- PYRROLO [2, 3-B] PYRIDINES OR PYRROLO [2, 3-B] PYRAZINES AS HPK1 INHIBITOR AND THE USE THEREOF
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Disclosed herein is a compound of Formula (AIII) or (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising thereof. Also disclosed is a method of treating HPK1 related disorders or diseases by using the compound disclosed herein.
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Paragraph 0401; 0898-0900
(2020/01/08)
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- TRIAZINE COMPOUNDS AS PI3 KINASE AND MTOR INHIBITORS
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Compounds of formula I wherein: R1 is and R2, R4, and R6-9 are defined herein, and pharmaceutically acceptable salts and esters thereof. These compounds inhibit PI3 kinase and mTOR, and may be used to treat diseases mediated by PI3 kinase and mTOR, such as a variety of cancers. Methods for making and using the compounds of this invention are disclosed. Various compositions containing the compounds of this invention are also disclosed.
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Paragraph 1776-1777
(2017/05/19)
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- Discovery of AZD3147: A potent, selective dual inhibitor of mTORC1 and mTORC2
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High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identifying compounds with improved cellular potency, improved aqueous solubility, and good stability in human hepatocyte incubations. Knowledge from empirical SAR investigations was combined with an understanding of the molecular interactions in the crystal lattice to improve both cellular potency and solubility, and the composite parameters of LLE and pIC50-pSolubility were used to assess compound quality and progress. Predictive models were employed to efficiently mine the attractive chemical space identified resulting in the discovery of 42 (AZD3147), an extremely potent and selective dual inhibitor of mTORC1 and mTORC2 with physicochemical and pharmacokinetic properties suitable for development as a potential clinical candidate.
- Pike, Kurt G.,Morris, Jeff,Ruston, Linette,Pass, Sarah L.,Greenwood, Ryan,Williams, Emma J.,Demeritt, Julie,Culshaw, Janet D.,Gill, Kristy,Pass, Martin,Finlay, M. Raymond V.,Good, Catherine J.,Roberts, Craig A.,Currie, Gordon S.,Blades, Kevin,Eden, Jonathan M.,Pearson, Stuart E.
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p. 2326 - 2349
(2015/03/30)
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- QUINAZOLINES AND AZAQUINAZOLINES AS DUAL INHIBITORS OF RAS/RAF/MEK/ERK AND PI3K/AKT/PTEN/MTOR PATHWAYS
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The present application provides novel quinazolines and azaquinazolines and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful in for co-regulating RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways by administering a therapeutically effective amount of one or more of the compounds of formula (I), wherein X, Y, T and R4, and R6 to R8' are defined herein, to a patient. By doing so, these compounds are effective in treating conditions associated with the dysregulation of the RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways. A variety of conditions can be treated using these compounds and include diseases which are characterized by abnormal cellular proliferation. In one embodiment/ the disease is cancer.
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- 5,6,7,8-TETRAHYDROPYRIDO[3,4-D]PYRIMIDINE COMPOUNDS, THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESES
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A compound of the Formula I: 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 48
(2010/11/04)
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- 5, 6, 7, 8-TETRAHYDROPYRIDO[4,3-D]PYRIMIDINE COMPOUNDS, THEIR USE AS MTOR, PI3, AND HSMG-1 KINASE INHIBITORS, AND THEIR SYNTHESES
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A compound of the Formula I: 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 43
(2010/11/04)
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- PYRROLO[3,2-d]PYRIMIDINE COMPOUNDS AND THEIR USE AS PI3 KINASE AND mTOR KINASE INHIBITORS
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A pyrrolo[3,2-d]pyrimidine compound, such as a compound of the formula (I): 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
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Page/Page column 26
(2009/06/27)
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- ATP-competitive inhibitors of the mammalian target of rapamycin: Design and synthesis of highly potent and selective pyrazolopyrimidines
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The mammalian target of rapamycin (mTOR), a central regulator of growth, survival, and metabolism, is a validated target for cancer therapy. Rapamycin and its analogues, allosteric inhibitors of mTOR, only partially inhibit one mTOR protein complex. ATP-competitive, global inhibitors of mTOR that have the potential for enhanced anticancer efficacy are described. Structural features leading to potency and selectivity were identified and refined leading to compounds with in vivo efficacy in tumor xenograft models.
- Zask, Arie,Verheijen, Jeroen C.,Curran, Kevin,Kaplan, Joshua,Richard, David J.,Nowak, Pawel,Malwitz, David J.,Brooijmans, Natasja,Bard, Joel,Svenson, Kristine,Lucas, Judy,Toral-Barza, Lourdes,Zhang, Wei-Guo,Hollander, Irwin,Gibbons, James J.,Abraham, Robert T.,Ayral-Kaloustian, Semiramis,Mansour, Tarek S.,Yu, Ker
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supporting information; experimental part
p. 5013 - 5016
(2010/03/04)
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- Discovery of 4-morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as highly potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): Optimization of the 6-aryl substituent
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Design and synthesis of a series of 4-morpholino-6-aryl-1H-pyrazolo[3,4-d] pyrimidines as potent and selective inhibitors of the mammalian target of rapamycin (mTOR) are described. Optimization of the 6-aryl substituent led to the discovery of inhibitors carrying 6-ureidophenyl groups, the first reported active site inhibitors of mTOR with subnanomolar inhibitory concentrations. The data presented in this paper show that 6-arylureidophenyl substituents led to potent mixed inhibitors of mTOR and phosphatidylinositol 3-kinase α (PI3K-α), whereas 6-alkylureidophenyl appendages gave highly selective mTOR inhibitors. Combination of 6-alkylureidophenyl groups with 1-carbamoylpiperidine substitution resulted in compounds with subnanomolar IC50 against mTOR and greater than 1000-fold selectivity over PI3K-α. In addition, structure based drug design resulted in the preparation of several 6-arylureidophenyl-1H-pyrazolo[3,4-d]pyrimidines, substituted in the 4-position of the arylureido moiety with water solubilizing groups. These compounds combined potent mTOR inhibition (IC50501 nM). 2009 American Chemical Society.
- Verheijen, Jeroen C.,Richard, David J.,Curran, Kevin,Kaplan, Joshua,Lefever, Mark,Nowak, Pawel,Malwitz, David J.,Brooijmans, Natasja,Toral-Barza, Lourdes,Zhang, Wei-Guo,Lucas, Judy,Hollander, Irwin,Ayral-Kaloustian, Semiramis,Mansour, Tarek S.,Yu, Ker,Zask, Arie
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experimental part
p. 8010 - 8024
(2010/07/04)
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