Hsp90 inhibitors
View Patent ↗The disclosure relates to Compounds of Formula (1) : and pharmaceutically acceptable salts thereof wherein Z 1 , Z 2 , Z 3 , Xa, Xb, Xc, Y, X 2 , and X 4 are as defined herein, compositions comprising an effective amount of a Compound of Formula (1) or a pharmaceutically acceptable salt thereof, and methods to treat or prevent a condition, such as cancer which overexpresses Her-kinases, comprising administering to an patient in need thereof a therapeutically effective amount of a Compound of Formula (1) or a pharmaceutically acceptable salt thereof.
1. A compound of Formula (1):
or a pharmaceutically acceptable salt thereof, wherein:
(a) each of Z 1 , Z 2 and Z 3 is independently CH or N;
(b) Y is S;
(c) Xa and Xb are O;
(d) Xc is —CH 2 —;
(e) X 2 is —NR 1 R 2 , wherein R 1 and R 2 are each independently H, C 1-6 alkyl, C 2 -C 6 alkenyl, C 2-6 alkenyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl;
(f) X 4 is hydrogen or halogen;
(g) R is —R 10 —NH—R 11 wherein R 10 is ethylene or propylene, and
(i) R 11 is isopropyl or t-butyl, or
(ii) R 11 is a branched alkyl, Z 1 , Z 2 and Z 3 are each N, and R 1 and R 2 are each independently alkyl which has 1, 3, 4, 5, or 6 carbon atoms, C 2 -C 6 alkenyl, C 2-6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, or alkylheteroarylalkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 2 is dimethylamine.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 11 is neopentyl.
4. The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R 11 is isopropyl.
5. The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein R 11 is t-butyl.
6. The compound of any of claims 1 or a pharmaceutically acceptable salt thereof, wherein Z 1 , Z 2 and Z 3 are each N.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 1 , Z 2 and Z 3 are each N, X 2 is dimethlyamine, Y is S, R 10 is ethylene, R 11 is neopentyl, and X, is H.
8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z 1 , Z 2 and Z 3 are each N, X 2 is dimethlyamine, Y is S, R 10 is propylene, R 11 is isopropyl, and X 4 is H.
9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z 1 , Z 2 and Z 3 are each N, X 2 is dimethlyamine, Y is S, R 10 is propylene, R 11 is t-butyl, and X 4 is H.
10. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. A method for the inhibition of Hsp90, comprising contacting Hsp90 with an Hsp90 function inhibiting amount of a compound of claims 1 .