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WO2009075890A2 - Composés triazole qui modulent l'activité de hsp90 - Google Patents

Composés triazole qui modulent l'activité de hsp90 Download PDF

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Publication number
WO2009075890A2
WO2009075890A2 PCT/US2008/013671 US2008013671W WO2009075890A2 WO 2009075890 A2 WO2009075890 A2 WO 2009075890A2 US 2008013671 W US2008013671 W US 2008013671W WO 2009075890 A2 WO2009075890 A2 WO 2009075890A2
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
independently
occurrence
alkyl
heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2008/013671
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English (en)
Other versions
WO2009075890A8 (fr
WO2009075890A3 (fr
Inventor
Dinesh U. Chimmanamada
Shijie Zhang
Chi-Wan Lee
Teresa Przewloka
Weiwen Ying
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synta Phamaceuticals Corp
Original Assignee
Synta Phamaceuticals Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synta Phamaceuticals Corp filed Critical Synta Phamaceuticals Corp
Publication of WO2009075890A2 publication Critical patent/WO2009075890A2/fr
Publication of WO2009075890A3 publication Critical patent/WO2009075890A3/fr
Publication of WO2009075890A8 publication Critical patent/WO2009075890A8/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/56—Amides of thiocarboxylic acids having nitrogen atoms of thiocarboxamide groups further bound to another hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/14—Nitrogen atoms

Definitions

  • R 20 is -OH, -SH, or -NH 2 ;
  • R 2 is O, NH or NR 26 ;
  • R 2U is OH, SH, NH 2 or NHR 26 ; and R 26 is a Cl -C6 alkyl.
  • R 20 is -OH, -SH, or -NH 2 ;
  • R 2 1 is O, NH or NR 26 ;
  • alkyl means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms.
  • Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n- heptyl, n-octyl, n-nonyl and n-decyl; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4- methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4- dimethylpentyl
  • haloalkyl means and alkyl group in which one or more (including all) the hydrogen radicals are replaced by a halo group, wherein each halo group is independently selected from -F, -Cl, -Br, and -I.
  • halomethyl means a methyl in which one to three hydrogen radical(s) have been replaced by a halo group.
  • Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1 ,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like.
  • an "alkoxy” is an alkyl group which is attached to another moiety via an oxygen linker.
  • aralkyl means an aryl group that is attached to another group by a (Ci-C 6 )alkylene group.
  • Representative aralkyl groups include benzyl, 2-phenyl-ethyl, naphth-3-yl -methyl and the like.
  • Aralkyl groups may be optionally substituted with one or more substituents.
  • heteroaryl groups include pyridyl, 1-oxo-pyridyl, furanyl, benzo[l,3]dioxolyl, benzo[l,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, a isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, a triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroind
  • R 28 and R 29 for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 28 and R 2 9 taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optional
  • lower alkyl refers to an alkyl radical having from 1 to 4 carbon atoms
  • lower alkoxy refers to "-O-(C
  • a “lower alkenyl” or “lower alkynyl” refers to an alkenyl or alkynyl radical having from 2 to 4 carbon atoms, respectively.
  • one enantiomer, diastereomer or geometric isomer will possess superior activity or an improved toxicity or kinetic profile compared to other isomers. In those cases, such enantiomers, diastereomers and geometric isomers of compounds of this invention are preferred.
  • hydrate means a compound of the present invention or a salt thereof, that further includes a stoichiometric or non- stoichiometric amount of water bound by non-covalent intermolecular forces.
  • clathrate means a compound of the present invention or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.
  • pharmaceutically acceptable salt also refers to a salt prepared from a obtained by the synthetic methods of the present invention having a basic functional group, such as an amine functional group, and a pharmaceutically acceptable inorganic or organic acid.
  • Suitable acids include, but are not limited to, hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid, lactic acid, salicylic acid, tartaric acid, bitartratic acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R 2 o;
  • R 5 is an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, a substituted alkyl, a substituted phenyl, an optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl;
  • the invention is a compound of formula (IV):
  • the compound of formula (II) is represented by structural formula (X):
  • R 33 is H or C1-C6 alkyl; and R 34 is a C1-C6 alkyl. Values and preferred values for the remainder of the substituents are as defined above with reference to formulas (IA) and (II).
  • X 4 1 is NR 42 , and R 42 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, and -C(O)N(R 27 ) 2 , wherein each R 27 is independently -H or a lower alkyl.
  • R 43 and R 44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • X 42 is CR 44 ;
  • Y 40 is CR 43 ; and
  • R 43 and R 44 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.
  • R 43 and R 44 together with the carbon atoms to which they are attached form a C 5 -C 8 cycloalkenyl or a C 5 -C 8 aryl.
  • R 45 is selected from the group consisting of -H, -OH, methoxy and ethoxy.
  • X 4I is O.
  • R 2 is O.
  • Values and preferred values for the remainder of the substituents are as defined above with reference to formulas (IA), (II), and (XIII).
  • R 43 and R 44 taken together with the carbon atoms to which they are attached, can form a C 5 -C 8 cycloalkenyl or a C 5 -C 8 aryl;
  • X 42 can be CR 44 ;
  • X 42 is CR 44 , and R 43 and R 44 , taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring. In one aspect, R 43 and R 44 , taken together with the carbon atoms to which they are attached, form a C 5 -C 8 cycloalkenyl or a C 5 -C 8 aryl. In one aspect, X 42 is CR 44 . In one aspect, X 42 is N.
  • X 45 is CR 54 or N;
  • R 56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl;
  • R 52 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, and -(CH 2 ) 2 OCH 3 ;

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé de synthèse de composés qui inhibent l'activité de Hsp90. Dans un mode de réalisation, la présente invention est un procédé de synthèse d'un composé de formule (IA), par cyclisation d'un composé de formule (II) : dans un mélange base/solvant, en produisant ainsi un composé de formule (IA). La définition des substituants et les conditions des réactions sont données ici.
PCT/US2008/013671 2007-12-12 2008-12-12 Composés triazole qui modulent l'activité de hsp90 Ceased WO2009075890A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US739107P 2007-12-12 2007-12-12
US61/007,391 2007-12-12

Publications (3)

Publication Number Publication Date
WO2009075890A2 true WO2009075890A2 (fr) 2009-06-18
WO2009075890A3 WO2009075890A3 (fr) 2009-08-13
WO2009075890A8 WO2009075890A8 (fr) 2009-10-01

Family

ID=40451133

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/013671 Ceased WO2009075890A2 (fr) 2007-12-12 2008-12-12 Composés triazole qui modulent l'activité de hsp90

Country Status (1)

Country Link
WO (1) WO2009075890A2 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011027081A2 (fr) 2009-09-03 2011-03-10 Sanofi-Aventis Nouveaux derives de 5,6,7,8-tetrahydroindolizine inhibiteurs d'hsp90, compositions les contenant et utilisation
WO2012026931A1 (fr) * 2010-08-25 2012-03-01 Synta Pharmaceuticals Corp. Procédé de synthèse de 2-alkylphénols substitués
US9573936B2 (en) 2015-05-20 2017-02-21 Amgen Inc. Triazole agonists of the APJ receptor
US9988369B2 (en) 2016-05-03 2018-06-05 Amgen Inc. Heterocyclic triazole compounds as agonists of the APJ receptor
US10689367B2 (en) 2016-11-16 2020-06-23 Amgen Inc. Triazole pyridyl compounds as agonists of the APJ receptor
US10736883B2 (en) 2016-11-16 2020-08-11 Amgen Inc. Triazole furan compounds as agonists of the APJ receptor
US10906890B2 (en) 2016-11-16 2021-02-02 Amgen Inc. Triazole phenyl compounds as agonists of the APJ receptor
US11020395B2 (en) 2016-11-16 2021-06-01 Amgen Inc. Cycloalkyl substituted triazole compounds as agonists of the APJ receptor
US11046680B1 (en) 2016-11-16 2021-06-29 Amgen Inc. Heteroaryl-substituted triazoles as APJ receptor agonists
US11149040B2 (en) 2017-11-03 2021-10-19 Amgen Inc. Fused triazole agonists of the APJ receptor
US11191762B2 (en) 2016-11-16 2021-12-07 Amgen Inc. Alkyl substituted triazole compounds as agonists of the APJ Receptor
US11807624B2 (en) 2018-05-01 2023-11-07 Amgen Inc. Substituted pyrimidinones as agonists of the APJ receptor

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI490212B (zh) * 2006-05-25 2015-07-01 Synta Pharmaceuticals Corp 調節ｈｓｐ９０活性之三唑化合物
RS53446B (sr) * 2006-05-25 2014-12-31 Synta Pharmaceuticals Corp. Triazolska jedinjenja koja modulišu aktivnost hsp90

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011027081A2 (fr) 2009-09-03 2011-03-10 Sanofi-Aventis Nouveaux derives de 5,6,7,8-tetrahydroindolizine inhibiteurs d'hsp90, compositions les contenant et utilisation
WO2012026931A1 (fr) * 2010-08-25 2012-03-01 Synta Pharmaceuticals Corp. Procédé de synthèse de 2-alkylphénols substitués
US10058550B2 (en) 2015-05-20 2018-08-28 Amgen Inc. Methods of treating heart failure
US10221162B2 (en) 2015-05-20 2019-03-05 Amgen Inc. Triazole agonists of the APJ receptor
US9656997B2 (en) 2015-05-20 2017-05-23 Amgen Inc. Triazole agonists of the APJ receptor
US9745286B2 (en) 2015-05-20 2017-08-29 Amgen Inc. Triazole agonists of the APJ receptor
US9751864B2 (en) 2015-05-20 2017-09-05 Amgen Inc. Methods for preparing triazole agonists of the APJ receptor
US9845310B2 (en) 2015-05-20 2017-12-19 Amgen Inc. Intermediates for preparing triazole agonists of the APJ receptor
US9868721B2 (en) 2015-05-20 2018-01-16 Amgen Inc. Triazole agonists of the APJ receptor
US10344016B2 (en) 2015-05-20 2019-07-09 Amgen Inc. Bromotriazole intermediates
US9573936B2 (en) 2015-05-20 2017-02-21 Amgen Inc. Triazole agonists of the APJ receptor
US9656998B2 (en) 2015-05-20 2017-05-23 Amgen Inc. Intermediates for preparing triazole agonists of the APJ receptor
US10150760B2 (en) 2016-05-03 2018-12-11 Amgen Inc. Compounds for use in preparing heterocyclic triazole agonists of the APJ receptor
US9988369B2 (en) 2016-05-03 2018-06-05 Amgen Inc. Heterocyclic triazole compounds as agonists of the APJ receptor
US10689367B2 (en) 2016-11-16 2020-06-23 Amgen Inc. Triazole pyridyl compounds as agonists of the APJ receptor
US10736883B2 (en) 2016-11-16 2020-08-11 Amgen Inc. Triazole furan compounds as agonists of the APJ receptor
US10906890B2 (en) 2016-11-16 2021-02-02 Amgen Inc. Triazole phenyl compounds as agonists of the APJ receptor
US11020395B2 (en) 2016-11-16 2021-06-01 Amgen Inc. Cycloalkyl substituted triazole compounds as agonists of the APJ receptor
US11046680B1 (en) 2016-11-16 2021-06-29 Amgen Inc. Heteroaryl-substituted triazoles as APJ receptor agonists
US11191762B2 (en) 2016-11-16 2021-12-07 Amgen Inc. Alkyl substituted triazole compounds as agonists of the APJ Receptor
US11149040B2 (en) 2017-11-03 2021-10-19 Amgen Inc. Fused triazole agonists of the APJ receptor
US11807624B2 (en) 2018-05-01 2023-11-07 Amgen Inc. Substituted pyrimidinones as agonists of the APJ receptor

Also Published As

Publication number Publication date
WO2009075890A8 (fr) 2009-10-01
WO2009075890A3 (fr) 2009-08-13

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