GRP94 inhibitors
The present disclosure provides a series of compounds which exhibit isoform selective inhibition of GRP94, a homologue of Hsp90 that is localized to the endoplasmic recticulum. Through GRP94 inhibition, these compounds are likely to manifest anti-cancer, anti-inflammatory, anti-metastasis, and immunosuppressive activities, as well as utility in the treatment of neurodegenerative diseases, and diabetes.
1. A compound or pharmaceutically acceptable salt of Formula (I):
wherein:
V is N;
X is CH;
Y is CH;
Z is selected from C or N;
R 1 is selected from the group consisting of H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, butyl, phenyl, and benzyl;
R 2 is selected from the group consisting of H, OH, SH, and NH 2 ;
R 3 is selected from the group consisting of H, OH, SH, and NH 2 ;
R′ is selected from the group consisting of
R 4 is selected from the group consisting of
R 5 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl;
R 6 is selected from the group consisting of O, S, NH, and CH 2 ;
R 7 is selected from the group consisting of H, and methyl; and
R 8 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl;
R 9 is selected from the group consisting of H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, halogen, OH, NH 2 , NR 10 H, N(R 10 ) 2 , and NCOR 10 ;
R 10 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl;
n is selected from 0, 1, 2, or 3, wherein
when n is 1, represents a single or a double bond, wherein the double bond is in the cis or trans configuration, and
when n is 0, 2 or 3, represents a single bond; and
m is selected from 0, 1, 2, 3 or 4.
2. The compound or pharmaceutically acceptable salt according to claim 1 :
wherein
Z is N.
3. The compound or pharmaceutically acceptable salt according to claim 1 wherein R′ is
4. The compound or pharmaceutically acceptable salt according to claim 1 wherein
Z is N.
5. The compound or pharmaceutically acceptable salt according to claim 1 wherein R 1 is F, Cl, Br, or I.
6. The compound or pharmaceutically acceptable salt according to claim 1 wherein
R 1 is Cl;
R 2 is OH; and
R 3 is OH.
7. The compound or pharmaceutically acceptable salt according to claim 1 wherein R 4 is selected from the group consisting of
8. The compound according to claim 1 selected from the group consisting of:
9. The compound according to claim 8 selected from:
10. The compound according to claim 9 :
11. The compound according to claim 9 :
12. The compound or pharmaceutically acceptable salt according to claim 1 of Formula VI:
wherein
R′ is selected from the group consisting of
R 4 is selected from the group consisting of
R 5 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl;
R 6 is selected from the group consisting of O, S, NH, and CH 2 ;
R 7 is selected from the group consisting of H, and methyl; and
R 8 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl;
R 9 is selected from the group consisting of H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, halogen, OH, NH 2 , NR 10 H, N(R 10 ) 2 , and NCOR 10 ;
R 10 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl;
m is selected from 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a compound or salt according to claim 1 and a pharmaceutically acceptable carrier.