- RET INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
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Provided herein are a RET inhibitor, a pharmaceutical composition thereof and uses thereof. In particular, provided is a compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof. Provided is a pharmaceutical composition comprising the compound, and uses of the compound and pharmaceutical composition thereof for the preparation of a medicament, in particular for treatment and prevention of RET-related diseases and conditions, including cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.
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Paragraph 00230; 00343
(2020/07/05)
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- A copper (II) (II) composite chlorinating agent and copper-based composite chlorinating agent synthesis of 1-chloro-2-aryl acetylene method
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The invention discloses a copper (II) composite chlorinating agent and a method for synthesizing 1-chlorine-2-aryl acetylene based on the copper (II) composite chlorinating agent. The structural formula of the copper (II) composite chlorinating agent is CuCl2.xNaCl.yAl2O3. The chlorinating agent is applicable to chlorination of various substituted aryl acetylene substrates, and is high in universality; the chlorinating agent can directly carry out chlorination reaction on aryl acetylene so as to obtain a 1-chlorine-2-aryl acetylene product; the method is mild in reaction condition, 1-chlorine-2-aryl acetylene can be synthesized with high yield and high selectivity, and the production cost of the 1-chlorine-2-aryl acetylene derivative is greatly lowered.
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Paragraph 0023; 0132; 0133
(2016/11/24)
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- Synthesis and biological evaluation of GPR40/FFAR1 agonists containing 3,5-dimethylisoxazole
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GPR40 is an attractive target due to its glucose-stimulated insulin secretion effect with low risk of causing hypoglycemia, which also can be seen from the clinical studies using TAK-875 (fasiglifam). In the present studies, we discovered a series of anal
- Yang, Lingyun,Zhang, Jian,Si, Lianghui,Han, Li,Zhang, Bo,Ma, Hui,Xing, Junhao,Zhao, Leilei,Zhou, Jinpei,Zhang, Huibin
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- A structure-activity relationship of non-peptide macrocyclic histone deacetylase inhibitors and their anti-proliferative and anti-inflammatory activities
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Inhibition of the enzymatic activity of histone deacetylase (HDAC) is a promising therapeutic strategy for cancer treatment and several distinct small molecule histone deacetylase inhibitors (HDACi) have been reported. We have previously identified a new class of non-peptide macrocyclic HDACi derived from 14- and 15-membered macrolide skeletons. In these HDACi, the macrocyclic ring is linked to the zinc chelating hydroxamate moiety through a para-substituted aryl-triazole cap group. To further delineate the depth of the SAR of this class of HDACi, we have synthesized series of analogous compounds and investigated the influence of various substitution patterns on their HDAC inhibitory, anti-proliferative and anti-inflammatory activities. We identified compounds 25b and 38f with robust anti-proliferative activities and compound 26f (IC50 47.2 nM) with superior anti-inflammatory (IC50 88 nM) activity relative to SAHA.
- Tapadar, Subhasish,Fathi, Shaghayegh,Raji, Idris,Omesiete, Wilson,Kornacki, James R.,Mwakwari, Sandra C.,Miyata, Masanori,Mitsutake, Kazunori,Li, Jian-Dong,Mrksich, Milan,Oyelere, Adegboyega K.
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p. 7543 - 7564
(2015/12/18)
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- A one-pot allylation-hydrostannation sequence with recycling of the intermediate tin waste
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A one-pot allylation and hydrostannation of alkynals where the tin byproduct formed in the first step of the reaction is recycled and used in the second step of the sequence is presented. Specifically, a BF3· OEt2-promoted allylstannation of the aldehyde moiety in the alkynal is followed by the introduction of polymethylhydrosiloxane (PMHS) and catalytic B(C6F5)3, which convert the tin byproduct of the allylation into Bu3SnH, which then hydrostannates the alkyne in the molecule. 119Sn and 11B NMR data suggest an organotin fluoride species is formed during the allylation step and involved in the tin recycling step.
- Ghosh, Banibrata,Amado-Sierra, Maria Del Rosario I.,Holmes, Daniel,Maleczka, Robert E.
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supporting information
p. 2318 - 2321
(2014/05/20)
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- Pin-point chemical modification of RNA with diverse molecules through the functionality transfer reaction and the copper-catalyzed azide-alkyne cycloaddition reaction
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The internal modification of RNA has been successfully achieved by the functionality transfer reaction (FTR) and following click chemistry with diverse azide compounds. The benefits of the FTR have been demonstrated by its specificity, rapidity, broad applicability, and procedure simplicity.
- Onizuka, Kazumitsu,Shibata, Atsushi,Taniguchi, Yosuke,Sasaki, Shigeki
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p. 5004 - 5006
(2011/06/10)
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- Triazole bridges as versatile linkers in electron donor-acceptor conjugates
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Aromatic triazoles have been frequently used as π-conjugated linkers in intramolecular electron transfer processes. To gain a deeper understanding of the electron-mediating function of triazoles, we have synthesized a family of new triazole-based electron donor-acceptor conjugates. We have connected zinc(II)porphyrins and fullerenes through a central triazole moiety-(ZnP-Tri-C60)-each with a single change in their connection through the linker. An extensive photophysical and computational investigation reveals that the electron transfer dynamics-charge separation and charge recombination-in the different ZnP-Tri-C60 conjugates reflect a significant influence of the connectivity at the triazole linker. Except for the m4m-ZnP-Tri-C6017, the conjugates exhibit through-bond photoinduced electron transfer with varying rate constants. Since the through-bond distance is nearly the same for all the synthesized ZnP-Tri-C60 conjugates, the variation in charge separation and charge recombination dynamics is mainly associated with the electronic properties of the conjugates, including orbital energies, electron affinity, and the energies of the excited states. The changes of the electronic couplings are, in turn, a consequence of the different connectivity patterns at the triazole moieties.
- De Miguel, Gustavo,Wielopolski, Mateusz,Schuster, David I.,Fazio, Michael A.,Lee, Olivia P.,Haley, Christopher K.,Ortiz, Angy L.,Echegoyen, Luis,Clark, Timothy,Guldi, Dirk M.
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experimental part
p. 13036 - 13054
(2011/10/07)
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- Chiral donor photoinduced-electron-transfer (d-PET) boronic acid chemosensors for the selective recognition of tartaric acids, disaccharides, and ginsenosides
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A modular approach was proposed for the preparation of chiral fluorescent molecular sensors, in which the fluorophore, scaffold, and chirogenic center can be connected by ethynyl groups, and these modules can easily be changed to other structures to optim
- Wu, Yubo,Guo, Huimin,Zhang, Xin,James, Tony D.,Zhao, Jianzhang
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experimental part
p. 7632 - 7644
(2011/08/05)
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- Self-association and electron transfer in donor-acceptor dyads connected by meta-substituted oligomers
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The synthesis of a new series of electron donor-acceptor conjugates (5, 10, 13, and 16) in which the electron acceptor - C60 - and the electron donor - π-extended tetrathiafulvalene (exTTF) - are bridged by means of m-phenyleneethynylene spacer
- Molina-Ontoria, Agustin,Fernandez, Gustavo,Wielopolski, Mateusz,Atienza, Carmen,Sanchez, Luis,Gouloumis, Andreas,Clark, Timothy,Martin, Nazario,Guldi, Dirk M.
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scheme or table
p. 12218 - 12229
(2010/01/30)
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- Chelation of charged and uncharged molecules with porphyrin-based compounds
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Porphyrins containing one or more neutral or negatively-charged, closo- or nido-carborane substituents are useful as chelators. The carbon-carbon bonds linking the boron-containing groups to the porphyrin ring make the compounds highly resistant to hydrolysis. These compounds have potential for use in selective binding to specific ligands. These compounds are highly stable, soluble in water and organic solvents, and have low toxicity.
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- Treating and preventing viral infections with porphyrin-based compounds
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Porphyrins containing one or more negatively-charged, amphiphilic nido-carborane substituents have antiviral or virucidal activity. The most active compounds tested to date are negatively charged, amphiphilic, and water-soluble. The negative charges lie primarily in the boron clusters. The carbon-carbon bonds linking the boron-containing groups to the porphyrin ring make the compounds highly resistant to hydrolysis. These compounds have strong potential for use as antiviral and virucidal drugs, as they are highly stable, water-soluble, negatively-charged, amphiphilic, and have low toxicity to normal mammalian cells. Preliminary tests in vitro have shown high activity against HIV.
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- Porphyron based neuton capture agents for cancer therapy
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The invention describes the synthesis of a panel of novel carbon-carbon linked carboranyl-containng 5,10,15,20-tetraphenylporphyrins bearing 25-44% boron by weight. Preliminary in vitro evaluation of several of these compounds, using both rat and human br
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- Green-emitting PPE-PPV hybrid polymers: Efficient energy transfer across the m-phenylene bridge
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Novel π-conjugated polymers (7) consisting of both poly(phenylenevinylene) (PPV) and poly(phenyleneethynylene) (PPE) blocks are synthesized by using a combination of Heck-type coupling and Horner-Wadsworth-Emmons condensation reactions. These polymers hav
- Chu, Qinghui,Pang, Yi,Ding, Liming,Karasz, Frank E.
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p. 3848 - 3853
(2007/10/03)
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- Synthesis of meso-substituted porphyrins carrying carboranes and oligo(ethylene glycol) units for potential applications in boron neutron capture therapy
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Selective delivery of 10B to tumours is one of the major remaining problems in boron neutron capture therapy (BNCT) of cancer. Porphyrins are selectively accumulated in tumours. Thus two series of carborane-carrying porphyrins were constructed, with additional functionality for attachment of uncharged potentially water-solubilising polyethers 3-(1,2-Dicarbaclosododecaboran(12)-1-ylmethoxy)benzaldehyde was prepared by protection of the aldehyde of 3-(prop-2-ynyloxy)benzaldehyde as a dithioacetal, treatment with decaborane(14) and deprotection. Condensation with a 3-nitrophenyldipyrromethane gave a separable mixture of meso-(3-nitrophenyl)-meso-(3-carboranylmethoxyphenyl)porphyrins, resulting from extensive scrambling at the porphyrinogen stage. Similarly, condensation of 3-(1,2-dicarbaclosododecaboran(12)-1-yl)benzaldehyde with this dipyrromethane gave an analogous mixture of meso-(3-nitrophenyl)-meso-(3-carboranylpheneyl)porphyrins. In this second series, the two regioisomeric bis(nitrophenyl)bis(carboranylphenyl)porphyrins could only be distinguished by X-ray crystallography, their NMR spectra being identical. The nitro groups of the mono(nitrophenyl)porphyrins and the bis(nitrophenyl)-porphyrins were reduced to the corresponding amines with tin(II) chloride and the monoamines were coupled with a ω-methoxy poly(ethylene glycol) chloroformate of mean MW 600 to give the MeOPEGylated tricarboranyl porphyrins.
- Frixa, Christophe,Mahon, Mary F.,Thompson, Andrew S.,Threadgill, Michael D.
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p. 306 - 317
(2007/10/03)
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- Cross-coupling of aryl iodides with paramagnetic terminal acetylenes derived from 4,4,5,5-tetramethyl-2-imidazoline-2-oxyl 3-oxide
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2-(Arylylethynylphenyl)-4,4,5,5-tetramethyl-2-imidazoline-1-oxyl 3-oxides 12 and 13 were synthesized by cross-coupling of aryl iodides with 1-alkynes containing the 4,4,5,5-tetramethyl-2-imidazoline-1-oxyl 3-oxide fragment. A procedure was developed for the preparation of 3-and 4-ethynyibenzaldehydes with the use of 2-methylbut-3-yn-2-ol.
- Klyatskaya, S. V.,Tretyakov, E. V.,Vasilevsky, S. F.
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p. 128 - 134
(2007/10/03)
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- Syntheses of carbon-carbon linked carboranylated porphyrins for boron neutron capture therapy of cancer
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Total syntheses of six carboranyl-containing porphyrins bearing 33-44% boron by weight for potential application in boron neutron capture therapy of tumors, are described; these novel compounds feature carbon-carbon linkages between the carboranyl groups
- Vicente, M. Gra?a H.,Shetty, Shankar J.,Wickramasinghe, Anura,Smith, Kevin M.
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p. 7623 - 7627
(2007/10/03)
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- Trans-substituted porphyrin building blocks bearing iodo and ethynyl groups for applications in bioorganic and materials chemistry
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The modular synthesis of linear or cyclic multiporphyrin arrays relies on the availability of trans-substituted porphyrin building blocks with high solubility in organic solvents. Eleven porphyrin building blocks were synthesized bearing iodo, ethynyl, an
- Ravikanth,Strachan, Jon-Paul,Li, Feirong,Lindsey, Jonathan S.
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p. 7721 - 7734
(2007/10/03)
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- Process for the preparation of ethynylbenzaldehydes
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A multi-step process for the preparation of ethynylbenzaldehydes from bromo- or iodobenzaldehydes is disclosed. The arylhalogen is replaced with a protected ethynyl compound which is subsequently cleaved by base to form the arylacetylene. The aldehydic functionality is preserved by formation of a corresponding Schiff's base or acetal, and its subsequent regeneration by treatment with aqueous acid.
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- Process for preparing ethynylated benzoic acid derivatives
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A novel ethynylation process is disclosed which provides an expanded series of novel ethylnyl-terminated aromatic compounds having base sensitive substituents and which facilitates the economic preparation of prior art ethynyl-substituted aromatic compounds.
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- Facile Synthesis of Ethynylated Benzoic Acid Derivatives and Aromatic Compounds via Ethynyltrimethylsilane
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The coupling reaction between an aromatic halide and ethynyltrimethylsilane under the catalysis of palladium(0) generated in situ, followed by treatment of the (trimethylsilyl)ethynyl product with potassium carbonate in methanol at ambient temperatures, provides a simple approach to various ethynylated benzoic acid derivatives and other aromatic compounds.The conditions for the removal of the trimethylsilyl group were very mild, so that base-sensitive functionalities on the aromatic moiety could be tolerated.
- Austin, William B.,Bilow, Norman,Kelleghan, William J.,Lau, Kreisler S. Y.
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p. 2280 - 2286
(2007/10/02)
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