- THERAPEUTIC COMPOUNDS AND METHODS OF USE
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The invention relates to compounds and methods of using said compounds, as well as pharmaceutical compositions containing such compounds, for treating diseases and conditions mediated by TEAD, such as cancer.
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Paragraph 0732; 0733; 0734
(2021/05/21)
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- High-selectivity fibroblast growth factor receptor inhibitor and application
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The invention discloses a high-selectivity fibroblast growth factor receptor inhibitor and application, and particularly relates to a compound shown in a formula (I) or a pharmaceutically acceptable salt, a solvate, a geometric isomer, a stereoisomer, a tautomer and any mixture thereof. The compound shown in the formula (I) or the pharmaceutically acceptable salt, the solvate and the pharmaceutical composition thereof can be applied to prevention or treatment of diseases related to FGFR4 activity or overexpression, and can also be combined with other medicines to be used for treating various related diseases, especially for treating various cancers, wherein the cancers may be liver cancer, lung cancer, gastric cancer, breast cancer, ovarian cancer, prostate cancer, renal cell carcinoma, skin cancer, colon cancer, bile duct cancer, glioma or sarcoma.
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Paragraph 0075; 0079-0081
(2021/07/08)
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- Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies
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A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.
- Barlaam, Bernard,Casella, Robert,Cidado, Justin,Cook, Calum,De Savi, Chris,Dishington, Allan,Donald, Craig S.,Drew, Lisa,Ferguson, Andrew D.,Ferguson, Douglas,Glossop, Steve,Grebe, Tyler,Gu, Chungang,Hande, Sudhir,Hawkins, Janet,Hird, Alexander W.,Holmes, Jane,Horstick, James,Jiang, Yun,Lamb, Michelle L.,McGuire, Thomas M.,Moore, Jane E.,O'Connell, Nichole,Pike, Andy,Pike, Kurt G.,Proia, Theresa,Roberts, Bryan,San Martin, Maryann,Sarkar, Ujjal,Shao, Wenlin,Stead, Darren,Sumner, Neil,Thakur, Kumar,Vasbinder, Melissa M.,Varnes, Jeffrey G.,Wang, Jianyan,Wang, Lei,Wu, Dedong,Wu, Liangwei,Yang, Bin,Yao, Tieguang
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supporting information
p. 15564 - 15590
(2021/01/09)
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- Halogen acid salt product of urea compound, and preparation method thereof
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The invention particularly relates to a salt of a urea compound, and a preparation method thereof. According to the method, an organic solvent and water mixed crystallization solvent system is adopted, an free alkali and an acid are paired to form ion pairs, crystallization is conducted, and then heat preservation pulping crystallization is conducted within a certain temperature range to obtain the novel crystal form, wherein the product is high in solubility in water, simple in preparation method, high in yield, stable in property and easy to store, transport and use in the later period. Thepreparation method provided by the invention is good in process reproducibility, simple to operate and suitable for industrial production.
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Paragraph 0033-0034; 0039
(2020/07/06)
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- Novel crystal form product of urea compound, and preparation method thereof
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The invention particularly relates to a novel crystal form of a urea compound, and a preparation method thereof. According to the method, an organic solvent crystallization solvent system is adopted,an free alkali and an acid are paired to form ion pairs, crystallization is conducted, and then heat preservation pulping crystallization is conducted within a certain temperature range to obtain thenovel crystal form, wherein the crystal form product is high in water solubility, simple in preparation method, high in yield, stable in property and easy to store, transport and use in the later period. The preparation method provided by the invention is good in process reproducibility, simple to operate and suitable for industrial production.
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Paragraph 0033-0034; 0039
(2020/07/06)
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- Malate product of urea compound, and preparation method thereof
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The invention particularly relates to a salt of a urea compound, and a preparation method thereof. According to the method, an organic solvent and water mixed crystallization solvent system is adopted, an free alkali and an acid are paired to form ion pairs, crystallization is conducted, and then heat preservation pulping crystallization is conducted within a certain temperature range to the novelcrystal form, wherein the product is high in solubility in water, simple in preparation method, high in yield, stable in property and easy to store, transport and use in the later period. The preparation method provided by the invention is good in process reproducibility, simple to operate and suitable for industrial production.
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Paragraph 0032-0033; 0038
(2020/07/06)
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- A class of intermediates for preparing anticancer drugs
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The invention discloses a raw material for synthesizing an anticancer drug, and a key intermediate for synthesizing an anticancer drug. The invention further discloses a preparation method of an anticancer drug. According to the present invention, the syn
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Paragraph 0057; 0058; 0061
(2019/07/04)
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- COMPOUND FOR SELECTIVELY INHIBITING KINASE AND USE THEREOF
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Provided are a compound of formula (I), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, use thereof as a selective inhibitor for FGFR4 kinase and use thereof in manufacturing a medicament or pharmaceutical composition for treating diseases due to FGFR4 or FGF19. The compound disclosed by the invention has selective and significant inhibitory activities against FGFR4, and has wide application prospect in the field of tumor treatment.
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Paragraph 0068; 0073
(2019/11/14)
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- Chemical Compounds
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Provided are a series of novel pyridine or pyrimidine derivatives which inhibit CDK9 and may be useful for the treatment of hyperproliferative diseases. In particular the compounds are of use in the treatment of proliferative disease such as cancer including hematological malignancies such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt's lymphoma, follicular lymphoma and solid tumors such as breast cancer, lung cancer, neuroblastoma and colon cancer.
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Paragraph 0888
(2017/01/19)
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- Ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors
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The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; a method for manufacturing said compound, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition comprising said compound.
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Paragraph 0583
(2015/05/05)
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- RING-FUSED BICYCLIC PYRIDYL DERIVATIVES AS FGFR4 INHIBITORS
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The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; a method for manufacturing said compound, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition comprising said compound.
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Page/Page column 82; 83
(2015/05/06)
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- NEW SUBSTITUTED BIPHENYL ANALOGUES AS DUAL INHIBITORS OF AROMATASE AND SULFATASE
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Provided are new biphenyl derivatives of formula (Ia). These compounds act as aromatase and sulfatase inhibitors. They are particularly useful for treating pathological conditions or diseases in which aromatase and sulfatase are involved. Moreover, provided are processes for the preparation of these compounds and pharmaceutical compositions containing said products and their use for the preparation of a medicament, in particular for the treatment of diseases characterized by aromatase and sulfatase activity such as hormone-dependent cancers.
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Page/Page column 47
(2015/07/16)
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- Pyridine-3-carboxamide-6-yl-ureas as novel inhibitors of bacterial DNA gyrase: Structure based design, synthesis, SAR and antimicrobial activity
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The development of antibacterial drugs based on novel chemotypes is essential to the future management of serious drug resistant infections. We herein report the design, synthesis and SAR of a novel series of N-ethylurea inhibitors based on a pyridine-3-carboxamide scaffold targeting the ATPase sub-unit of DNA gyrase. Consideration of structural aspects of the GyrB ATPase site has aided the development of this series resulting in derivatives that demonstrate excellent enzyme inhibitory activity coupled to potent Gram positive antibacterial efficacy.
- Yule, Ian A.,Czaplewski, Lloyd G.,Pommier, Stephanie,Davies, David T.,Narramore, Sarah K.,Fishwick, Colin W.G.
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supporting information
p. 31 - 38
(2014/09/17)
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- Synthesis and pharmacological evaluation of 6-aminonicotinic acid analogues as novel GABAA receptor agonists
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A series of 6-aminonicotinic acid analogues have been synthesized and pharmacologically characterized at native and selected recombinant GABA A receptors. 6-Aminonicotinic acid (3) as well as 2- and 4-alkylated analogues (9-11, 14-16) display low to mid-micromolar GABAAR binding affinities to native GABAA receptors (Ki 1.1-24 μM). The tetrahydropyridine analogue of 3 (22) shows low-nanomolar affinity (K i 0.044 μM) and equipotency as an agonist to GABA itself as well as the standard GABAA agonist isoguvacine. Cavities surrounding the core of the GABA binding pocket were predicted by molecular interaction field calculations and docking studies in a α1β 2γ2 GABAA receptor homology model, and were confirmed by affinities of substituted analogues of 3. The tight steric requirements observed for the remarkably few GABAAR agonists reported to date is challenged by our findings. New openings for agonist design are proposed which potentially could facilitate the exploration of different pharmacological profiles within the GABAAR area.
- Petersen, Jette G.,S?rensen, Troels,Damgaard, Maria,Nielsen, Birgitte,Jensen, Anders A.,Balle, Thomas,Bergmann, Rikke,Fr?lund, Bente
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p. 404 - 416
(2014/08/05)
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- HETEROCYCLIC UREA COMPOUNDS
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The present invention provides a compound of the following formula, racemates, enantiomers and salts thereof. Also provided is the use of these compounds as antibacterials, compositions comprising them and processes for their manufacture
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Page/Page column 64; 65
(2013/07/05)
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- AZAARENE DERIVATIVES
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A compound represented by the general formula: wherein X1 represents a nitrogen atom or a group represented by the formula -CR10=; X2 represents a nitrogen atom or a group represented by the formula -CR11=; Y represents an oxygen atom or the like; R1 represents a C1-6 alkoxy group, an optionally substituted C6-10 aryloxy group, a group represented by the formula -NR12aR12b or the like; R2 represents a hydrogen atom, an optionally substituted C1-6 alkyl group, or the like; R3, R4, R5, R6, R7, R8, R10 and R11 each independently represent a hydrogen atom, a halogen atom, an optionally substituted C1-6 alkyl group, or the like; R9 represents a group represented by the formula -NR16aR16b or the like; and R12a, R12b, R16a and R16b each independently represent a hydrogen atom, an optionally substituted C1-6 alkyl group, or the like, a salt thereof, or a hydrate of the foregoing.
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Page/Page column 125
(2008/06/13)
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