- Expanding the scope of native chemical ligation - templated small molecule drug synthesisviabenzanilide formation
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We describe a reaction system that enables the synthesis of Bcr-Abl tyrosine kinase inhibitors (TKI)viabenzanilide formation in water. The reaction is based on native chemical ligation (NCL). In contrast to previous applications, we used the NCL chemistry to establish aromatic rather than aliphatic amide bonds in coupling reactions between benzoyl ando-mercaptoaniline fragments. The method was applied for the synthesis of thiolated ponatinib and GZD824 derivatives. Acid treatment provided benzothiazole structures, which opens opportunities for diversification. Thiolation affected the affinity for Abl1 kinase only moderately. Of note, a ponatinib-derived benzothiazole also showed nanomolar affinity. NCL-enabled benzanilide formation may prove useful for fragment-based drug discovery. To show that benzanilide synthesis can be put under the control of a template, we connected the benzoyl ando-mercaptoaniline fragments to DNA and peptide nucleic acid (PNA) oligomers. Complementary RNA templates enabled adjacent binding of reactive conjugates triggering a rapid benzoyl transfer from a thioester-linked DNA conjugate to ano-mercaptoaniline-DNA or -PNA conjugate. We evaluated the influence of linker length and unpaired spacer nucleotides within the RNA template on the product yield. The data suggest that nucleic acid-templated benzanilide formation could find application in the establishment of DNA-encoded combinatorial libraries (DEL).
- Houska, Richard,Seitz, Oliver,Stutz, Marvin Bj?rn
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p. 13450 - 13457
(2021/10/29)
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- COMPOUNDS USEFUL FOR INHIBITING RAF DIMERS
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The disclosure provides compounds of Formula I (Formula I) (c) And the pharmaceutically acceptable salts thereof. The A, B, C, and D rings and the variables, RA, RB, RC, RD, L0, L1, L2
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- Design, Synthesis, and in vitro Evaluation of P2X7 Antagonists
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The P2X7 receptor is a promising target for the treatment of various diseases due to its significant role in inflammation and immune cell signaling. This work describes the design, synthesis, and in vitro evaluation of a series of novel derivatives bearing diverse scaffolds as potent P2X7 antagonists. Our approach was based on structural modifications of reported (adamantan-1-yl)methylbenzamides able to inhibit the receptor activation. The adamantane moieties and the amide bond were replaced, and the replacements were evaluated by a ligand-based pharmacophore model. The antagonistic potency of the synthesized analogues was assessed by two-electrode voltage clamp experiments, using Xenopus laevis oocytes that express the human P2X7 receptor. SAR studies suggested that the replacement of the adamantane ring by an aryl-cyclohexyl moiety afforded the most potent antagonists against the activation of the P2X7 cation channel, with analogue 2-chloro-N-[1-(3-(nitrooxymethyl)phenyl)cyclohexyl)methyl]benzamide (56) exhibiting the best potency with an IC50 value of 0.39 μΜ.
- Durner, Anna,Koufaki, Maria,Kritsi, Eftichia,Nicke, Annette,Papakostas, Alexios,T. Pournara, Dimitra,Zoumpoulakis, Panagiotis
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p. 2530 - 2543
(2020/10/19)
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- Alkynyl pyrimidine or alkynyl pyridine compound as well as composition and application thereof
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The invention relates to alkynyl pyrimidine or alkynyl pyridine compounds represented by a formula (I) or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof. The invention also discloses a pharmaceutical composition contain
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Paragraph 0119; 0120; 0122
(2020/08/18)
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- NEW COMPOUNDS AND METHODS
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The present invention relates to compounds of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, optical isomer, N-oxide, and/or prodrug thereof. The present invention also relates to pharmaceutical compositions comprising the compounds of the invention, and to their use in the treatment or prevention of medical conditions in which inhibition of c-ABL is beneficial. (I)
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Page/Page column 56-57
(2021/01/23)
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- Ppm Pd-catalyzed, Cu-free Sonogashira couplings in water using commercially available catalyst precursors
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A new catalyst that derives from commercially available precursors for copper-free, Pd-catalyzed Sonogashira reactions at the sustainable ppm level of precious metal palladium under mild aqueous micellar conditions has been developed. Both the palladium pre-catalyst and ligand are commercially available, bench stable, and highly cost-effective. The catalyst is applicable to both aryl- and heteroaryl-bromides as educts. A wide range of functional groups are tolerated and the aqueous reaction medium can be recycled. An application to a key intermediate associated with an active pharmaceutical ingredient (ponatinib) is discussed.
- Jin, Bo,Gallou, Fabrice,Reilly, John,Lipshutz, Bruce H.
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p. 3481 - 3485
(2019/03/28)
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- Sonogashira Couplings Catalyzed by Fe Nanoparticles Containing ppm Levels of Reusable Pd, under Mild Aqueous Micellar Conditions
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Nanoparticles derived from FeCl3 containing the ligand XPhos and only 500 ppm Pd effect Sonogashira couplings in water between rt and 45 °C. The entire aqueous reaction medium can be easily recycled using an "in-flask" extraction. Several tande
- Handa, Sachin,Jin, Bo,Bora, Pranjal P.,Wang, Ye,Zhang, Xiaohua,Gallou, Fabrice,Reilly, John,Lipshutz, Bruce H.
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p. 2423 - 2431
(2019/03/08)
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- Design, Synthesis, and Biological Evaluation of 3-(Imidazo[1,2- a]pyrazin-3-ylethynyl)-4-isopropyl- N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide as a Dual Inhibitor of Discoidin Domain Receptors 1 and 2
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Discoidin-domain receptors 1 and 2 (DDR1 and DDR2) are new potential targets for anti-inflammatory-drug discovery. A series of heterocycloalkynylbenzimides were designed and optimized to coinhibit DDR1 and DDR2. One of the most promising compounds, 5n, ti
- Wang, Zhen,Zhang, Yali,Pinkas, Daniel M.,Fox, Alice E.,Luo, Jinfeng,Huang, Huocong,Cui, Shengyang,Xiang, Qiuping,Xu, Tingting,Xun, Qiuju,Zhu, Dongsheng,Tu, Zhengchao,Ren, Xiaomei,Brekken, Rolf A.,Bullock, Alex N.,Liang, Guang,Ding, Ke,Lu, Xiaoyun
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p. 7977 - 7990
(2018/09/06)
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- 3-ACETYLENYL-PYRAZOLE-PYRIMIDINE DERIVATIVE, AND PREPARATION METHOD THEREFOR AND USES THEREOF
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The present invention relates to the field of chemical and medicine, more particularly, 3-ethynylpyrazolopyrimidine derivatives and their preparation methods and uses. The invention provides a 3-ethynylpyrazolopyrimidine derivative, and the structure is shown in formula I. The present invention also provides preparation methods and use of 3-ethynylpyrazolopyrimidine derivatives, comprising the compounds and derivatives, and their pharmaceutical compositions for the use of the treatment and prevention of tumors.
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- Novel imidazo[1,2-b]diazine amide type Bcr-Abl kinase inhibitors and preparing method and applications thereof
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Novel imidazo[1,2-b]diazine amide type Bcr-Abl kinase inhibitors and a preparing method and applications thereof are disclosed. The general structure formula of the inhibitors is shown as a formula I. The invention also provides pharmaceutically acceptable salts and compositions including compounds of the formula I, and methods of utilizing the salts and the compositions to prepare medicines preventing and/or treating protein kinase abnormity related diseases, particularly medicines for diseases related to Bcr-Abl protein kinase activity abnormity.
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Paragraph 0048; 0049
(2017/12/09)
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- Synthesis and identification of GZD856 as an orally bioavailable Bcr-AblT315I inhibitor overcoming acquired imatinib resistance
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Bcr-AblT315I induced drug resistance remains a major challenge to chronic myelogenous leukemia (CML) treatment. Herein, we reported GZD856 as a novel orally bioavailable Bcr-AblT315I inhibitor, which strongly suppressed the kinase activities of both native Bcr-Abl and the T315I mutant with IC50 values of 19.9 and 15.4 nM, and potently inhibited proliferation of corresponding K562, Ba/F3WT and Ba/F3T315I cells with IC50 values of 2.2, 0.64 and 10.8 nM. Furthermore, GZD856 potently suppressed tumor growth in mouse bearing xenograft K562 and Ba/F3 cells expressing Bcr-AblT315I. Thus, GZD856 may serve as a promising lead for the development of Bcr-Abl inhibitors overcoming acquired imatinib resistance.
- Lu, Xiaoyun,Zhang, Zhang,Ren, Xiaomei,Wang, Deping,Ding, Ke
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p. 331 - 336
(2017/11/10)
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- PROCESSES FOR MAKING PONATINIB AND INTERMEDIATES THEREOF
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Novel synthetic approaches to make 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide, intermediates and pharmaceutically acceptable salts thereof are provided.
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Paragraph 0074; 0097
(2014/12/09)
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- Discovery and optimization of 3-(2-(Pyrazolo[1,5- a ]pyrimidin-6-yl) ethynyl)benzamides as novel selective and orally bioavailable discoidin domain receptor 1 (DDR1) inhibitors
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Discoidin domain receptor 1 (DDR1) is an emerging potential molecular target for new anticancer drug discovery. We have discovered a series of 3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl) ethynyl)benzamides that are selective and orally bioavailable DDR1 inhibitors. The two most promising compounds (7rh and 7rj) inhibited the enzymatic activity of DDR1, with IC50 values of 6.8 and 7.0 nM, respectively, but were significantly less potent in suppressing the kinase activities of DDR2, Bcr-Abl, and c-Kit. Further study revealed that 7rh bound with DDR1 with a Kd value of 0.6 nM, while it was significantly less potent to the other 455 kinases tested. The S(35) and S(10) selectivity scores of 7rh were 0.035 and 0.008, respectively. The compounds also potently inhibited the proliferation of cancer cells expressing high levels of DDR1 and strongly suppressed cancer cell invasion, adhesion, and tumorigenicity. Preliminary pharmacokinetic studies suggested that they possessed good PK profiles, with oral bioavailabilities of 67.4% and 56.2%, respectively.
- Gao, Mingshan,Duan, Lei,Luo, Jinfeng,Zhang, Lianwen,Lu, Xiaoyun,Zhang, Yan,Zhang, Zhang,Tu, Zhengchao,Xu, Yong,Ren, Xiaomei,Ding, Ke
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p. 3281 - 3295
(2013/06/04)
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- DIARYLACETYLENE HYDRAZIDE CONTAINING TYROSINE KINASE INHIBITORS
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The present invention relates to novel diarylacetylene hydrazide compounds of formula (I) or pharmaceutically acceptable salt thereof, as tyrosine kinase inhibitors, the process for their preparation, and to the use of the compounds of formula (I) in the preparation of pharmaceutical compositions for the therapeutic treatment of disorders related to tyrosine kinases, in warm blooded animals.
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Page/Page column 40-41
(2012/08/07)
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- NEW CHEMICAL COMPOUNDS
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The present invention encompasses compounds of general formula (1) wherein the groups R2 to R4, L, Q and n are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and their use for preparing a pharmaceutical composition with the above-mentioned properties.
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Page/Page column 30-31
(2009/03/07)
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