cas 4489-34-3, 4,6-Dichloro-2-(methylsulfonyl)pyrimidine

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An analysis of structural and spectroscopic signatures, the reactivity study of synthetized 4,6-dichloro-2-(methylsulfonyl)pyrimidine: A potential third-order nonlinear optical material
In this work the 4,6-dichloro-2-(methylsulfonyl)pyrimidine (DCMSP) has been synthesized from 4,6-dichloro-2-(methylthio)pyrimidine, its molecular and electronic structure was authenticated by detailed spectroscopic signature studies (via SCXRD, FT-Raman, FT-IR and (1H & 13C) NMR), Hirshfeld surface analysis and DFT calculations. The solid-state crystal structure of DCMSP corroborated by the single crystal X-ray diffraction studies, features C[sbnd]H?O and π···π interactions. Quantum chemical calculations of DCMSP have been performed at DFT/B3LYP/6-311++G (d,p) level of theory. The detailed assignment of each the vibrational mode was done on the basis of potential energy distribution (PED) by using the VEDA4 program and these results have been correlated with the experimental data. We calculated the linear and nonlinear optical properties of the title compound to understand the linear and nonlinear optical behavior in both static and dynamic fields using an iterative electrostatic embedding scheme and density functional theory (DFT) methods with standard and long-range corrected functionals. We also performed a study of the linear refractive index and nonlinear optical susceptibility χ(3) of the crystal as a function of frequency. An estimate of linear and nonlinear macroscopic quantities confirms their suitability for nonlinear optical devices such as optical limiting and optical switching. Investigation of local and global reactivity parameters of DCMSP was carried out by the calculation of molecular electrostatic potential (MEP), average local ionization energies (ALIE) surfaces and atomic Fukui indices in the gas phase. Stability in water and sensitivity towards autoxidation process has been investigated by radial distribution function (RDF) and bond dissociation energies (BDE) calculation after molecular dynamic simulations.
Murthy, P. Krishna,Valverde, Clodoaldo,Suneetha,Armakovi?, Stevan,Armakovi?, Sanja J.,Rani, N. Usha,Naidu, N. Venkatasubba
p. 263 - 275
(2019)
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Phenotypic Identification of a Novel Autophagy Inhibitor Chemotype Targeting Lipid Kinase VPS34
Autophagy is a critical regulator of cellular homeostasis and metabolism. Interference with this process is considered a new approach for the treatment of disease, in particular cancer and neurological disorders. Therefore, novel small-molecule autophagy modulators are in high demand. We describe the discovery of autophinib, a potent autophagy inhibitor with a novel chemotype. Autophinib was identified by means of a phenotypic assay monitoring the formation of autophagy-induced puncta, indicating accumulation of the lipidated cytosolic protein LC3 on the autophagosomal membrane. Target identification and validation revealed that autophinib inhibits autophagy induced by starvation or rapamycin by targeting the lipid kinase VPS34.
Robke, Lucas,Laraia, Luca,Carnero Corrales, Marjorie A.,Konstantinidis, Georgios,Muroi, Makoto,Richters, André,Winzker, Michael,Engbring, Tobias,Tomassi, Stefano,Watanabe, Nobumoto,Osada, Hiroyuki,Rauh, Daniel,Waldmann, Herbert,Wu, Yao-Wen,Engel, Julian
p. 8153 - 8157
(2017)
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PIKFYVE KINASE INHIBITORS
The present invention relates to compounds useful as inhibitors of phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) as well as their use for treating diseases and disorders associated with PIKfyve.
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Page/Page column 140-141

(2021/08/20)

TREATMENT OF VIRAL INFECTIONS WITH COMBINATION OF PIKFYVE KINASE INHIBITORS AND TMPRSS-2 INHIBITORS
The present invention relates to methods of treating viral infections including COVID-19 and compositions with a combination of (i) an inhibitor of phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) and (ii) an inhibitor of transmembrane serine proteinase 2 (TMPRSS-2).
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Paragraph 0176-0179

(2021/11/05)

SUBSTITUTED AMINO TRIAZOLOPYRIMIDINE AND AMINO TRIAZOLOPYRAZINE ADENOSINE RECEPTOR ANTAGONISTS, PHARMACEUTICAL COMPOSITIONS AND THEIR USE
In its many embodiments, the present invention provides certain substituted amino triazolopyrimidine and amino triazolopyrazine compounds of Formula (IA) and Formula (IB): and, and pharmaceutically acceptable salts thereof, wherein, R1, n, R2, and R3 are as defined herein, pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other therapeutically active agents), and methods for their preparation and use, alone and in combination with other therapeutic agents, as antagonists of A2a and/or A2b receptors, and their use in the treatment of a variety of diseases, conditions, or disorders that are mediated, at least in part, by the adenosine A2a receptor and/or the adenosine A2b receptor.
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Page/Page column 58; 69-70

(2020/06/10)

A modular approach for the installation of functionalized phosphonates to heterocycles
Phosphonic acids and esters are pervasive throughout the discovery sciences, from medicine and agriculture, to materials and asymmetric synthesis. The ability to install and construct molecular architecture containing phosphonic functionality has led to t
Shultz, Zachary,Shan, Chuan,Wojtas, Lukasz,Lopchuk, Justin M.
p. 73 - 96
(2021/04/09)

PIKFYVE KINASE INHIBITORS
The present invention relates to compounds of formula (I) (shown below) useful as inhibitors of phosphatidylinositol- 3 -phosphate 5-kinase (PIKfyve) as well as their use for treating diseases and disorders associated with PIKfyve.
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Page/Page column 42; 43

(2019/03/17)

PYRIMIDINE DERIVATIVES AS TROPOMYOSIN RECEPTOR KINASE A (TRKA) INHIBITORS
The present invention relates to novel TrkA inhibitors ofofmrula (1) which are useful in the treatment or prevention of acute and chronic pain but also for other abnormal activities of TrkA beyond pain therapy, such as inflammation and cancer.
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Page/Page column 21-22

(2019/06/11)

Switchable Synthesis of Aryl Sulfones and Sulfoxides through Solvent-Promoted Oxidation of Sulfides with O2/Air
A practical and switchable method for the synthesis of aryl sulfones and sulfoxides via sulfide oxidation was developed. The chemoselectivities of products were simply controlled by reaction temperature using O2/air as the terminal oxidant and oxygen source. The broad substrate scope, easy realization of gram-scale production, and the simplification of a sulfide oxidation system render the strategy attractive and valuable.
Cheng, Zhen,Sun, Pengchao,Tang, Ailing,Jin, Weiwei,Liu, Chenjiang
supporting information
p. 8925 - 8929
(2019/11/14)

From Cancer to Pain Target by Automated Selectivity Inversion of a Clinical Candidate
Elimination of inadvertent binding is crucial for inhibitor design targeting conserved protein classes like kinases. Compounds in clinical trials provide a rich source for initiating drug design efforts by exploiting such secondary binding events. Considering both aspects, we shifted the selectivity of tozasertib, originally developed against AurA as cancer target, toward the pain target TrkA. First, selectivity-determining features in binding pockets were identified by fusing interaction grids of several key and off-target conformations. A focused library was subsequently created and prioritized using a multiobjective selection scheme that filters for selective and highly active compounds based on orthogonal methods grounded in computational chemistry and machine learning. Eighteen high-ranking compounds were synthesized and experimentally tested. The top-ranked compound has 10000-fold improved selectivity versus AurA, nanomolar cellular activity, and is highly selective in a kinase panel. This was achieved in a single round of automated in silico optimization, highlighting the power of recent advances in computer-aided drug design to automate design and selection processes.
Turk, Samo,Merget, Benjamin,Eid, Sameh,Fulle, Simone
p. 4851 - 4859
(2018/05/23)

Convenient synthesis of 2-(methylsulfonyl)pyrimidine derivatives
An efficient and convenient approach for the preparation of functionalized 2-(methylsulfonyl)pyrimidine derivatives has been developed through cyclic condensation of malonate derivatives with S-methylisothiouronium sulfate followed by derivation and oxidation in water–acetone mixture using oxone as the oxidant. This synthetic strategy provides an efficient and environmentally friendly approach for easy access to 2-(methylsulfonyl)pyrimidine derivatives with considerable yields.
Huang, Tong-Hui,Zhou, Shan-Shan,Wu, Xin,An, Lin,Yin, Xiao-Xing
supporting information
p. 714 - 720
(2018/02/16)

Oxidative kinetic resolution of heterocyclic sulfoxides with a porphyrin-inspired manganese complex by hydrogen peroxide
We have successfully reported here the low loading porphyrin-inspired high-valent manganese (IV)-oxo complex was applied in oxidative kinetic resolution (OKR) of racemic heterocyclic sulfoxides using the environmentally benign hydrogen peroxide for the first time. This approach allows for rapid OKR (0.5 h) of a variety of racemic sulfoxides (including pyridine, pyrimidine, pyrazine, thiazole, benzothiazole, thiophene) in excellent enantioselectivity (up to > 99% ee), simultaneously generating the corresponding sulfones in high yield (up to 80%). The catalytic system also showed an unexceptionable chemoselectivity for the sulfoxide substrates with hydroxyl groups in which only the sulfoxide group was oxidized. The practical utility of the method has been demonstrated in the OKR of gram-scale sulfoxides.
Yang, Jinchuang,Wang, Lianyue,Lv, Ying,Li, Ning,An, Yue,Gao, Shuang
supporting information
p. 156 - 159
(2017/12/15)

A synthetic method for 2-ethoxy-4,6-dichloropyrimidine
A synthetic method for 2-ethoxy-4,6-dichloropyrimidine is disclosed. 4,6-dichloro-2-methylthio-pyrimidine is adopted as a raw material and subjected to an oxidation reaction to obtain 2-methylsulfonyl-4,6-dichloropyrimidine, and then the 2-methylsulfonyl-4,6-dichloropyrimidine and sodium ethoxide are subjected to a substitution reaction to obtain the 2-ethoxy-4,6-dichloropyrimidine. The oxidation reaction is performed with the existence of an alcohol solvent, and the alcohol solvent is methanol, ethanol, isopropanol or n-butanol. In the substitution reaction, the mole ratio of the 2-methylsulfonyl-4,6-dichloropyrimidine to the sodium ethoxide is 1:1-1:3, and the temperature of the substitution reaction is -20 DEG C to 20 DEG C. According to the method, the raw material adopted by the method is cheap and easily available, the production cost is low, the process is simple, convenient and safe to operate, a product the purity of which is 95% or above can be obtained without the need of purification, the yield is 90% or above, and the method is suitable for industrial large-scale production.
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Paragraph 0015; 0016

(2017/07/21)

Protein Kinase Conjugates and Inhibitors
The invention relates to protein conjugates that contain a protein kinase containing a cysteine residue in the ATP binding site and an inhibitor that is covalently and irreversibly bonded to said cysteine residue, such that the activity of the protein kin
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Paragraph 0734; 0735

(2017/07/14)

PYRIMIDINE AND TRIAZINE DERIVATIVES AND THEIR USE AS AXL INHIBITORS
Compounds of the general formula(I): (I) processes for the preparation of these compounds, compositions containing these compounds, and the uses of these compounds.
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Page/Page column 122

(2016/07/05)

Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach
Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as the dysregulation of these elementary transducers of extracellular signals, like the epidermal growth factor receptor (EGFR), contributes to the onset of cancer, such as non-small cell lung cancer (NSCLC). Strong efforts were directed to the development of irreversible inhibitors and led to compound CO-1686, which takes advantage of increased residence time at EGFR by alkylating Cys797 and thereby preventing toxic effects. Here, we present a structure-based approach, rationalized by subsequent computational analysis of conformational ligand ensembles in solution, to design novel and irreversible EGFR inhibitors based on a screening hit that was identified in a phenotype screen of 80 NSCLC cell lines against approximately 1500 compounds. Using protein X-ray crystallography, we deciphered the binding mode in engineered cSrc (T338M/S345C), a validated model system for EGFR-T790M, which constituted the basis for further rational design approaches. Chemical synthesis led to further compound collections that revealed increased biochemical potency and, in part, selectivity toward mutated (L858R and L858R/T790M) vs nonmutated EGFR. Further cell-based and kinetic studies were performed to substantiate our initial findings. Utilizing proteolytic digestion and nano-LC-MS/MS analysis, we confirmed the alkylation of Cys797.
Engel, Julian,Richters, André,Getlik, Matth?us,Tomassi, Stefano,Keul, Marina,Termathe, Martin,Lategahn, Jonas,Becker, Christian,Mayer-Wrangowski, Svenja,Grütter, Christian,Uhlenbrock, Niklas,Krüll, Jasmin,Schaumann, Niklas,Eppmann, Simone,Kibies, Patrick,Hoffgaard, Franziska,Heil, Jochen,Menninger, Sascha,Ortiz-Cuaran, Sandra,Heuckmann, Johannes M.,Tinnefeld, Verena,Zahedi, René P.,Sos, Martin L.,Schultz-Fademrecht, Carsten,Thomas, Roman K.,Kast, Stefan M.,Rauh, Daniel
p. 6844 - 6863
(2015/09/22)

Design, synthesis, and in vitro antitumor evaluation of novel phenylaminopyrimidine derivatives
Two series of novel phenylaminopyrimidine derivatives were designed and synthesized. All target compounds were determined against the human acute monocytic leukemia cell line U937 and the human chronic myeloid leukemia cell line K562 in vitro. Some of the
Zheng, Youguang,Zheng, Ming,Liu, Yi,Xue, Yunsheng,Zhang, Ling,An, Lin,Liu, Ling,Ji, Min
p. 340 - 350
(2013/07/28)

Aminopyrimidinone Cdc7 Kinase Inhibitors
We have investigated the SAR of a series of pyrimidinone-containing Cdc7 kinase inhibitors. A wide range of amine substitutions give potent compounds with activities (Ki) less than 1 nM. Kinase selectivity is reasonable and cytotoxicity corresponds to inhibition of MCM2 phosphorylation.
Woods, Keith W.,Lai, Chunqiu,Miyashiro, Julie M.,Tong, Yunsong,Florjancic, Alan S.,Han, Edward K.,Soni, Niru,Shi, Yan,Lasko, Loren,Leverson, Joel D.,Johnson, Eric F.,Shoemaker, Alexander R.,Penning, Thomas D.
supporting information; scheme or table
p. 1940 - 1943
(2012/04/17)

DRUG DISCOVERY METHODS
The present invention relates to drug discovery methods, particularly methods for assaying compounds for activity as Aurora kinase inhibitors. This invention also relates to a pharmacophore describing compounds that are able to promote a conformational ch
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Page/Page column 21-22

(2011/11/12)

PYRAZOLYL-PYRIMIDINE DERIVATIVES AND THEIR USE AS POTASSIUM CHANNEL MODULATORS
This invention relates to novel pyrazolyl-pyrimidine derivatives and their use as potassium channel modulating agents. In another aspect the invention is directed to pharmaceutical compositions useful for the treatment or alleviation of diseases or disord
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Page/Page column 7

(2011/10/10)

AMINOPYRIMIDINES USEFUL AS KINASE INHIBITORS
The present invention relates to compounds useful as inhibitors of Aurora protein kinases. The invention also provides pharmaceutically acceptable compositions comprising those compounds and methods of using the compounds and compositions in the treatment
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Page/Page column 29

(2010/06/16)

Synthesis of 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1H-β- carbolinesas antileishmanial agents
A series of 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1H-β- carboline derivatives has been synthesized and evaluated for antileishmanial activity against Leishmania donovani. Compound 8 exhibited best antileishmanial activity with IC50 val
Kumar, Ravi,Khan, Shahnawaz,Verma, Aditya,Srivastava, Saumya,Viswakarma, Preeti,Gupta, Suman,Meena, Sanjeev,Singh, Neetu,Sarkar, Jayanta,Chauhan, Prem M.S.
experimental part
p. 3274 - 3280
(2010/08/06)

Kinase inhibition and anticancer therapy
This invention relates to novel uses for Compound E in the treatment of diseases, in particular cancer, associated with aberrant kinase expression.
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(2009/05/29)

AURORA INHIBITORS CONTAINING A ZINC BINDING MOIETY
The present invention relates to Aurora inhibitors and their use in the treatment of cell proliferative diseases such as cancer. The said derivatives may further act as HDAC inhibitors.
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Page/Page column 56

(2009/08/14)

The discovery of the potent aurora inhibitor MK-0457 (VX-680)
The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) containing the T315I mutation.
Bebbington, David,Binch, Hayley,Charrier, Jean-Damien,Everitt, Simon,Fraysse, Damien,Golec, Julian,Kay, David,Knegtel, Ronald,Mak, Chau,Mazzei, Francesca,Miller, Andrew,Mortimore, Michael,O'Donnell, Michael,Patel, Sanjay,Pierard, Francoise,Pinder, Joanne,Pollard, John,Ramaya, Sharn,Robinson, Daniel,Rutherford, Alistair,Studley, John,Westcott, James
scheme or table
p. 3586 - 3592
(2010/03/31)

A NOVEL LACTIC ACID FORMULATION OF MK-0457 USEFUL FOR THE TREATMENT OF CANCER
A lactic acid formulation, and a process to prepare that formulation, of MK-0457 is disclosed:. Such a formulation is useful in the treatment of cancer.
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Page/Page column 6

(2008/06/13)

ABL KINASE INHIBITION
The present invention relates to inhibition of AbI kinase.
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Page/Page column 17-18

(2008/06/13)

RET TYROSINE KINASE INHIBITION
The present invention provides methods for inhibiting RET tyrosine kinase. Further, the present invention also provides methods of treating or preventing thyroid cancer.
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Page/Page column 27

(2008/06/13)

JAK2 TYROSINE KINASE INHIBITION
The present invention provides methods for inhibiting JAK2 tyrosine kinase. Further, the present invention also provides methods of treating or preventing myeloproliferative disorders.
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Page/Page column 27

(2008/06/13)

COMBINATION CANCER THERAPY
The present invention relates to a method of treating cancer in a subject in need thereof, by administering to a subject in need thereof a first amount of an Aurora kinase inhibitor or a pharmaceutically acceptable salt or hydrate thereof, in a first trea
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Page/Page column 33-34

(2008/06/13)

SUBSTITUTED PYRAZOLE COMPOUNDS
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Page/Page column 93-94

(2008/06/13)

PROCESSES FOR PREPARING SUBSTITUTED PYRIMIDINES AND PYRIMIDINE DERIVATIVES AS INHIBITORS OF PROTEIN KINASE
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Page 45

(2008/06/13)

Herbicidal composition containing 2-benzyloxypyrimidine derivatives, processes for producing the derivatives and 2-benzyloxypyrimidine derivatives
A herbicidal composition comprising a herbicidally effective amount of a 2-benzyloxypyrimidine derivative represented by the formula (I): STR1 wherein R1 and R2 are each independently H, a halogen, hydroxyl, C1 -C4 alkyl, C1 -C4 haloalkyl, C3 -C5 alkenyl, C3 -C5 alkynyl, C1 -C4 alkoxy, C1 -C4 haloalkoxy, C3 -C5 alkenyloxy, C3 -C5 alkynyloxy, C1 -C4 alkylthio, or phenyl; n is an integer of 0 to 5; and each X which may be identical or different if n is greater than 1, is a halogen, C1 -C4 alkyl, C1 -C4 haloalkyl, C1 -C4 alkoxy, C1 -C4 alkylthio, C7 -C9 aralkyloxy, phenyl, hydroxymethyl, hydroxycarbonyl, C1 -C4 alkoxycarbonyl, or nitro, and an adjuvant.
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(2008/06/13)