Spiro-oxindole MDM2 antagonists
Provided herein are compounds, compositions, and methods in the field of medicinal chemistry. The compounds and compositions provided herein relate to spiro-oxindoles which function as antagonists of the interaction between p53 and MDM2, and their use as therapeutics for the treatment of cancer and other diseases.
1. A compound that is:
2. A method of preparing the compound of claim 1 , the method comprising reacting
with
3. A method of preparing a compound having Formula II:
wherein:
R 1a , R 1b , R 1c , and R 1d are independently selected from the group consisting of hydrogen and halogen;
R 2 is optionally substituted aryl;
R 3 is alkyl;
R 4 is hydrogen;
R 5 is:
wherein:
each R 12a , R 12b , R 12c and R 12d is independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 6 alkyl;
R 13 is selected from the group consisting of hydrogen and optionally substituted C 1 -C 6 alkyl;
R 14 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, and optionally substituted cycloalkyl;
Z is —OR 15 ;
R 15 is hydrogen;
o is 1, 2, or 3; and
p is 0, 1, 2, or 3;
X is NR′;
Y is NR″;
R′ is hydrogen; and
R″ is hydrogen;
the method comprising treating a compound having Formula F:
with an oxidizing agent.
4. The method of claim 3 , wherein R 5 is selected from the group consisting of:
5. The method of claim 4 further comprising reacting HNR 4 R 5 with a compound having the general formula:
to give the compound having Formula F.
6. The method of claim 5 further comprising reacting a compound having Formula C:
with a compound having Formula D:
and a compound having Formula E:
R 3 CHO E
to give the compound having the general formula:
7. The method of claim 6 further comprising reacting a compound having Formula A:
with a compound having Formula B:
R 2 CHO B
to give the compound having Formula C.
8. The method of claim 3 , wherein the compound having Formula II is:
9. The method of claim 5 , wherein HNR 4 R 5 is:
10. The method of claim 5 , wherein the compound having the general formula is:
11. The method of claim 6 , wherein the compound having Formula C is:
12. The method of claim 6 , wherein the compound having Formula E is:
13. The method of claim 7 , wherein the compound having Formula A is:
14. The method of claim 7 , wherein the compound having Formula B is:
15. The method of claim 3 , wherein the oxidizing agent is selected from the group consisting of Pb(OAc) 2 and cerium (IV) ammonium nitrate.