Therapeutically active compositions and their methods of use
Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
1. A method of making a compound of structural formula (A) or a pharmaceutically acceptable salt, tautomer or hydrate thereof, wherein:
R 1 is optionally substituted C 4 -C 6 carbocyclyl;
each R 2 and R 3 is independently selected from optionally substituted aryl or optionally substituted heteroaryl;
R 4 is optionally substituted aryl or optionally substituted heteroaryl,
n is 1 or 2; and
X is —CH 2 —, O, —NH—, —CH(OH)—, or —CH(F)—,
the method comprising:
reacting a compound of formula B:
with R 4 —Br under Buchwald conditions to provide the compound of structural formula (A).
2. The method of claim 1 wherein the Buchwald conditions comprise use of a palladium catalyst, a ligand and a base in an organic solvent.
3. The method of claim 2 wherein the solvent is dioxane, the palladium catalyst is Pd 2 (dba) 3 , the ligand is Xphos and the base is cesium carbonate.
4. A method of making a compound of structural formula (B) or a pharmaceutically acceptable salt, tautomer, or hydrate thereof,
the method comprising:
reacting a compound of structural formula (C):
with R 1 NC, R 2 CHO and R 3 —NH 2 under Ugi coupling reaction conditions to provide the compound of structural formula (B).
5. The method of claim 4 wherein the Ugi coupling takes place in a solvent.
6. The method of claim 5 wherein the solvent is methanol.