Small-molecule HSP90 inhibitors
Purine scaffold Hsp90 inhibitors are useful in therapeutic applications and as radioimaging ligands.
1. A method of preparing a compound of formula:
or a pharmaceutically acceptable salt thereof;
the method comprising reacting the compound of formula IN-2:
with a compound of formula X 1 OTs in the presence of a base,
wherein:
X 3 is hydrogen or halogen;
X 1 is a C 1 to C 10 alkyl, alkenyl, or alkynyl group, wherein the alkyl, alkenyl, or alkynyl group includes a heteroatom;
the linker is S;
X 2 is halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, COO-alkyl, NH 2 , OH, CN, SO 2 X 7 , NO 2 , NO, C═SR 2a , NHSO 2 X 7 , or C═OR 2a , where X 7 is F, NH 2 , alkyl or H, and R 2a is alkyl, NH 2 , NH-alkyl or O-alkyl; and
n is 1 or 2.
2. A method of preparing a compound of formula:
or a pharmaceutically acceptable salt thereof;
the method comprising reacting a compound of formula IN-12:
with the compound of formula IN-6:
wherein:
X 3 is hydrogen or halogen;
X 1 is a C 1 to C 10 alkyl, alkenyl, or alkynyl group, wherein the alkyl, alkenyl, or alkynyl group includes a heteroatom;
the linker S;
X 2 is halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, COO-alkyl, NH 2 , OH, CN, SO 2 X 7 , NO 2 , NO, C═SR 2a , NHSO 2 X 7 , or C═OR 2a ,
where X 7 is F, NH 2 , alkyl or H, and R 2a is alkyl, NH 2 , NH-alkyl or O-alkyl; and
n is 1 or 2; and
the halo group is Cl, Br, or I.
3. The method of claim 2 , further comprising the step of preparing the compound of formula IN-12 by reacting a compound of formula IN-13:
with a compound of formula IN-14:
4. The method of claim 3 , further comprising the step of preparing the compound of formula IN-13 by reacting the compound a formula IN-15:
with the compound of formula X 1 OTs in the presence of a base.
5. A method of preparing a compound of formula:
or a pharmaceutically acceptable salt thereof;
the method comprising reacting a compound of formula IN-2:
with a compound of formula X 1 OH;
wherein:
X 1 is C 2 -C 10 alkynyl group;
X 3 is hydrogen or halogen;
the linker is CH 2 or S;
X 2 is halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, COO-alkyl, NH 2 , OH, CN, SO 2 X 7 , NO 2 , NO, C═SR 2a , NHSO 2 X 7 , or C═OR 2a , where X 7 is F, NH 2 , alkyl or H, and R 2a is alkyl, NH 2 , NH-alkyl or O-alkyl;
n is 1 or 2.
6. The method of claim 5 , wherein reaction is carried out in the presence of PPh 3 and an azodicarboxylate.