Sloan-kettering Institute for Cancer Research

Memorial Sloan Kettering Cancer Center

Laura Llauger-Bufi

Gabriela Chiosis

Peter Smith-Jones

Huazhong He

Joungnam Kim

Steve Larson

Steven M Larson

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

Small-molecule HSP90 inhibitors

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

Laura Llauger-Bufi