177
4207
4222
4257
4262
4284
4287
4290
4295
4308
4313
4318
4327
4328
and
2. The method of claim 1 , wherein said disease or disorder is cardiovascular disease, cognitive or neurodegenerative disease, a fungal infection, or a protozoal infection.
3. The method of claim 1 , wherein said disease or disorder is cognitive or neurodegenerative disease.
4. The method of claim 1 , wherein said disease or disorder is Alzheimer's disease.
5. The method of claim 4 , further comprising administering to said patient, simultaneously or sequentially, at least one additional active agent selected from:
a cholinesterase inhibitor; a muscarinic m 1 , agonist; a muscarinic m 2 antagonist; a N-methyl-D-aspartate receptor antagonist; a beta secretase inhibitor other than a compound of claim 1 ; a gamma secretase inhibitor; an HMG-CoA reductase inhibitor; a cholesterol absorption inhibitor; a non-steroidal anti-inflammatory agent; an anti-amyloid antibody; vitamin E; a nicotinic acetylcholine receptor agonist; a CB1 receptor inverse agonist; a CB1 receptor antagonist; an antibiotic; a growth hormone secretagogue; a histamine H3 antagonist; an AMPA agonist; a PDE4 inhibitor; a GABA A inverse agonist; an inhibitor of amyloid aggregation; a glycogen synthase kinase beta inhibitor; and a promoter of alpha secretase activity.
6. The method of either of claim 4 or 5 , comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is selected from the group consisting of:
Str #
Structure
2106
2782
3306
3383
3659
3783
3884
3963
3986
4308
4327
1945
2118
2130
2174
2178
2388
2438
2723
2759
2833
2937
2983
3368
4069
4088
4115
4165
4177
4328
7. The method of claim 4 , comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
2106
8. The method of claim 4 , comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
4327
9. The method of claim 4 , comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
2782
10. The method of claim 4 , comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
3306
11. The method of claim 4 , comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
3383
12. The method of claim 4 , comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
3659
13. The method of claim 4 , comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
3783
14. The method of claim 4 , comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
3884
15. The method of claim 4 , comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
3963
16. The method of claim 4 , comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
3986
17. The method of claim 4 , comprising administering an effective amount of a compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
4308
18. The method according to any one of claims 7 to 17 , further comprising administering, simultaneously or sequentially, at least one additional active agent selected from:
a cholinesterase inhibitor; a muscarinic m 1 agonist; a muscarinic m 2 antagonist; a N-methyl-D-aspartate receptor antagonist; a beta secretase inhibitor other than a compound of claim 1 ; a gamma secretase inhibitor; an HMG-CoA reductase inhibitor; a cholesterol absorption inhibitor; a non-steroidal anti-inflammatory agent; an anti-amyloid antibody; vitamin E; a nicotinic acetylcholine receptor agonist; a CB1 receptor inverse agonist; a CB1 receptor antagonist; an antibiotic; a growth hormone secretagogue; a histamine H3 antagonist; an AMPA agonist; a PDE4 inhibitor; a GABA A inverse agonist; an inhibitor of amyloid aggregation; a glycogen synthase kinase beta inhibitor; and a promoter of alpha secretase activity; and a pharmaceutically acceptable carrier.