Hsp90 inhibitors

Patent metadata

Field	Value
Publication number	US-9328114-B2
Application number	US-201013500809-A
Country	US
Kind code	B2
Filing date	Oct 7, 2010
Priority date	Oct 7, 2009
Publication date	May 3, 2016
Grant date	May 3, 2016

Abstract

The present application provides compounds useful in the inhibition of Hsp90, and hence in the treatment of disease.

First claim

The invention claimed is:

1. A compound of the formula:

wherein
(a) each of Z 1 , Z 2 and Z 3 is independently N;
(b) Xa and Xb are O and Xc is CH 2 ;
(c) Y is —CH 2 — or —S—;
(d) X 4 is hydrogen or halogen; and
(e) X 2 is an aryl, an alkynyl, a cycloalkyl, or a cycloalkenyl group, each of which is optionally substituted, and R is:
(a) hydrogen; or
(b) a straight-chain- or branched-C 1 to C 10 alkyl, C 2 to C 6 alkenyl, or C 2 to C 6 alkynyl, which is unsubstituted or substituted; or
(c) aryl, heteroaryl, heterocyclic, cycloalkyl, alkylaryl, or arylalkyl, which is unsubstituted or substituted; or
(d) —SR 71 , —S(O)R 71 , —SO 2 R 71 , —OR 71 , —COOR 71 , —CONR 71 R 72 , —CN, —R 7A OR 7B , —R 7A NR 7B , —R 7A NR 71 R 7B , —R 7A SR 7B , —R 7A S(O)R 7B , —R 7A SO 2 R 7B , —NR 71 R 72 , —OSO 2 N(R 7C ) 2 , —N(R 7C )SO 2 OH, —N(R 7C )SO 2 R 7C , —R 7A OSO 2 N(R 7C ) 2 , or —R 7A N(R 7C )OSO 2 R 7C ,
wherein each R 71 and R 72 is independently selected from the group consisting of hydrogen, COOR 7B , CON(R 7C ) 2 , C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, —R 7A OR 7B , —R 7A NR 7B , —R 7A SR 7B , —R 7A S(O)R 7B , —R 7A SO 2 R 7B , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, and heteroarylalkyl,
each R 7A is independently C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, and
each R 7B is independently hydrogen, C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, —SO 2 OH, —SO 2 N(R 7A ) 2 , —SO 2 NHR 7A , or —SO 2 NH 2 ; and
each R 7C is independently hydrogen, C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, or heteroarylalkyl.

2. The compound of claim 1 wherein Y is S, X 4 is H, and X 2 is acetylenyl, 2-furanyl, 3-furanyl, 5-methyl-2-furanyl, 2-thiophene, 3-thiophene, 2-pyrazolyl, 3-pyrazolyl, 2-thiazolyl, 5-methyl-2-thiazolyl, 2-oxazolyl, 5-methyl-2-oxazolyl, or optionally substituted imidazole.

3. The compound of claim 1 wherein Y is S, X 4 is H, and X 2 is acetylenyl, 2-furanyl, 3-furanyl, 5-methyl-2-furanyl, 2-pyrazolyl, 3-pyrazolyl, 2-thiazolyl, 5-methyl-2-thiazolyl, 2-oxazolyl, or 5-methyl-2-oxazolyl.

4. The compound of claim 1 wherein X 2 is optionally substituted alkynyl.

5. The compound of claim 4 wherein R is 2-(methyl(t-butyl)amino)ethyl, 2-(methyl(isopropyl)amino)ethyl, 3-(neopentyl-amino)propyl, 2-(isobutyl-amino)ethyl, 2-(ethyl(isopropyl)amino)ethyl, 3-(isopropyl-amino)propyl, 3-(t-butyl-amino)propyl, 2-(isopropyl-amino)ethyl, 2-(hydroxyethyl(isopropyl)amino)ethyl, 3-(cyclopentylamino)propyl, 3-(cyclopentyl(methyl)amino)propyl, 3-(ethylamino)propyl, 3-(ethyl(methyl)amino)propyl, 2-(neopentyl-amino)ethyl, 3-(methyl(isopropyl)amino)propyl, 3-(ethyl(isopropyl)amino)propyl, 3-(hydroxyethyl(isopropyl)amino)propyl, 3-(methyl(propargyl)amino)propyl, 2-(methyl(propargyl)amino)ethyl, 3-(allyl(methyl)amino)propyl, 3-(propyl(cyclopropyl)methyl-amino)propyl, 3-(hydroxyethyl(cyclohexyl)amino)propyl, 2-(cyclopropylmethyl-amino)ethyl, and 2-(methyl(isobutyl)amino)ethyl.

6. The compound of claim 5 wherein R is 3-(isopropyl-amino)propyl.

7. The compound of claim 4 wherein the compound is selected from the group consisting of: 8-[6(3,3dimethyl-but-1-ynyl)-benzo[1,3]dioxol-5-ylsulfanyl]9-(3-(isopropylaminopropyl)-9H-purin-6-ylamine, 9-(3-isopropylamino-propyl)-8-(6-phenylethynyl-benzo[1,3]dioxol-5-ylsulfanyl)-9H-purin-6-ylamine; 8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine, 8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9-(2-(isobutylamino)ethyl)-9H-purin-6-amine, 1-(3-(2-(6-amino-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone, 8-(6-ethynylbenzo[d][1,3]dioxol-5-ylyhio)-9-(2-(1-(methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine, N-(2-((2-(6-amino-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)thio)-9H-purin-9-yl)ethyl)amino)ethyl)sulfamide, 3-(2-(6-amino-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)ethylamino)-N-hydroxypropanamide, 8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine, 8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2-(isobutylamino)ethyl)-9H-purin-6-amine, 9-(3-aminopropyl)-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine, 9-(2-aminoethyl)-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine, 9-(3-(tert-butylamino)propyl)-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine, 1-(3-(6-amino-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)propyl)pyrrolidin-3-one, 3-(2-(6-amino-8-((6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)ethyl)piperidine-1-sulfonamide, 6-(6-amino-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)hexanamide, 1-(6-amino-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)-3-(tert-butylamino)propan-2-ol, 1-(2-((2-(6-amino-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)ethylamino)methyl)pyrrolidin-1-yl)ethanone, 5-(6-amino-8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9H-purin-9-yl)pentane-1-sulfonamide, 8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9-(2-(1-methylpiperidin-2-yl)ethyl)-9H-purin-6-amine, 8-(6-ethynylbenzo[d][1,3]dioxol-5-ylthio)-9-(2-(1-methylpiperidin-3-yl)ethyl)-9H-purin-6-amine, 1-(3-(4-(6-amino-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9H-purin-9-yl)butyl)pyrrolidin-1-yl)ethanone; 5-(6-amino-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9H-purin-9-yl)pentane-1-sulfonamide, 3-(2-(6-amino-2-chloro-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-9-yl)ethyl)piperidine-1-carbaldehyde, 3-(2(6-amino-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9H-purin-9-yl)ethyl)piperidine-1-sulfonamide, 8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2-(isobutylamino)ethyl)-9H-purin-6-amine, 6-(6-amino-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9H-purin-9-yl)hexanamide, 1-(3-(2-(6-amino-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9H-purin-9-yl)ethyl)piperidin-1-yl)ethanone, 8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2-(neopentylamino)ethyl)-9H-purin-6-amine, 8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9-(3-(isopropylamino)propyl)-9H-purin-6-amine, 9-(3-(tert-butylamino)propyl)-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9H-purin-6-amine, 8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2-(1-(methylsulfonyl)piperidin-3-yl)ethyl)-9H-purin-6-amine, 1-(3-(6-amino-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9H-purin-9-yl)propyl)pyrrolidin-3-one, 8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2-(1-methylpiperidin-3-yl)ethyl)-9H-purin-6-amine, 1-(2-((2-(6-amino-8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9H-purin-9-yl)ethylamino)methyl)pyrrolidin-1-yl)ethanone, and 8-((6-ethynylbenzo[d][1,3]dioxol-5-yl)methyl)-2-fluoro-9-(2-(1-methylpiperidin-2-yl)ethyl)-9H-purin-6-amine.

8. The compound of claim 1 wherein X 2 is an optionally substituted heteroaryl group.

9. The compound of claim 8 wherein X 2 is optionally substituted furanyl.

10. The compound of claim 9 wherein the compound is selected from the group consisting of: 8-(6-(furan-3-yl)benzo[d][1,3]dioxol-5-ylthio)-9-(3-(isopropylamino)propyl)-9H-purin-6-amine, 2-fluoro-8-((6-(furan-3-yl)benzo[d][1,3]dioxol-5-yl)methyl)-9-(2-(isobutylamino)ethyl)-9H-purin-6-amine, 8-((6-(furan-2-yl)benzo[d][1,3]dioxol-5-yl)thio)-9-(3-(isopropylamino)propy

Assignees

• Chiosis Gabriela
• Taldone Tony
• Sun Weilin
• Sloan Kettering Inst Cancer

Inventors

• Chiosis Gabriela
• Taldone Tony
• Sun Weilin

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title