Macrocyclic heterocyclic aspartyl protease inhibitors
View Patent ↗Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt, solvate or ester thereof, wherein U, W, X, L, Y, M, Z, c, d, e, f, g, h, s, t, R 1 , R 2 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 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. 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 having the structural formula
or a pharmaceutically acceptable salt or solvate thereof, wherein
q is 1, 2, or 3;
R 2 , R 3 , R 4 , R 15 and R 16 are each independently selected from the group consisting of H, alkyl, and —CF 3 ;
R 24 is present or absent and, when present, is 1 to 5 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, halo, —CF 3 —SH, —OR 19 , —CN, —C(O)R 20 , —C(O)R 19 , —S(O) 0-2 R 21 , —S(O) 1-2 N(R 22 )(R 23 ), —C(O)N(R 22 )(R 23 ), —N(R 22 )C(O)R 20 , —N(R 22 )C(O)N(R 22 )(R 23 ), —N(R 22 )C(O)OR 19 , —N(R 22 )S(O) 1-2 R 21 , —NO 2 , —N═C(R 22 )(R 23 ) and —N(R 22 )(R 23 );
each R 19 (when present) is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl;
each R 20 (when present) is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl and amino);
each R 21 (when present) is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl; and
each R 22 and each R 23 (when present) is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl.
2. A compound of claim 1 wherein q is 2.
3. A compound of claim 1 wherein R 2 is —CH 3 .
4. A compound of claim 1 wherein R 3 and R 4 are each H.
5. A compound of claim 1 wherein R 15 and R 16 are each independently selected from the group consisting of H, methyl, ethyl, and CF 3 .
6. A compound of claim 1 wherein R 15 and R 16 are each independently selected from the group consisting of H, methyl, and ethyl.
7. A compound of claim 1 wherein R 24 is absent.
8. A compound of claim 1 wherein R 24 is present and is 1 to 5 groups independently selected from the group consisting of lower alkyl, halo, —CF 3 , —OR 19 —CN, —C(O)R 20 , —C(O)R 19 , —C(O)—N(R 22 )(R 23 ), —N(R 22 )C(O)R 20 , —N(R 22 )C(O)N(R 22 )(R 23 ), —N(R 22 )C(O)OR 19 , —NO 2 , —N═C(R 22 )(R 23 ) and —N(R 22 )(R 23 ).
9. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically effective carrier.
10. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , and an effective amount of a cholinesterase inhibitor or a muscarinic m 1 agonist or m 2 antagonist in a pharmaceutically effective carrier.
11. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , and an effective amount of a gamma secretase inhibitor; an HMG-CoA reductase inhibitor or a non-steroidal anti-inflammatory agent.