Indole inhibitors of MDM2 and the uses thereof
View Patent ↗The invention relates to small molecules which function as inhibitors of the interaction between p53 and MDM2. The invention also relates to the use of these compounds for inhibiting cell growth, inducing cell death, inducing cell cycle arrest and/or sensitizing cells to additional agent(s).
1. A compound having Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X is N;
Y is O, or S;
R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are independently H or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclic, CO 2 R′, OCOR′, CONR′R″, NR″COR′, NR′SO 2 R″, SO 2 NR′R″, (C═NR′)NR″R′″, or NR′R″; or
R 7 forms an aryl, cycloalkyl, or heterocyclic group with one of R 5 or R 6 ;
R 8 is H or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclic, CO 2 R′, OCOR′, CONR′R″, SO 2 NR′R″, or (C═NR′)NR″R′″;
each R′, R″ and R′″ is independently H or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic; or
R′ and R″, or R″ and R′″, form a ring; and
R 3 is CONHR 11 wherein R 11 is an optionally substituted cycloalkyl-alkyl or monoheterocycloalkyl-alkyl group or a dihydroxyalkyl group not containing a hydroxyl group at the 3-position of the alkyl group.
2. The compound of claim 1 , having Formula II or Formula III:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , having Formula IV:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 3 , having Formula V or Formula VI:
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , having Formula VII:
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 5 , having Formula VIII or Formula IX:
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , wherein one of R 1 and R 2 is optionally substituted aryl or heteroaryl.
8. The compound of claim 1 , wherein one of R 1 and R 2 is cycloalkyl, straight or branched alkyl, amide or ester.
9. The compound of claim 1 , wherein one of R 5 and R 6 is C 3-18 alkyl, aryl, or heteroaryl.
10. A compound having Formula X:
or a pharmaceutically acceptable salt thereof, wherein:
R 10 is hydrogen, and
R 11 is an optionally substituted cycloalkyl-alkyl or monoheterocycloalkyl-alkyl group or a dihydroxyalkyl group not containing a hydroxyl group at the 3-position of the alkyl group;
or R 10 and R 11 together form an optionally substituted monocyclo-heterocycloalkyl group;
R 1 , R 5 , and R 7 are independently H or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclic, CO 2 R′, OCOR′, CONR′R″, NR″COR′, NR′SO 2 R″, SO 2 NR′R″, (C═NR′)NR″R′″, or NR′R″; or
R 7 forms an aryl, cycloalkyl, or heterocyclic group with one of R 5 or R 6 ;
R 8 is H or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclic, CO 2 R′, OCOR′, CONR′R″, SO 2 NR′R″, or (C═NR′)NR″R′″; and
each R′, R″and R′″is independently H or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic; or
R′and R″, or R″and R′″, form a ring.
11. The compound of claim 10 , having one of Formulae XI-XXVI:
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 10 , having Formula XXVII or Formula XXVIII:
or a pharmaceutically acceptable salt thereof.
13. A compound of claim 1 selected from the group consisting of:
14. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
15. A compound
or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising a compound of claims 1 , 14 , or 15 and a pharmaceutically acceptable carrier.
17. A method of treating a disorder in an animal, comprising administering to said animal a therapeutically effective amount of a compound of claims 1 , 14 , or 15 , wherein said disorder is selected from the group consisting of colon cancer and prostate cancer.
18. The method of claim 17 , further comprising administering an additional agent(s), wherein said additional agent(s) is selected from the group consisting of a chemotherapeutic agent and radiation.
19. The method of claim 18 , wherein said compound of claim 1 is administered prior to said additional agent(s).
20. The method of claim 18 , wherein said compound of claim 1 is administered after said additional agent(s).
21. The method of claim 18 , wherein said compound of claim 1 is administered concurrently with said additional agent(s).
22. A kit comprising a compound of claims 1 , 14 , or 15 and instructions for administering said compound to an animal having cancer, wherein said cancer is selected from the group consisting of prostate cancer and colon cancer.
23. The kit of claim 22 , further comprising a chemotherapeutic agent.
24. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof, or a different pharmaceutically acceptable salt thereof.
25. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof, or a different pharmaceutically acceptable salt thereof.