Pyrrolidin-2-ones
The present invention provides compounds of formula (I) or (Ia) which are ligands binding to the HDM2 protein, inducing apoptosis and inhibiting proliferation, and having therapeutic utility in cancer therapy and prevention. Compounds of formula (I) or (Ia) can be used as therapeutics for treating stroke, myocardial infarction, ischemia, multi-organ failure, spinal cord injury, Alzheimer's Disease, injury from ischemic events and heart valvular degenerative disease. Moreover, compounds of formula (I) or (Ia) can be used to decrease the side effects from cytotoxic cancer agents, radiation and to treat viral infections.
1. A compound of formula (I):
wherein
V is C═O;
X is oxygen or a group of formula CH 2 , CR 4b R 4c , NH, NR 4b , SO, SO 2 or a bond;
Y is a group of formula CONR 6 , CH 2 NR 6 , CH 2 O, SO 2 NR 6 , NR 6 CO, NR 6 SO 2 , NR 5a CONR 6 , NR 6 COO, OCONR 6 , CONR 5a NR 6 , CONR 5a OR 6 , CH 2 CO CH 2 CONR 6 , CH 2 COO, or COCR 5a R 6 ;
n is 1;
R 1 is an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 2 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 3 is an optionally substituted heteroaryl residue having two rings and a total of 9 ring atoms including 1, 2, 3, or 4 heteroatoms selected from O, S, and N;
R 4 is an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 4b is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 4c is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 5 is an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 5a is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 6 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 7 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 8 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
or the radicals R 5 and R 6 together are part of an optionally substituted heterocycloalkyl, heteroalkylcycloalkyl, heteroaryl, or heteroarylalkyl ring system, and/or R 2 and R 3 together are part of an optionally substituted cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, aralkyl, or heteroaralkyl ring system;
or a pharmaceutically acceptable salt, ester or a pharmaceutically acceptable formulation thereof.
2. The compound of claim 1 , wherein R 1 is an aryl, heteroaryl, aralkyl or heteroaralkyl radical.
3. The compound of claim 1 , wherein R 1 is a group of formula -A-Ar or A-Cy wherein A is a bond, C 1 -C 4 alkyl or C 1 -C 6 heteroalkyl or wherein A is a group of formula —CHR 1a — wherein R 1a is a C 1 -C 6 heteroalkyl group, Cy is an optionally substituted C 3 -C 7 cycloalkyl group or an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms and Ar is an optionally substituted phenyl ring or an optionally substituted heteroaryl ring containing 5 or 6 ring atoms.
4. The compound of claim 3 , wherein Ar is an optionally substituted phenyl or an optionally substituted pyridyl residue.
5. The compound of claim 1 , wherein R 2 is hydrogen.
6. The compound of claim 1 , wherein R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, optionally substituted C 1 -C 4 alkyl-C 3 -C 7 cycloalkyl, an optionally substituted phenyl ring, an optionally substituted benzyl group or an optionally substituted heteroaryl ring having 5 or 6 ring atoms and including from 1 to 3 heteroatoms selected from O, S and N.
7. The compound of claim 1 , wherein R 5 is an alkyl, heteroalkyl, heterocycloalkyl, heteroalkylcycloalkyl or heteroaralkyl group, all of which groups may be substituted.
8. The compound of claim 1 , wherein R 5 is selected from the following groups:
C 1 -C 6 alkyl;
heteroalkyl containing 1-6 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S and N;
heteroalkylcycloalkyl comprising a C 1 -C 4 alkyl group or a C 1 -C 4 heteroalkyl group and an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms and 1, 2 or 3 heteroatoms selected from O, S and N;
heteroaralkyl comprising a C 1 -C 4 alkyl group or a C 1 -C 4 heteroalkyl group and an optionally substituted heteroaryl group containing 5 or 6 ring atoms and 1, 2 or 3 heteroatoms selected from O, S and N;
optionally substituted heteroaryl containing 5 or 6 ring atoms and 1, 2 or 3 heteroatoms selected from O, S and N; and
optionally substituted heterocycloalkyl containing 5 or 6 ring atoms and 1, 2 or 3 heteroatoms selected from O, S and N.
9. The compound of claim 1 , wherein R 6 is hydrogen or C 1 -C 4 alkyl.
10. The compound of claim 1 , wherein R 5 and R 6 together are part of an optionally substituted heterocycloalkyl ring containing 4, 5, 6 or 7 ring atoms and 1, 2 or 3 heteroatoms selected from O, S and N.
11. The compound of claim 1 , wherein R 5 and R 6 together are part of an optionally substituted piperazine or piperidine ring.
12. A compound of formula (I):
wherein
V is C═O;
X is oxygen or a group of formula CH 2 , CR 4b R 4c , NH, NR 4b , SO, SO 2 or a bond;
Y is a group of formula CONR 6 , CH 2 NR 6 , CH 2 O, SO 2 NR 6 , NR 6 CO, NR 6 SO 2 , NR 5a CONR 6 , NR 6 COO, OCONR 6 , CONR 5a NR 6 , CONR 5a OR 6 , CH 2 CO CH 2 CONR 6 , CH 2 COO, or COCR 5a R 6 ;
n is 1;
R 1 is an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 2 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 3 has the following structure
wherein E is N or CH, R 3a is H, C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl, R 3b is H, F, Cl, Br, CH 3 , OCH 3 or CF 3 and R 3c is H, F, Cl, Br, CH 3 , OCH 3 or CF 3 ;
R 4 is an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 4b is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 4c is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 5 is an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 5a is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 6 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 7 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
R 8 is a hydrogen atom or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical;
or the radicals R 5 , and R 6 together are part of an optionally substituted heterocycloalkyl, heteroalkylcycloalkyl, heteroaryl, or heteroarylalkyl ring system, and/or R 2 and R 3 together are part of an optionally substituted cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, aralkyl, or heteroaralkyl ring system;
or a pharmaceutically acceptable salt, ester or a pharmaceutically acceptable formulation thereof.
13. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable ester, prodrug, or salt thereof, optionally in combination with a pharmaceutically acceptable carrier.