Purine derivatives useful as HSP90 inhibitors

Patent metadata

Field	Value
Publication number	US-10172863-B2
Application number	US-201615135121-A
Country	US
Kind code	B2
Filing date	Apr 21, 2016
Priority date	Oct 7, 2009
Publication date	Jan 8, 2019
Grant date	Jan 8, 2019

Abstract

The present application provides substituted purine derivatives and related compounds of the formulas shown. These compounds are useful as inhibitors of HSP90, and hence in the treatment of related diseases. (Formulae) Z 1 -Z 3 , X a -X c , X 2 , X 4 , Y and R are as defined in the specification.

First claim

The invention claimed is:

1. A method of treating cancer or neurodegenerative disease by inhibition of Hsp90 in a subject in need thereof, comprising administering a therapeutically effective amount of 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,

wherein the cancer is breast cancer, brain cancer, lung cancer, leukemia, prostate cancer, colon cancer, neuroblastoma, vulvar cancer, lymphoma, pancreatic cancer, multiple myeloma, hepatocellular cancer, glioma, gastric cancer, melanoma, ovarian cancer, head and neck cancer, bladder cancer, thyroid cancer, osteosarcoma, Ewing sarcoma, renal cancer, cervical cancer, mesothelioma, or medulloblastoma; and
wherein the neurodegenerative disease is Complete androgen insensitivity syndrome (CAIS), spinal and bulbar muscular atrophy (Kennedy's disease), Parkinson's disease, Huntington disease, or a tauopathy.

2. The method 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 method 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 method of claim 1 , wherein X 2 is optionally substituted alkynyl.

5. The method 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 method of claim 5 , wherein R is 3-(isopropyl-amino)propyl.

7. The method of claim 4 , wherein the compound is selected from the group consisting of: 8-[6-(3,3-dimethyl-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-ylthio)-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-yl)thio)-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-ethynylbenz

Assignees

• Sloan Kettering Inst Cancer Res

Inventors

• Chiosis Gabriela
• Taldone Tony
• Sun Weilin

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · 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