- PYRIMIDINE AMIDE COMPOUNDS AND USE THEREOF
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Disclosed are compounds of formula (I) below or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof: (I), in which each of variables each of variables R, R1, R2, X1, X2, X3 and n is defined herein. Also disclosed is a method for treating a cancer with a compound of formula (I) or a salt thereof and a pharmaceutical composition containing same.
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Page/Page column 28
(2021/04/30)
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- Discovery of 4-methyl-N-(4-((4-methylpiperazin- 1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-oxy)benzamide as a potent inhibitor of RET and its gatekeeper mutant
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The receptor tyrosine kinase rearranged during transfection (RET) plays pivotal roles in several cancers, including thyroid carcinoma and non-small cell lung cancer (NSCLC). Currently, there are several FDA-approved RET inhibitors, but their indication is limited to thyroid cancer, and none can overcome their gatekeeper mutants (V804L and V804M). Here, we report the discovery of 9x representing a new chemotype of potent and selective RET inhibitors, using a rational design strategy of type II kinase inhibitors. 9x exhibited both superior antiproliferative activities against NSCLC-related carcinogenic fusions KIF5B-RET and CCDC6-RET and gatekeeper mutant-transformed Ba/F3 cells, with the lowest GI50 of 9 nM, and substantial inhibitory activities against wild-type RET and RET mutant proteins, with the best IC50 of 4 nM. More importantly, 9x also showed nanomole potency against RET-positive NSCLC cells LC-2/ad, but not against a panel of RET-negative cancer cells, such as A549, H3122, A375 or parental Ba/F3 cells, demonstrating its selective ‘on-target’ effect. In mouse xenograft models, 9x repressed tumor growth driven by both wild type KIF5B-RET-Ba/F3 and gatekeeper mutant KIF5B-RET(V804M)-Ba/F3 cells in a dose-dependent manner. Together, these data establish that 9x provides a good starting point for the development of targeted therapeutics against RET-positive cancers, especially NSCLC.
- Chen, Guyue,Deng, Xianming,Deng, Zhou,Dong, Chao,Hu, Zhiyu,Li, Li,Li, Xiaoyang,Lian, Wenhua,Liu, Xueyan,Su, Jingyi,Wang, Zheng,Xu, Qingyan,Yang, Yanru,Yang, Zaiyou,Zhang, Baoding
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- SUBSTITUTED PENTA-FUSED HEXA-HETEROCYCLIC COMPOUNDS, PREPARATION METHOD THEREFOR, DRUG COMBINATION AND USE THEREOF
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A type of substituted penta-fused hexa-heterocyclic compounds having selective inhibition for PIKfyve kinase, a pharmaceutically acceptable salt and pharmaceutically acceptable solvate thereof, a method for the preparation thereof, a pharmaceutical composition comprising the same, and use of these compounds in the manufacture of a medicament for preventing or treating a disease associated with PIKfyve in vivo, in particular in the manufacture of a medicament for preventing or treating tumor growth and metastasis.
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Paragraph 0317-0322
(2020/06/16)
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- INHIBITORS OF INFLUENZA VIRUS REPLICATION, APPLICATION METHODS AND USES THEREOF
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A class of compounds as inhibitors of influenza virus replication, preparation methods thereof, pharmaceutical compositions containing these compounds, and uses of these compounds and pharmaceutical compositions thereof in the treatment of influenza.
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Paragraph 00366
(2018/03/09)
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- INHIBITORS OF INFLUENZA VIRUS REPLICATION, APPLICATION METHODS AND USES THEREOF
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The invention provides a novel class of compounds as inhibitors of influenza virus replication, preparation methods thereof, pharmaceutical compositions containing these compounds, and uses of these compounds and pharmaceutical compositions thereof in the treatment of influenza.
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Paragraph 00368
(2017/07/04)
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- BICYCLIC PYRIDINE AND PYRIMIDINE DERIVATIVES AND THEIR USE IN THE TREATMENT, AMELIORATION OR PREVENTION OF INFLUENZA
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The present invention relates to a compound having the formula (I), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, prodrug, codrug, cocrystal, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, which is useful in treating, ameloriating or preventing influenza.
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Page/Page column 83
(2017/12/27)
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- ALKYNYL ALCOHOLS AND METHODS OF USE
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The invention relates to compounds of Formula (0): wherein A1-A8, R4 and R5 each has the meaning as described herein. Compounds of Formula (0) and pharmaceutical compositions thereof are useful in the treatment of diseases and disorders in which undesired or over-activation of NF-kB signaling is observed.
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Paragraph 0414; 0415
(2015/03/04)
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- ALKYNYL ALCOHOLS AND METHODS OF USE
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The invention relates to compounds of Formula (0): wherein A1-A8, R4 and R5 each has the meaning as described herein. Compounds of Formula (0) and pharmaceutical compositions thereof are useful in the treatment of diseases and disorders in which undesired or over-activation of NF-kB signaling is observed.
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Page/Page column 114
(2015/03/13)
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- Discovery of dual orexin receptor antagonists with rat sleep efficacy enabled by expansion of the acetonitrile-assisted/diphosgene-mediated 2,4-dichloropyrimidine synthesis
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Recent clinical studies have demonstrated that dual orexin receptor antagonists (OX1R and OX2R antagonists or DORAs) represent a novel treatment option for insomnia patients. Previously we have disclosed several compounds in the diazepane amide DORA series with excellent potency and both preclinical and clinical sleep efficacy. Additional SAR studies in this series were enabled by the expansion of the acetonitrile-assisted, diphosgene-mediated 2,4-dichloropyrimidine synthesis to novel substrates providing an array of Western heterocycles. These heterocycles were utilized to synthesize analogs in short order with high levels of potency on orexin 1 and orexin 2 receptors as well as in vivo sleep efficacy in the rat.
- Roecker, Anthony J.,Mercer, Swati P.,Harrell, C. Meacham,Garson, Susan L.,Fox, Steven V.,Gotter, Anthony L.,Prueksaritanont, Thomayant,Cabalu, Tamara D.,Cui, Donghui,Lemaire, Wei,Winrow, Christopher J.,Renger, John J.,Coleman, Paul J.
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p. 2079 - 2085
(2014/05/06)
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- PYRAZOLOPYRIMIDINE DERIVATIVES
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Compounds of the formula (I), in which X, R1 and R2 have the meanings indicated in claim 1, are PI3K inhibitors and can be employed, inter alia, for the treatment of autoimmune diseases, inflammation, cardiovascular diseases, neurode
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Page/Page column 17-18
(2012/08/28)
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- ANTIVIRAL PYRIMIDINES
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Disclosed herein are novel compounds comprising substituted pyrimidines, pyrazolopyrimtdines, and imidazolopyrimidines, the syntheses thereof, and compositions thereof, including pharmaceutical compositions, comprising the novel pyrimidines, pyrazolopyrimtdines, imidazolpyrimidines and related compounds. Such compounds function to inhibit entry of viruses of the Flaviviridae family, including Hepatitis C virus (HCV), into cells that are susceptible to virus infection. These compounds are useful for the treatment, therapy and/or prophylaxis of viral diseases and infection, including HCV infection.
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Page/Page column 94
(2010/11/03)
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- Structure-based optimization of pyrazolo-pyrimidine and -pyridine inhibitors of PI3-kinase
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Starting from HTS hit 1a, X-ray co-crystallization and molecular modeling were used to design potent and selective inhibitors of PI3-kinase. Bioavailablity in this series was improved through careful modulation of physicochemical properties. Compound 12 d
- Staben, Steven T.,Heffron, Timothy P.,Sutherlin, Daniel P.,Bhat, Seema R.,Castanedo, Georgette M.,Chuckowree, Irina S.,Dotson, Jenna,Folkes, Adrian J.,Friedman, Lori S.,Lee, Leslie,Lesnick, John,Lewis, Cristina,Murray, Jeremy M.,Nonomiya, Jim,Olivero, Alan G.,Plise, Emile,Pang, Jodie,Prior, Wei Wei,Salphati, Laurent,Rouge, Lionel,Sampath, Deepak,Tsui, Vickie,Wan, Nan Chi,Wang, Shumei,Weismann, Christian,Wu, Ping,Zhu, Bing-Yan
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scheme or table
p. 6048 - 6051
(2010/11/17)
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- 4-PHENOXY-6-ARYL-1H-PYRAZOLO[3,4-D]PYRIMIDINE AND N-ARYL-6-ARYL-1H-PYRAZOLO[3,4-D]PYRIMIDIN-4-AMINE COMPOUNDS, THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESES
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The invention relates to 4,6-disubstituted-1H-pyrazolo[3,4-d]pyrimidin-4-amine compounds, including 4-phenoxy-6-aryl-1H-pyrazolo[3,4-d]pyrimidine and N-aryl-6-aryl-1H-pyrazolo[3,4-d]pyrimidin-4-amine compounds of the Formula I: or a pharmaceutically accep
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Page/Page column 17
(2010/02/17)
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- Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): Optimization of the 1-substituent
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A series of pyrazolopyrimidine mammalian Target Of Rapamycin (mTOR) inhibitors with various substituents at the 1-position have been prepared, resulting in compounds with excellent potency, selectivity and microsomal stability. Combination of a 1-cyclohexyl ketal group with a 2,6-ethylene bridged morpholine in the 4-position and a ureidophenyl group in the 6-positon resulted in compound 8a, that selectively suppressed key mTOR biomarkers in vivo for at least 8 h following iv administration and showed excellent oral activity in a xenograft tumor model.
- Curran, Kevin J.,Verheijen, Jeroen C.,Kaplan, Joshua,Richard, David J.,Toral-Barza, Lourdes,Hollander, Irwin,Lucas, Judy,Ayral-Kaloustian, Semiramis,Yu, Ker,Zask, Arie
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scheme or table
p. 1440 - 1444
(2010/07/06)
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- PYRAZOLOPYRIMIDINE PI3K INHIBITOR COMPOUNDS AND METHODS OF USE
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Compounds of Formula I, and including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting lipid kinases including p110 alpha and other isoforms of PI3K, and for treating disorders such as cancer mediated by lipid kinases. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed. [Fomula I]
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Page/Page column 64; 65
(2009/09/05)
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- Pyrazolo[3,4-d]pyrimidine compounds and their use as modulators of protein kinase
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The invention relates to pyrazolo[3,4-d]pyrimidine compounds of formual I and its salts wherein the substitents are as defined in the specification, their use for the treatment of protein kinase modulation responsive diseases or in the manufacture of phar
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Page/Page column 19
(2009/03/07)
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- THIENOPYRIMIDINE AND PYRAZOLOPYRIMIDINE COMPOUNDS AND THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS
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The invention relates to thienopyrimidine and pyrazolopyrimidine compounds of the Formulas (Ia) and (IIa), or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined herein compositions comprising the compounds, and methods for making and using the compounds.
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Page/Page column 59
(2009/04/24)
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- PYRAZOLOPYRIMIDINE ANALOGS AND THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS
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The present invention relates to Pyrazolopyrimidine Analogs, methods of making Pyrazolopyrimidine Analogs, compositions comprising a Pyrazolopyrimidine Analog, and methods for treating mTOR-related disorders comprising administering to a subject in need thereof an effective amount of a Pyrazolopyrimidine Analog. The invention also relates to treating PI3K-related disorders comprising administering to a subject in need thereof an effective amount of a Pyrazolopyrimidine Analog.
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Page/Page column 83-84
(2008/12/08)
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