Substituted isoindolines as aspartyl protease inhibitors
View Patent ↗Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein Q is a bond or —N(R 5 )—; T is a bond, —O—, —C(O)—; S, —N(R 5 )—, or —C(R 6′ R 7′ ); U is a bond or —C(R 6 )(R 7 )— Y is C or N; Z is C or N; ring A, including variables Y and Z, is a three to nine membered cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, and heteroaryl ring having 0 to 4, preferably 0 to 2, heteroatoms independently selected from the group consisting of O, S, N and —N(R)—, wherein ring A is unsubstituted or substituted with 1 to 5 independently selected R 1 moieties and/or oxo when ring A is cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl; and R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 6 , R 7 and R 7′ are as defined in the specification; pharmaceutical compositions comprising the compounds of formula I and the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases.
1. A compound having the Formula (IA):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt of said compound, stereoisomer, or tautomer, wherein:
R 1 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR 15 ;
R 3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 -heterocycloalkyl or R 21 -heterocycloalkylalkyl;
R 4 is cycloalkylalkyl, cycloalkyl, aryl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 -heterocycloalkyl or R 21 -heterocycloalkylalkyl;
R 15 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, and arylheterocycloalkyl; and
each R 21 is independently H, alkyl, halo, CN, —OR 24 , optionally substituted phenyl or optionally substituted heteroaryl, wherein the optional substituents on said optionally substituted phenyl or said optionally substituted heteroaryl are alkyl, halo, CN or —OR 24 , where each R 24 is independently alkyl, aryl or heteroaryl and wherein when R 3 is methyl or ethyl, R 4 is not methyl or ethyl.
2. A compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt of said compound, stereoisomer, or tautomer, wherein R 1 is hydrogen, lower alkyl, halogen, alkoxy, or cyano.
3. A compound of claim 1 , or a stereoisomer, tautomer,
or pharmaceutically acceptable salt of said compound, stereoisomer, or tautomer, wherein:
R 3 is alkyl:
R 4 is
and
R 21 is optionally substituted phenyl or optionally substituted heteroaryl, wherein the optional substituents on said optionally substituted phenyl or said optionally substituted heteroaryl are alkyl, halo, CN or —OR 24 , where each R 24 is independently alkyl, aryl or heteroaryl.
4. A compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt of said compound, stereoisomer, or tautomer, wherein R 3 and R 4 are each independently
5. A compound of claim 1 , or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
6. A compound of claim 1 , wherein:
R 3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroaryl, R 21 -heterocycloalkyl or R 21 -heterocycloalkylalkyl; and
R 4 is cycloalkylalkyl, cycloalkyl, aryl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroaryl, R 21 -heterocycloalkyl or R 21 -heterocycloalkylalkyl.
7. The compound according to claim 1 , wherein:
R 3 is alkyl, aryl, R 21 -aryl, heteroaryl, or R 21 -heteroaryl; and
R 4 is aryl, R 21 -aryl, heteroaryl, or R 21 -heteroaryl.
8. The compound according to claim 6 , wherein R 4 is phenyl or R 21 -phenyl, where said R 21 is aryl or heteroaryl wherein said aryl and said heteroaryl group is optionally substituted by halo, haloalkyl, —CN or —OR 24 , where R 24 is alkyl.
9. A pharmaceutical composition comprising a compound according to any one of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 , or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective carrier.