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 W is a bond, —C(═S)—, —S(O)—, —S(O) 2 —, —C(═O)—, —O—, —C(R 6 )(R 7 )—, —N(R 5 )— or —C(═N(R 5 ))—; X is —O—, —N(R 5 )— or —C(R 6 )(R 7 )—; provided that when X is —O—, U is not —O—, —S(O)—, —S(O) 2 —, —C(═O)— or —C(═NR 5 )—; U is a bond, —S(O)—, —S(O) 2 —, —C(O)—, —O—, —P(O)(OR 15 )—, —C(═NR 5 )—, —(C(R 6 )(R 7 )) b — or —N(R 5 )—; wherein b is 1 or 2; provided that when W is —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—, U is not —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—; provided that when X is —N(R 5 )— and W is —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—, then U is not a bond; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined in the specification; and pharmaceutical compositions comprising the compounds of formula I. Also disclosed is the method 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 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
2. A pharmaceutically acceptable salt of a compound, or a tautomer thereof, according to claim 1 , wherein said salt is selected from:
acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, and hexanoate.
3. A pharmaceutically acceptable salt of a compound, or a tautomer thereof, according to claim 1 , wherein said salt is selected from:
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, methyl sulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, sulfonates, tartarate, thiocyanate, tosylate, and undecanoate.
4. A pharmaceutically acceptable salt of claim 1 , wherein said salt is the tosylate salt.
5. A pharmaceutical composition comprising a compound of claim 1 , or said tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
6. 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. A pharmaceutically acceptable salt of a compound, or a tautomer thereof, according to claim 6 , wherein said salt is selected from:
acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, and hexanoate.
8. A pharmaceutically acceptable salt of a compound, or a tautomer thereof, according to claim 6 , wherein said salt is selected from:
hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, methyl sulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, sulfonates, tartarate, thiocyanate, tosylate, and undecanoate.
9. A pharmaceutically acceptable salt of a compound, or a tautomer thereof, according to claim 6 , wherein said salt is the tosylate salt.
10. A pharmaceutical composition comprising a compound of claim 6 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
11. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
2106
12. A pharmaceutically acceptable salt of said compound of claim 11 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
13. A pharmaceutical composition comprising a compound of claim 11 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
14. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, vvherein said compound is:
Structure
15. A pharmaceutically acceptable salt of said compound of claim 14 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
16. A pharmaceutical composition comprising a compound of claim 14 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
17. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer wherein said compound is:
Str #
Structure
4327
18. A pharmaceutically acceptable salt of said compound of claim 17 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
19. A pharmaceutical composition comprising a compound of claim 17 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
20. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Structure
21. A pharmaceutically acceptable salt of said compound of claim 20 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
22. A pharmaceutical composition comprising a compound of claim 20 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
23. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
2782
24. A pharmaceutically acceptable salt of said compound of claim 23 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
25. A pharmaceutical composition comprising a compound of claim 23 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
26. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Structure
27. A pharmaceutically acceptable salt of said compound of claim 26 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
28. A pharmaceutical composition comprising a compound of claim 26 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
29. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer wherein said compound is selected from:
Str #
Structure
3306
30. A pharmaceutically acceptable salt of said compound of claim 29 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
31. A pharmaceutical composition comprising a compound of claim 29 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
32. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is selected from:
Str #
Structure
4207
33. A pharmaceutically acceptable salt of said compound of claim 32 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
34. A pharmaceutical composition comprising a compound of claim 32 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
35. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
3383
36. A pharmaceutically acceptable salt of said compound of claim 35 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
37. A pharmaceutical composition comprising a compound of claim 35 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
38. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Structure
39. A pharmaceutically acceptable salt of said compound of claim 38 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
40. A pharmaceutical composition comprising a compound of claim 38 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
41. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
3659
42. A pharmaceutically acceptable salt of said compound of claim 41 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
43. A pharmaceutical composition comprising a compound of claim 41 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
44. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Structure
45. A pharmaceutically acceptable salt of said compound of claim 44 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
46. A pharmaceutical composition comprising a compound of claim 44 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
47. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
3783
48. A pharmaceutically acceptable salt of said compound of claim 47 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
49. A pharmaceutical composition comprising a compound of claim 47 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
50. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Structure
51. A pharmaceutically acceptable salt of said compound of claim 50 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
52. A pharmaceutical composition comprising a compound of claim 50 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
53. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
3884
54. A pharmaceutically acceptable salt of said compound of claim 53 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
55. A pharmaceutical composition comprising a compound of claim 53 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
56. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Structure
57. A pharmaceutically acceptable salt of said compound of claim 56 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
58. A pharmaceutical composition comprising a compound of claim 56 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
59. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
3963
60. A pharmaceutically acceptable salt of said compound of claim 59 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
61. A pharmaceutical composition comprising a compound of claim 59 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
62. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Structure
63. A pharmaceutically acceptable salt of said compound of claim 62 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
64. A pharmaceutical composition comprising a compound of claim 62 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
65. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
3986
66. A pharmaceutically acceptable salt of said compound of claim 65 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
67. A pharmaceutical composition comprising a compound of claim 65 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
68. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Structure
69. A pharmaceutically acceptable salt of said compound of claim 68 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
70. A pharmaceutical composition comprising a compound of claim 68 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
71. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is:
Str #
Structure
4308
72. A pharmaceutically acceptable salt of said compound of claim 71 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
73. A pharmaceutical composition comprising a compound of claim 71 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
74. A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said comnound or said tautomer, wherein said compound is:
Structure
75. A pharmaceutically acceptable salt of said compound of claim 74 , or said tautomer thereof, wherein said salt of said compound or said tautomer is the tosylate salt.
76. A pharmaceutical composition comprising a compound of claim 74 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier.
77. A pharmaceutical composition according to any one of claims 5 , 10 , 13 , 16 , 19 , 22 , 25 , 28 , 31 , 34 , 37 , 40 , 43 , 46 , 49 , 52 , 55 , 58 , 61 , 64 , 67 , 70 , 73 , or 76 , further comprising 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.
78. A pharmaceutical composition of claim 77 , wherein said at least one additional active agent is a cholinesterase inhibitor selected from tacrine, donepezil, rivastigmine, galantamine, pyridostigmine and neostig mine.
79. A pharmaceutical composition of claim 78 , wherein said cholinesterase inhibitor is selected from tacrine, donepezil, rivastigmine and galantamine.
80. A pharmaceutical composition of claim 77 , wherein said at least one additional active agent is a muscarinic m 1 agonist and a muscarinic m 2 antagonist.
81. A pharmaceutical composition of claim 77 , wherein said at least one additional active agent is an N-methyl-D-aspartate receptor antagonist.
82. A pharmaceutical composition of claim 81 , wherein said N-methyl-D-aspartate receptor antagonist is memantine.
83. A pharmaceutical composition of claim 77 , wherein said at least one additional active agent is a gamma secretase inhibitor.
84. A pharmaceutical composition of claim 77 , wherein said at least one additional active agent is at least one agent selected from an HMG-CoA reductase inhibitor and a cholesterol absorption inhibitor.
85. A pharmaceutical composition of claim 84 , wherein said HMG-CoA reductase inhibitor selected from atorvastatin, lovastatin, simvistatin, pravastatin, fluvastatin and rosuvastatin.
86. A pharmaceutical composition of claim 84 , wherein said at least one additional active agent is ezetimibe.
87. A pharmaceutical composition of claim 77 , wherein said at least one additional active agent is at least one non-steroidal anti-inflammatory agent.
88. A pharmaceutical composition of claim 87 , wherein said at least one non-steroidal anti-inflammatory agent is selected from ibuprofen, relafen and naproxen.