WO2009036066A1 - Inhibiteurs du récepteur du facteur de croissance endothélial vasculaire (vegfr) contenant une fraction de liaison au zinc - Google Patents

Inhibiteurs du récepteur du facteur de croissance endothélial vasculaire (vegfr) contenant une fraction de liaison au zinc Download PDF

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Publication number
WO2009036066A1
WO2009036066A1 PCT/US2008/075857 US2008075857W WO2009036066A1 WO 2009036066 A1 WO2009036066 A1 WO 2009036066A1 US 2008075857 W US2008075857 W US 2008075857W WO 2009036066 A1 WO2009036066 A1 WO 2009036066A1
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WO
WIPO (PCT)
Prior art keywords
substituted
compound
absent
aliphatic
alkyl
Prior art date
Application number
PCT/US2008/075857
Other languages
English (en)
Inventor
Changgeng Qian
Xiong Cai
Haixiao Zhai
Original Assignee
Curis, Inc.
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 Curis, Inc. filed Critical Curis, Inc.
Publication of WO2009036066A1 publication Critical patent/WO2009036066A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • R 7 and R9 are independently hydrogen, OR', aliphatic or substituted aliphatic, wherein R' is hydrogen, aliphatic, substituted aliphatic or acyl; provided that if R 7 and R9 are both present, one of R 7 or Rg must be OR' and if Yi is absent, Rg must be OR'; and Rs is hydrogen, acyl, aliphatic or substituted aliphatic;
  • Xi-Xg are independently C, N or CR 2 i;
  • X 1 -X 13 are independently N or CR 2I , where R 2 i is independently selected from hydrogen, hydroxy, amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, CF 3 , CN, NO 2 , N 3 , sulfonyl, acyl, aliphatic, and substituted aliphatic; Bi is absent, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocyclic or aryl; B 2 is absent, O, S, SO, SO 2 , N(R 8 ) or CO; B 3 is absent, O, S, SO, SO 2 , N(R 8 ), CO, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycl
  • R50 and R 6 O are independently selected from hydrogen, substituted or unsubstituted aliphatic and R 50 and R 6 o can be taken together with the nitrogen they are attached to form a substituted or unsubstituted heterocyclic;
  • X1-X3 and X5-X13 are independently N or CR21, where R21 is independently selected from hydrogen, hydroxy, substituted hydroxy, amino, substituted amino, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted thiol, CF3, CN, NO 2 , N 3 , substituted carbonyl, sulfonyl, acyl, aliphatic, and substituted aliphatic; Bi is absent, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl,
  • the invention further provides methods for the prevention or treatment of diseases or conditions involving aberrant proliferation, differentiation or survival of cells.
  • the invention further provides for the use of one or more compounds of the invention in the manufacture of a medicament for halting or decreasing diseases involving aberrant proliferation, differentiation, or survival of cells.
  • the disease is cancer.
  • the invention relates to a method of treating cancer in a subject in need of treatment comprising administering to said subject a therapeutically effective amount of a compound of the invention.
  • cancer refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like.
  • compositions suitable for administration can be incorporated into pharmaceutical compositions suitable for administration, together with a pharmaceutically acceptable carrier or excipient.
  • Such compositions typically comprise a therapeutically effective amount of any of the compounds above, and a pharmaceutically acceptable carrier.
  • the effective amount when treating cancer is an amount effective to selectively induce terminal differentiation of suitable neoplastic cells and less than an amount which causes toxicity in a patient.
  • heteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H- 1,2,4- triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.) tetrazolyl (e.g.
  • benzoxazolyl, benzoxadiazolyl, etc. unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, etc.) and the like.
  • thiazolyl, thiadiazolyl e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.
  • unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g., be
  • linker means an organic moiety that connects two parts of a compound.
  • Linkers typically comprise a direct bond or an atom such as oxygen or sulfur, a unit such as NR 8 , C(O), C(O)NH, SO, SO 2 , SO 2 NH or a chain of atoms, such as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenyl
  • angiogenesis refers to the formation of blood vessels. Specifically, angiogenesis is a multi-step process in which endothelial cells focally degrade and invade through their own basement membrane, migrate through interstitial stroma toward an angiogenic stimulus, proliferate proximal to the migrating tip, organize into blood vessels, and reattach to newly synthesized basement membrane (see Folkman et al., Adv. Cancer Res., Vol. 43, pp. 175-203 (1985)). Anti-angiogenic agents interfere with this process.
  • hypoplasia refers to excessive cell division or growth.
  • Neoplasm refers to an abnormal mass of tissue that results from excessive cell division. Neoplasms may be benign (not cancerous), or malignant (cancerous) and may also be called a tumor. The term “neoplasia” is the pathological process that results in tumor formation.
  • recurrence refers to the return of cancer after a period of remission. This may be due to incomplete removal of cells from the initial cancer and may occur locally (the same site of initial cancer), regionally (in vicinity of initial cancer, possibly in the lymph nodes or tissue), and/or distally as a result of metastasis.
  • the mixture was then carefully added to an aqueous solution of 10% NaHCO 3 (11. Ig OfNaHCO 3 dissolved in 111 g water) while the solution temperature was maintained at room temperature. The mixture was agitated for 1 h at 25 0 C and the layers separated. The organic layer was washed with an aqueous solution of 10% NaCl (120 g) and layers separated. The organic layer was concentrated at 50 0 C under reduced pressure to remove the remaining solvents. The resulting slurry was diluted with acetonitrile (50 g) and was agitated for 2 h at -5 0 C. The slurry was filtered, and the solids were rinsed with cold acetonitrile (20 g).
  • the mixture was agitated for 1 h at room temperature, and filtered through diatomaceous earth.
  • the cake was rinsed with THF (60 mL), and the filtrate was concentrated at 50 0 C under reduced pressure to a volume of ca. 50 ml.
  • the concentrate was cooled to room temperature, diluted with water (200 mL), and agitated at room temperature for 1 h.
  • PDGFR-beta tyrosine kinase was produced using a baculovirus expression system from a construct containing a human PDGFR-beta c- DNA (GenBank Accession No. NM 002600) fragment (amino acids 558-1106) amino-terminally fused to 6-histidine.
  • the proteins were purified using M2+/NTA agarose affinity column to purity >85% as determined by coomassie blue-stained SDS-PAGE gel.
  • VEGFR2/KDR assay p33 ATP tracers were incubated with purified recombinant VEGFR2 kinase to monitor the enzyme activity.
  • reactions were carried out in the presence of 0.1 mg/ml VEGFR2 kinase and 0.33mg/ml myelin basic protein. The reaction was carried out at 30 0 C for 120 minutes in a final assay condition contained 5OmM Tris-HCl, pH 7.5, 30OmM NaCl, 0.ImM EGTA, 0.03% Brij 35, 27OmM sucrose, ImM benzamidine, 0.2mM PMSF, 0.1% 2- mercaptoethanol and lOO ⁇ M ATP.

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

Abstract

La présente invention porte sur des inhibiteurs du VEGFR et sur leur utilisation dans le traitement de maladies à prolifération cellulaire telles que le cancer. Lesdits dérivés peuvent de plus jouer le rôle d'inhibiteurs de l'histone désacétylase (HDAC).
PCT/US2008/075857 2007-09-10 2008-09-10 Inhibiteurs du récepteur du facteur de croissance endothélial vasculaire (vegfr) contenant une fraction de liaison au zinc WO2009036066A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US97105107P 2007-09-10 2007-09-10
US60/971,051 2007-09-10
US3518908P 2008-03-10 2008-03-10
US61/035,189 2008-03-10

Publications (1)

Publication Number Publication Date
WO2009036066A1 true WO2009036066A1 (fr) 2009-03-19

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/075857 WO2009036066A1 (fr) 2007-09-10 2008-09-10 Inhibiteurs du récepteur du facteur de croissance endothélial vasculaire (vegfr) contenant une fraction de liaison au zinc

Country Status (1)

Country Link
WO (1) WO2009036066A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8242125B2 (en) 2008-12-09 2012-08-14 Novartis Ag Heterobicyclic carboxamides as inhibitors for kinases
US8367663B2 (en) 2009-01-08 2013-02-05 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US8710219B2 (en) 2011-04-01 2014-04-29 Curis, Inc. Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
JP2017515848A (ja) * 2014-05-14 2017-06-15 ザ リージェント オブ ザ ユニバーシティー オブ コロラド、ア ボディー コーポレート タンパク質脱アセチル化酵素阻害剤およびタンパク質脱アセチル化酵素−タンパク質キナーゼ二重阻害剤としての複素環式ヒドロキサム酸ならびにその使用方法
US9815841B2 (en) 2014-01-29 2017-11-14 Glaxosmithkline Intellectual Property Development Limited Compounds
US10087186B2 (en) 2014-01-29 2018-10-02 Glaxosmithkline Intellectual Property Development Limited Compounds as LRRK2 kinase inhibitors
CN109928964A (zh) * 2017-12-18 2019-06-25 江苏开元药业有限公司 一种阿西替尼中间体的合成方法
US10858359B2 (en) 2016-06-07 2020-12-08 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic ring derivatives useful as SHP2 inhibitors
US10988466B2 (en) 2017-03-23 2021-04-27 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors
US11234986B2 (en) 2018-09-11 2022-02-01 Curis, Inc. Combination therapy with a phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US11760761B2 (en) 2020-08-17 2023-09-19 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050004142A1 (en) * 2001-09-11 2005-01-06 Adams Jerry Leroy Chemical compounds
WO2005027972A2 (fr) * 2003-09-23 2005-03-31 Novartis Ag Polytherapie combinant un inhibiteur des recepteurs du facteur vegf avec un agent chimiotherapeutique
US20050234083A1 (en) * 2002-03-01 2005-10-20 Chamberlain Stanley D Diamino-pyrimidines and their use as angiogenesis inhibitors
US20060128709A1 (en) * 1999-05-21 2006-06-15 Bristol-Myers Squibb Company Pyrrolotriazine inhibitors of kinases
US20070015794A1 (en) * 2002-07-31 2007-01-18 Andreas Huth VEGFR-2 and VEGFR-3 inhibitory anthranilamide pyridines
US20070129389A1 (en) * 2003-10-27 2007-06-07 Graeme Bilbe Use of pyridinyl-pyrimidinylamino-benzamide derivatives for the treatment of amyloid related disorders

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060128709A1 (en) * 1999-05-21 2006-06-15 Bristol-Myers Squibb Company Pyrrolotriazine inhibitors of kinases
US20050004142A1 (en) * 2001-09-11 2005-01-06 Adams Jerry Leroy Chemical compounds
US20050234083A1 (en) * 2002-03-01 2005-10-20 Chamberlain Stanley D Diamino-pyrimidines and their use as angiogenesis inhibitors
US20070015794A1 (en) * 2002-07-31 2007-01-18 Andreas Huth VEGFR-2 and VEGFR-3 inhibitory anthranilamide pyridines
WO2005027972A2 (fr) * 2003-09-23 2005-03-31 Novartis Ag Polytherapie combinant un inhibiteur des recepteurs du facteur vegf avec un agent chimiotherapeutique
US20070129389A1 (en) * 2003-10-27 2007-06-07 Graeme Bilbe Use of pyridinyl-pyrimidinylamino-benzamide derivatives for the treatment of amyloid related disorders

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8431584B2 (en) 2008-12-09 2013-04-30 Novartis Ag Heterobicyclic carboxamides as inhibitors for kinases
US8486954B2 (en) 2008-12-09 2013-07-16 Novartis Ag Heterobicyclic carboxamides as inhibitors for kinases
US8492393B2 (en) 2008-12-09 2013-07-23 Novartis Ag Heterobicyclic carboxamides as inhibitors for kinases
US8501756B2 (en) 2008-12-09 2013-08-06 Novartis Ag Heterobicyclic carboxamides as inhibitors for kinases
US8541432B2 (en) 2008-12-09 2013-09-24 Novartis Ag Heterobicyclic carboxamides as inhibitors for kinases
US8242125B2 (en) 2008-12-09 2012-08-14 Novartis Ag Heterobicyclic carboxamides as inhibitors for kinases
US10894795B2 (en) 2009-01-08 2021-01-19 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US8367663B2 (en) 2009-01-08 2013-02-05 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US8461157B2 (en) 2009-01-08 2013-06-11 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US8906909B2 (en) 2009-01-08 2014-12-09 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US11597732B2 (en) 2009-01-08 2023-03-07 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US11261195B2 (en) 2009-01-08 2022-03-01 Curis, Inc. Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
US8710219B2 (en) 2011-04-01 2014-04-29 Curis, Inc. Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US11654136B2 (en) 2011-04-01 2023-05-23 Curis, Inc. Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US10543197B2 (en) 2011-04-01 2020-01-28 Curis, Inc. Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US11135205B2 (en) 2011-04-01 2021-10-05 Curis, Inc. Phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US9815841B2 (en) 2014-01-29 2017-11-14 Glaxosmithkline Intellectual Property Development Limited Compounds
US10618901B2 (en) 2014-01-29 2020-04-14 Glaxosmithkline Intellectual Property Development Limited LRRK2 inhibitors for the treatment of Parkinson's disease
US10087186B2 (en) 2014-01-29 2018-10-02 Glaxosmithkline Intellectual Property Development Limited Compounds as LRRK2 kinase inhibitors
USRE47690E1 (en) 2014-05-14 2019-11-05 The Regents Of The University Of Colorado, A Body Corporate Heterocyclic hydroxamic acids as protein deacetylase inhibitors and dual protein deacetylase-protein kinase inhibitors and methods of use thereof
US10508122B2 (en) 2014-05-14 2019-12-17 The Regents Of The University Of Colorado, A Body Corporate Heterocyclic hydroxamic acids as protein deacetylase inhibitors and dual protein deacetylase-protein kinase inhibitors and methods of use thereof
EP3142652A4 (fr) * 2014-05-14 2017-11-29 The Regents of the University of Colorado, a body corporate Acides hydroxamiques hétérocycliques comme inhibiteurs de protéine désacétylase et inhibiteurs doubles de protéine kinase-protéine désacétylase, et leurs procédés d'utilisation
JP2017515848A (ja) * 2014-05-14 2017-06-15 ザ リージェント オブ ザ ユニバーシティー オブ コロラド、ア ボディー コーポレート タンパク質脱アセチル化酵素阻害剤およびタンパク質脱アセチル化酵素−タンパク質キナーゼ二重阻害剤としての複素環式ヒドロキサム酸ならびにその使用方法
US10858359B2 (en) 2016-06-07 2020-12-08 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic ring derivatives useful as SHP2 inhibitors
US10988466B2 (en) 2017-03-23 2021-04-27 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors
CN109928964B (zh) * 2017-12-18 2022-04-15 江苏开元药业有限公司 一种阿西替尼中间体的合成方法
CN109928964A (zh) * 2017-12-18 2019-06-25 江苏开元药业有限公司 一种阿西替尼中间体的合成方法
US11234986B2 (en) 2018-09-11 2022-02-01 Curis, Inc. Combination therapy with a phosphoinositide 3-kinase inhibitor with a zinc binding moiety
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11919887B2 (en) 2019-12-06 2024-03-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11760761B2 (en) 2020-08-17 2023-09-19 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels

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