- WEE1 Protein degradation agent
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WEE1 Protein degradation agents are provided. , The invention provides a compound as shown V, or a pharmaceutically acceptable salt thereof, or a stereoisomer, Y-L-M thereof. WEE1 (V) Wherein M. WEE1 A WEE1 binding moiety capable of binding to WEE1 protein kinase is provided. Y Is E3 ubiquitin ligase ligand moiety, and L Is a linking group.
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Paragraph 0301-0304
(2021/09/21)
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- METHODS OF MAKING WEE1 INHIBITOR COMPOUNDS
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The invention relates to a method of producing a WEE1 inhibitor of formula (1A) useful in the treatment of pathological conditions characterized by excessive cell proliferation, such as cancer. In some embodiments, the invention relates to methods for producing intermediate compounds of formulas (3), (5) and (6) as defined in the description.
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Paragraph 0089
(2021/12/31)
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- BIMP-Catalyzed 1,3-Prototropic Shift for the Highly Enantioselective Synthesis of Conjugated Cyclohexenones
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A bifunctional iminophosphorane (BIMP)-catalysed enantioselective synthesis of α,β-unsaturated cyclohexenones through a facially selective 1,3-prototropic shift of β,γ-unsaturated prochiral isomers, under mild reaction conditions and in short reaction times, on a range of structurally diverse substrates, is reported. α,β-Unsaturated cyclohexenone products primed for downstream derivatisation were obtained in high yields (up to 99 %) and consistently high enantioselectivity (up to 99 % ee). Computational studies into the reaction mechanism and origins of enantioselectivity, including multivariate linear regression of TS energy, were carried out and the obtained data were found to be in good agreement with experimental findings.
- Carter, Eve M.,Dixon, Darren J.,Golec, Jonathan C.,Paton, Robert S.,Simón, Luis,Ward, John W.,Whittingham, William G.
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supporting information
p. 17417 - 17422
(2020/08/10)
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- WEE1 KINASE INHIBITORS AND METHODS OF TREATING CANCER USING THE SAME
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A compound, or a pharmaceutically acceptable salts or prodrugs thereof, having the chemical structure (I) and methods of using these compounds to inhibit WEE1 kinase and treat cancer in a subject.
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Page/Page column 37
(2019/09/18)
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- 1,2-DIHYDRO-3H-PYRAZOLO[3,4-D]PYRIMIDINE-3-ONE COMPOUNDS AS INHIBITORS OF WEE-1 KINASE
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The disclosure includes compounds of Formula (I) wherein Q, R1, R2, and m are defined herein. Also disclosed is a method for treating a neoplastic disease with these compounds.
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Page/Page column 30-31
(2019/09/12)
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- HETEROCYCLIC COMPOUNDS AND USES THEREOF
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Heterocyclic compounds as Wee1 inhibitors are provided. The compounds may find use as therapeutic agents for the treatment of diseases and may find particular use in oncology.
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Paragraph 0315-0317
(2019/04/25)
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- Regiocontrolled and Stereoselective Syntheses of Tetrahydrophthalazine Derivatives using Radical Cyclizations
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Tetrahydrophthalazine derivatives have found important applications in pharmaceutical research, but existing synthetic methods are unable to access them regio- and stereoselectively. Here, a new approach is presented that addresses these challenges by utilizing a 6-endo-trig radical cyclization in the key step. The desired tetrahydrophthalazines can be accessed in high yields (55–98 %) and high diastereoselectivities for the trans-product (>95:5) starting either from readily accessible hydrazones, or from the corresponding aldehydes and substituted Boc-hydrazides in a one-pot process. The synthetic versatility of the tetrahydrophthalazine core was demonstrated by its straightforward conversion to dihydro-phthalazines, phthalazines, or pyrazolo dione derivatives. Furthermore, the N?N bond was reduced to afford a new route to 1,4-diamines.
- Zhang, Wei,Mo, Jia Yi,He, Weiying,Kennepohl, Pierre,Sammis, Glenn M.
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supporting information
p. 976 - 980
(2019/01/04)
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- Development of Potent Pyrazolopyrimidinone-Based WEE1 Inhibitors with Limited Single-Agent Cytotoxicity for Cancer Therapy
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WEE1 kinase regulates the G2/M cell-cycle checkpoint, a critical mechanism for DNA repair in cancer cells that can confer resistance to DNA-damaging agents. We previously reported a series of pyrazolopyrimidinones based on AZD1775, a known WEE1 inhibitor, as an initial investigation into the structural requirements for WEE1 inhibition. Our lead inhibitor demonstrated WEE1 inhibition in the same nanomolar range as AZD1775, and potentiated the effects of cisplatin in medulloblastoma cells, but had reduced single-agent cytotoxicity. These results prompted the development of a more comprehensive series of WEE1 inhibitors. Herein we report a series of pyrazolopyrimidinones and identify a more potent WEE1 inhibitor than AZD1775 and additional compounds that demonstrate that WEE1 inhibition can be achieved with reduced single-agent cytotoxicity. These studies support that WEE1 inhibition can be uncoupled from the potent cytotoxic effects observed with AZD1775, and this may have important ramifications in the clinical setting where WEE1 inhibitors are used as chemosensitizers for DNA-targeted chemotherapy.
- Matheson, Christopher J.,Casalvieri, Kimberly A.,Backos, Donald S.,Reigan, Philip
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supporting information
p. 1681 - 1694
(2018/08/01)
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- A photo-auxiliary approach - enabling excited state classical phototransformations with metal free visible light irradiation
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Most traditional photoreactions require UV light to yield the desired product. To address this issue, photoreaction of hydrazide based chromophores was evaluated with visible light using a metal free photocatalyst to afford photoproducts in high yields. This hydrazide functionality itself may be removed/modified after the photoreaction, highlighting its role as a “photo-auxiliary”. A preliminary mechanistic model based on photophysical experiments is provided to highlight the generality of the strategy.
- Iyer, Akila,Jockusch, Steffen,Sivaguru, Jayaraman
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supporting information
p. 1692 - 1695
(2017/02/10)
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- WEE 1 KINASE INHIBITORS AND METHODS OF MAKING AND USING THE SAME
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A compound, or a pharmaceutically acceptable salt thereof, having a chemical structure of formula (I) or formula (II), and methods of using these compounds to treat cancer in an individual.
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Page/Page column 32
(2017/05/17)
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- A WEE1 Inhibitor Analog of AZD1775 Maintains Synergy with Cisplatin and Demonstrates Reduced Single-Agent Cytotoxicity in Medulloblastoma Cells
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The current treatment for medulloblastoma includes surgical resection, radiation, and cytotoxic chemotherapy. Although this approach has improved survival rates, the high doses of chemotherapy required for clinical efficacy often result in lasting neurocognitive defects and other adverse events. Therefore, the development of chemosensitizing agents that allow dose reductions of cytotoxic agents, limiting their adverse effects but maintaining their clinical efficacy, would be an attractive approach to treat medulloblastoma. We previously identified WEE1 kinase as a new molecular target for medulloblastoma from an integrated genomic analysis of gene expression and a kinome-wide siRNA screen of medulloblastoma cells and tissue. In addition, we demonstrated that WEE1 prevents DNA damage-induced cell death by cisplatin and that the WEE1 inhibitor AZD1775 displays synergistic activity with cisplatin. AZD1775 was developed as a WEE1 inhibitor from an initial hit from a high-throughput screen. However, given the lack of structure-activity data for AZD1775, we developed a small series of analogs to determine the requirements for WEE1 inhibition and further examine the effects of WEE1 inhibition in medulloblastoma. Interestingly, the compounds that inhibited WEE1 in the same nanomolar range as AZD1775 had significantly reduced single-agent cytotoxicity compared with AZD1775 and displayed synergistic activity with cisplatin in medulloblastoma cells. The potent cytotoxicity of AZD1775, unrelated to WEE1 inhibition, may result in dose-limiting toxicities and exacerbate adverse effects; therefore, WEE1 inhibitors that demonstrate low cytotoxicity could be dosed at higher concentrations to chemosensitize the tumor and potentiate the effect of DNA-damaging agents such as cisplatin.
- Matheson, Christopher J.,Venkataraman, Sujatha,Amani, Vladimir,Harris, Peter S.,Backos, Donald S.,Donson, Andrew M.,Wempe, Michael F.,Foreman, Nicholas K.,Vibhakar, Rajeev,Reigan, Philip
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p. 921 - 930
(2016/05/19)
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- PYRAZOLOQUINOLINE DERIVATIVES
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A compound and/or pharmacologically acceptable salt thereof represented by the formula (I) has PDE9 inhibitory action, so that the intracerebral cGMP concentration is anticipated to be elevated. The PDE9 inhibitory action and the increase in cGMP lead to the improvement of learning and memory behaviors, and the compound (I) has applicability as a therapeutic agent for cognitive dysfunctions in Alzheimer's disease. wherein R1 is a hydrogen atom; R2 is an aromatic ring group, etc.; R3 is a hydrogen atom, etc; R4 is a hydrogen atom; R5 is an oxepanyl group, etc.; R6 is a hydrogen atom.
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Paragraph 0346; 0347
(2013/06/26)
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- NOVEL AZAPEPTIDE OR AZAPEPTIDOMIMETIC COMPOUNDS INHIBITING BCRP AND/OR P-GP
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The present invention relates to compounds of azapeptide or azapeptidomimetic type of formula (I): in which R1, R2, R3, X1, X2, X3, X4 and Y are as defined in claim 1, to pharmaceutical compositions containing them and to such compounds as adjuvant for an anticancer or anti-infectious medicament.
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Page/Page column 14
(2012/01/15)
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- 2-(3-AMINOPIPERIDIN-1-YL)-[1,2,4]TRIAZOLO[1,5-C]PYRIMIDINE-5,7(3H,6H)-DIONE DERIVATES AS DIPEPTIDYL PEPTIDASE IV(DPP-IV) INHIBITORS
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Provided are 2-(3-aminopiperidin-1-yl)-[1,2,4]triazolo[1,5-c]pyrimidine-5,7(3H,6H)-dione derivates as dipeptidyl peptidase IV (DPP-IV) inhibitors, pharmaceutical compositions thereof, and methods of use thereof
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Page/Page column 47
(2012/07/14)
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- CERTAIN DIPEPTIDYL PEPTIDASE INHIBITORS
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Provided are certain dipeptidyl peptidase inhibitors, pharmaceutical compositions thereof, and methods of use therefor.
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Page/Page column 47
(2012/07/14)
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- PYRIDONE-SUBSTITUTED-DIHYDROPYRAZOLOPYRIMIDINONE DERIVATIVE
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The invention relates to a compound of general formula (I-0): wherein R1 means a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, or a C3-C6 cycloalkyl group; R2, R3, R4 and R5 mean a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a halo-C1-C6 alkyl group, a C1-C6 alkoxy group, or a halo-C1-C6 alkoxy group; R6 means a hydrogen atom, or a C1-C6 alkyl group; R7a means a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a halo-C1-C6 alkyl group, a C1-C6 alkoxy group, a hydroxy-C1-C6 alkyl group, -Q2-N(R1c)R1d or a nitrogen-containing heterocyclic group; R8a means a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a halo-C1-C6 alkyl group, a C1-C6 alkoxy group or a hydroxy-C1-C6 alkyl group; or R7a and R8a form, as taken together, a C2-C6 alkylene group, or R7a and R8a and the ring atoms to which they bond may form a spiro ring or a bicyclo ring; and X and Y mean a methine group or a nitrogen atom. The compound of the invention has, based on its excellent Wee1 kinase-inhibitory effect, a cell growth-inhibitory effect and an additive/synergistic effect with any other anticancer agent, and is therefore useful in the field of medicine.
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Page/Page column 39
(2010/08/09)
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- Macrocyclic Inhibitors of Hepatitis C Virus
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Compounds of the formula (I): and N-oxides, salts and stereoisomers thereof wherein A is OR1, NHS(═O)pR2, NHR3, NRaRb, C(═O)NHR3 or C(═O)NRaRb wherein; R1 is hydrogen, C1-C6alkyl, C0-C3alkylenecarbocyclyl, C0-C3alkyleneheterocyclyl; R2 is C1-C6alkyl, C0-C3alkylenecarbocyclyl, C0-C3alkyleneheterocyclyl or NRaRb; R3 is C1-C6alkyl, C0-C3alkylenecarbocyclyl, C0-C3alkyleneheterocyclyl, —OC1-C6alkyl, —OC0-C3alkylenecarbocyclyl, —OC0-C3alkyleneheterocyclyl; wherein any alkyl, carbocyclyl or heterocycylyl in R1, R2 or R3 are optionally substituted p is independently 1 or 2; n is 3, 4, 5 or 6; denotes an optional double bond; Rq is H or when L is CRz, Rq can also be C1-C6alkyl; Ry and Ry′ are independently C1-C6alkyl; L is N or CRz; Rz is H or forms a double bond with the asterisked carbon; W is —CH2—, —O—, —OC(═O)NH—, —OC(═O)—, —S—, —NH—, —NRa, —NHS(═O)2—, —NHC(=0)NH— or —NHC(═O)—, —NHC(═S)NH— or a bond; R8 is an optionally substituted ring system containing 1 or 2 saturated, partially saturated or unsaturated carbo or heterocyclic rings have utility in the inhibition of NS-3 serine proteases, such as flavivirus infections.
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Page/Page column 62
(2009/02/11)
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- Original and efficient synthesis of 2:1-[α/aza]-oligomer precursors
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The preparation of 2:1-[α/aza]-oligomer precursors is described via Mitsunobu and exchange of protecting groups protocols in four steps in good yields starting from N-tert-butyloxycarbonylaminophtalimide. Conformational studies showed that these building blocks further led to β-turn-like folded 2:1-[α/aza]-trimer which suggests that they are good candidates to form foldamers.
- Abbas, Cécile,Pickaert, Guillaume,Didierjean, Claude,Grégoire, Brigitte Jamart,Vanderesse, Régis
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supporting information; experimental part
p. 4158 - 4160
(2009/10/26)
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- POLYMORPH OF DIHYDROPYRAZOLOPYRIMIDINONE DERIVATIVE AS WEEL KINASE.INHIBITOR
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The present invention relates to the crystalline forms of 2-allyl-l -[6-(I -hydroxy- 1 methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-l-yl)phenyl]amino}-l,2-dihydro-3H- pyrazolo[3,4-d]pyrirnidin-3-one or a salt thereof, which are useful in the field of treatment of various cancers as a kinase inhibitor, especially as a Weel kinase inhibitor.
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Page/Page column 27
(2008/12/08)
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- Dihydropyrazolopyrimidinone derivatives
-
The invention relates to compounds of a general formula (I): wherein Ar1 is an optionally-substituted aryl or heteroaromatic group; R1 is an optionally-substituted lower alkyl, lower alkenyl, lower alkynyl or cyclo-lower alkyl group, or is an aryl, aralkyl or heteroaromatic group optionally having a substituent; R2 is a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group, or is an aryl, aralkyl or heteroaromatic group optionally having a substituent; R3 is a hydrogen atom or a lower alkyl group; R4 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a group of —N(R1k)R1m; T and U are a nitrogen atom or a methine group, etc. The compounds of the invention have excellent Weel kinase-inhibitory effect and are therefore useful in the field of medicines, especially treatment of various cancers.
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Page/Page column 30
(2008/06/13)
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- Preparation of Multiply Protected Alkylhydrazine Derivatives by Mitsunobu and PTC Approaches
-
Alkylation reactions of hydrazine derivatives by Mitsunobu or PTC approaches are described. It has been shown that aminophthalimide derivatives are better acidic partners than their aminoimidodicarbonate (NBoc2) analogues, the presence of the phthaloyl group increasing the acidity of the sole proton and concomitantly reducing steric hindrance. Moreover, N-aminophthalimide derivatives can be efficiently converted into the corresponding N-amino-imidodicarbonates by a three-stage, one-flask procedure under very mild conditions. These procedures can also be efficiently used for the preparation of orthogonally Nα,Nβ -diprotected α-hydrazino esters. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).
- Brosse, Nicolas,Pinto, Maria-Fatima,Jamart-Gregoire, Brigitte
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p. 4757 - 4764
(2007/10/03)
-
- PEPTIDE DEFORMYLASE INHIBITORS
-
Novel PDF inhibitors and novel methods for their use are provided.
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-
-
- New Synthesis of 1,1-Substituted Hydrazines by Alkylation of N-Acyl- or N-alkyloxycarbonylaminophthalimide Using the Mitsunobu Protocol
-
N-acyl- and N-alkoxycarbonylaminophthalimides are prepared using a convenient reaction and are efficiently used as acid partners in Mitsunobu reaction. This reaction allows them to be alkylated by primary, secondary or benzyl groups. Comparison of the reactivities and pKa values of these N-substituted aminophthalimides suggest that the success of the Mitsunobu reaction in this case seems to be governed more by steric than by electronic effects. A final dephthaloylation step results in an efficient method for the preparation of 1,1-substituted hydrazines.
- Brosse, Nicolas,Pinto, Maria-Fatima,Jamart-Gregoire, Brigitte
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p. 4370 - 4374
(2007/10/03)
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