Sloan-kettering Institute for Cancer Research

Memorial Sloan Kettering Cancer Center

The Rockefeller University

Huazhong He

Gabriela Chiosis

Peter Smith-Jones

Laura Llauger-Bufi

Joungnam Kim

Steve Larson

Steven M Larson

Danuta Zatorska

Paul Greengard

Wenjie Luo

Fei Dou

Treatment of neurodegenerative diseases is achieved using small molecule purine scaffold compounds that inhibit Hsp90 and that possess the ability to cross the blood-brain barrier or are otherwise delivered to the brain.

Treatment of neurodegenerative diseases through inhibiton of Hsp90

Purine scaffold Hsp90 inhibitors are useful in therapeutic applications and as radioimaging ligands.

Small-molecule HSP90 inhibitors

Treatment of neurodegenerative diseases is achieved using small molecule purine scaffold compounds that inhibit Hsp90 and that possess the ability to cross the blood-brain barrier or are other wise delivered to the brain.

Treatment of neurodegenerative diseases through inhibition of HSP90

Hsp90 inhibitors havin are provided havin the formula: (I) with a 2',4&#x2032;,5&#x2032;-substitution pattern on the right-side aryl moiety. X1 represents two substituents, which may be the same or different, disposed in the 4&#x2032; and 5&#x2032; positions on the aryl group, wherein X1 is selected from halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SOalkyl, COO-alkyl, KH, OH, CN, SOX, NO, NO, C&#x2550;SRNSOX, C&#x2550;OR, where Xis F, NH2, alkyl or H, and Ris alkyl, NH, NH-alkyl or O-alkyl, Cto Calkyl or alkoxy; or wherein Xhas the formula &#x2014;O&#x2014;(CH)&#x2014;O&#x2014;, wherein n is an integer from 0 to 2, preferably 1 or 2, and one of the oxygens is bonded at the 5&#x2032;-position and the other at the 4&#x2032;-position of the aryl ring. The compounds are useful in cancer therapy and as radioimaging ligands. 

Hsp90 inhibitors having are provided having the formula: (I) with a 2',4&#x2032;,5&#x2032;-substitution pattern on the right-side aryl moiety. X1 represents two substituents, which may be the same or different, disposed in the 4&#x2032; and 5&#x2032; positions on the aryl group, wherein X1 is selected from halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO-alkyl, COO-alkyl, KH, OH, CN, SOX, NO, NO, C&#x2550;SRNSOX, C&#x2550;OR, where Xis F, NH2, alkyl or H, and Ris alkyl, NH, NH-alkyl or O-alkyl, Cto Calkyl or alkoxy; or wherein Xhas the formula &#x2014;O&#x2014;(CH)&#x2014;O&#x2014;, wherein n is an integer from 0 to 2, preferably 1 or 2, and one of the oxygens is bonded at the 5&#x2032;-position and the other at the 4&#x2032;-position of the aryl ring. The compounds are useful in cancer therapy and as radioimaging ligands. 

The present disclosure provides inhibitors of Hsp90 and methods of making and using the same. Such compounds are useful as radioimaging ligands and for the treatment of cancer and other conditions where cell growth or maintenance depend on Hsp90 activity.

Small-molecule Hsp90 inhibitors

Hsp90 inhibitors are provided having the formula: with a 2',4&#x2032;,5&#x2032;-substitution pattern on the right-side aryl moiety. Xrepresents two substituents, which may be the same or different, disposed in the 4&#x2032; and 5&#x2032; positions on the aryl group, wherein Xis selected from halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SOalkyl, COO-alkyl, KH, OH, CN, SOX, NO, NO, C&#x2550;SRNSOX, C&#x2550;OR, where Xis F, NH2, alkyl or H, and Ris alkyl, NH, NH-alkyl or O-alkyl, Cto Calkyl or alkoxy; or wherein Xhas the formula &#x2014;O&#x2014;(CH)&#x2014;O&#x2014;, wherein n is an integer from 0 to 2, preferably 1 or 2, and one of the oxygen is bonded at the 5&#x2032;-position and the other at the 4&#x2032;-position of the aryl ring. The compounds are useful in cancer therapy and as radioimaging ligands.

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New York, NY, United States of America

Huazhong He